C.W. Olanow Abstracts 2009

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1. Ann Neurol. 2009 Oct;66(4):432-6.

Modeling Parkinson's disease.

Olanow CW, Kordower JH.

Comment on:
Ann Neurol. 2009 Oct;66(4):472-84.

PMID: 19847894 [PubMed - in process]

2. N Engl J Med. 2009 Sep 24;361(13):1268-78.

A double-blind, delayed-start trial of rasagiline in Parkinson's disease.

Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, Lang A, Langston W, Melamed
E, Poewe W, Stocchi F, Tolosa E; ADAGIO Study Investigators.

Collaborators: Bueri J, Garretto N, Gershanik O, Giannaula R, Micheli F, Wolf E,
Guttman M, Hobson D, Jog M, King D, Mendis T, Miyasaki J, Panisset M, Pourcher E,
Rajput A, Ranawaya R, Tsui J, Cesaro P, Damier P, Destee A, Durif F, Slaoui T,
Tison F, Viallet F, Deuschl G, Gasser T, Ludolph A, Oehlwein C, Przuntek H,
Reifschneider G, Schnitzler A, Trenkwalder C, Bokor M, Katona A, Lajtos J, Nikl
J, Takats A, Valikovics A, Badarny S, Djaldetti R, Giladi N, Hassin S, Rabey JM,
Reches A, Schwartz M, Wirguin I, Albanese A, Bentivoglio A, Bonuccelli U,
Calzetti S, Comi G, Curatola L, Ferrarese C, Lamberti P, Marconi R, Martignoni E,
Meco G, Ruggieri S, Stocchi F, Bomhof MA, Hovestadt A, Krul JM, Leenders KL,
Cunha L, Ferreira J, Bajenaru OA, Carciumaru N, Bulboaca AC, Pascu I, Simu M,
Calopa M, Fernández García JM, Kulisevsky J, Linazasoro C, Miquel F, Posada IJ,
Martí MJ, Burn D, MacMahon D, Barker R, Allen N, Barbour P, Bertoni J, Bharucha
K, Bose S, Drasby E, Elble R, Elmer L, Evans B, Factor S, Fernandez H, Friedman
J, Hull K, Golbe L, Goudreau J, Guttuso T, Hassan M, Hauser R, Hermanowicz N,
Houser M, Hurtig H, Isaacson S, Jennings D, Kompoliti A, Morgan J, Murphy J,
Nausieda P, Pahwa R, Parashos S, O'Suilleabhain P, Racette B, Reich S, Roberts J,
Rothstein T, Sahay A, Saint-Hilaire M, Schiess M, Scott B, Shahed J, Simuni T,
Singer C, Smith R, Struck L, Sutton J, Swope D, Tagliati M, Tetrud J, Togasaki D,
Watts R.

Department of Neurology and Neuroscience, Mount Sinai School of Medicine, New
York, NY 10029, USA. warren.olanow@mssm.edu

BACKGROUND: A therapy that slows disease progression is the major unmet need in
Parkinson's disease. METHODS: In this double-blind trial, we examined the
possibility that rasagiline has disease-modifying effects in Parkinson's disease.
A total of 1176 subjects with untreated Parkinson's disease were randomly
assigned to receive rasagiline (at a dose of either 1 mg or 2 mg per day) for 72
weeks (the early-start group) or placebo for 36 weeks followed by rasagiline (at
a dose of either 1 mg or 2 mg per day) for 36 weeks (the delayed-start group). To
determine a positive result with either dose, the early-start treatment group had
to meet each of three hierarchical end points of the primary analysis based on
the Unified Parkinson's Disease Rating Scale (UPDRS, a 176-point scale, with
higher numbers indicating more severe disease): superiority to placebo in the
rate of change in the UPDRS score between weeks 12 and 36, superiority to
delayed-start treatment in the change in the score between baseline and week 72,
and noninferiority to delayed-start treatment in the rate of change in the score
between weeks 48 and 72. RESULTS: Early-start treatment with rasagiline at a dose
of 1 mg per day met all end points in the primary analysis: a smaller mean
(+/-SE) increase (rate of worsening) in the UPDRS score between weeks 12 and 36
(0.09+/-0.02 points per week in the early-start group vs. 0.14+/-0.01 points per
week in the placebo group, P=0.01), less worsening in the score between baseline
and week 72 (2.82+/-0.53 points in the early-start group vs. 4.52+/-0.56 points
in the delayed-start group, P=0.02), and noninferiority between the two groups
with respect to the rate of change in the UPDRS score between weeks 48 and 72
(0.085+/-0.02 points per week in the early-start group vs. 0.085+/-0.02 points
per week in the delayed-start group, P<0.001). All three end points were not met
with rasagiline at a dose of 2 mg per day, since the change in the UPDRS score
between baseline and week 72 was not significantly different in the two groups
(3.47+/-0.50 points in the early-start group and 3.11+/-0.50 points in the
delayed-start group, P=0.60). CONCLUSIONS: Early treatment with rasagiline at a
dose of 1 mg per day provided benefits that were consistent with a possible
disease-modifying effect, but early treatment with rasagiline at a dose of 2 mg
per day did not. Because the two doses were associated with different outcomes,
the study results must be interpreted with caution. (ClinicalTrials.gov number,
NCT00256204.) 2009 Massachusetts Medical Society

PMID: 19776408 [PubMed - indexed for MEDLINE]

3. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12571-2. Epub 2009 Jul 28.

Is Parkinson's disease a prion disorder?

Olanow CW, Prusiner SB.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
warren.olanow@mssm.edu

Comment on:
Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):13010-5.

PMCID: 2722298
PMID: 19666621 [PubMed - indexed for MEDLINE]

4. Exp Neurol. 2009 Oct;219(2):533-42. Epub 2009 Jul 18.

Continuous administration of rotigotine to MPTP-treated common marmosets enhances
anti-parkinsonian activity and reduces dyskinesia induction.

Stockwell KA, Scheller D, Rose S, Jackson MJ, Tayarani-Binazir K, Iravani MM,
Smith LA, Olanow CW, Jenner P.

Neurodegenerative Disease Research Group, School of Health and Biomedical
Sciences, King's College, London, London, SE1 1UL, UK.

Rotigotine is a novel, non-ergoline dopamine D(3)/D(2)/D(1)-receptor agonist for
the treatment of Parkinson's disease that can be continuously delivered by the
transdermal route to provide stable plasma levels. Continuous drug delivery
should reduce the risk of dyskinesia induction in comparison to pulsatile
dopaminergic treatment. Thus the aim of the study was to compare the reversal of
motor disability and induction of dyskinesia produced by continuous compared to
pulsatile rotigotine administration in MPTP-treated common marmosets. The study
also investigated whether pulsatile or continuous rotigotine administration in
combination with l-DOPA prevented l-DOPA-induced dyskinesia. Animals were treated
for 28 days with vehicle or pulsatile (twice daily) or continuous delivery of
rotigotine (via an osmotic minipump). Subsequently, l-DOPA was then
co-administered for a further 28 days. Animals were assessed for locomotor
activity, motor disability and dyskinesia induction. The study showed that both
continuous and pulsatile administration of rotigotine improved motor deficits and
normalized motor function in MPTP-treated monkeys. However, continuous rotigotine
delivery reduced dyskinesia expression compared to pulsatile treatment. Both
pulsatile and continuous rotigotine administration produced less dyskinesia than
administration of l-DOPA alone. The addition of l-DOPA to either pulsatile or
continuous rotigotine treatment resulted in the induction of marked dyskinesia
similar to that produced by treatment with l-DOPA alone. These data further
support the hypothesis that continuous delivery of a dopaminergic agent reduces
the risk of dyskinesia induction. However, continuous rotigotine administration
did not prevent l-DOPA from inducing dyskinesia suggesting that l-DOPA may induce
dyskinesia by mechanisms different from dopamine agonist drugs.

PMID: 19619533 [PubMed - indexed for MEDLINE]

5. Neurobiol Dis. 2009 Sep;35(3):385-98. Epub 2009 Jun 6.

Alterations in lysosomal and proteasomal markers in Parkinson's disease:
relationship to alpha-synuclein inclusions.

Chu Y, Dodiya H, Aebischer P, Olanow CW, Kordower JH.

Department of Neurological Sciences, Rush University Medical Center, 1735 West
Harrison Street, Chicago, IL 60612, USA.

We explored the relationship between ubiquitin proteasome system (UPS) and
lysosomal markers and the formation of alpha-synuclein (alpha-syn) inclusions in
nigral neurons in Parkinson disease (PD). Lysosome Associated Membrane Protein
1(LAMP1), Cathepsin D (CatD), and Heat Shock Protein73 (HSP73) immunoreactivity
were significantly decreased within PD nigral neurons when compared to
age-matched controls. This decrease was significantly greater in nigral neurons
that contained alpha-syn inclusions. Immunoreactivity for 20S proteasome was
similarly reduced in PD nigral neurons, but only in cells that contained
inclusions. In aged control brains, there is staining for alpha-syn protein, but
it is non-aggregated and there is no difference in LAMP1, CatD, HSP73 or 20S
proteasome immunoreactivity between alpha-syn positive or negative
neuromelanin-laden nigral neurons. Targeting over-expression of mutant human
alpha-syn in the rat substantia nigra using viral vectors revealed that lysosomal
and proteasomal markers were significantly decreased in the neurons that
displayed alpha-syn-ir inclusions. These findings suggest that alpha-syn
aggregation is a key feature associated with decline of proteasome and lysosome
and support the hypothesis that cell degeneration in PD involves proteosomal and
lysosomal dysfunction, impaired protein clearance, and protein accumulation and
aggregation leading to cell death.

PMID: 19505575 [PubMed - in process]

6. Neurology. 2009 May 26;72(21 Suppl 4):S1-136.

The scientific and clinical basis for the treatment of Parkinson disease (2009).

Olanow CW, Stern MB, Sethi K.

Department of Neurology, Mount Sinai School of Medicine, 1 Gustave Levy Place,
Annenberg 14-94, New York, NY 10029, USA. warren.olanow@mssm.edu

Parkinson disease (PD) is an age-related neurodegenerative disorder that affects
as many as 1-2% of persons aged 60 years and older. With the aging of the
population, the frequency of PD is expected to increase dramatically in the
coming decades. Current therapy is largely based on a dopamine replacement
strategy, primarily using the dopamine precursor levodopa. However, chronic
treatment is associated with the development of motor complications, and the
disease is inexorably progressive. Further, advancing disease is associated with
the emergence of features such as freezing, falling, and dementia which are not
adequately controlled with dopaminergic therapies. Indeed, it is now appreciated
that these nondopaminergic features are common and the major source of disability
for patients with advanced disease. Many different therapeutic agents and
treatment strategies have been evaluated over the past several years to try and
address these unmet medical needs, and many promising approaches are currently
being tested in the laboratory and in the clinic. As a result, there are now many
new therapies and strategic approaches available for the treatment of the
different stages of PD, with which the treating physician must be familiar in
order to provide patients with optimal care. This monograph provides an overview
of the management of PD patients, with an emphasis on pathophysiology, and the
results of recent clinical trials. It is intended to provide physicians with an
understanding of the different treatment options that are available for managing
the different stages of the disease and the scientific rationale of the different
approaches.

PMID: 19470958 [PubMed - indexed for MEDLINE]

7. Ann Neurol. 2009 Apr;65(4):485.

Withdrawal of figure 2 from McNaught and Olanow's article, "Proteasome
inhibitor-induced model of Parkinson's disease" (Ann Neurol 2006;60:243-247).

McNaught KS, Olanow CW.

Partial retraction of:
McNaught KS, Olanow CW. Ann Neurol. 2006 Aug;60(2):243-7.

PMID: 19399884 [PubMed - indexed for MEDLINE]

8. Neurology. 2009 Feb 17;72(7 Suppl):S59-64.

Can we achieve neuroprotection with currently available anti-parkinsonian
interventions?

Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.
warren.olanow@mssm.edu

A disease-modifying therapy is the most important unmet medical need in the
treatment of Parkinson disease (PD). Laboratory studies have identified many
promising candidate agents, but none has been proven to be neuroprotective in PD.
A major limitation has been the development of an endpoint that accurately
reflects the underlying disease state. This dramatically limits the potential for
a new drug being approved as a disease-modifying agent in PD. For the present,
the best opportunity to provide patients with PD with a disease-modifying effect
is with agents that have been approved for their symptomatic effects. This
article reviews currently available drugs for PD and considers the evidence that
they might have neuroprotective effects in PD.

PMID: 19221316 [PubMed - indexed for MEDLINE]

9. Eur J Neurol. 2009 Apr;16(4):493-7.

Subthalamic deep brain stimulation and impulse control in Parkinson's disease.

Hälbig TD, Tse W, Frisina PG, Baker BR, Hollander E, Shapiro H, Tagliati M,
Koller WC, Olanow CW.

Fédération de Neurologie, Centre Hospitalier Universitaire Pitié-Salpêtrière,
Paris, France. halbig.psl@gmail.com

Comment in:
Eur J Neurol. 2009 Apr;16(4):440-1.

BACKGROUND AND PURPOSE: Experimental studies suggest that deep brain stimulation
(DBS) of the subthalamic nucleus (STN) induces impulsivity in patients with
Parkinson's disease (PD). The purpose of this study was to assess various
measures of impulse control in PD patients with STN DBS in comparison to patients
receiving medical therapy. METHODS: In a cross-sectional evaluation, 53
consecutively eligible patients were assessed for impulsivity with the Barratt
Impulsiveness Scale, for impulse control disorders (ICDs) using the Minnesota
Impulsive Disorders Interview, and for obsessive-compulsive symptoms using the
Maudsley Obsessional-Compulsive Inventory. RESULTS: Independent samples t-tests
revealed that compulsivity scores were not different between DBS patients and
patients without DBS. However, impulsivity scores were significantly higher in
DBS patients. Additionally, ICDs were observed in 3 of 16 (19%) DBS patients and
in 3 of 37 (8%) medically treated patients. No association was found between the
use of dopamine agonists and impulsivity in DBS patients. CONCLUSIONS: Our data
suggest that screening for impulsivity and ICDs should be performed prior to DBS,
and that patients should be monitored for these problems during follow-up.
Prospective trials are needed to confirm the findings of this exploratory study
and to elucidate the reasons of a possible induction of impulsivity by STN DBS.

PMID: 19236471 [PubMed - indexed for MEDLINE]

10. Ann Neurol. 2008 Dec;64 Suppl 2:S30-46.

The basal ganglia in Parkinson's disease: current concepts and unexplained
observations.

Obeso JA, Marin C, Rodriguez-Oroz C, Blesa J, Benitez-Temiño B, Mena-Segovia J,
Rodríguez M, Olanow CW.

Departments of Neurology, Neurophysiology and Neurosurgery, Clinica Universitaria
and Medical School, Neuroscience Centre, Center for Applied Medical Research,
University of Navarra, Pamplona, Spain.

Comment in:
Ann Neurol. 2009 May;65(5):618; author reply 618-9.

The pathophysiology of Parkinson's disease is reviewed in light of recent
advances in the understanding of the functional organization of the basal ganglia
(BG). Current emphasis is placed on the parallel interactions between
corticostriatal and corticosubthalamic afferents on the one hand, and internal
feedback circuits modulating BG output through the globus pallidus pars interna
and substantia nigra pars reticulata on the other. In the normal BG network, the
globus pallidus pars externa emerges as a main regulatory station of output
activity. In the parkinsonian state, dopamine depletion shifts the BG toward
inhibiting cortically generated movements by increasing the gain in the globus
pallidus pars externa-subthalamic nucleus-globus pallidus pars interna network
and reducing activity in "direct" cortico-putaminal-globus pallidus pars interna
projections. Standard pharmacological treatments do not mimic the normal
physiology of the dopaminergic system and, therefore, fail to restore a
functional balance between corticostriatal afferents in the so-called direct and
indirect pathways, leading to the development of motor complications. This review
emphasizes the concept that the BG can no longer be understood as a "go-through"
station in the control of movement, behavior, and emotions. The growing
understanding of the complexity of the normal BG and the changes induced by DA
depletion should guide the development of more efficacious therapies for
Parkinson's disease.

PMID: 19127584 [PubMed - indexed for MEDLINE]

11. Ann Neurol. 2008 Dec;64 Suppl 2:S101-10.

Why have we failed to achieve neuroprotection in Parkinson's disease?

Olanow CW, Kieburtz K, Schapira AH.

Department of Neurology, Mount Sinai School of Medicine, New York, USA.
warren.olanow@mssm.edu

The development of a neuroprotective therapy that slows, stops, or reverses
neurodegeneration in Parkinson's disease (PD) is the single most important
unresolved issue in the management of this disorder. Current therapies provide
effective control of symptoms, particularly in the early stages of the disease,
but disease progression is associated with the development of "nondopaminergic"
features such as postural instability, falling, and dementia that are not
adequately controlled with existing medications. There are many promising
candidate neuroprotective agents based on pathological and laboratory studies,
but to date, it has not been possible to determine that any drug has a
disease-modifying effect in PD. Obstacles to the development of a neuroprotective
therapy in PD include: (1) uncertainty as to the precise cause of cell death in
PD and what to target; (2) the lack of an animal model of PD that precisely
reflects the etiopathogenesis of the disease, the pattern of dopaminergic and
nondopaminergic pathology, and its chronic, progressive nature; (3) determination
of the correct dose to use in clinical trials; and (4) delineation of a clinical
end point that is an accurate measure of the underlying disease and is not
confounded by potential symptomatic effects of a study intervention. New
developments in understanding the cause of the disease, in the development of
animal models of PD, and in clinical trial methodology will hopefully hasten the
resolution of these problems.

PMID: 19127580 [PubMed - indexed for MEDLINE]

12. Ann Neurol. 2008 Dec;64 Suppl 2:S47-55.

Drug selection and timing of initiation of treatment in early Parkinson's
disease.

Schapira AH, Olanow CW.

University Department of Clinical Neuroscience, Institute of Neurology, London,
United Kingdom. a.schapira@medsch.ucl.ac.uk

Comment in:
Ann Neurol. 2009 Apr;65(4):480-1; author reply 481.

There is increasing evidence to challenge the traditional view that the
initiation of drug treatment in Parkinson's disease (PD) should be delayed until
the patient has significant disability such as to affect work or social function.
Firstly, to delay treatment sentences the patient to protracted impairment of
quality of life that could be improved by therapy. Secondly, there is evidence to
support the notion that earlier rather than later initiation of treatment leads
to better long term motor benefit. The selection of which drug to begin must be
tailored to the patient's individual characteristics and circumstances. Monoamine
oxidase B inhibitors result in a mild improvement in motor function compared to
dopamine agonists or levodopa. They are well tolerated, easy to use once a day
drugs and there is evidence that early use of Rasagiline improves motor outcome.
Dopamine agonists lead to a substantial improvement in motor function and are, or
will shortly be, available as once a day drugs. They are generally well tolerated
but can be associated with exacerbating confusion or hallucinations and with
behavioral changes. Levodopa is the most potent of the dopaminergic drugs. It is
routinely combined with a dopa decarboxylase inhibitor and can also be used with
a catecholo-o-methyl transferase inhibitor for enhanced absorption. The most
important limiting factor for the use of levodopa is the emergence of motor
complications. These are related to a number of factors including the dose of
levodopa and the duration of its use.

PMID: 19127579 [PubMed - indexed for MEDLINE]

13. Ann Neurol. 2008 Dec;64 Suppl 2:S1-2.

Parkinson's disease: unresolved issues.

Olanow CW, Stern MB.

PMID: 19127574 [PubMed - indexed for MEDLINE]

14. Mov Disord. 2008 Nov 15;23(15):2129-70.

Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease
Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results.

Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, Poewe
W, Sampaio C, Stern MB, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J,
Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag
A, Teresi JA, van Hilten JJ, LaPelle N; Movement Disorder Society UPDRS Revision
Task Force.

Department of Neurological Sciences, Rush University Medical Center, Chicago,
Illinois 60612, USA. cgoetz@rush.edu

We present a clinimetric assessment of the Movement Disorder Society
(MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale
(MDS-UPDRS). The MDS-UDPRS Task Force revised and expanded the UPDRS using
recommendations from a published critique. The MDS-UPDRS has four parts, namely,
I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living;
III: Motor Examination; IV: Motor Complications. Twenty questions are completed
by the patient/caregiver. Item-specific instructions and an appendix of
complementary additional scales are provided. Movement disorder specialists and
study coordinators administered the UPDRS (55 items) and MDS-UPDRS (65 items) to
877 English speaking (78% non-Latino Caucasian) patients with Parkinson's disease
from 39 sites. We compared the two scales using correlative techniques and factor
analysis. The MDS-UPDRS showed high internal consistency (Cronbach's alpha =
0.79-0.93 across parts) and correlated with the original UPDRS (rho = 0.96).
MDS-UPDRS across-part correlations ranged from 0.22 to 0.66. Reliable factor
structures for each part were obtained (comparative fit index > 0.90 for each
part), which support the use of sum scores for each part in preference to a total
score of all parts. The combined clinimetric results of this study support the
validity of the MDS-UPDRS for rating PD.

PMID: 19025984 [PubMed - indexed for MEDLINE]

15. Mov Disord. 2008 Dec 15;23(16):2303-6.

Transplanted dopaminergic neurons develop PD pathologic changes: a second case
report.

Kordower JH, Chu Y, Hauser RA, Olanow CW, Freeman TB.

Department of Neurological Sciences, Rush University Medical Center, Chicago,
Illinois 60612, USA. jkordowe@rush.edu

This report describes pathological changes within the grafted neurons of another
patient with Parkinson's disease (PD) who died 14 years posttransplantation.
Although numerous healthy appearing grafted neurons were present at this
long-term time point, some displayed Lewy bodies as evidenced by alpha-synuclein,
ubiquitin, and thioflavin-S staining. Additionally, there was a general loss of
dopamine transporter-immunoreactivity in grafted neurons. Some grafted cell
displayed a loss of tyrosine hydroxylase. These data support the emerging concept
that PD-like pathology is seen in young grafted neurons when they survive long
term. (c) 2008 Movement Disorder Society.

PMID: 19006193 [PubMed - indexed for MEDLINE]

16. Mov Disord. 2009 Feb 15;24(3):336-43.

Clinical pattern and risk factors for dyskinesias following fetal nigral
transplantation in Parkinson's disease: a double blind video-based analysis.

Olanow CW, Gracies JM, Goetz CG, Stoessl AJ, Freeman T, Kordower JH, Godbold J,
Obeso JA.

Department of Neurology, Mount Sinai School of Medicine, New York, New York
10029-6574, USA. warren.olanow@mssm.edu

The objective of this study is to assess dyskinesias in 34 Parkinson's disease
patients randomized to receive bilateral fetal nigral transplantation with 4
donors per side (12), 1 donor per side (11), or placebo (11). Videotape
recordings were performed at the baseline, 3, 6, 12, 18, and 24 month visits
during the "practically defined off" (12 hours after last evening dopaminergic
therapy) and "best on" (best response following morning dopaminergic therapy)
states. Videotapes were analyzed in random order by a blinded investigator.
Dyskinesias during "best on" (on-medication dyskinesia) were observed in all, but
1 patient at baseline, and in all patients at each subsequent visit. There were
no differences between groups. No patient had dyskinesia at baseline in
"practically-defined off" ("off-medication" dyskinesia). Following
transplantation, off-medication dyskinesia was observed in 13 of 23 patients, but
not in any patient in the placebo group (P = 0.019). There was no difference in
dyskinesia score between patients in the 1 and 4 donor groups. On-medication
dyskinesias were typically generalized and choreiform, whereas off-medication
dyskinesias were usually repetitive, stereotypic movements in the lower
extremities with residual Parkinsonism in other body regions. Off-medication
dyskinesias are common following transplantation and may represent a prolonged
form of diphasic dyskinesias. (c) 2008 Movement Disorder Society.

PMID: 19006186 [PubMed - indexed for MEDLINE]

17. Mov Disord. 2008 Nov 15;23(15):2194-201.

A randomized, double-blind, placebo-controlled, delayed start study to assess
rasagiline as a disease modifying therapy in Parkinson's disease (the ADAGIO
study): rationale, design, and baseline characteristics.

Olanow CW, Hauser RA, Jankovic J, Langston W, Lang A, Poewe W, Tolosa E, Stocchi
F, Melamed E, Eyal E, Rascol O.

Department of Neurology, Mount Sinai School of Medicine, New York, New York
10029, USA. warren.olanow@mssm.edu

A neuroprotective therapy is the single most important unmet medical need in
Parkinson's disease. Several promising agents in the laboratory have been tested
in the clinic, but none has been established in clinical trials to have a disease
modifying effect despite positive results because of potential confounding
symptomatic or pharmacologic effects. The delayed start design was developed to
try to avoid a symptomatic confound when testing a putative neuroprotective
therapy. In this study design, patients are randomly assigned to study drug or
placebo in the first phase of the study, and both groups receive the active drug
in the second phase. If benefits seen at the end of phase I persist through the
end of phase II, they cannot be readily explained by a symptomatic effect (as
patients in both groups are receiving the same medication) and benefits in the
early start group must relate to the early initiation of the treatment. Although
the precise mechanism responsible for such an effect can be debated, positive
results in a delayed start study indicate that patients who receive early
treatment have a better outcome than those where the treatment is delayed. We are
using the delayed start design to assess the potential disease modifying effects
of rasagiline in a prospective double blind controlled trial (the ADAGIO study).
We here describe the rationale for the study and baseline characteristics of the
1,176 patients who have been enrolled into the trial.

PMID: 18932271 [PubMed - indexed for MEDLINE]

18. Mov Disord. 2008;23 Suppl 3:S599-612.

Treatment of levodopa-induced motor complications.

Stocchi F, Tagliati M, Olanow CW.

IRCCS San Raffaele, Via della Pisana 235, Roma, Italy.
fabrizio.stocchi@fastwebnet.it

Chronic levodopa treatment for Parkinson's disease patients is frequently
associated with the development of motor complications such as end-of-dose
wearing-off and dyskinesias. In this review, we provide an overview of the
strategies available for dealing with these problems. Medical management includes
manipulation of levodopa dosing to establish the optimum treatment schedule,
improving levodopa absorption, catechol-O-methyl transferase-inhibition (COMT),
Monoamine oxidase-B (MAO-B) inhibition, dopaminergic agonists, amantadine, and
continuous dopaminergic infusions. Surgical procedures and particularly deep
brain stimulation are also reviewed. It should be noted that none of these
treatments has been shown to provide anti-parkinsonian efficacy that is greater
than what can be achieved with levodopa. We highlight the importance of
initiating therapy with a treatment strategy that reduces the risk that a
Parkinson's disease patient will develop motor complications in the first place.
Key Words: Advanced PD, dyskinesias, motor fluctuations, levodopa, dopamine
agonists, COMT inhibitors, MAO-B inhibitors. (c) 2008 Movement Disorder Society.

PMID: 18781681 [PubMed - indexed for MEDLINE]

19. Mov Disord. 2008;23 Suppl 3:S495-6.

Levodopa therapy for Parkinson's disease: challenges and future prospects.

Olanow CW, Lees A, Obeso J.

Department of Neurology, Mount Sinai School of Medicine, New York, New York, USA.
warren.olanow@mssm.edu

PMID: 18781670 [PubMed - indexed for MEDLINE]

20. Mov Disord. 2008;23 Suppl 3:S613-22.

Levodopa/dopamine replacement strategies in Parkinson's disease--future
directions.

Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, New York, USA.
warren.olanow@mssm.edu

After 40 years, levodopa remains the most effective therapy for the treatment of
PD. However, long-term therapy is complicated by motor fluctuations and
dyskinesia that can represent a source of significant disability for some
patients. Other medical therapies that are currently available for the treatment
of PD primarily represent an attempt to prevent or treat motor complications.
Surgical therapies improve motor complications in appropriate candidates, but do
not provide antiparkinsonian benefits that are superior to levodopa, and are
themselves associated with potentially serious side effects. Increasing
information suggests that levodopa-induced motor complications relate to
pulsatile, nonphysiologic dopamine replacement. A therapeutic strategy that could
deliver levodopa/dopamine to the brain in a more continuous and physiologic
manner might be expected to provide all of the benefits of standard levodopa with
reduced motor complications. Such a levodopa formulation might replace all
current dopaminergic antiparkinsonian medications and avoid the need for surgery
in most PD patients. However, problems of continuous dopaminergic stimulation
must be addressed and avoided, and the issue of nondopaminergic features remains
to be addressed. (c) 2008 Movement Disorder Society.

PMID: 18781663 [PubMed - indexed for MEDLINE]

21. Neurology. 2008 Aug 12;71(7):481-5.

Fatigue in levodopa-naive subjects with Parkinson disease.

Schifitto G, Friedman JH, Oakes D, Shulman L, Comella CL, Marek K, Fahn S;
Parkinson Study Group ELLDOPA Investigators.

Collaborators: Fahn S, Oakes D, Shoulson I, Kieburtz K, Rudolph A, Marek K,
Seibyl J, Lang A, Olanow CW, Tanner C, Schifitto G, Zhao H, Reyes L, Shinaman A,
Comella C, Goetz C, Blasucci L, Samanta J, Stacy M, Williamson K, Harrigan M,
Greene P, Ford B, Moskowitz C, Truong D, Pathak M, Jankovic J, Ondo W, Atassi F,
Hunter C, Jacques C, Friedman JH, Lannon M, Russell DS, Jennings D, Fussell B,
Standaert D, Schwarzschild MA, Growdon J, Tennis M, Gauthier S, Panisset M, Hall
J, Gancher S, Hammerstad J, Stone C, Alexander-Brown B, Factor S, Molho E, Brown
D, Evans S, Clark J, Manyam B, Simpson P, Wulbrecht B, Whetteckey J, Martin W,
Roberts T, King P, Hauser R, Zesiewicz T, Gauger L, Trugman J, Wooten GF,
Rost-Ruffner E, Perlmutter J, Racette B, Suchowersky O, Ranawaya R, Wood S,
Pantella C, Kurlan R, Richard I, Pearson N, Caviness J, Adler C, Lind M, Simuni
T, Siderowf A, Colcher A, Lloyd M, Weiner W, Shulman L, Koller W, Lyons K,
Feldman R, St-Hilaire MH, Ellias S, Thomas CA, Juncos J, Watts R, Partlow A,
Tetrud J, Togasaki DM, Welsh M, Stewart T, Mark MH, Sage JI, Caputo D, Gould H,
Rao J, McKendrick A, Brin M, Danisi F, Benabou R, Hubble J, Paulson G, Reider C,
Birnbaum A, Miyasaki J, Johnston L, So J, Pahwa R, Dubinsky R, Wszolek Z, Uitti
R, Turk M, Tuite P, Rottenberg D, Hansen J, Ramos CS, Waters C, Lew M, Welsh M,
Kawai C, O'Brien C, Kumar R, Seeberger L, Judd D, Mendis T, Barclay CL, Grimes
DA, Sutherland L, Dawson T, Reich S, Dunlop R, Albin R, Frey K, Wernette K.

University of Rochester, NY, USA. giovanni.schifitto@ctcc.rochester.edu

BACKGROUND: Fatigue is a common complaint in Parkinson disease (PD). We
investigated fatigue in a cohort of previously untreated patients with early PD
enrolled in the Earlier vs Later Levodopa (ELLDOPA) clinical trial. METHODS: A
total of 361 patients were enrolled in the randomized, double-blind,
placebo-controlled ELLDOPA trial and assigned to receive placebo or
carbidopa-levodopa 37.5/150 mg, 75/300 mg, or 150/600 mg daily for 40 weeks,
followed by a 2-week medication washout period. Subjects who scored >4 on the
Fatigue Severity Scale were classified as fatigued. PD severity was assessed
using the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn-Yahr scale, and
Schwab-England Activities of Daily Living Scale. A subgroup of subjects underwent
[(123)I]-beta-CIT SPECT to measure striatal dopamine transporter density.
RESULTS: Of the 349 ELLDOPA subjects who completed fatigue measures, 128 were
classified as fatigued at baseline. The fatigued group was significantly more
impaired neurologically (UPDRS, all subscales and Hoehn and Yahr staging) and
functionally (Schwab-England Scale) but no significant differences were observed
in beta-CIT measurements between the two groups. Analysis of covariance showed a
greater increase in fatigue score from baseline to the end of the 2-week washout
in the placebo group (0.75 points) than in the three groups receiving levodopa
(increases of 0.30 [150 mg/day], 0.36 [300 mg/day], and 0.33 [600 mg/day]; p =
0.03 for heterogeneity). CONCLUSIONS: Fatigue is a frequent symptom in early,
untreated, non-depressed patients with Parkinson disease (PD), affecting over 1/3
of the patients in this cohort at baseline and 50% by week 42. Fatigue was
associated with the severity of PD, and progressed less in patients treated with
levodopa.

PMID: 18695158 [PubMed - indexed for MEDLINE]

22. Parkinsonism Relat Disord. 1999 Dec;5(4):217-20.

A rational approach to the treatment of early Parkinson's disease.

Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029-6574,
USA.

Parkinson's disease (PD) is an age-related, inexorably progressive,
neurodegenerative disorder. The mean age of onset is approximately 60 years, but
many cases begin in their 40's and 50's and cases beginning before the age of 40
are not rare. This implies that many PD patients will suffer from this disorder
for the bulk of their adult lives. The introduction of levodopa in the late 1960s
revolutionized treatment for this disorder and provided PD patients with reduced
morbidity and decreased mortality. However, chronic levodopa treatment is
associated with the development of adverse events in the majority of patients,
primarily in the form of motor complications (dyskinesia and motor fluctuations).
Further, despite levodopa, PD patients continue to progress and eventually
develop "non-dopaminergic features" such as freezing, gait and balance disorders,
autonomic dysfunction etc. that do not respond to levodopa treatment. It is now
becoming clear that the approach to the treatment of early PD is of great
importance and may very well influence the likelihood that motor complications
will develop and the rate at which the disease will progress. This article will
review these issues and suggest a treatment approach to the early stages of PD.

PMID: 18591143 [PubMed - in process]

23. Nat Med. 2008 May;14(5):504-6. Epub 2008 Apr 6.

Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's
disease.

Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW.

Department of Neurological Sciences and Center for Brain Repair, Rush University
Medical Center, 1735 West Harrison Street, Chicago, Illinois 60612, USA.
jkordowe@rush.edu

Comment in:
Nat Med. 2008 May;14(5):483-5.

Fourteen years after transplantation into the striatum of an individual with
Parkinson's disease, grafted nigral neurons were found to have Lewy body-like
inclusions that stained positively for alpha-synuclein and ubiquitin and to have
reduced immunostaining for dopamine transporter. These pathological changes
suggest that Parkinson's disease is an ongoing process that can affect grafted
cells in the striatum in a manner similar to host dopamine neurons in the
substantia nigra. These findings have implications for cell-based therapies and
for understanding the cause of Parkinson's disease.

PMID: 18391962 [PubMed - indexed for MEDLINE]

24. J Biol Chem. 2008 May 30;283(22):15469-78. Epub 2008 Apr 3.

Differential modulation of Akt/glycogen synthase kinase-3beta pathway regulates
apoptotic and cytoprotective signaling responses.

Nair VD, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy
Place, New York, NY 10029, USA. venugopalan.nair@mssm.edu

We have previously reported that specific dopamine agonists mediate protection
against apoptosis induced by oxidative stress by activating the D2
receptor-coupled phosphoinositide 3-kinase (PI-3K)/Akt pathway. In the present
study we examined the downstream effectors of PI-3K/Akt signaling and their role
in cell death after oxidative stress and protection provided by ropinirole, a D2
receptor agonist in PC12 cells and primary cultures of dopamine neurons.
Ropinirole treatment was associated with rapid translocation and phosphorylation
of the PI-3K substrate Akt and phosphorylation of Akt substrates. One of these
Akt downstream substrates was identified as the pro-apoptotic factor glycogen
synthase kinase-3beta (GSK-3beta). Ropinirole-induced protection was associated
with phosphorylation of GSK-3beta (inactivation). In contrast, inhibition of
PI-3K blocked the phosphorylation of Akt and GSK-3beta (activation) and prevented
the protection mediated by ropinirole. Suppression of Akt with specific short
hairpin RNA in normal PC12 cells caused cell death, which was associated with
reduced phosphorylation of GSK-3beta and reduced levels of beta-catenin, a
transcriptional activator that is regulated by GSK-3beta. Knock-out of GSK-3beta
expression with a short hairpin RNA alone was itself sufficient to cause cell
death. We further demonstrated that oxidative stress induced by hydrogen peroxide
(H2O2) dephosphorylates Akt and GSK-3beta, increases GSK-3beta activity, and
promotes an interaction with beta-catenin and its degradation. Inhibition of
GSK-3beta activity by inhibitor VIII protects cells from H2O2 similar to
ropinirole. These results indicate that GSK-3beta downstream of Akt plays a
critical role in cell death and survival in these models.

PMID: 18387957 [PubMed - indexed for MEDLINE]

25. Lancet Neurol. 2008 May;7(5):400-8. Epub 2008 Apr 2.

Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated
virus serotype 2-neurturin) to patients with idiopathic Parkinson's disease: an
open-label, phase I trial.

Marks WJ Jr, Ostrem JL, Verhagen L, Starr PA, Larson PS, Bakay RA, Taylor R,
Cahn-Weiner DA, Stoessl AJ, Olanow CW, Bartus RT.

Department of Neurology, University of California, San Francisco, San Francisco,
CA 94143-0138, USA. william.marks@ucsf.edu

Comment in:
Lancet Neurol. 2008 May;7(5):375-6.

BACKGROUND: There is an urgent need for therapies that slow or reverse the
progression of Parkinson's disease (PD). Neurotrophic factors can improve the
function of degenerating neurons and protect against further neurodegeneration,
and gene transfer might be a means to deliver effectively these factors to the
brain. The aim of this study was to assess the safety, tolerability, and
potential efficacy of gene delivery of the neurotrophic factor neurturin.
METHODS: In this phase I, open-label clinical trial, 12 patients aged 35-75 years
with a diagnosis of PD for at least 5 years in accordance with the UK Brain Bank
Criteria received bilateral, stereotactic, intraputaminal injections of
adeno-associated virus serotype 2-neurturin (CERE-120). The first six patients
received doses of 1.3x10(11) vector genomes (vg)/patient, and the next six
patients received 5.4x10(11) vg/patient. This trial is registered with
ClinicalTrials.gov, number NCT00252850. FINDINGS: The procedure was well
tolerated. Extensive safety monitoring in all patients revealed no clinically
significant adverse events at 1 year. Several secondary measures of motor
function showed improvement at 1 year; for example, a mean improvement in the
off-medication motor subscore of the Unified Parkinson's Disease Rating Scale
(UPDRS) of 14 points (SD 8; p=0.000121 [36% mean increase; p=0.000123]) and a
mean increase of 2.3 h (2; 25% group mean increase; p=0.0250) in on time without
troublesome dyskinesia were seen. Improvements in several secondary measures were
not significant, including the timed walking test in the off condition (p=0.053),
the Purdue pegboard test of hand dexterity (p=0.318), the reduction in off time
(p=0.105), and the activities of daily living subscore (part II) of the UPDRS
(p=0.080). (18)F-levodopa-uptake PET did not change after treatment with either
dose of CERE-120. INTERPRETATION: The initial data support the safety,
tolerability, and potential efficacy of CERE-120 as a possible treatment for PD;
however, these results must be viewed as preliminary until data from blinded,
controlled clinical trials are available. FUNDING: Ceregene; Michael J Fox
Foundation for Parkinson's Research.

PMID: 18387850 [PubMed - indexed for MEDLINE]

26. Mov Disord. 2007 Sep;22 Suppl 17:S335-42.

The pathogenesis of cell death in Parkinson's disease--2007.

Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, New York
10029, USA. warren.olanow@mssm.edu

A number of factors have been implicated in the pathogenesis of cell death in
Parkinson's disease (PD). These include oxidative stress, mitochondrial
dysfunction, inflammation, excitotoxicity, and apoptosis. While the precise
pathogenic mechanism leading to neurodegeneration in PD is not known, there is
considerable evidence suggesting that cell death occurs by way of a
signal-mediated apoptotic process. PD is also characterized by intracellular
proteinaceous inclusions or Lewy bodies. Proteolytic stress arises as a
consequence of the excessive production of misfolded proteins, which exceed the
capacity of the ubiquitin-proteasome system to degrade them. Recent genetic and
laboratory studies support the possible relevance of proteolytic stress to both
familial and sporadic forms of PD. Postmortem studies have shown that in the SNc
of sporadic PD patients there are reduced levels of the alpha subunit of the 20S
proteasome and reduced proteolytic enzyme activities. A determination as to the
precise cause of cell death in PD, and the identification of specific targets for
the development of drugs that might modify disease progression is one of the most
critical goals in PD research. It is anticipated that over the next few years
there will be a flurry of scientific activity examining the mechanism of cell
death and putative neuroprotective interventions.

PMID: 18175394 [PubMed - indexed for MEDLINE]

27. Mov Disord. 2007 Dec;22(16):2314-24.

Diagnostic procedures for Parkinson's disease dementia: recommendations from the
movement disorder society task force.

Dubois B, Burn D, Goetz C, Aarsland D, Brown RG, Broe GA, Dickson D, Duyckaerts
C, Cummings J, Gauthier S, Korczyn A, Lees A, Levy R, Litvan I, Mizuno Y, McKeith
IG, Olanow CW, Poewe W, Sampaio C, Tolosa E, Emre M.

INSERM-UPMC UMRS 610, Federation of Neurology, AP-HP, Salpêtrière Hospital;
Université Paris6, Paris, France. bruno.dubois@psl.aphp.fr

A preceding article described the clinical features of Parkinson's disease
dementia (PD-D) and proposed clinical diagnostic criteria for "probable" and
"possible" PD-D. The main focus of this article is to operationalize the
diagnosis of PD-D and to propose practical guidelines based on a two level
process depending upon the clinical scenario and the expertise of the evaluator
involved in the assessment. Level I is aimed primarily at the clinician with no
particular expertise in neuropsychological methods, but who requires a simple,
pragmatic set of tests that are not excessively time-consuming. Level I can be
used alone or in concert with Level II, which is more suitable when there is the
need to specify the pattern and the severity on the dementia of PD-D for clinical
monitoring, research studies or pharmacological trials. Level II tests can also
be proposed when the diagnosis of PD-D remains uncertain or equivocal at the end
of a Level I evaluation. Given the lack of evidence-based standards for some
tests when applied in this clinical context, we have tried to make practical and
unambiguous recommendations, based upon the available literature and the
collective experience of the Task Force. We accept, however, that further
validation of certain tests and modifications in the recommended cut off values
will be required through future studies. 2007 Movement Disorder Society

PMID: 18098298 [PubMed - indexed for MEDLINE]

28. Mov Disord. 2007 Dec 14;22(S17):S335-S342. [Epub ahead of print]

The pathogenesis of cell death in Parkinson's disease - 2007.

Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, New York, USA.

PMID: 18081137 [PubMed - as supplied by publisher]

29. Mov Disord. 2008 Apr 15;23(5):653-9; quiz 776.

Predictors of deterioration in health-related quality of life in Parkinson's
disease: results from the DATATOP trial.

Marras C, McDermott MP, Rochon PA, Tanner CM, Naglie G, Lang AE; Parkinson Study
Group DATATOP Investigators.

Collaborators: Shoulson I, Oakes D, Fahn S, Lang A, Langston JW, LeWitt P, Olanow
CW, Penney JB, Tanner C, Kieburtz K, Koller W, Olanow CW, Rodnitzky R, Fink JS,
Growdon JH, Paulson G, Kurlan R, Friedman JH, Gancher S, Nutt J, Rajput AH,
Bennett JB, Wooten GF, LeWitt P, Goetz C, Tanner C, Shannon K, Suchowersky O,
Brin MF, Bressman SB, Weiner WJ, Sanchez-Ramos J, Jankovic J, Penney JB, Lang A,
Hoehn M, Tetrud J, Grimes JD, Pfeiffer R, Shults C, Thal L, Gauthier S, Golbe LI,
Perlmutter JS, Moses H 3rd, Reich SG, Hurtig HI, Stern M, Barter R,
Vetere-Overfield B, Gauger L, Malapira T, Dobson J, Atamian S, Tennis M, Cohen
JB, Desclos G, Hoffman E, Graefe K, Burke C, Marcus A, Denio L, Huber S, Woike T,
Zoog K, Mendell R, Dudte K, Behr J, Gardiner IF, Lannon M, Carter J, Northrup S,
Kanigan B, Turk M, Landow E, Schlick P, Mistura K, Carroll VS, Thelen JA, Demong
C, Winfield L, Moskowitz C, Ingenito A, Sheldon C, Cornelius L, Heiberg D, Dunne
C, Brady J, Kierans C, Belle-Scantlebury L, Duff J, Weber H, Savioni D, Lewis P,
Kutner SJ, Gray P, Glaeske C, Hofman R, Pay MM, Salmon D, McFaul F, Amyot D,
Bergen M, McGee-Minnich L, O'Donnell P, Ferrise S, Shallow K, Axtell C, Baker D,
Casaceli C, Eberly S, McDermott M, Marshall F, Nobel R, Orme C, Pelusio RM, Plumb
S, Rudolph A, Randolph H, Sotack J, Watts A.

Division of Neurology, Toronto Western Hospital, University Health Network,
University of Toronto, Toronto, Ontario, Canada. connie.marras@utoronto.ca

The aim of this study was to investigate factors associated with decline in
health-related quality of life in Parkinson's disease, by a retrospective cohort
study from referral centers in Canada and the United States. Subjects were
patients with early Parkinson's disease (N = 362) enrolled in a clinical trial of
deprenyl (selegiline) and tocopherol (DATATOP) and followed prospectively. The
main outcome measure was change in health-related quality of life using SF-36
Mental and Physical Component Summary scores. The mean interval between SF-36
measurements was 1.7 +/- 0.1 years, beginning 5 to 6 years after enrolment into
the trial. In multivariable analysis, baseline Hamilton Depression Scale scores
and self-rated cognitive function were associated with subsequent decline in
Physical Component Summary scores, while older age and Schwab and England
activities of daily living scores were associated with decline in Mental
Component Summary scores. The Postural Instability Gait Disorder score was the
only variable found to decline concurrently with HRQOL. Our results suggest that
depression, self-rated cognitive function, and one's degree of functional
independence are predictors of subsequent changes in HRQOL. Our focus in clinical
care needs to be broadened beyond assessing and treating Parkinsonism,
recognizing the impact of mood, cognition and function on HRQOL. 2007 Movement
Disorder Society

PMID: 18076084 [PubMed - indexed for MEDLINE]

30. Conf Proc IEEE Eng Med Biol Soc. 2006;1:1228-31.

A model-based approach for assessing parkinsonian gait and effects of levodopa
and deep brain stimulation.

Cho C, Osaki Y, Kunin M, Cohen B, Olanow CW, Raphan T.

Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.
catherine.cho@mssm.edu

Gait and balance disturbances are amongst the most disabling features of
Parkinson's disease (PD), and are not adequately controlled with currently
available medical and surgical therapies. Development of objective quantitative
measures of these abnormalities would greatly help in the assessment and the
development of therapeutic interventions. Recently, we developed a methodology,
using dynamical system theory, for testing gait with a state-of-the-art
motion-detection system (OPTOTRAK 3020, Northern Digital, Inc.). We also
developed a model of the dynamics of the foot that predicts the stance and swing
phase dynamics of normal walking. In the present study, we determined whether
model parameters were altered in subjects with PD when they were tested on/off
levodopa (LD) and on/off deep brain stimulation (DBS) in a 2 x 2 matrix.

PMID: 17946882 [PubMed - indexed for MEDLINE]

31. Clin Neuropharmacol. 2007 Sep-Oct;30(5):287-94.

Tolcapone: an efficacy and safety review (2007).

Olanow CW, Watkins PB.

Department of Neurology, Mount Sinai School of Medicine, 1 Gustave Levy Place,
New York, NY 10029, USA. warren.olanow@mssm.edu

Tolcapone (Tasmar), an inhibitor of catechol-O-methyltransferase, is an effective
antiparkinsonian agent when used as an adjunct to levodopa in patients with
Parkinson disease who have end-of-dose motor fluctuations. In clinical trials,
tolcapone significantly reduced "off" time and levodopa requirements. The drug is
generally well tolerated, with the most common adverse events being dopaminergic
related. However, clinical trials demonstrated dose-related increases in liver
enzymes, and postmarketing surveillance noted 4 cases of acute hepatotoxicity
with 3 fatalities that were attributed to tolcapone. For this reason, the drug
was withdrawn from the market in some countries, and its use was severely
restricted in the United States. An analysis of safety data indicates that, since
the labeling restrictions in 1998, there have been more than 40,000 patient-years
of tolcapone treatment worldwide, with only 3 reports of severe, but reversible,
liver injury and no reports of hepatic fatality. It can be concluded that severe
liver injury due to tolcapone is a rare event. Based on these data, the drug has
been reintroduced to the market in several European countries, and the Food and
Drug Administration in the United States has modified monitoring requirements.
The new labeling recommends monitoring of liver function every 2 to 4 weeks for 6
months and at the physician's discretion thereafter. In addition, patients must
be taken off the drug if blood tests show enzyme elevation of greater than twice
the upper limit of normal. This article reviews the data pertaining to the safety
and efficacy of tolcapone.

PMID: 17909307 [PubMed - indexed for MEDLINE]

32. Exp Neurol. 2008 Jan;209(1):34-40. Epub 2007 Aug 22.

Regulatable promoters and gene therapy for Parkinson's disease: is the only thing
to fear, fear itself?

Kordower JH, Olanow CW.

Department of Neurological Sciences, Rush University Medical Center, Chicago, IL
60612, USA. jkordowe@rush.edu

Gene therapy for Parkinson's disease has become a clinical reality with three
different approaches currently being tested in patients. All three trials employ
an adeno-associated virus with a type two serotype (AAV2). To date, no serious
adverse events related to the injections of therapeutic vectors have been
reported in any patient. This safety profile was predicted based upon, in some
cases, exhaustive preclinical testing in both rodent and primate species. Still
some argue that regulatable promoters are required so that expression of the
transgene can be halted should untoward side effects arise. We argue that given
the current empirical data base of AAV2, the lack of regulatable promoters that
have been proven to be safe and effective, and the pressing clinical needs of PD
patients, the mandatory use of regulatable vectors is not only unnecessary but,
in some instances, misguided and potentially dangerous. This commentary will
outline the issues related to the use of regulatable promoters for gene therapy
for PD and express our opinion as to why mandating the use of such promoters
might result in outcomes that are unsafe, unproductive, and counter to the
progress of scientifically sound, clinical research.

PMID: 17888424 [PubMed - indexed for MEDLINE]

33. J Neuropathol Exp Neurol. 2007 Aug;66(8):675-82.

The neuropathology of manganese-induced Parkinsonism.

Perl DP, Olanow CW.

Department of Pathology, Mount Sinai School of Medicine, New York, NY 10029-6574,
USA. daniel.perl@mssm.edu

Manganese is an essential trace metal that is widely used in industry,
particularly in the manufacture of steel. Exposure to high levels of manganese
can cause neurotoxicity with the development of a form of parkinsonism known as
manganism. It has recently been hypothesized that manganese exposure might also
cause or accelerate the development of Parkinson disease (PD). This article is a
review of the pathologic studies that have been reported in patients with
manganism and in primates experimentally intoxicated with manganese. They
demonstrate a consistent pattern characterized by damage to the globus pallidus
(particularly the internal segment) with sparing of the substantia nigra pars
compacta and the absence of Lewy bodies. This finding contrasts with what is seen
in PD, in which there is preferential degeneration of dopamine neurons in the
substantia nigra pars compacta coupled with Lewy bodies and preservation of the
pallidum. These pathologic findings do not support the notion that manganese
causes PD but rather argues that manganese-induced parkinsonism and PD are
distinct and separate disease entities.

PMID: 17882011 [PubMed - indexed for MEDLINE]

34. J Neurochem. 2007 Oct;103(1):238-47. Epub 2007 Jul 10.

Leucine-rich repeat kinase 2 (LRRK2)/PARK8 possesses GTPase activity that is
altered in familial Parkinson's disease R1441C/G mutants.

Li X, Tan YC, Poulose S, Olanow CW, Huang XY, Yue Z.

Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New
York, USA.

Mutations in Leucine-rich repeat kinase 2 (LRRK2) are linked to the most common
familial forms and some sporadic forms of Parkinson's disease (PD). The LRRK2
protein contains two well-known functional domains, MAPKKK-like kinase and
Rab-like GTPase domains. Emerging evidence shows that LRRK2 contains kinase
activity which is enhanced in several PD-associated mutants of LRRK2. However,
the GTPase activity of LRRK2 has yet to be formally demonstrated. Here, we
produced and purified the epitope-tagged LRRK2 protein from transgenic mouse
brain, and showed that purified brain LRRK2 possesses both kinase and GTPase
activity as assayed by GTP binding and hydrolysis. The brain LRRK2 is associated
with elevated kinase activity in comparison to that from transgenic lung or
transfected cultured cells. In transfected cell cultures, we detected GTP
hydrolysis activity in full-length as well as in GTPase domain of LRRK2. This
result indicates that LRRK2 GTPase can be active independent of LRRK2 kinase
activity (while LRRK2 kinase activity requires the presence of LRRK2 GTPase as
previously shown). We further found that PD mutation R1441C/G in the GTPase
domain causes reduced GTP hydrolysis activity, consistent with the altered
enzymatic activity in the mutant LRRK2 carrying PD familial mutations. Therefore,
our study shows the biochemical characteristics of brain-specific LRRK2 which is
associated with robust kinase and GTPase activity. The distinctive levels of
kinase/GTPase activity in brain LRRK2 may help explain LRRK2-associated neuronal
functions or dysfunctions in the pathogenesis of PD.

PMID: 17623048 [PubMed - indexed for MEDLINE]

35. Arch Gerontol Geriatr. 2008 May-Jun;46(3):359-66. Epub 2007 Jun 26.

Prevalence of movement disorders in an elderly nursing home population.

Tse W, Libow LS, Neufeld R, Lesser G, Frank J, Dolan S, Tarshish C, Gracies JM,
Olanow CW, Koller WC, Hälbig TD.

Department of Neurology, Mount Sinai Medical Center, One Gustave L. Levy Place,
Box 1052, New York, NY 10029, USA. winona.tse@mssm.edu

We studied the prevalence of movement disorders in a large nursing home
population (397 patients, mean age 86 years) in New York City. Patients were
first evaluated by specially trained research coordinators and final clinical
diagnoses were confirmed by a movement disorder specialist. A movement disorder
was identified in 21% of patients (83/397). The most frequent movement disorders
were essential tremor (ET) (8.8%) and parkinsonism (7.1%). Only half of those
admitted with a diagnosis of parkinsonism were confirmed in their diagnosis by
the movement disorder specialists. Three percent of patients exhibited
drug-induced tremor, 1.3% had dystonia, 0.5% had myoclonus and 0.3% had
generalized dyskinesias. Overall, our findings underline the high frequency of
movement disorders in a nursing home population. The discrepancy between our
findings and the prevalence rates for parkinsonism reported on the initial
transfer diagnosis emphasizes the difficulty of accurate diagnosis of movement
disorders and in particular parkinsonism.

PMID: 17597235 [PubMed - indexed for MEDLINE]

36. Mov Disord. 2007 Aug 15;22(11):1623-9.

Prevalence of nonmotor symptoms in Parkinson's disease in an international
setting; study using nonmotor symptoms questionnaire in 545 patients.

Martinez-Martin P, Schapira AH, Stocchi F, Sethi K, Odin P, MacPhee G, Brown RG,
Naidu Y, Clayton L, Abe K, Tsuboi Y, MacMahon D, Barone P, Rabey M, Bonuccelli U,
Forbes A, Breen K, Tluk S, Olanow CW, Thomas S, Rye D, Hand A, Williams AJ, Ondo
W, Chaudhuri KR.

Unit of Neuroepidemiology, National Center for Epidemiology, Carlos III Institute
of Health, Madrid, Spain.

2006, there was, no single instrument (questionnaire or scale) for attempting a
comprehensive assessment of the wide range of nonmotor symptoms (NMS) of
Parkinson's disease (PD). The PD nonmotor group, a multidisciplinary group of
experts including patient group representatives developed and validated the NMS
screening questionnaire (NMSQuest) comprising 30 items. The NMSQuest is a self
completed screening tool designed to draw attention to the presence of NMS. In
this paper, we present the results gathered from 545 patients using the
definitive version of the NMSQuest highlighting the prevalence of the wide range
of NMS flagged in the NMSQuest from consecutive PD patients in an international
setting. Copyright (c) 2007 Movement Disorder Society.

PMID: 17546669 [PubMed - indexed for MEDLINE]

37. Mt Sinai J Med. 2007 Apr;74(1):7-14.

Translational experimental therapeutics: The translation of laboratory-based
discovery into disease-related therapy.

Kieburtz K, Olanow CW.

Neurology Department, University of Rochester Medical Center, Rochester, New York
14620, USA. karl.kieburtz@ctcc.rochester.edu

In the past decade, there has been an increasing emphasis on laboratory-based
translational research. This has led to significant scientific advances in our
understanding of disease mechanisms and in the development of novel approaches to
therapy such as gene therapy, RNA interference, and stem cells. However, the
translation of these remarkable scientific achievements into new and effective
disease-modifying therapies has lagged behind these scientific accomplishments.
We use the term "translational experimental therapeutics" to describe the pathway
between the discovery of a basic disease mechanism or novel therapeutic approach
and its translation into an effective treatment for patients with a specific
disease. In this article, we review the components of this pathway, and discuss
issues that might impede this process. Only by optimizing this pathway can we
realize the full therapeutic potential of current scientific discoveries and
translate the astounding advances that have been accomplished in the laboratory
into effective treatments for our patients. Copyright (c) 2007 Mount Sinai School
of Medicine.

PMID: 17516559 [PubMed - indexed for MEDLINE]

38. Neurology. 2007 Mar 13;68(11):812-9.

DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and
biomarkers.

Lippa CF, Duda JE, Grossman M, Hurtig HI, Aarsland D, Boeve BF, Brooks DJ,
Dickson DW, Dubois B, Emre M, Fahn S, Farmer JM, Galasko D, Galvin JE, Goetz CG,
Growdon JH, Gwinn-Hardy KA, Hardy J, Heutink P, Iwatsubo T, Kosaka K, Lee VM,
Leverenz JB, Masliah E, McKeith IG, Nussbaum RL, Olanow CW, Ravina BM, Singleton
AB, Tanner CM, Trojanowski JQ, Wszolek ZK; DLB/PDD Working Group.

Department of Neurology, Drexel University College of Medicine, Philadelphia, PA
19102, USA. clippa@drexelmed.edu

For more than a decade, researchers have refined criteria for the diagnosis of
dementia with Lewy bodies (DLB) and at the same time have recognized that
cognitive impairment and dementia occur commonly in patients with Parkinson
disease (PD). This article addresses the relationship between DLB, PD, and PD
with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the
umbrella term for PD, PDD, and DLB, to promote the continued practical use of
these three clinical terms, and to encourage efforts at drug discovery that
target the mechanisms of neurodegeneration shared by these disorders of
alpha-synuclein metabolism. We concluded that the differing temporal sequence of
symptoms and clinical features of PDD and DLB justify distinguishing these
disorders. However, a single Lewy body disorder model was deemed more useful for
studying disease pathogenesis because abnormal neuronal alpha-synuclein
inclusions are the defining pathologic process common to both PDD and DLB. There
was consensus that improved understanding of the pathobiology of alpha-synuclein
should be a major focus of efforts to develop new disease-modifying therapies for
these disorders. The group agreed on four important priorities: 1) continued
communication between experts who specialize in PDD or DLB; 2) initiation of
prospective validation studies with autopsy confirmation of DLB and PDD; 3)
development of practical biomarkers for alpha-synuclein pathologies; 4)
accelerated efforts to find more effective treatments for these diseases.

PMID: 17353469 [PubMed - indexed for MEDLINE]

39. Mov Disord. 2007 Jan;22(1):41-7.

Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease
Rating Scale (MDS-UPDRS): Process, format, and clinimetric testing plan.

Goetz CG, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stebbins GT, Stern MB,
Tilley BC, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees
A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA,
Van Hilten JJ, LaPelle N.

Department of Neurological Sciences, Rush University Medical Center, Chicago,
Illinois 60612, USA. cgoetz@rush.edu

This article presents the revision process, major innovations, and clinimetric
testing program for the Movement Disorder Society (MDS)-sponsored revision of the
Unified Parkinson's Disease Rating Scale (UPDRS), known as the MDS-UPDRS. The
UPDRS is the most widely used scale for the clinical study of Parkinson's disease
(PD). The MDS previously organized a critique of the UPDRS, which cited many
strengths, but recommended revision of the scale to accommodate new advances and
to resolve problematic areas. An MDS-UPDRS committee prepared the revision using
the recommendations of the published critique of the scale. Subcommittees
developed new material that was reviewed by the entire committee. A 1-day
face-to-face committee meeting was organized to resolve areas of debate and to
arrive at a working draft ready for clinimetric testing. The MDS-UPDRS retains
the UPDRS structure of four parts with a total summed score, but the parts have
been modified to provide a section that integrates nonmotor elements of PD: I,
Nonmotor Experiences of Daily Living; II, Motor Experiences of Daily Living; III,
Motor Examination; and IV, Motor Complications. All items have five response
options with uniform anchors of 0 = normal, 1 = slight, 2 = mild, 3 = moderate,
and 4 = severe. Several questions in Part I and all of Part II are written as a
patient/caregiver questionnaire, so that the total rater time should remain
approximately 30 minutes. Detailed instructions for testing and data acquisition
accompany the MDS-UPDRS in order to increase uniform usage. Multiple language
editions are planned. A three-part clinimetric program will provide testing of
reliability, validity, and responsiveness to interventions. Although the
MDS-UPDRS will not be published until it has successfully passed clinimetric
testing, explanation of the process, key changes, and clinimetric programs allow
clinicians and researchers to understand and participate in the revision process.
Copyright 2006 Movement Disorder Society.

PMID: 17115387 [PubMed - indexed for MEDLINE]

40. Lancet Neurol. 2006 Dec;5(12):1013-20.

TCH346 as a neuroprotective drug in Parkinson's disease: a double-blind,
randomised, controlled trial.

Olanow CW, Schapira AH, LeWitt PA, Kieburtz K, Sauer D, Olivieri G, Pohlmann H,
Hubble J.

Department of Neurology and Neuroscience, Mount Sinai School of Medicine, New
York, NY 10029, USA. warren.olanow@mssm.edu

Comment in:
Lancet Neurol. 2006 Dec;5(12):990-1.

BACKGROUND: There is an important unmet medical need in Parkinson's disease for a
neuroprotective treatment that slows or stops disease progression. TCH346 is a
potent anti-apoptotic drug that protects against loss of dopaminergic neurons in
laboratory models. Our aim was to assess TCH346 as a neuroprotective drug in
patients with Parkinson's disease. METHODS: Patients presenting at 45
international movement disorder clinics with early untreated Parkinson's disease
were assessed as part of this parallel-group, double-blind, randomised controlled
trial. 301 eligible patients were randomly assigned 12-18 months' treatment with
TCH346 at a daily dose of 0.5 mg (n=78), 2.5 mg (n=79), or 10 mg (n=73), or
placebo (n=71), followed by a 4 week washout period. The primary outcome measure
was time to development of a disability requiring dopaminergic treatment.
Secondary outcome measures were the annual rate of change in the unified
Parkinson's disease rating scale (UPDRS) and the PDQ-39, a measure of quality of
life. Analyses were by intention-to-treat. This study is pending registration
with . FINDINGS: 255 patients completed the study. TCH346 did not differ from
placebo for any of the study outcomes. Treatment was needed in 26 (34%) patients
in the TCH346 0.5 mg group, 30 (38%) in the TCH346 2.5 mg group, 24 (33%) in the
TCH346 10 mg group, and 23 (32%) in the placebo group. There were no significant
differences between groups. There were no differences between groups in the
annual change in the UPDRS or PDQ-39 either. Few patients withdrew because of
adverse events and none was judged to be related to the study intervention.
INTERPRETATION: TCH346 did not show evidence of a neuroprotective effect. The
discrepancy between the preclinical promise of TCH346 and the clinical outcome
could have arisen because of the use of laboratory models that do not accurately
reflect the pathogenesis of Parkinson's disease, the doses of study drug used,
insensitive clinical endpoints, and the patient population selected for study.

PMID: 17110281 [PubMed - indexed for MEDLINE]

41. Mov Disord. 2007 Jan 15;22(2):179-86.

Sarizotan as a treatment for dyskinesias in Parkinson's disease: a double-blind
placebo-controlled trial.

Goetz CG, Damier P, Hicking C, Laska E, Müller T, Olanow CW, Rascol O, Russ H.

Rush University Medical Center, Chicago, Illinois 60612, USA. cgoetz@rush.edu

The objective of this study is to conduct a dose-finding study of sarizotan in
Parkinson's disease (PD) patients with dyskinesia to identify a safe dose and to
identify a sensitive dyskinesia rating measure. Sarizotan is a novel compound
with full 5-HT(1A) agonist properties and additional high affinity for D(3) and
D(4) receptors. An open label study documented improvements in PD patients with
levodopa-induced dyskinesia. There is no precedent for study designs or outcome
measures in pivotal trials of antidyskinesia therapies. The approach used here
was a multicenter, randomized, placebo-controlled, double-blind, parallel study.
Included were PD patients optimized to levodopa and dopaminergic drugs with
moderately disabling dyskinesias present greater than or equal to 25% of the
waking day. Interventions included sarizotan 2, 4, or 10 mg/day or matching
placebo, given in two doses. There were two outcome measures: the primary measure
was change from baseline in diary-based on time without dyskinesia; the secondary
measures were change from baseline in scores on the Abnormal Involuntary Movement
Scale (AIMS), the composite score of Unified Parkinson's Disease Rating Scale
(UPDRS) Items 32+33 (dyskinesia duration and disability) and total UPDRS. A total
of 398 subjects were randomized, with 381 included in the intention-to-treat
population. No significant changes occurred on sarizotan compared to placebo on
any diary-based measure of dyskinesia or the AIMS score. The composite score of
UPDRS Items 32+33 was significantly improved with 2 mg/day sarizotan, with a
trend at 10 mg/day. Adverse events were not significantly different in sarizotan-
and placebo-treated patients, but off time significantly increased with sarizotan
10 mg/day. Sarizotan 2 mg/day is a safe agent in PD patients with dyskinesia. To
test its role in abating dyskinesia, future studies should focus on this dose and
will use the composite score of UPDRS Items 32+33 as the primary outcome. (c)
2006 Movement Disorder Society.

PMID: 17094088 [PubMed - indexed for MEDLINE]

42. J Biol Chem. 2006 Dec 22;281(51):39550-60. Epub 2006 Oct 23.

p53 mediates nontranscriptional cell death in dopaminergic cells in response to
proteasome inhibition.

Nair VD, McNaught KS, González-Maeso J, Sealfon SC, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, New York
10029, USA. Venugopalan.Nair@mssm.edu

Proteasome dysfunction has been demonstrated in Parkinson disease (PD), and
proteasome inhibitors have been shown to induce degeneration of dopaminergic
neurons in vitro and in vivo. The mechanism whereby proteasome dysfunction leads
to dopaminergic cell death, however, is unknown. In this study, we show that
proteasome inhibition in both PC12 cells and dopaminergic neurons derived from
embryonic stem cells is associated with mitochondrial membrane permeabilization,
activation of caspase-3, and nuclear changes consistent with apoptosis. Prior to
the emergence of apoptotic features, we found that proteasome inhibition induced
increased levels of phosphorylated p53. Inhibition of p53 by pifithrin-alpha or
by RNA interference prevented mitochondrial membrane permeabilization and
cytotoxicity. There was no increase in p53 mRNA in proteasome-inhibited cells,
suggesting that p53 was increased in a transcription-independent manner. Further,
there was no increase in Puma or Bax mRNA and p53 co-immunoprecipitated with
Bcl-xL and Mdm2. These findings suggest that p53 mediates cell death by way of a
direct mitochondrial effect in this model. We also observed increased levels of
phosphorylated p53 in dopamine neurons of the substantia nigra pars compacta of
mice following systemic administration of a proteasome inhibitor. These changes
preceded degeneration of dopaminergic neurons. Increased phosphorylated p53 was
also demonstrated in the substantia nigra pars compacta of post-mortem PD brains.
These results suggest that abnormalities in p53 signaling play a role in
dopaminergic cell death induced by proteasome inhibition and may be relevant to
neurodegeneration in PD.

PMID: 17060322 [PubMed - indexed for MEDLINE]

43. Mov Disord. 2006 Nov;21(11):1806-23.

Ubiquitin-proteasome system and Parkinson's disease.

Olanow CW, McNaught KS.

Department of Neurology, Mount Sinai School of Medicine, New York, New York10029,
USA. warren.olanow@mssm.edu

Increasing genetic, pathological, and experimental evidence suggest that
neurodegeneration in both familial and sporadic forms of Parkinson's disease (PD)
may be related to a defect in the capacity of the ubiquitin-proteasome system
(UPS) to clear unwanted proteins, resulting in protein accumulation, aggregation,
and cytotoxicity. This concept is supported by in vitro and in vivo laboratory
experiments which show that inhibition of UPS function can cause
neurodegeneration coupled with the formation of Lewy body-like inclusions. This
hypothesis could account for the presence of protein aggregates and Lewy bodies
in PD, the other biochemical features seen in the disorder, and the age-related
vulnerability of the substantia nigra pars compacta. It also suggests novel
targets for putative neuroprotective therapies for PD.

PMID: 16972273 [PubMed - indexed for MEDLINE]

44. Nat Clin Pract Neurol. 2006 Jul;2(7):382-92.

Drug insight: Continuous dopaminergic stimulation in the treatment of Parkinson's
disease.

Olanow CW, Obeso JA, Stocchi F.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
warren.olanow@mssm.edu

Continuous dopaminergic stimulation is a therapeutic strategy for the management
of Parkinson's disease, which proposes that dopaminergic agents that provide
continuous stimulation of striatal dopamine receptors will delay or prevent the
onset of levodopa-related motor complications. Dopaminergic neurons in the basal
ganglia normally fire in a random but continuous manner, so that striatal
dopamine concentrations are maintained at a relatively constant level. In the
dopamine-depleted state, however, intermittent oral doses of levodopa induce
discontinuous stimulation of striatal dopamine receptors. This pulsatile
stimulation leads to molecular and physiologic changes in basal ganglia neurons
and the development of motor complications. These effects are reduced or avoided
when dopaminergic therapies are delivered in a more continuous and physiologic
manner. Studies in primate models and patients with Parkinson's disease have
shown that continuous or long-acting dopaminergic agents are associated with a
decreased risk of motor complications compared with short-acting dopamine
agonists or levodopa formulations. Continuous dopaminergic stimulation can be
achieved with a continuous infusion, but infusion therapies are cumbersome and
not likely to be acceptable to patients with early disease. The current challenge
is to develop a long-acting oral formulation of levodopa that provides comparable
anti-parkinsonian benefits without motor complications.

PMID: 16932589 [PubMed - indexed for MEDLINE]

45. Ann Neurol. 2006 Aug;60(2):243-7.

Proteasome inhibitor-induced model of Parkinson's disease.

McNaught KS, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.
kevin.mcnaught@mssm.edu

Partial retraction in:
McNaught KS, Olanow CW. Ann Neurol. 2009 Apr;65(4):485.

We recently reported that systemic administration of a proteasome inhibitor
induced a progressive levodopa-responsive, bradykinetic syndrome in rats with
imaging, pathological, and biochemical features that strikingly resemble what is
found in PD. This model has the potential to be a useful tool for studying the
mechanism of cell death in Parkinson's disease and for testing putative
neuroprotective agents. Since publication of these findings, several laboratories
have sought to reproduce the model; some have been successful in replicating our
findings, but others have not. The reason for this variability is not known, but
resolution is critically important given the potential utility of this model. We
have begun to examine various factors that alone or in combination might explain
these differences, and we present in this article preliminary results from these
studies.

PMID: 16862580 [PubMed - indexed for MEDLINE]

46. Lancet Neurol. 2006 Aug;5(8):677-87.

Continuous dopamine-receptor treatment of Parkinson's disease: scientific
rationale and clinical implications.

Olanow CW, Obeso JA, Stocchi F.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
warren.olanow@mssm.edu

Levodopa-induced motor complications are a common source of disability for
patients with Parkinson's disease. Evidence suggests that motor complications are
associated with non-physiological, pulsatile stimulation of dopamine receptors.
In healthy brains, dopamine neurons fire continuously, striatal dopamine
concentrations are relatively constant, and there is continuous activation of
dopamine receptors. In the dopamine-depleted state, standard levodopa therapy
does not normalise the basal ganglia. Rather, levodopa or other short-acting
dopaminergic drugs induce molecular changes and altered neuronal firing patterns
in basal ganglia neurons leading to motor complications. The concept of
continuous dopaminergic stimulation proposes that continuous delivery of a
dopaminergic drug will prevent pulsatile stimulation and avoid motor
complications. In monkeys treated with MPTP
(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and patients with Parkinson's
disease, long-acting or continuous infusion of a dopaminergic drug reduces the
risk of motor complications. The current challenge is to develop a long-acting
oral formulation of levodopa that provides clinical benefits but avoids motor
complications.

PMID: 16857573 [PubMed - indexed for MEDLINE]

47. Neurology. 2006 May 23;66(10 Suppl 4):S89-103.

Gene transfer of trophic factors and stem cell grafting as treatments for
Parkinson's disease.

Dass B, Olanow CW, Kordower JH.

Department of Neurological Sciences, Rush University Medical Center, Chicago, IL
60657, USA.

Current therapies for Parkinson's disease (PD) are limited in their ability to
control PD symptomatology, are associated with motor and psychiatric side
effects, and do not prevent disease progression. Considerable scientific and
media interest has focused on the potential value of gene and stem cell therapies
to overcome these problems and to enhance the quality of life for PD patients.
Gene therapies utilize a viral vector to deliver a protein of interest to
specific brain region. Clinical trials of gene therapy are currently underway
using adeno-associated virus to deliver AADC to the striatum, the trophic factor
nurturin to the striatum, and GAD to the STN. To date, no serious adverse effects
have been noted, but only a small number of patients have been studied. Stem
cells are pluripotential cells that offer the potential of generating unlimited
numbers of optimized dopamine cells for transplantation. Stem cells can be grown
and expanded in tissue culture and then induced to differentiate into dopamine
neuronal phenotypes. Transplantation of these cells into the striatum is
associated with behavioral improvement in 6-OHDA rodents and MPTP monkeys. Still,
only small numbers of transplanted dopaminergic cells survive, and benefits are
modest. Clinical trials in PD have not yet been performed. There is considerable
enthusiasm for the potential of these procedures, but there remains much to learn
in the laboratory and neither has been established to be effective as a treatment
for PD. Long term safety and efficacy trials have not been performed in PD
patients and the potential of unanticipated side effects must be addressed.
Further, neither treatment is expected to improve the non-dopaminergic features
of PD.

PMID: 16717256 [PubMed - indexed for MEDLINE]

48. Neurology. 2006 May 23;66(10 Suppl 4):S69-79.

Rationale for considering that propargylamines might be neuroprotective in
Parkinson's disease.

Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
warren.olanow@mssm.edu

A neuroprotective therapy that slows or stops disease progression is the major
unmet medical need in Parkinson's disease (PD). Current evidence indicates that
cell death in PD occurs, at least in part, by way of a signal-mediated apoptotic
process. This raises the possibility that anti-apoptotic agents might be
neuroprotective in PD. Propargylamines have been demonstrated to be potent
anti-apoptotic agents in both in vitro and in vivo studies, presumably by
maintaining glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a dimer and
thereby preventing its nuclear translocation where it blocks upregulation of
anti-apoptotic proteins. Selegiline is a monamine oxidase type B (MAO-B)
inhibitor that incorporates a propargyl ring within its molecular structure. It
was shown to delay the need for symptomatic therapy in untreated PD patients in
the DATATOP study, but interpretation is confounded by its symptomatic effects.
Rasagiline is another MAO-B inhibitor that contains a propargyl ring and has
protective effects in laboratory models. A clinical trial utilizing a delayed
start design demonstrated that patients initiated on rasagiline at baseline are
improved at one year in comparison to patients initiated on placebo and switched
to rasagiline at 6 months even though both groups were on the same treatment for
the last 6 months of the study. These results argue against the benefit being due
to a symptomatic effect and are consistent with rasagiline having a protective
effect.

PMID: 16717254 [PubMed - indexed for MEDLINE]

49. Neurology. 2006 May 23;66(10 Suppl 4):S37-49.

Proteasomal dysfunction in sporadic Parkinson's disease.

McNaught KS, Jackson T, JnoBaptiste R, Kapustin A, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
kevin.mcnaught@mssm.edu

The cause and mechanism of neuronal death in sporadic Parkinson's disease (PD)
continue to elude investigators. Recently, alterations in proteasomal function
have been detected in the brain of patients with the illness. The biochemical
basis of the defect and its relevance to the disease process are now being
studied. The available results suggest that proteasomal dysfunction could
underlie protein accumulation, Lewy body formation, and neuron death in PD. The
cause of proteasomal dysfunction is unknown at present, but this could relate to
gene mutations, oxidative damage, ATP depletion, or the actions of environmental
toxins. It remains to be established if proteasomal dysfunction plays a primary
or a secondary role in the initiation or progression of the neurodegenerative
process in PD.

PMID: 16717251 [PubMed - indexed for MEDLINE]

50. Neurology. 2006 May 23;66(10 Suppl 4):S24-36.

The pathogenesis of cell death in Parkinson's disease.

Jenner P, Olanow CW.

Neurodegenerative Diseases Research Centre, School of Health and Biomedical
Sciences, King's College, London, United Kingdom. peter.jenner@kcl.ac.uk

Concepts of pathogenesis in Parkinson's disease (PD) have been based on attempts
to understand the mechanisms responsible for nigral dopaminergic cell death.
Pathogenesis has been proposed to involve oxidative and nitrative stress,
excitotoxicity, inflammation, mitochondrial dysfunction, and altered proteolysis.
These processes are considered to form a complex cascade of interrelated events
that lead to neuron death by way of apoptosis. However, current views on
pathogenic mechanisms in PD may not be as exact as commonly proposed. Future
concepts of pathogenesis in PD need to incorporate events leading to the
destruction of non-dopaminergic nuclei and to distinguish between primary factors
that are responsible for disease initiation and secondary factors that contribute
to disease progression. Importantly, there is a need to determine whether PD is a
single illness with a common pathogenesis or a group of related illnesses with
different pathogenic mechanisms. This is an essential step to understanding
pathogenesis and is critical to the development of comprehensive neuroprotective
approaches to treatment.

PMID: 16717250 [PubMed - indexed for MEDLINE]

51. Mov Disord. 2006 Jul;21(7):916-23.

International multicenter pilot study of the first comprehensive self-completed
nonmotor symptoms questionnaire for Parkinson's disease: the NMSQuest study.

Chaudhuri KR, Martinez-Martin P, Schapira AH, Stocchi F, Sethi K, Odin P, Brown
RG, Koller W, Barone P, MacPhee G, Kelly L, Rabey M, MacMahon D, Thomas S, Ondo
W, Rye D, Forbes A, Tluk S, Dhawan V, Bowron A, Williams AJ, Olanow CW.

Movement Disorders Unit, Kings College Hospital, University Hospital Lewisham,
Guy's King's and St. Thomas' School of Medicine, London, United Kingdom.
ray.chaudhuri@uhl.nhs.uk

Nonmotor symptoms (NMS) of Parkinson's disease (PD) are not well recognized in
clinical practice, either in primary or in secondary care, and are frequently
missed during routine consultations. There is no single instrument (questionnaire
or scale) that enables a comprehensive assessment of the range of NMS in PD both
for the identification of problems and for the measurement of outcome. Against
this background, a multidisciplinary group of experts, including patient group
representatives, has developed an NMS screening questionnaire comprising 30
items. This instrument does not provide an overall score of disability and is not
a graded or rating instrument. Instead, it is a screening tool designed to draw
attention to the presence of NMS and initiate further investigation. In this
article, we present the results from an international pilot study assessing
feasibility, validity, and acceptability of a nonmotor questionnaire (NMSQuest).
Data from 123 PD patients and 96 controls were analyzed. NMS were highly
significantly more prevalent in PD compared to controls (PD NMS, median = 9.0,
mean = 9.5 vs. control NMS, median = 5.5, mean = 4.0; Mann-Whitney,
Kruskal-Wallis, and t test, P < 0.0001), with PD patients reporting at least 10
different NMS on average per patient. In PD, NMS were highly significantly more
prevalent across all disease stages and the number of symptoms correlated
significantly with advancing disease and duration of disease. Furthermore,
frequently, problems such as diplopia, dribbling, apathy, blues, taste and smell
problems were never previously disclosed to the health professionals. (c) 2006
Movement Disorder Society.

PMID: 16547944 [PubMed - indexed for MEDLINE]

52. Lancet Neurol. 2006 Jan;5(1):3-5.

Movement disorders: a step in the right direction.

Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.
Warren.olanow@mssm.edu

PMID: 16361007 [PubMed - indexed for MEDLINE]

53. Can J Neurol Sci. 2005 Aug;32(3):277-86.

Progress in clinical neurosciences: a forum on the early management of
Parkinson's disease.

Lang AE, Miyasaki J, Olanow CW, Stoessl AJ, Suchowersky O.

Division of Neurology, Department of Medicine, University of Toronto, Toronto
Western Hospital, Canada.

There are numerous concerns related to treatment choices involving early
dopaminergic therapy in Parkinson's disease. These include the effect on the
underlying progression of the neurodegenerative process as well as the
development of motor complications such as fluctuations and dyskinesias. A number
of recent basic and clinical studies have provided new insights but have also
added confusion and controversy. This report summarizes presentations and
discussion dealing with these issues from a one-day symposium involving Canadian
Movement Disorders neurologists.

PMID: 16225167 [PubMed - indexed for MEDLINE]

54. Neurobiol Aging. 2006 Apr;27(4):530-45. Epub 2005 Oct 3.

Protein aggregation in the pathogenesis of familial and sporadic Parkinson's
disease.

McNaught KS, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, Annenberg 14-73, One
Gustave L. Levy Place, New York, NY 10029, USA. kevin.mcnaught@mssm.edu

Parkinson's disease (PD) is a slowly progressive, age-related, neurodegenerative
disorder. The cause and mechanism of neuronal death have been elusive. However,
recent genetic, postmortem and experimental evidence show that protein
accumulation and aggregation are prominent occurrences in both sporadic and
familial PD. The relevance of these events to other cellular and biochemical
changes, and to the neurodegenerative process, is being unraveled. It is
increasingly evident that one or a combination of defects, including mutations,
oxidative stress, mitochondrial impairment and dysfunction of the
ubiquitin-proteasome system, lead to an excess production and aggregation of
abnormal proteins in PD. In this respect, altered protein handling appears to be
a central factor in the pathogenic process occurring in the various hereditary
and sporadic forms of PD. This suggests that manipulation of proteolytic systems
is a rational approach in the development of neuroprotective therapies that could
modify the pathological course of PD.

PMID: 16207501 [PubMed - indexed for MEDLINE]

55. Neurology. 2005 Nov 8;65(9):1430-5. Epub 2005 Sep 14.

Occupation and parkinsonism in three movement disorders clinics.

Goldman SM, Tanner CM, Olanow CW, Watts RL, Field RD, Langston JW.

The University of California, San Francisco, CA, USA. sgoldman@thepi.org

BACKGROUND: Few occupational risk factors for Parkinson disease (PD) have been
identified. Healthcare, teaching, and farming have been associated with increased
risk, while welding has been proposed to accelerate age at PD onset. The aim of
the present study was to investigate occupational associations with PD or
parkinsonism drawing from three different movement disorders clinics. METHODS:
Medical records of 2,249 consecutive patients with PD or parkinsonism from
specialty clinics in Sunnyvale, CA, New York, NY, and Atlanta, GA, were reviewed
for primary lifetime occupation. Job frequencies were compared with Department of
Labor regional statistics. PD diagnosis age and risk of diagnosis < or =50 were
determined for each job. RESULTS: Physicians/dentists, farmers, and teachers were
significantly more common than expected among PD patients, as were lawyers,
scientists, and religion-related jobs. Computer programmers had a younger age at
PD diagnosis, and risk of diagnosis < or =50 was greater in computer programmers
and technicians. CONCLUSIONS: Consistent with prior studies, healthcare,
teaching, and farming were common occupations in Parkinson disease (PD) patients,
but welders were not over-represented. Even though several occupations were
associated with younger age at PD diagnosis, these results may reflect biases
inherent in specialty clinic surveys, including over-representation of younger,
employed, and insured patients. Carefully designed analytic studies utilizing
appropriate control populations will be required to test hypotheses regarding
occupation and PD risk.

PMID: 16162857 [PubMed - indexed for MEDLINE]

56. Arch Neurol. 2005 Sep;62(9):1343-4.

Double-blind, placebo-controlled trials for surgical interventions in Parkinson
disease.

Olanow CW.

Comment on:
Arch Neurol. 2005 Sep;62(9):1357-60.

PMID: 16157740 [PubMed - indexed for MEDLINE]

57. Curr Opin Neurol. 2005 Aug;18(4):376-85.

Stem cell treatment for Parkinson's disease: an update for 2005.

Snyder BJ, Olanow CW.

Department of Neurosurgery, Mount Sinai School of Medicine, New York, NY 10029,
USA.

PURPOSE OF REVIEW: The hallmark pathologic feature of Parkinson's disease is loss
of melanized dopaminergic neurons within the substantia nigra pars compacta
coupled with depletion of striatal dopamine. This is responsible for the major
motor features of the disease. Whereas dopaminergic replacement therapy is
effective in the early stages of the illness, chronic treatment is associated
with motor complications and development of features that do not respond to
levodopa therapy. Development of cellular therapies offers the potential to
provide more effective treatment for the disease without motor complications.
RECENT FINDINGS: Two clinical trials of fetal nigral transplantation failed to
meet their primary endpoint and were complicated by the development of dyskinesia
that persisted after withdrawal of levodopa ('off-medication' dyskinesia).
However, recent studies suggest that both the limited clinical response and
off-medication dyskinesia may be related to partial, but incomplete, dopaminergic
reinnervation of the striatum and that both might be improved by transplantation
of more dopamine neurons. Stem cells offer the potential to provide a virtually
unlimited supply of optimized dopaminergic neurons that can provide enhanced
benefits in comparison to fetal mesencephalic transplants. Stem cells have now
been shown to be capable of differentiating into dopamine neurons that provide
benefits following transplantation in animal models of Parkinson's disease.
However, cell survival and behavioral responses are limited. There have been
numerous advances in enhancing the yield of dopamine neurons from stem cells, and
promoting their survival and consequent clinical effects. SUMMARY: Stem cells
offer great promise as a therapy for Parkinson's disease, but numerous hurdles
remain to be overcome with stem cell therapy. The adverse event profile of
transplantation must be determined, and societal and ethical issues addressed. As
Parkinson's disease involves degeneration of both dopaminergic and
non-dopaminergic neurons, it also remains to be determined if transplantation of
even the ideal dopamine neuron will improve non-dopaminergic features of the
disease or provide benefits superior to existing therapies.

PMID: 16003112 [PubMed - indexed for MEDLINE]

58. Arch Neurol. 2005 Jun;62(6):905-10.

Intermittent vs continuous levodopa administration in patients with advanced
Parkinson disease: a clinical and pharmacokinetic study.

Stocchi F, Vacca L, Ruggieri S, Olanow CW.

Institute of Neurology, IRCCS Neuromed, Pozzilli [IS], Italy. fabstocc@tin.it

BACKGROUND: Levodopa-related motor complications can be an important source of
disability for patients with advanced Parkinson disease. Current evidence
suggests that these motor complications are related to the relatively short
half-life of levodopa and its potential to induce pulsatile stimulation of
striatal dopamine receptors. Motor complications can be diminished with a
continuous infusion of levodopa. OBJECTIVE: To investigate the specific
pharmacokinetic changes associated with the benefits of levodopa infusion.
DESIGN: We performed an open-label study in 6 patients with Parkinson disease who
experienced severe motor complications while receiving standard oral formulations
of levodopa/carbidopa. Patients were subsequently treated for 6 months with
continuous daytime intraintestinal infusions of levodopa methyl ester. Levodopa
pharmacokinetic studies were performed at baseline and 6 months in 3 of these
patients. RESULTS: Compared with treatment with intermittent doses of a standard
oral formulation of levodopa, continuous infusion provided significant
improvement in both "off periods" and dyskinesia. Results of plasma
pharmacokinetic studies demonstrated that compared with oral administration,
continuous levodopa infusion was associated with a significant increase in the
levodopa area under the curve and avoided the low plasma trough levels seen with
oral drug administration. CONCLUSIONS: This study confirms that a continuous
levodopa infusion is associated with reduced motor complications compared with
the standard oral formulation of the drug in patients with advanced PD.
Pharmacokinetic studies demonstrate that reduced motor complications are
associated with avoiding low plasma levodopa trough levels and are not adversely
affected by relatively high plasma levodopa concentrations. We propose that if
levodopa/carbidopa could be administered orally in a manner that mirrors the
pharmacokinetic pattern of the infusion, it might lead to a similar reduction in
motor complications.

PMID: 15956161 [PubMed - indexed for MEDLINE]

59. Parkinsonism Relat Disord. 2005 Aug;11(5):317-21.

Clinical usefulness of the Parkinson's disease sleep scale.

Tse W, Liu Y, Barthlen GM, Hälbig TD, Tolgyesi SV, Gracies JM, Olanow CW, Koller
WC.

Department of Neurology, The Mount Sinai School of Medicine, One Gustave L. Levy
Place, New York, NY 10029, USA. winona.tse@mssm.edu

OBJECTIVE: To test the usefulness of the Parkinson's disease sleep scale (PDSS)
in identifying sleep disorders in the clinical practice setting. METHODS:
Sixty-two PD patients were evaluated with the PDSS and the Epworth sleepiness
scale (ESS). A cut-off of less than five for each PDSS item as an indicator of
substantial sleep disturbance was chosen. If the ESS was equal to or greater than
eight, patients were referred to a sleep disorder specialist and possible
polysomnography. RESULTS: The mean total PDSS score was 104.7+/-21.5,which
correlated with the mean Hoehn and Yahr score (1.9+/-0.9) as well as the mean ESS
score (9.7+/-4.7). A significant correlation was also found between the ESS score
and several items of the PDSS. CONCLUSIONS: The PDSS was useful in identifying
sleep disturbances which were not previously diagnosed, such as sleep maintenance
insomnia and excessive daytime sleepiness. Problems with the PDSS include
ambiguities of some questions, lack of quantification and an inability to
identify specific sleep disturbances such as sleep apnea.

PMID: 15882956 [PubMed - indexed for MEDLINE]

60. Mov Disord. 2005;20 Suppl 11:S3-10.

Neuroprotective therapy in Parkinson's disease and motor complications: a search
for a pathogenesis-targeted, disease-modifying strategy.

Olanow CW, Jankovic J.

Department of Neurology, Mount Sinai School of Medicine, Annenberg 14-94, One
Gustave L. Levy Place, New York, NY 10029, USA. warren.olanow@mssm.edu

The introduction of levodopa in the late 1960s represented a landmark in the
therapy of Parkinson's disease (PD). However, motor complications of chronic
levodopa therapy have emerged as a major limitation of this otherwise effective
therapy. Advancing medical and surgical treatment of these complications has been
the main objective of clinical trials during the past few decades. In addition,
basic research has focused on better understanding of the mechanisms of motor
complications and how to prevent them. Slowing or delaying the progression of the
disease delays the need for levodopa therapy; therefore, neuroprotective
strategies may play an important role in preventing the onset and reducing the
severity of levodopa-related adverse effects. In this introductory review, we
present the rationale for current and experimental therapies designed to
favorably modify the progression of PD. If implemented early in the course of the
disease, such treatments, if found effective, may not only alter the natural
progression of the disease but may also delay or minimize motor and nonmotor
complications associated with levodopa. (c) 2005 Movement Disorder Society.

PMID: 15822111 [PubMed - indexed for MEDLINE]

61. N Engl J Med. 2004 Dec 9;351(24):2498-508.

Levodopa and the progression of Parkinson's disease.

Fahn S, Oakes D, Shoulson I, Kieburtz K, Rudolph A, Lang A, Olanow CW, Tanner C,
Marek K; Parkinson Study Group.

Columbia University, New York, USA. fahn@neuro.columbia.edu

Comment in:
N Engl J Med. 2004 Dec 9;351(24):2547-9. N Engl J Med. 2005 Mar 31;352(13):1386; author reply 1386.

BACKGROUND: Despite the known benefit of levodopa in reducing the symptoms of
Parkinson's disease, concern has been expressed that its use might hasten
neurodegeneration. This study assessed the effect of levodopa on the rate of
progression of Parkinson's disease. METHODS: In this randomized, double-blind,
placebo-controlled trial, we evaluated 361 patients with early Parkinson's
disease who were assigned to receive carbidopa-levodopa at a daily dose of 37.5
and 150 mg, 75 and 300 mg, or 150 and 600 mg, respectively, or a matching placebo
for a period of 40 weeks, and then to undergo withdrawal of treatment for 2
weeks. The primary outcome was a change in scores on the Unified Parkinson's
Disease Rating Scale (UPDRS) between baseline and 42 weeks. Neuroimaging studies
of 142 subjects were performed at baseline and at week 40 to assess striatal
dopamine-transporter density with the use of iodine-123-labeled
2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane ([123I]beta-CIT) uptake.
RESULTS: The severity of parkinsonism increased more in the placebo group than in
all the groups receiving levodopa: the mean difference between the total score on
the UPDRS at baseline and at 42 weeks was 7.8 units in the placebo group, 1.9
units in the group receiving levodopa at a dose of 150 mg daily, 1.9 in those
receiving 300 mg daily, and -1.4 in those receiving 600 mg daily (P<0.001). In
contrast, in a substudy of 116 patients the mean percent decline in the
[123I]beta-CIT uptake was significantly greater with levodopa than placebo (-6
percent among those receiving levodopa at 150 mg daily, -4 percent in those
receiving it at 300 mg daily, and -7.2 percent among those receiving it at 600 mg
daily, as compared with -1.4 percent among those receiving placebo; 19 patients
with no dopaminergic deficits on the baseline scans were excluded from the
analysis) (P=0.036). The subjects receiving the highest dose of levodopa had
significantly more dyskinesia, hypertonia, infection, headache, and nausea than
those receiving placebo. CONCLUSIONS: The clinical data suggest that levodopa
either slows the progression of Parkinson's disease or has a prolonged effect on
the symptoms of the disease. In contrast, the neuroimaging data suggest either
that levodopa accelerates the loss of nigrostriatal dopamine nerve terminals or
that its pharmacologic effects modify the dopamine transporter. The potential
long-term effects of levodopa on Parkinson's disease remain uncertain. Copyright
2004 Massachusetts Medical Society.

PMID: 15590952 [PubMed - indexed for MEDLINE]

62. Hum Mol Genet. 2005 Jan 1;14(1):125-33. Epub 2004 Nov 17.

Transgenic mouse model of early-onset DYT1 dystonia.

Shashidharan P, Sandu D, Potla U, Armata IA, Walker RH, McNaught KS, Weisz D,
Sreenath T, Brin MF, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy
Place, NY 10029, USA. pullani.shashi@mssm.edu

Early-onset dystonia is an autosomal dominant movement disorder associated with
deletion of a glutamic acid residue in torsinA. We generated four independent
lines of transgenic mice by overexpressing human DeltaE-torsinA using a neuron
specific enolase promoter. The transgenic mice developed abnormal involuntary
movements with dystonic-appearing, self-clasping of limbs, as early as 3 weeks
after birth. Animals also showed hyperkinesia and rapid bi-directional circling.
Approximately 40% of transgenic mice from each line demonstrated these severe
behavioral abnormalities. Neurochemical analyses revealed decreases in striatal
dopamine in affected transgenic mice, although levels were increased in those
that had no behavioral changes. Immunohistochemistry demonstrated perinuclear
inclusions and aggregates that stained positively for ubiquitin, torsinA and
lamin, a marker of the nuclear envelope. Inclusions were detected in neurons of
the pedunculopontine nucleus and in other brain stem regions in a pattern similar
to what has been described in DYT1 patients. This transgenic mouse model
demonstrates behavioral and pathologic features similar to patients with
early-onset dystonia and may help to better understand the pathophysiology of
this disorder and to develop more effective therapies.

PMID: 15548549 [PubMed - indexed for MEDLINE]

63. Neurol Clin. 2004 Oct;22(3 Suppl):S1-S17.

Neuroprotective agents in Parkinson's disease: clinical evidence and caveats.

Hälbig TD, Tse W, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy
Place, New York, NY 10029, USA.

PMID: 15501359 [PubMed - indexed for MEDLINE]

64. J Neural Transm. 2004 Oct;111(10-11):1333-41. Epub 2004 May 12.

Effects of levodopa on cognitive functioning in moderate-to-severe Parkinson's
disease (MSPD).

Morrison CE, Borod JC, Brin MF, Hälbig TD, Olanow CW.

Comprehensive Epilepsy, New York University Medical Center, New York, NY 10016,
USA. c.morrison@med.nyu.edu

Although improved cognition has been reported in patients with mild Parkinson's
disease (PD) following the administration of levodopa, mixed results have been
found in moderately-to-severely affected PD patients (MSPD), particularly in
studies conducted since 1980. In the present study, 16 MSPD patients were tested
on separate days, once following overnight levodopa withdrawal and once while
optimally treated. A battery of neuropsychological tests that assess a range of
cognitive functions (i.e., attention, language, visuospatial, memory, and
executive), as well as a measure of depression, were used. Although patients
performed better on a measure of confrontation naming in the untreated than in
the treated condition, there were no significant differences for any of the other
cognitive variables or for the depression scale variable. Thus, these data
suggest that there are generally no adverse or beneficial effects of levodopa
therapy on cognition in MSPD patients.

PMID: 15480842 [PubMed - indexed for MEDLINE]

65. J Neural Transm. 2004 Oct;111(10-11):1237-51.

Inhibition of proteasome activity sensitizes dopamine neurons to protein
alterations and oxidative stress.

Mytilineou C, McNaught KS, Shashidharan P, Yabut J, Baptiste RJ, Parnandi A,
Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.

Impairment in the capacity of the ubiquitin-proteasome pathway to clear unwanted
proteins has been implicated in the cell death that occurs in Parkinson's disease
(PD). In support of this concept, defects in proteasomal structure and function,
as well as protein aggregates and increased levels of oxidized proteins are found
in the substantia nigra of PD patients. We have previously demonstrated that
inhibition of proteasome activity in mesencephalic cultures induces degeneration
of dopaminergic neurons coupled with the formation of proteinaceous intracellular
inclusions. In this study we examined the effect of proteasome inhibition on
cultured dopamine neurons when combined with oxidative stress and protein
misfolding, in order to better simulate the condition in PD. We demonstrate that
two structurally unrelated inhibitors of proteasome activity, lactacystin and
carbobenzoxy-L-leucul-L-leucyl-L-leucinal (MG132), cause dose-dependent cell loss
that preferentially affects dopaminergic neurons. Conditions that promote protein
damage and misfolding such as oxidative stress, heat shock, and canavanine also
induce neuronal degeneration with preferential loss of dopamine neurons and cell
death is markedly increased when any of these is combined with a proteasome
inhibitor. These studies demonstrate a synergistic effect between conditions that
promote the formation of damaged proteins and those in which proteasomal function
is impaired, and provide further support for the notion that cell loss in PD
could be related to a defect in protein handling.

PMID: 15480836 [PubMed - indexed for MEDLINE]

66. Arch Neurol. 2004 Oct;61(10):1563-8.

Double-blind, placebo-controlled study of entacapone in levodopa-treated patients
with stable Parkinson disease.

Olanow CW, Kieburtz K, Stern M, Watts R, Langston JW, Guarnieri M, Hubble J; US01
Study Team.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
warren.olanow@MSSM.edu

BACKGROUND: The catechol O-methyltransferase inhibitor entacapone acts by
extending the elimination half-life of levodopa and is currently approved as an
adjunct to levodopa for the treatment of patients with Parkinson disease (PD)
with motor fluctuations. OBJECTIVE: To determine if the addition of entacapone
administration provides benefit to levodopa-treated PD patients who have a stable
response to levodopa and do not experience motor complications. DESIGN:
Prospective, double-blind, placebo-controlled trial. SETTING: Outpatient
multicenter study. PATIENTS: Female and male patients 30 years or older with
idiopathic PD receiving stable doses of levodopa or carbidopa with or without
other dopaminergic therapies and who did not experience motor fluctuations were
eligible for the study. MAIN OUTCOME MEASURES: Parkinsonian function and quality
of life. RESULTS: The addition of entacapone did not improve motor scores on the
Unified Parkinson's Disease Rating Scale in levodopa-treated PD patients who did
not experience motor fluctuations. The mean +/- SE adjusted change between
baseline and final treatment visit was -0.9 +/- 0.35 in the entacapone group and
-0.8 +/- 0.35 in the placebo group (P = .83). Significant improvement with
entacapone treatment was detected in several quality-of-life measures, including
the Parkinson Disease Questionnaire 39, the 36-item Short-Form Health Survey, the
Parkinson's Symptom Inventory, and investigator and subject Clinical Global
Assessments. The drug was well tolerated by patients in this population.
CONCLUSIONS: The catechol O-methyltransferase inhibitor entacapone, used as an
adjunct to levodopa in PD patients who do not experience motor fluctuations, does
not improve Unified Parkinson's Disease Rating Scale motor scores but does
improve a variety of quality-of-life measures.

PMID: 15477510 [PubMed - indexed for MEDLINE]

67. Ann Neurol. 2004 Oct;56(4):540-7.

Brainstem pathology in DYT1 primary torsion dystonia.

McNaught KS, Kapustin A, Jackson T, Jengelley TA, Jnobaptiste R, Shashidharan P,
Perl DP, Pasik P, Olanow CW.

Department of Neurology, Neuropathology Division, Mount Sinai School of Medicine,
New York, NY 10029, USA. kevin.mcnaught@mssm.edu

Erratum in:
Ann Neurol. 2004 Nov;56(5):750.

DYT1 dystonia is a severe form of young-onset dystonia caused by a mutation in
the gene that encodes for the protein torsinA, which is thought to play a role in
protein transport and degradation. We describe, for the first time to our
knowledge, perinuclear inclusion bodies in the midbrain reticular formation and
periaqueductal gray in four clinically documented and genetically confirmed DYT1
patients but not in controls. The inclusions were located within cholinergic and
other neurons in the pedunculopontine nucleus, cuneiform nucleus, and griseum
centrale mesencephali and stained positively for ubiquitin, torsinA, and the
nuclear envelope protein lamin A/C. No evidence of inclusion body formation was
detected in the substantia nigra pars compacta, striatum, hippocampus, or
selected regions of the cerebral cortex. We also noted
tau/ubiquitin-immunoreactive aggregates in pigmented neurons of the substantia
nigra pars compacta and locus coeruleus in all four DYT1 dystonia cases, but not
in controls. This study supports the notion that DYT1 dystonia is associated with
impaired protein handling and the nuclear envelope. The role of the
pedunculopontine and cuneiform nuclei, and related brainstem brainstem
structures, in mediating motor activity and controlling muscle tone suggests that
alterations in these structures could underlie the pathophysiology of DYT1
dystonia [corrected]

PMID: 15455404 [PubMed - indexed for MEDLINE]

68. Mov Disord. 2004 Sep;19(9):997-1005.

Levodopa in the treatment of Parkinson's disease: current controversies.

Olanow CW, Agid Y, Mizuno Y, Albanese A, Bonuccelli U, Damier P, De Yebenes J,
Gershanik O, Guttman M, Grandas F, Hallett M, Hornykiewicz O, Jenner P,
Katzenschlager R, Langston WJ, LeWitt P, Melamed E, Mena MA, Michel PP,
Mytilineou C, Obeso JA, Poewe W, Quinn N, Raisman-Vozari R, Rajput AH, Rascol O,
Sampaio C, Stocchi F.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
warren.olanow@mssm.edu

Erratum in:
Mov Disord. 2005 May;20(5):645. Bonucelli, U [corrected to Bonuccelli, Ubaldo].

Comment in:
Mov Disord. 2005 May;20(5):642-3; author reply 643-4. Mov Disord. 2005 May;20(5):643; author reply 643-4.

Levodopa is the most effective symptomatic agent in the treatment of Parkinson's
disease (PD) and the "gold standard" against which new agents must be compared.
However, there remain two areas of controversy: (1) whether levodopa is toxic,
and (2) whether levodopa directly causes motor complications. Levodopa is toxic
to cultured dopamine neurons, and this may be a problem in PD where there is
evidence of oxidative stress in the nigra. However, there is little firm evidence
to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not
clarified this situation. Levodopa is also associated with motor complications.
Increasing evidence suggests that they are related, at least in part, to the
short half-life of the drug (and its potential to induce pulsatile stimulation of
dopamine receptors) rather than to specific properties of the molecule. Treatment
strategies that provide more continuous stimulation of dopamine receptors provide
reduced motor complications in MPTP monkeys and PD patients. These studies raise
the possibility that more continuous and physiological delivery of levodopa might
reduce the risk of motor complications. Clinical trials to test this hypothesis
are underway. We review current evidence relating to these areas of controversy.

PMID: 15372588 [PubMed - indexed for MEDLINE]

69. Mov Disord. 2004 Aug;19(8):916-23.

Double-blind, randomized, controlled trial of rasagiline as monotherapy in early
Parkinson's disease patients.

Stern MB, Marek KL, Friedman J, Hauser RA, LeWitt PA, Tarsy D, Olanow CW.

University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Rasagiline (N-propargyl-1(R)-aminoindan) mesylate is a potent, selective, and
irreversible monoamine oxidase-B inhibitor. This study was designed to evaluate
the safety, tolerability, and preliminary efficacy of rasagiline monotherapy in
early Parkinson's disease (PD) patients not receiving levodopa. The study was
performed as a multicenter, parallel-group, double-blind, randomized,
placebo-controlled, 10-week study. Fifty-six PD patients were randomly assigned
to rasagiline mesylate 1, 2, or 4 mg once daily, or placebo. A 3-week
dose-escalation period was followed by a 7-week maintenance phase. At week 10,
the mean (+/-SE) changes from baseline in total Unified Parkinson's Disease
Rating Scale (UPDRS) score were -1.8 (+/-1.3), -3.6 (+/-1.7), -3.6 (+/-1.2), and
-0.5 (+/-0.8) in the rasagiline 1, 2, and 4 mg/day and placebo groups,
respectively. Analysis of responders showed that 28% of patients (12 of 43)
receiving rasagiline had an improvement in total UPDRS score of greater than 30%,
compared with none of the patients receiving placebo (P < 0.05, Fisher's exact
test). The frequency and types of adverse events reported by rasagiline-treated
and placebo-treated patients were similar. These results suggest that rasagiline
monotherapy is well tolerated and efficacious in early PD. Copyright 2004
Movement Disorder Society

PMID: 15300656 [PubMed - indexed for MEDLINE]

70. Parkinsonism Relat Disord. 2004 Aug;10(6):323-34.

Movement disorders and AIDS: a review.

Tse W, Cersosimo MG, Gracies JM, Morgello S, Olanow CW, Koller W.

Department of Neurology, Mount Sinai Medical Center, One Gustave L. Levy Place,
Box 1052, New York, NY 10029, USA. winonatse@hotmail.com

Movement disorders are a potential neurologic complication of acquired immune
deficiency syndrome (AIDS), and may sometimes represent the initial manifestation
of HIV infection. Dopaminergic dysfunction and the predilection of HIV infection
to affect subcortical structures are thought to underlie the development of
movement disorders such as parkinsonism in AIDS patients. In this review, we will
discuss the clinical presentations, etiology and treatment of the various
AIDS-related hypokinetic and hyperkinetic movement disorders, such as
parkinsonism, chorea, myoclonus and dystonia. This review will also summarize
current concepts regarding the pathophysiology of parkinsonism in HIV infection.

PMID: 15261874 [PubMed - indexed for MEDLINE]

71. Lancet Neurol. 2004 Aug;3(8):496-503.

Lewy-body formation is an aggresome-related process: a hypothesis.

Olanow CW, Perl DP, DeMartino GN, McNaught KS.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
warren.olanow@mssm.edu

Parkinson's disease (PD) is an age-related neurodegenerative disorder that is
associated with the formation of intracytoplasmic protein aggregates (Lewy-body
inclusions) in neurons of the substantia nigra pars compacta and other brain
areas. These inclusions were discovered over 90 years ago, but the mechanism
underlying their formation and their relevance to the neurodegenerative process
are unknown. Recent studies have begun to shed light on the biogenesis of Lewy
bodies and suggest that they are related to aggresomes. Aggresomes are
cytoprotective proteinaceous inclusions formed at the centrosome that segregate
and facilitate the degradation of excess amounts of unwanted and possibly
cytotoxic proteins. The concept of Lewy bodies as aggresome-related inclusions
fits well with ongoing discoveries suggesting that altered protein handling might
contribute to the neurodegenerative process in familial and sporadic forms of PD.

PMID: 15261611 [PubMed - indexed for MEDLINE]

72. J Neurosurg. 2004 Jul;101(1):36-42.

Unilateral stimulation of the subthalamic nucleus in Parkinson disease: a
double-blind 12-month evaluation study.

Germano IM, Gracies JM, Weisz DJ, Tse W, Koller WC, Olanow CW.

Department of Neurosurgery, The Mount Sinai School of Medicine, New York, New
York 10029-6574, USA. isabelle.germano@msnyuhealth.org

OBJECT: Bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN)
has been established as an effective treatment for Parkinson disease (PD).
Nevertheless, bilateral surgical procedures can be associated with frequent and
severe complications. The aim in the present study was to assess the safety and
efficacy of unilateral STN stimulation, and the need for a second procedure.
METHODS: Twelve patients with PD underwent unilateral DBS of the STN and were
followed up for 12 months. Patients were assessed at baseline and at each visit
in a double-blind fashion by analyzing the Unified PD Rating Scale (UPDRS),
ambulation speed, and home diaries. Levodopa-off/stimulation-on UPDRS motor
scores were improved by 26 +/- 8% (p < 0.05, mean +/- standard deviation [SD])
compared with the baseline levodopa-off score; there was a 50% improvement in
contralateral features, a 17% improvement ipsilaterally, and a 36% improvement in
axial features. The mean ambulation speed increased by 83 +/- 44% (p < 0.01, mean
+/- SD). The medication-on time with dyskinesias was significantly reduced (p <
0.01) and the daily levodopa dose was reduced by 19 +/- 6% (p < 0.05, mean +/-
SD). There were no clinically significant side effects. CONCLUSIONS: Unilateral
DBS of the STN is safe and well tolerated, and may provide sufficient benefit so
that additional surgery is not required.

PMID: 15255249 [PubMed - indexed for MEDLINE]

73. Clin Neuropharmacol. 2004 Mar-Apr;27(2):58-62.

Multicenter, open-label, trial of sarizotan in Parkinson disease patients with
levodopa-induced dyskinesias (the SPLENDID Study).

Olanow CW, Damier P, Goetz CG, Mueller T, Nutt J, Rascol O, Serbanescu A, Deckers
F, Russ H.

Department of Neurology, Mount Sinai School of Medicine, New York, New York, USA.

PMID: 15252265 [PubMed - indexed for MEDLINE]

74. Ann Neurol. 2004 Jul;56(1):149-62.

Systemic exposure to proteasome inhibitors causes a progressive model of
Parkinson's disease.

McNaught KS, Perl DP, Brownell AL, Olanow CW.

Department of Neurology, Neuropathology Division, Mount Sinai School of Medicine,
New York, NY 10029, USA. kevin.mcnaught@mssm.edu

Comment in:
Ann Neurol. 2006 Aug;60(2):248-52. Ann Neurol. 2006 Aug;60(2):253-5. Ann Neurol. 2006 Aug;60(2):256-60. Ann Neurol. 2006 Aug;60(2):260-4. Ann Neurol. 2006 Aug;60(2):264-8.

Environmental toxins have been implicated in the etiology of Parkinson's disease.
Recent findings of defects in the ubiquitin-proteasome system in hereditary and
sporadic forms of the illness suggest that environmental proteasome inhibitors
are candidate PD-inducing toxins. Here, we systemically injected six doses of
naturally occurring (epoxomicin) or synthetic (Z-lle-Glu(OtBu)-Ala-Leu-al [PSI])
proteasome inhibitors into adult rats over a period of 2 weeks. After a latency
of 1 to 2 weeks, animals developed progressive parkinsonism with bradykinesia,
rigidity, tremor, and an abnormal posture, which improved with apomorphine
treatment. Positron emission tomography demonstrated reduced carbon-11-labeled
2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT) binding to dopaminergic
nerve terminals in the striatum, indicative of degeneration of the nigrostriatal
pathway. Postmortem analyses showed striatal dopamine depletion and dopaminergic
cell death with apoptosis and inflammation in the substantia nigra pars compacta.
In addition, neurodegeneration occurred in the locus coeruleus, dorsal motor
nucleus of the vagus, and the nucleus basalis of Meynert. At neurodegenerative
sites, intracytoplasmic, eosinophilic, alpha-synuclein/ubiquitin-containing,
inclusions resembling Lewy bodies were present in some of the remaining neurons.
This animal model induced by proteasome inhibitors closely recapitulates key
features of PD and may be valuable in studying etiopathogenic mechanisms and
putative neuroprotective therapies for the illness.

PMID: 15236415 [PubMed - indexed for MEDLINE]

75. Neurology. 2004 Jun 8;62(11):1932-3.

Melvin David Yahr, MD (1917-2004).

Olanow CW.

PMID: 15184591 [PubMed - indexed for MEDLINE]

76. Ann N Y Acad Sci. 2004 Mar;1012:209-23.

Manganese-induced parkinsonism and Parkinson's disease.

Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, New York
10029, USA. warren.olanow@mssm.edu

It has long been appreciated that manganese exposure can cause neurotoxicity and
a neurologic syndrome that resembles Parkinson's disease (PD). Current evidence
indicates that manganese-induced parkinsonism can be differentiated from PD
because of its predilection to accumulate in and damage the pallidum and striatum
rather than the SNc. The clinical syndrome, response to levodopa, imaging studies
with MRI and PET, and pathologic features all help to distinguish these two
conditions and permit the correct diagnosis to be established. This is of
particular relevance in differentiating patients with parkinsonism due to
manganese intoxication from patients with idiopathic PD who have incidental
manganese exposure.

PMID: 15105268 [PubMed - indexed for MEDLINE]

77. J Biol Chem. 2004 Jun 25;279(26):27494-501. Epub 2004 Apr 12.

Early single cell bifurcation of pro- and antiapoptotic states during oxidative
stress.

Nair VD, Yuen T, Olanow CW, Sealfon SC.

Department of Neurology, Mount Sinai School of Medicine, New York, New York
10029, USA.

In a population of cells undergoing oxidative stress, an individual cell either
succumbs to apoptotic cell death or maintains homeostasis and survives. Exposure
of PC-12-D(2)R cells to 200 microm hydrogen peroxide (H(2)O(2)) induces apoptosis
in about half of cells after 24 h. After 1-h exposure to 200 microm H(2)O(2),
both antiapoptotic extracellular regulated kinase (ERK) phosphorylation and
pro-apoptotic Ser-15-p53 phosphorylation are observed. Microarray and real-time
PCR assays of gene expression after H(2)O(2) exposure identified several
transcripts, including egr1, that are rapidly induced downstream of ERK. Single
cell analysis of egr1 induction and of phospho-ERK and phospho-p53 formation
revealed the presence of two distinct cellular programs. Whereas the proportion
of cells activating ERK versus p53 at 1 h depended on H(2)O(2) concentration,
individual cells showed exclusively either phospho-p53 formation or activation of
ERK and egr1 induction. Exposure to H(2)O(2) for 1 h also elicited these two
non-overlapping cellular responses in both dopaminergic SN4741 cells and
differentiated postmitotic PC-12-D(2)R cells. Repressing p53 with pifithrin-alpha
or small interfering RNA increased ERK phosphorylation by H(2)O(2), indicating
that p53-dependent suppression of ERK activity may contribute to the bi-stable
single cell responses observed. By 24 h, the subset of cells in which ERK
activity was suppressed exhibit caspase 3 activation and the nuclear condensation
characteristic of apoptosis. These studies suggest that the individual cell
rapidly and stochastically processes the oxidative stress stimulus, leading to an
all-or-none cytoprotective or pro-apoptotic signaling response.

PMID: 15078887 [PubMed - indexed for MEDLINE]

78. Arch Clin Neuropsychol. 2004 Mar;19(2):165-81.

Neuropsychological functioning following bilateral subthalamic nucleus
stimulation in Parkinson's disease.

Morrison CE, Borod JC, Perrine K, Beric A, Brin MF, Rezai A, Kelly P, Sterio D,
Germano I, Weisz D, Olanow CW.

New York University Medical Center, New York, NY, USA. cmorrison@med.nyu.edu

The cognitive effects of subthalamic nucleus (STN) stimulation in Parkinson's
disease (PD) have been examined. However, there are no reported studies that
evaluate, by incorporating a disease control group, whether neuropsychological
performance in surgical patients changes beyond the variability of the assessment
measures. To examine this issue, 17 PD patients were tested before and after
bilateral STN stimulator implantation, both on and off stimulation. Eleven
matched PD controls were administered the same repeatable neuropsychological test
battery twice. Relative to changes seen in the controls, the surgery for
electrode placement mildly adversely affected attention and language functions.
STN stimulation, per se, had little effect on cognition. The STN DBS procedure as
a whole resulted in a mild decline in delayed verbal recall and language
functions. There were no surgery, stimulation, or procedure effects on depression
scale scores. In contrast to these group findings, one DBS patient demonstrated
significant cognitive decline following surgery.

PMID: 15010083 [PubMed - indexed for MEDLINE]

79. J Neurochem. 2004 Feb;88(4):1019-25.

Overexpression of torsinA in PC12 cells protects against toxicity.

Shashidharan P, Paris N, Sandu D, Karthikeyan L, McNaught KS, Walker RH, Olanow
CW.

Department of Neurology, Mount Sinai School of Medicine, New York 10029, USA.
pullani.shashi@mssm.edu

Childhood-onset dystonia is an autosomal dominant movement disorder associated
with a three base pair (GAG) deletion mutation in the DYT1 gene. This gene
encodes a novel ATP-binding protein called torsinA, which in the central nervous
system is expressed exclusively in neurons. Neither the function of torsinA nor
its role in the pathophysiology of DYT1 dystonia is known. In order to better
understand the cellular functions of torsinA, we established PC12 cell lines
overexpressing wild-type or mutant torsinA and subjected them to various
conditions deleterious to cell survival. Treatment of control PC12 cells with an
inhibitor of proteasomal activity, an oxidizing agent, or trophic withdrawal,
resulted in cell death, whereas PC12 cells that overexpressed torsinA were
significantly protected against each of these treatments. Overexpression of
mutant torsinA failed to protect cells against trophic withdrawal. These results
suggest that torsinA may play a protective role in neurons against a variety of
cellular insults.

PMID: 14756824 [PubMed - indexed for MEDLINE]

80. Annu Rev Med. 2004;55:41-60.

The scientific basis for the current treatment of Parkinson's disease.

Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, Annenberg 14-94, One
Gustave L. Levy Place, Box 1137, New York, New York 10029, USA.
warren.olanow@mssm.edu

Parkinson's disease (PD) is an age-related neurodegenerative disease that affects
approximately one million people in the United States. The introduction of
levodopa revolutionized the treatment for this disorder, but the long-term
utility of the drug is limited by motor complications, the development of
features such as postural instability and dementia that do not respond to
treatment, and continued disease progression. Insights into the organization of
the basal ganglia in the normal and PD conditions has permitted the design of new
treatment strategies that reduce the risk of developing motor complications.
Additionally, increased knowledge of the mechanisms responsible for cell death in
PD has permitted the development of putative neuroprotective drugs that might
slow or stop disease progression. No drug has yet been established to alter the
rate of disease progression, but the rapid pace of research offers reason for
optimism.

PMID: 14746509 [PubMed - indexed for MEDLINE]

81. JAMA. 2004 Jan 21;291(3):358-64.

Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions.

Schapira AH, Olanow CW.

University Department of Clinical Neurosciences, Royal Free and University
College Medical School, and Institute of Neurology, Queen Square, London,
England. warren.olanow@mssm.edu

Comment in:
JAMA. 2004 May 26;291(20):2430-1; author reply 2431.

Parkinson disease is an age-related neurodegenerative disease that affects
approximately 1 million persons in the United States. Current therapies provide
effective control of symptoms, particularly in the early stages of the disease,
but most patients develop motor complications with long-term treatment, and
features develop such as postural instability, falling, and dementia that are not
adequately controlled with existing medications. Accordingly, neuroprotective
therapy that might slow, stop, or reverse disease progression is urgently needed.
While many agents appear to be promising based on laboratory studies, selecting
clinical end points for clinical trials that are not confounded by symptomatic
effects of the study intervention has been difficult. More recently, neuroimaging
end points have been used as biomarkers of disease progression, but again there
are concerns that they may be influenced by regulatory effects of the drugs used.
We review clinical trials aimed at detecting neuroprotection in Parkinson disease
and address the controversies surrounding the interpretation of these studies.

PMID: 14734599 [PubMed - indexed for MEDLINE]

82. Eur J Neurosci. 2004 Jan;19(2):280-6.

Toxicity of glutathione depletion in mesencephalic cultures: a role for
arachidonic acid and its lipoxygenase metabolites.

Kramer BC, Yabut JA, Cheong J, Jnobaptiste R, Robakis T, Olanow CW, Mytilineou C.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.

The contribution of arachidonic acid (AA) release and metabolism to the toxicity
that results from glutathione (GSH) depletion was studied in rat mesencephalic
cultures treated with the GSH synthesis inhibitor l-buthionine sulfoximine. Our
data show that GSH depletion is accompanied by increased release of AA, which is
phosholipase A2 (PLA2) dependent. Exogenous AA is toxic to GSH-depleted cells.
This toxicity is prevented by inhibition of lipoxygenase activity, suggesting
participation of toxic byproducts of AA metabolism. Hydroxyperoxyeicosatetraenoic
acid (HPETE), one of the primary products of AA metabolism by lipoxygenase is
also toxic to GSH-depleted cells, whereas hydroeicosatetraenoic acid (HETE) is
not. Cell death caused by GSH depletion is prevented by: (i) replenishment of GSH
levels with GSH-ethyl ester; (ii) inhibition of PLA2 activity; (iii) inhibition
of lipoxygenase activity; and (iv), treatment with ascorbic acid. These data
suggest that the following events likely contribute to cell death when GSH levels
become depleted. Loss of GSH results in increased release of AA, which is PLA2
dependent. Metabolism of arachidonic acid via the lipoxygenase pathway results in
generation of oxygen free radicals possibly produced during conversion of HPETE
to HETE, which contribute to cellular damage and death. Our study suggests that
limiting AA release and metabolism may provide benefit in conditions with an
existing depletion of GSH, such as Parkinson's disease.

PMID: 14725622 [PubMed - indexed for MEDLINE]

83. Neurology. 2004 Jan 13;62(1 Suppl 1):S72-81.

COMT inhibitors in Parkinson's disease: can they prevent and/or reverse
levodopa-induced motor complications?

Olanow CW, Stocchi F.

Department of Neurology, Mount Sinai School of Medicine, New York, New York
10028, USA.

COMT inhibitors have historically been used as adjuncts to levodopa in
fluctuating PD patients to increase "on" time and reduce "off" time. Evidence
that motor complications are related to intermittent or pulsatile stimulation of
striatal dopamine receptors has led to the use of long-acting dopaminergic
therapies that provide more continuous dopaminergic stimulation (CDS). CDS-based
therapies are associated with the prevention and reversal of levodopa-related
motor complications in MPTP-lesioned primates and PD patients. However, levodopa
remains the most effective and widely used anti-parkinsonian agent and is
eventually required in all PD patients. The standard oral formulation of levodopa
has a relatively short half-life and is associated with the development of motor
complications when used as either initial or supplemental therapy. The CDS
concept raises the possibility that administration of levodopa in combination
with a COMT inhibitor to extend its half-life might reduce the risk of inducing
motor complications. This article considers the possibility that combining
levodopa with entacapone may prevent or reverse motor complications.

PMID: 14718683 [PubMed - indexed for MEDLINE]

84. Neurology. 2004 Jan 13;62(1 Suppl 1):S56-63.

Continuous dopaminergic stimulation in early and advanced Parkinson's disease.

Stocchi F, Olanow CW.

Department of Neuroscience and IRCCS Neuromed Pozzilli (IS), University La
Sapienza, Rome, Italy.

Evidence from preclinical and clinical studies indicates that pulsatile
stimulation of striatal dopamine receptors is a key factor in the development of
levodopa-associated motor complications. Therefore, in the de novo patient it is
believed that providing a more continuous dopaminergic stimulation from the start
of antiparkinson therapy may prevent priming for motor fluctuations and
dyskinesia. Conversely, in the more advanced patient who is already suffering
from motor complications, it is believed that providing a more continuous
stimulation may reverse the development of motor complications, enabling the
patient to enjoy more stable benefits from therapy. All PD patients eventually
require levodopa therapy during the course of their disease, and the benefits of
providing continuous dopaminergic stimulation with levodopa have been clearly
demonstrated in a number of studies. However, these studies have included the use
of approaches such as SC infusion or intra-intestinal infusion. Because these are
relatively difficult to handle and not very practical for the patient, compliance
is generally low. Therefore, the development of a simple treatment regimen using
an oral formulation of levodopa to provide a more continuous dopaminergic
stimulation will represent a significant advance in antiparkinsonian
pharmacotherapy.

PMID: 14718681 [PubMed - indexed for MEDLINE]

85. Sleep Med. 2003 Jul;4(4):275-80.

Assessment of sleepiness and unintended sleep in Parkinson's disease patients
taking dopamine agonists.

Roth T, Rye DB, Borchert LD, Bartlett C, Bliwise DL, Cantor C, Gorell JM, Hubble
JP, Musch B, Olanow CW, Pollak C, Stern MB, Watts RL.

Henry Ford Hospital, Sleep Disorders and Research Center, Clara Ford Pavilion,
3rd Floor, 2799 West Grand Boulevard CFP-3, Detroit, MI 48202, USA.
troth1@hfhs.org

Comment in:
Sleep Med. 2003 Jul;4(4):267-8.

OBJECTIVE: We sought to determine if patients with Parkinson's disease (PD),
taking dopamine agonists (DAs) and reporting unintended sleep episodes (SEs),
exhibit physiologically defined daytime sleepiness and can thus be differentiated
from those taking DAs but not reporting SEs. METHODS: Twenty-four patients with
abnormal Epworth Sleepiness Scale scores of >10 who were taking DAs were enrolled
into one of two groups: those with SEs (SE+, n=16) and those without (SE-, n=8).
Three consecutive days of testing included two nights of polysomnography followed
by the Multiple Sleep Latency Test (MSLT). RESULTS: Overall frequency of
pathological sleepiness (MSLT <5 min) was 42% (10/24). Mean levels of sleepiness,
frequencies of pathological sleepiness, and naps with stage 2 or REM-sleep were
similar between SE+ and SE- groups. Sleep tendency was similar in patients
prescribed pergolide, ropinirole, and pramipexole combined with levodopa.
Polysomnography testing revealed no significant differences between the groups in
total sleep time, sleep efficiency, sleep architecture, or presence of restless
legs syndrome or periodic leg movements. There was no relation between degree of
nocturnal sleep disturbance and level of daytime sleepiness. CONCLUSIONS: The
results of this study suggest SEs in PD patients occur upon a background of
excessive daytime sleepiness and are unrelated to nocturnal sleep or use of a
specific DA.

PMID: 14592299 [PubMed - indexed for MEDLINE]

86. Neurology. 2003 Sep 23;61(6 Suppl 3):S24-33.

Present and future directions in the management of motor complications in
patients with advanced PD.

Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, New York
10029, USA.

PMID: 14504377 [PubMed - indexed for MEDLINE]

87. Ann Neurol. 2003 Sep;54(3):403-14.

A double-blind controlled trial of bilateral fetal nigral transplantation in
Parkinson's disease.

Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, Brin MF, Shannon KM,
Nauert GM, Perl DP, Godbold J, Freeman TB.

Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy
Place, New York, NY 10029, USA. warren.olanow@mssm.edu

Comment in:
Ann Neurol. 2004 Jun;55(6):761-5. Ann Neurol. 2004 Jun;55(6):896; author reply 896-7.

Thirty-four patients with advanced Parkinson's disease participated in a
prospective 24-month double-blind, placebo-controlled trial of fetal nigral
transplantation. Patients were randomized to receive bilateral transplantation
with one or four donors per side or a placebo procedure. The primary end point
was change between baseline and final visits in motor component of the Unified
Parkinson's Disease Rating Scale in the practically defined off state. There was
no significant overall treatment effect (p = 0.244). Patients in the placebo and
one-donor groups deteriorated by 9.4 +/- 4.25 and 3.5 +/- 4.23 points,
respectively, whereas those in the four-donor group improved by 0.72 +/- 4.05
points. Pairwise comparisons were not significant, although the four-donor versus
placebo groups yielded a p value of 0.096. Stratification based on disease
severity showed a treatment effect in milder patients (p = 0.006). Striatal
fluorodopa uptake was significantly increased after transplantation in both
groups and robust survival of dopamine neurons was observed at postmortem
examination. Fifty-six percent of transplanted patients developed dyskinesia that
persisted after overnight withdrawal of dopaminergic medication ("off"-medication
dyskinesia). Fetal nigral transplantation currently cannot be recommended as a
therapy for PD based on these results.

PMID: 12953276 [PubMed - indexed for MEDLINE]

88. Lancet Neurol. 2003 Feb;2(2):74.

Dietary vitamin E and Parkinson's disease: something to chew on.

Olanow CW.

Department of Neurology, Box 1137, Mount Sinai School of Medicine, One Gustave L
Levy Place, New York, NY 10029, USA. Warren Olanow

PMID: 12849259 [PubMed - indexed for MEDLINE]

89. Mov Disord. 2003 Jun;18(6):668-72.

Sleepiness in Parkinson's disease: a controlled study.

Brodsky MA, Godbold J, Roth T, Olanow CW.

Mount Sinai School of Medicine, New York, New York 10029, USA.

Sudden-onset sleep episodes while driving have been reported in Parkinson's
disease (PD) patients, and termed sleep attacks because they were reported to be
irresistible and to occur without warning. We postulate that these episodes are
due to excessive daytime sleepiness secondary to the high frequency of sleep
disorders in PD patients and the sedative effects of dopaminergic medications. We
assessed the frequency and relationship between excess daytime sleepiness and
sleep episodes while driving (SE) in patients with PD. We evaluated 101
consecutive PD patients presenting to the Movement Disorder Center at the Mount
Sinai School of Medicine using a questionnaire that incorporated a subjective
estimate of sleepiness, the Epworth Sleepiness Scale (ESS) and information on
disease severity and dopaminergic medications. One hundred age-matched
respondents without PD served as a control population. Excess daytime sleepiness
was reported in 76% of PD patients compared to 47% of controls (P < 0.05). The
mean ESS scores for PD patients was 9.1 +/- 6.1 versus 5.7 +/- 4.4 in controls (P
< 0.001). ESS scores > or =10 were observed in 40.6% of PD patients compared to
19% of controls (P < 0.01) and 24% of PD patients had scores > or =15, compared
to 5% of controls (P < 0.001). Sleep episodes while driving were experienced by
20.8% of PD drivers compared to 6% of control drivers (P < 0.05). The mean daily
levodopa (L-dopa) dose equivalent was 1,142 +/- 858 mg in PD drivers who
experienced a SE while driving compared to 626 +/- 667 mg in those who had not (P
< 0.05). Similarly, ESS was significantly greater in drivers with a SE than in
those without (11.6 +/- 6.4 vs. 8.4 +/- 4.1; P < 0.05). Logistic regression
analysis demonstrated that ESS and mean daily L-dopa dose equivalents were
predictors of sleep episodes while driving, whereas age, gender, disease
severity, and individual dopaminergic agents were not. These findings support the
notion that sleep episodes while driving in PD patients are related to excess
daytime sleepiness and dopaminergic load. Physicians should advise and treat
patients accordingly. Copyright 2003 Movement Disorder Society

PMID: 12784270 [PubMed - indexed for MEDLINE]

90. Biochem J. 2003 Jul 1;373(Pt 1):25-32.

Activation of phosphoinositide 3-kinase by D2 receptor prevents apoptosis in
dopaminergic cell lines.

Nair VD, Olanow CW, Sealfon SC.

Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy
Place, New York, NY 10029, USA.

Whereas dopamine agonists are known to provide symptomatic benefits for
Parkinson's disease, recent clinical trials suggest that they might also be
neuroprotective. Laboratory studies demonstrate that dopamine agonists can
provide neuroprotective effects in a number of model systems, but the role of
receptor-mediated signalling in these effects is controversial. We find that
dopamine agonists have robust, concentration-dependent anti-apoptotic activity in
PC12 cells that stably express human D(2L) receptors from cell death due to
H(2)O(2) or trophic withdrawal and that the protective effects are abolished in
the presence of D(2)-receptor antagonists. D(2) agonists are also neuroprotective
in the nigral dopamine cell line SN4741, which express endogenous D(2) receptors,
whereas no anti-apoptotic activity is observed in native PC12 cells, which do not
express detectable D(2) receptors. Notably, the agonists studied differ in their
relative efficacy to mediate anti-apoptotic effects and in their capacity to
stimulate [(35)S]guanosine 5'-[gamma-thio]triphosphate ([(35)S]GTP[S]) binding,
an indicator of G-protein activation. Studies with inhibitors of phosphoinositide
3-kinase (PI 3-kinase), extracellular-signal-regulated kinase or p38
mitogen-activated protein kinase indicate that the PI 3-kinase pathway is
required for D(2) receptor-mediated cell survival. These studies indicate that
certain dopamine agonists can complex with D(2) receptors to preferentially
transactivate neuroprotective signalling pathways and to mediate increased cell
survival.

PMCID: 1223482
PMID: 12683952 [PubMed - indexed for MEDLINE]

91. Ann Neurol. 2003;53 Suppl 3:S149-57; discussion S157-9.

Rationale for the use of dopamine agonists as neuroprotective agents in
Parkinson's disease.

Schapira AH, Olanow CW.

University Department of Clinical Neurosciences, Royal Free and University
College Medical School, UCL, Queen Square, London, United Kingdom.
schapira@rfc.ucl.ac.uk

PMID: 12666106 [PubMed - indexed for MEDLINE]

92. Ann Neurol. 2003;53 Suppl 3:S87-97; discussion S97-9.

Neuroprotection in Parkinson's disease: clinical trials.

Stocchi F, Olanow CW.

Department of Neuroscience and Neuromed, University La Sapienza, Rome, Italy.
fabstocc@tin.it

Advances in our understanding of the cause and pathogenesis of Parkinson's
disease (PD) have permitted the rational selection of putative neuroprotective
agents for study in PD. However, the list of agents that might provide
neuroprotective effects derived from laboratory studies is daunting, and we face
the challenge of determining which agents to bring to the clinic and how to find
the resources (patients and funds) to properly study so many promising
therapeutic opportunities.1 Appropriate outcome variables that are not confounded
by any symptomatic effect of the drug and are acceptable to clinicians and
regulatory authorities also remain to be defined. The first clinical trials
designed to test the capacity of putative neuroprotective agents to alter the
natural history of PD have now been performed and illustrate some of these
problems. The DATATOP (Deprenyl and Tocopherol Antioxidant Therapy of PD) study
used the time to reach a disease milestone in untreated PD patients (ie, need for
levodopa) as the primary end point. However, interpretation of results was
confounded by the drug's symptomatic effect. The SINDEPAR
(Sinemet-Deprenyl-Parlodel) study used the change in motor score between initial
visit and final visit after washout of all study medications as the primary end
point. However, here too there were concerns about confounding symptomatic
effects, because antiparkinsonian medications have now been shown to have a long
duration response that can persist for weeks and perhaps even months after
withdrawal. More recent studies have used surrogate markers of the integrity of
nigrostriatal function such as striatal uptake of fluorodopa on positron emission
tomography (PET) or beta-CIT-on single-photon emission computerized tomography
(SPECT) as primary outcome measures. However, it has not yet been confirmed that
striatal uptake of these isotopes does in fact correlate with the remaining
number of dopamine neurons or terminals, and the possibility of a confounding
pharmacological effect has not yet been completely excluded. To date, no drug has
been established to have a neuroprotective effect in PD, and none has been
approved for a neuroprotective indication. Furthermore, regulatory agencies have
not yet agreed that any of the outcome measures currently used will be acceptable
for approval of a new drug. Resolution of these issues is of critical importance
to convince pharmaceutical companies to expend the hundreds of millions of
dollars necessary to bring a new drug to market. Drugs that already have been
approved in PD for their symptomatic effects, such as dopamine agonists or
propargylamines (eg, selegiline), offer the best opportunity for establishing
that a drug is neuroprotective in PD in the immediate future, but herein also
lies the difficulty of establishing that any benefits observed are not solely
because of the drug's symptomatic properties. Currently, this will most likely
entail demonstrating that the drug provides benefit for PD patients for both
imaging and clinical markers of disease progression.

PMID: 12666101 [PubMed - indexed for MEDLINE]

93. Ann Neurol. 2003;53 Suppl 3:S73-84; discussion S84-6.

Proteolytic stress: a unifying concept for the etiopathogenesis of Parkinson's
disease.

McNaught KS, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.

The etiopathogenesis of Parkinson's disease (PD) has been elusive. Recently,
several lines of evidence have converged to suggest that defects in the
ubiquitin-proteasome system and proteolytic stress underlie nigral pathology in
both familial and sporadic forms of the illness. In support of this concept,
mutations in alpha-synuclein that cause the protein to misfold and resist
proteasomal degradation cause familial PD. Similarly, mutations in two enzymes
involved in the normal function of the ubiquitin-proteasome system, parkin and
ubiquitin C-terminal hydrolase L1, are also associated with hereditary PD.
Furthermore, structural and function defects in 26/20S proteasomes with
accumulation and aggregation of potentially cytotoxic abnormal proteins have been
identified in the substantia nigra pars compacta of patients with sporadic PD.
Thus, a defect in protein handling appears to be a common factor in sporadic and
the various familial forms of PD. This hypothesis may also account for the
vulnerability of the substantia nigra pars compacta in PD, why the disorder is
age related, and the nature of the Lewy body. It has also facilitated the
development of experimental models that recapitulate the behavioral and
pathological features of PD, and hopefully will lead to the development of novel
neuroprotective therapies for the disorder.

PMID: 12666100 [PubMed - indexed for MEDLINE]

94. Ann Neurol. 2003;53 Suppl 3:S1-2.

Neuroprotection for Parkinson's disease: prospects and promises.

Olanow CW, Schapira AH, Agid Y.

PMID: 12666093 [PubMed - indexed for MEDLINE]

95. Parkinsonism Relat Disord. 2003 Mar;9(4):221-4.

Selegiline in the treatment of Parkinson's disease: its impact on orthostatic
hypotension.

Bhattacharya KF, Nouri S, Olanow CW, Yahr MD, Kaufmann H.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.

Less than a consensus exists as to whether chronic treatment with selegiline in
combination with levodopa/carbidopa in patients with Parkinson's disease, is
associated with more pronounced orthostatic hypotension than treatment with
levodopa/carbidopa alone. To resolve this issue, we compared orthostatic
tolerance and autonomic reflexes in 95 patients with Parkinson's disease treated
chronically with either selegiline alone (n = 10), levodopa/carbidopa alone (n =
49) or both agents combined (n = 36). Supine heart rate and blood pressure,
autonomic cardiovascular reflexes and the frequency and magnitude of orthostatic
hypotension were similar in all three treatment groups. Copyright 2003 Elsevier
Science Ltd.

PMID: 12618057 [PubMed - indexed for MEDLINE]

96. J Pharmacol Exp Ther. 2003 Feb;304(2):792-800.

Levodopa is toxic to dopamine neurons in an in vitro but not an in vivo model of
oxidative stress.

Mytilineou C, Walker RH, JnoBaptiste R, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, New York
10029, USA.

Levodopa is the "gold standard" for the symptomatic treatment of Parkinson's
disease (PD). There is a theoretical concern, however, that levodopa might
accelerate the rate of nigral degeneration, because it undergoes oxidative
metabolism and is toxic to cultured dopaminergic neurons. Most in vivo studies do
not show evidence of levodopa toxicity; levodopa is not toxic to normal rodents,
nonhuman primates, or humans and is not toxic to dopamine neurons in
dopamine-lesioned rodents or nonhuman primates in most studies. However, the
potential for levodopa to be toxic in vivo has not been tested under conditions
of oxidative stress such as exist in PD. To assess whether levodopa is toxic
under these circumstances, we have examined the effects of levodopa on dopamine
neurons in mesencephalic cultures and rat pups in which glutathione synthesis has
been inhibited by L-buthionine sulfoximine. Levodopa toxicity to cultured
dopaminergic neurons was enhanced by glutathione depletion and diminished by
antioxidants. In contrast, treatment of neonatal rats with levodopa, administered
either alone or in combination with glutathione depletion, did not cause damage
to the dopamine neurons of the substantia nigra or changes in striatal levels of
dopamine and its metabolites. This study provides further evidence to support the
notion that although levodopa can be toxic to dopamine neurons in vitro, it is
not likely to be toxic to dopamine neurons in vivo and specifically in conditions
such as PD.

PMID: 12538835 [PubMed - indexed for MEDLINE]

97. Exp Neurol. 2003 Jan;179(1):38-46.

Altered proteasomal function in sporadic Parkinson's disease.

McNaught KS, Belizaire R, Isacson O, Jenner P, Olanow CW.

Neurodegenerative Disease Research Centre, GKT School of Biomedical Sciences,
King's College, London Bridge, London SE1 1UL, UK.

Parkinson's disease (PD) is characterized pathologically by preferential
degeneration of the dopaminergic neurons in the substantia nigra pars compacta
(SNc). Nigral cell death is accompanied by the accumulation of a wide range of
poorly degraded proteins and the formation of proteinaceous inclusions (Lewy
bodies) in dopaminergic neurons. Mutations in the genes encoding alpha-synuclein
and two enzymes of the ubiquitin-proteasome system, parkin and ubiquitin
C-terminal hydrolase L1, are associated with neurodegeneration in some familial
forms of PD. We now show that, in comparison to age-matched controls,
alpha-subunits (but not beta-subunits) of 26/20S proteasomes are lost within
dopaminergic neurons and 20S proteasomal enzymatic activities are impaired in the
SNc in sporadic PD. In addition, while the levels of the PA700 proteasome
activator are reduced in the SNc in PD, PA700 expression is increased in other
brain regions such as the frontal cortex and striatum. We also found that levels
of the PA28 proteasome activator are very low to almost undetectable in the SNc
compared to other brain areas in both normal and PD subjects. These findings
suggest that failure of the ubiquitin-proteasome system to adequately clear
unwanted proteins may underlie vulnerability and degeneration of the SNc in both
sporadic and familial PD.

PMID: 12504866 [PubMed - indexed for MEDLINE]

98. Eur J Neurosci. 2002 Dec;16(11):2136-48.

Aggresome-related biogenesis of Lewy bodies.

McNaught KS, Shashidharan P, Perl DP, Jenner P, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, Annenberg 14-73, One
Gustave L Levy Place, New York, NY 10029, USA. Kevin.mcnaught@mssm.edu

Neurodegenerative disorders such as Parkinson's disease (PD) and 'dementia with
Lewy bodies' (DLB) are characterized pathologically by selective neuronal death
and the appearance of intracytoplasmic protein aggregates (Lewy bodies). The
process by which these inclusions are formed and their role in the
neurodegenerative process remain elusive. In this study, we demonstrate a close
relationship between Lewy bodies and aggresomes, which are cytoplasmic inclusions
formed at the centrosome as a cytoprotective response to sequester and degrade
excess levels of potentially toxic abnormal proteins within cells. We show that
the centrosome/aggresome-related proteins gamma-tubulin and pericentrin display
an aggresome-like distribution in Lewy bodies in PD and DLB. Lewy bodies also
sequester the ubiquitin-activating enzyme (E1), the proteasome activators PA700
and PA28, and HSP70, all of which are recruited to aggresomes for enhanced
proteolysis. Using novel antibodies that are specific and highly sensitive to
ubiquitin-protein conjugates, we revealed the presence of numerous discrete
ubiquitinated protein aggregates in neuronal soma and processes in PD and DLB.
These aggregates appear to be being transported from peripheral sites to the
centrosome where they are sequestered to form Lewy bodies in neurons. Finally, we
have shown that inhibition of proteasomal function or generation of misfolded
proteins cause the formation of aggresome/Lewy body-like inclusions and
cytotoxicity in dopaminergic neurons in culture. These observations suggest that
Lewy body formation may be an aggresome-related event in response to increasing
levels of abnormal proteins in neurons. This phenomenon is consistent with
growing evidence that altered protein handling underlies the etiopathogenesis of
PD and related disorders.

PMID: 12473081 [PubMed - indexed for MEDLINE]

99. Eur J Neurol. 2002 Nov;9 Suppl 3:31-9.

Surgical therapy for Parkinson's disease.

Olanow CW.

Mount Sinai School of Medicine, Department of Neurology, New York, NY 10029, USA.
warren.olanow@mssm.edu

Surgical therapies for Parkinson's disease (PD) are now being performed with
increasing frequency due to the limitations of conventional dopaminergic
therapies, improvements in operative procedures, and increased information on the
organization of the basal ganglia in normal and pathologic conditions. Ablation
procedures have now been largely replaced with deep brain stimulation, which
permits benefits to be obtained without the need to make a destructive brain
lesion. Several studies now demonstrate the value of stimulating the subthalamic
nucleus or the globus pallidus pars interna in patients with advanced PD.
Nonetheless, there are limitations associated with these procedures and benefits
do not exceed those obtained with levodopa, albeit with reduced motor
complications. Fetal transplantation remains an experimental procedure that has
shown limited benefits in a double-blind trial and is complicated by persistent
dyskinesia. Stem cell, trophic factor, and gene therapy approaches are promising
and are currently under intensive investigation.

PMID: 12464119 [PubMed - indexed for MEDLINE]

100. Lancet. 2002 Aug 17;360(9332):575.

Levodopa: why the controversy?

Agid Y, Olanow CW, Mizuno Y.

Comment in:
Lancet. 2003 Jan 4;361(9351):84; author reply 84.

PMID: 12241695 [PubMed - indexed for MEDLINE]

101. Neuroscience. 2002;114(2):361-72.

Lipopolysaccharide prevents cell death caused by glutathione depletion: possible
mechanisms of protection.

Kramer BC, Yabut JA, Cheong J, JnoBaptiste R, Robakis T, Olanow CW, Mytilineou C.

Department of Neurology, Box 1137, Mount Sinai School of Medicine, 1 Gustave L.
Levy Place, New York, NY 10029, USA.

Glutathione is an important cellular antioxidant present at high concentrations
in the brain. We have previously demonstrated that depletion of glutathione in
mesencephalic cultures results in cell death and that the presence of glia is
necessary for the expression of toxicity. Cell death following glutathione
depletion can be prevented by inhibition of lipoxygenase activity, implicating
arachidonic acid metabolism in the toxic events. In this study we examined the
effect of glial activation, known to cause secretion of cytokines and release of
arachidonic acid, on the toxicity induced by glutathione depletion. Our data show
that treatment with the endotoxin lipopolysaccharide activated glial cells in
mesencephalic cultures, increased interleukin-1beta in microglia and caused
depletion of glutathione. The overall effect of lipopolysaccharide treatment,
however, was protection from damage caused by glutathione depletion. Addition of
cytokines or growth factors, normally secreted by activated glia, did not modify
L-buthionine sulfoximine toxicity, although basic fibroblast growth factor
provided some protection. A large increase in the protein content and the
activity of Mn-superoxide dismutase, observed after lipopolysaccharide treatment,
may indicate a role for this mitochondrial antioxidant enzyme in the protective
effect of lipopolysaccharide. This was supported by the suppression of toxicity
by exogenous superoxide dismutase. Our data suggest that superoxide contributes
to the damage caused by glutathione depletion and that up-regulation of
superoxide dismutase may offer protection in neurodegenerative diseases
associated with glutathione depletion and oxidative stress.

PMID: 12204205 [PubMed - indexed for MEDLINE]

102. Brain. 2002 Sep;125(Pt 9):2058-66.

Prospective randomized trial of lisuride infusion versus oral levodopa in
patients with Parkinson's disease.

Stocchi F, Ruggieri S, Vacca L, Olanow CW.

Institute of Neurology and Neuromed, University La Sapienza, Viale
dell'Universita' 30, 00185 Rome, Italy. fabstocc@tin.it

Motor complications are a major source of disability for patients with advanced
Parkinson's disease. Surgical therapies provide benefit to some, but these
treatments are expensive and associated with adverse effects. Current research
indicates that motor complications are associated with abnormal, intermittent,
pulsatile stimulation of denervated dopamine receptors using short acting
dopaminergic agents such as levodopa. Retrospective studies suggest that the use
of longer-acting more continuous dopaminergic therapies can improve both motor
fluctuations and dyskinesia. We performed a prospective, long-term (4-year) trial
comparing patients randomized to receive subcutaneous infusion of the dopamine
agonist lisuride versus conventional therapy with oral levodopa and dopamine
agonists. We demonstrate that patients receiving lisuride infusions experienced a
significant reduction in both motor fluctuations and dyskinesia compared with
patients receiving standard dopaminergic therapies. Benefits persisted for the
4-year duration of the study. Mean Unified Parkinson's Disease Rating Scale
scores in "ON" and "OFF" states did not significantly change between baseline and
4 years for patients in the lisuride group, but deteriorated in patients in the
levodopa group. This study indicates that continuous lisuride infusion can be
beneficial for patients with advanced Parkinson's disease and reverse established
motor fluctuations and dyskinesia.

PMID: 12183351 [PubMed - indexed for MEDLINE]

103. Neuroreport. 2002 Aug 7;13(11):1437-41.

Proteasome inhibition causes nigral degeneration with inclusion bodies in rats.

McNaught KS, Björklund LM, Belizaire R, Isacson O, Jenner P, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, Annenberg 14-73, One
Gustave L. Levy Place, New York, NY 10029, USA.

Structural and functional defects in 26/20S proteasomes occur in the substantia
nigra pars compacta and may underlie protein accumulation, Lewy body formation
and dopaminergic neuronal death in Parkinson's disease. We therefore determined
the pathogenicity of proteasomal impairment following stereotaxic unilateral
infusion of lactacystin, a selective proteasome inhibitor, into the substantia
nigra pars compacta of rats. These animals became progressively bradykinetic,
adopted a stooped posture and displayed contralateral head tilting.
Administration of apomorphine to lactacystin-treated rats reversed behavioral
abnormalities and induced contralateral rotations. Lactacystin caused
dose-dependent degeneration of dopaminergic cell bodies and processes with the
cytoplasmic accumulation and aggregation of alpha-synuclein to form inclusion
bodies. These findings support the notion that failure of the
ubiquitin-proteasome system to degrade and clear unwanted proteins is an
important etiopathogenic factor in Parkinson's disease.

PMID: 12167769 [PubMed - indexed for MEDLINE]

104. Ann Neurol. 2002 May;51(5):604-12.

Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson's
disease: a randomized placebo-controlled extension of the deprenyl and tocopherol
antioxidative therapy of parkinsonism trial.

Shoulson I, Oakes D, Fahn S, Lang A, Langston JW, LeWitt P, Olanow CW, Penney JB,
Tanner C, Kieburtz K, Rudolph A; Parkinson Study Group.

University of Rochester Medical Center, Rochester, NY 14620, USA.
ishoulson@mct.rochester.edu

Deprenyl (selegiline) delays the need for levodopa therapy in patients with early
Parkinson's disease, but the long-term benefits of this treatment remain unclear.
During 1987 to 1988, 800 patients with early Parkinson's disease were randomized
in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism trial to
receive deprenyl, tocopherol, combined treatments, or a placebo and were then
placed on active deprenyl (10mg/day). A second, independent randomization was
carried out in early 1993 for 368 subjects who by that time had required levodopa
and who had consented to continuing the deprenyl treatment (D subjects) or
changing to a matching placebo (P subjects) under double-blind conditions. The
first development of wearing off, dyskinesias, or on-off motor fluctuations was
the prespecified primary outcome measure. During the average 2-year follow-up,
there were no differences between the treatment groups with respect to the
primary outcome measure (hazard ratio, 0.87; 95% confidence interval, 0.63, 1.19;
p = 0.38), withdrawal from the study, death, or adverse events. Although 34% of D
subjects developed dyskinesias and only 19% of P subjects did (p = 0.006), only
16% of D subjects developed freezing of gait but 29% of P subjects did (p =
0.0003). Decline in motor performance was less in D subjects than P subjects.
Levodopa-treated Parkinson's disease patients who had been treated with deprenyl
for up to 7 years, compared with patients who were changed to a placebo after
about 5 years, experienced slower motor decline and were more likely to develop
dyskinesias but less likely to develop freezing of gait.

PMID: 12112107 [PubMed - indexed for MEDLINE]

105. Neurosci Lett. 2002 Jul 5;326(3):155-8.

Selective loss of 20S proteasome alpha-subunits in the substantia nigra pars
compacta in Parkinson's disease.

McNaught KS, Belizaire R, Jenner P, Olanow CW, Isacson O.

Department of Neurology, Mount Sinai School of Medicine, Annenberg 14-73, One
Gustave L. Levy Place, New York, NY 10029, USA. kevin.mcnaught@mssm.edu

The proteolytic activities of 26/20S proteasomes are impaired in the substantia
nigra pars compacta (SNc) in sporadic Parkinson's disease (PD). In the present
study, we examined the structural integrity of the proteasome by determining the
levels of the beta- and alpha-subunits which together normally constitute the
catalytic core of 26/20S proteasomes. Western blot analyzes and
immunohistochemical staining revealed a major and selective loss of
alpha-subunits in dopaminergic neurons of the SNc but not in other brain regions
in sporadic PD. This defect is known to cause the proteasome to become unstable
and prevents its assembly with resultant impairment of enzymatic activity. Thus,
structural and function defects in 26/20S proteasomes may underlie protein
accumulation, formation of proteinaceous Lewy bodies and dopaminergic neuronal
death in the SNc in sporadic PD.

PMID: 12095645 [PubMed - indexed for MEDLINE]

106. J Neurochem. 2002 Apr;81(2):301-6.

Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and
inclusion body formation in ventral mesencephalic cultures.

McNaught KS, Mytilineou C, Jnobaptiste R, Yabut J, Shashidharan P, Jennert P,
Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, New York
10029, USA. kevin.mcnaught@mssm.edu

Mutations in alpha-synuclein, parkin and ubiquitin C-terminal hydrolase L1, and
defects in 26/20S proteasomes, cause or are associated with the development of
familial and sporadic Parkinson's disease (PD). This suggests that failure of the
ubiquitin-proteasome system (UPS) to degrade abnormal proteins may underlie
nigral degeneration and Lewy body formation that occur in PD. To explore this
concept, we studied the effects of lactacystin-mediated inhibition of 26/20S
proteasomal function and ubiquitin aldehyde (UbA)-induced impairment of ubiquitin
C-terminal hydrolase (UCH) activity in fetal rat ventral mesencephalic cultures.
We demonstrate that both lactacystin and UbA caused concentration-dependent and
preferential degeneration of dopaminergic neurons. Inhibition of 26/20S
proteasomal function was accompanied by the accumulation of alpha-synuclein and
ubiquitin, and the formation of inclusions that were immunoreactive for these
proteins, in the cytoplasm of VM neurons. Inhibition of UCH was associated with a
loss of ubiquitin immunoreactivity in the cytoplasm of VM neurons, but there was
a marked and localized increase in alpha-synuclein staining which may represent
the formation of inclusions bodies in VM neurons. These findings provide direct
evidence that impaired protein clearance can induce dopaminergic cell death and
the formation of proteinaceous inclusion bodies in VM neurons. This study
supports the concept that defects in the UPS may underlie nigral pathology in
familial and sporadic forms of PD.

PMID: 12064477 [PubMed - indexed for MEDLINE]

107. Neurology. 2002 Feb 26;58(4 Suppl 1):S33-41.

The role of dopamine agonists in the treatment of early Parkinson's disease.

Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.

Levodopa is the gold standard for the symptomatic treatment of Parkinson's
disease (PD). However, chronic treatment is associated with development of motor
complications in the majority of patients. Recent laboratory studies suggest that
pulsatile administration of a short-acting agent, such as levodopa, contributes
to the development of these problems and that they might be mitigated through the
use of longer-acting dopamine agonists. Placebo-controlled clinical trials have
shown that dopamine agonists have anti-parkinsonian effects in patients with
early PD. More importantly, four different prospective double-blind studies have
demonstrated that initiating symptomatic therapy with a dopamine agonist is
associated with a significantly reduced risk for development of motor
complications than is initial treatment with a dopamine agonist. Furthermore,
several lines of laboratory research suggest that dopamine agonists might protect
dopaminergic neurons in PD and retard the rate of disease progression.
Double-blind trials using clinical and imaging end points are now testing this
hypothesis and the results should soon be available. On the basis of this
evidence, a rational approach to the treatment of PD patients who are not elderly
or cognitively impaired is to initiate therapy with a dopamine agonist and
supplement with levodopa when dopamine agonist monotherapy can no longer provide
satisfactory clinical control.

PMID: 11909983 [PubMed - indexed for MEDLINE]

108. Arch Neurol. 2001 Sep;58(9):1379-82.

Early morning off-medication dyskinesias, dystonia, and choreic subtypes.

Cubo E, Gracies JM, Benabou R, Olanow CW, Raman R, Leurgans S, Goetz CG.

Department of Neurological Sciences, Rush-Presbyterian-St Luke's Medical Center,
Chicago, IL, USA. 35350ecd@comb.es

BACKGROUND: Abnormal involuntary movements (dyskinesias) are common in patients
with Parkinson disease (PD) as a consequence of the disease and dopaminergic
replacement therapy. Early morning off-medication choreic dyskinesias have been
recently reported after fetal dopaminergic cell transplantations in patients with
advanced PD. OBJECTIVE: To determine the frequency and severity of the early
morning off-medication dyskinesias in consecutive patients with advanced PD and
an insufficient response to medical management before they undergo neurosurgery.
METHODS: Consecutive patients with advanced idiopathic PD were examined and
videotaped before undergoing neurosurgery that included pallidotomy, fetal
transplantation, or deep brain stimulation. The examination took place in the
morning in the practically defined off state, at least 12 hours after the last
dose of dopaminergic drugs. Parkinson disease was characterized using the Unified
Parkinson's Disease Rating Scale and the Hoehn and Yahr stage. Dyskinesias were
rated with the Abnormal Involuntary Movements Scale and the Rush Dyskinesia
Rating Scale. Patients' characteristics and medications were compared using the
Wilcoxon rank sum and the Fisher exact tests. RESULTS: Of 68 consecutive patients
(44 [65%] men and 24 [35%] women), 11 (16%) had early morning off-medication
dyskinesia, with a 95% upper confidence limit of 24%. Focal dystonia was the most
common off-medication dyskinesia, and occurred in 10 patients (15%), with a 95%
upper confidence limit of 22%; and off-choreic dyskinesia occurred in 1 patient
(1.5%), with a 95% upper confidence limit of 4%. There was no difference in PD
medications between the patients with and those without dyskinesias. CONCLUSIONS:
The most common form of off-medication dyskinesia seen in patients with advanced
PD is dystonia. Early morning off-medication choreic dyskinesias are rare but do
occur in patients with advanced PD before surgical intervention. The presence and
type of off-medication dyskinesias should be monitored in clinical and surgical
studies in patients with PD as part of the safety and evaluation of clinical
benefits.

PMID: 11559308 [PubMed - indexed for MEDLINE]

109. Adv Neurol. 2001;86:421-33.

Surgical therapies for Parkinson's disease. A physician's perspective.

Olanow CW, Brin MF.

Department of Neurology, Mount Sinai School of Medicine, New York, New York
10029, USA.

PMID: 11554005 [PubMed - indexed for MEDLINE]

110. Nat Rev Neurosci. 2001 Aug;2(8):589-94.

Failure of the ubiquitin-proteasome system in Parkinson's disease.

McNaught KS, Olanow CW, Halliwell B, Isacson O, Jenner P.

Neuroregeneration Laboratory, Harvard Medical School and McLean Hospital, 115
Mill Street, Belmont, MA 02478, USA. kevin.mcnaught@mclean.harvard.edu

PMID: 11484002 [PubMed - indexed for MEDLINE]

111. N Engl J Med. 2001 Jul 12;345(2):146; author reply 147.

Transplantation of embryonic dopamine neurons for severe Parkinson's disease.

Olanow CW, Freeman T, Kordower J.

Comment on:
N Engl J Med. 2001 Mar 8;344(10):710-9.

PMID: 11450669 [PubMed - indexed for MEDLINE]

112. Neurology. 2001 Jun;56(11 Suppl 5):S1-S88.

An algorithm (decision tree) for the management of Parkinson's disease (2001):
treatment guidelines.

Olanow CW, Watts RL, Koller WC.

Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.
warren.olanow@mssm.edu

PMID: 11402154 [PubMed - indexed for MEDLINE]

113. Neurology. 2000;55(12 Suppl 6):S60-6.

The role of deep brain stimulation as a surgical treatment for Parkinson's
disease.

Olanow CW, Brin MF, Obeso JA.

Department of Neurology, Mount Sinai School of Medicine, New York, New York
10029, USA.

Patients with advanced Parkinson's disease (PD) frequently suffer disabling motor
complications that cannot be satisfactorily controlled with medical therapy. Deep
brain stimulation (DBS) has recently been introduced by Benabid and his
colleagues in Grenoble, France, as a new surgical procedure for the treatment of
PD patients. DBS simulates the effects of a lesion without the need to make a
destructive brain lesion. In this procedure, an electrode is implanted in the
brain target and connected to a subcutaneous pacemaker. DBS of the
ventro-intermediate (Vim) nucleus of the thalamus has been shown to ameliorate
tremor in patients with tremor-dominant PD. DBS of the subthalamic nucleus (STN)
and globus pallidus pars interna (GPi) have been shown to improve all of the
cardinal features of PD and to markedly reduce dyskinesia and motor fluctuations.
Adverse events are associated with the surgical procedure, the device, and
stimulation, but the procedure is usually well tolerated. On the basis of these
findings, the FDA has recently approved unilateral DBS of the Vim for treatment
of tremor in PD and is currently considering approval of DBS for STN and GPi.
This article reviews existing information with respect to DBS.

PMID: 11188977 [PubMed - indexed for MEDLINE]

114. Neurology. 2000;55(11 Suppl 4):S72-7; discussion S78-81.

Pulsatile stimulation of dopamine receptors and levodopa-induced motor
complications in Parkinson's disease: implications for the early use of COMT
inhibitors.

Olanow CW, Obeso JA.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.

Increasing laboratory and clinical evidence indicates that pulsatile stimulation
of dopamine receptors contributes to the development of levodopa-related motor
complications in PD. In keeping with this concept, clinical trials have
demonstrated that initiating therapy with a long-acting dopamine agonist reduces
the risk of inducing motor complications in comparison to levodopa. However, the
introduction of levodopa is associated with the development of motor
complications even in the presence of a long-acting dopamine agonist in both PD
patients or MPTP treated monkeys. Administration of levodopa with a
catechol-O-methyl transferase (COMT) inhibitor increases its plasma half-life,
smoothes out peaks and troughs, and delivers levodopa to the brain in a more
continuous fashion. We hypothesize that the risk of developing motor
complications in PD patients when levodopa is introduced can be reduced if the
levodopa is coupled with a COMT inhibitor so as to provide more continuous
dopaminergic stimulation of dopamine receptors. A proposed algorithm for the
treatment of the early PD patient is to initiate therapy with a dopamine agonist,
and supplement with levodopa coupled with a COMT inhibitor when the dopamine
agonist cannot provide satisfactory clinical benefits.

PMID: 11147513 [PubMed - indexed for MEDLINE]

115. Neurology. 2000;55(11 Suppl 4):S65-8; discussion S69-71.

The place of COMT inhibitors in the armamentarium of drugs for the treatment of
Parkinson's disease.

Schapira AH, Obeso JA, Olanow CW.

University Department of Clinical Neurosciences, Royal Free and University
College Medical School, and Institute of Neurology, University College London,
UK.

Catechol-O-methyl transferase (COMT) inhibitors block the peripheral metabolism
of levodopa, increase its plasma half-life, and enhance its brain availability.
Two COMT inhibitors, tolcapone and entacapone, have recently been made available
as adjunctive agents to levodopa. In PD patients with motor fluctuations, they
have been shown to increase "on" time and reduce "off" time. In patients with
more advanced disease, they provide similar benefits, but patients tend to
experience less overall benefit and a greater likelihood of developing
dopaminergic adverse events. Accordingly, closer monitoring is required. In
stable patients who have not yet developed motor complications, there are
preliminary data suggesting that they experience improvements in motor function
and in activities of daily living. Finally, there are theoretical reasons to
consider administering a COMT inhibitor to patients from the onset of levodopa
therapy in order to reduce the likelihood that motor complications will develop.
COMT inhibitors are easy to administer, do not require titration, and are
generally well tolerated particularly in patients with relatively mild disease.
Adverse events are primarily dopaminergic and can usually be controlled by
levodopa dose adjustments. COMT inhibitors have thus proven to be a useful
addition to the therapeutic armamentarium of PD.

PMID: 11147512 [PubMed - indexed for MEDLINE]

116. Neurology. 2000;55(11 Suppl 4):S13-20; discussion S21-3.

The evolution and origin of motor complications in Parkinson's disease.

Obeso JA, Rodriguez-Oroz MC, Chana P, Lera G, Rodriguez M, Olanow CW.

Department of Neurology and Neurosurgery, Clinica Universitaria and Medical
School, University of Navarra, Pamplona, Spain.

Levodopa is the major symptomatic therapy for Parkinson's disease (PD), having
revolutionized the treatment of PD and provided benefit to virtually all
patients. However, after 5-10 years of treatment, levodopa therapy is complicated
by the development of motor complications, which include dyskinesia and motor
fluctuations. The initial long duration response to a dose of levodopa becomes
progressively shorter, and periods in which the patient responds to the drug
become complicated by involuntary dyskinetic movements. Thus, patients may cycle
between "on" periods that are complicated by dyskinesia and "off" periods in
which they are severely parkinsonian. As a consequence they may experience
profound disability despite the fact that levodopa remains an effective
anti-parkinson agent throughout the course of the disease. In this article we
review the various motor complications associated with the treatment of PD and
present current concepts on the origin of these problems.

PMID: 11147505 [PubMed - indexed for MEDLINE]

117. Eur J Neurol. 2000 May;7 Suppl 1:3-8.

Why delaying levodopa is a good treatment strategy in early Parkinson's disease.

Olanow CW, Stocchi F.

Department of Neurology, Mount Sinai School of Medicine, New York, New York
10029, USA. warren.olanow@mssm.edu

PMID: 11054152 [PubMed - indexed for MEDLINE]

118. Trends Neurosci. 2000 Oct;23(10 Suppl):S34-40.

Dopamine receptors: from structure to behavior.

Sealfon SC, Olanow CW.

Dept of Neurology, Fishberg Center for Neurobiology, Mount Sinai School of
Medicine, New York, NY 10029, USA.

The responses obtained with drugs that act at dopamine receptors depend on the
spectrum of receptors stimulated, the pattern of stimulation and the neuronal
signal-transduction pathways that are activated. In the absence of drugs that
reliably discriminate between the various cloned receptors, elucidating the role
of these receptors has largely relied on molecular genetic approaches that
include expression of genes for receptors in cell lines and manipulation of this
expression in animal models. Connecting molecular events that occur consequent to
receptor stimulation with the resulting physiological effects entails bridging a
complex network of interactions. This article reviews the current understanding
of the molecular, cellular and systemic consequences of activation of the
different dopamine receptors.

PMID: 11052218 [PubMed - indexed for MEDLINE]

119. Trends Neurosci. 2000 Oct;23(10 Suppl):S8-19.

Pathophysiology of the basal ganglia in Parkinson's disease.

Obeso JA, Rodríguez-Oroz MC, Rodríguez M, Lanciego JL, Artieda J, Gonzalo N,
Olanow CW.

Dept of Neurology, Neuroscience Centre, Clinica Universitaria and Medical School,
University of Navarra, Pamplona, Spain.

Insight into the organization of the basal ganglia in the normal, parkinsonian
and L-dopa-induced dyskinesia states is critical for the development of newer and
more effective therapies for Parkinson's disease. We believe that the basal
ganglia can no longer be thought of as a unidirectional linear system that
transfers information based solely on a firing-rate code. Rather, we propose that
the basal ganglia is a highly organized network, with operational characteristics
that simulate a non-linear dynamic system.

PMID: 11052215 [PubMed - indexed for MEDLINE]

120. Trends Neurosci. 2000 Oct;23(10 Suppl):S2-7.

Levodopa motor complications in Parkinson's disease.

Obeso JA, Olanow CW, Nutt JG.

Dept of Neurology and Neurosurgery, Neuroscience Center, Clínica Universitaria
and Medical School, Pamplona, Spain.

Parkinson's disease (PD) is an age-related neurodegenerative disorder with an
average onset age of 60 years. In the United States, approximately one million
persons suffer from PD, and there are 60,000 newly diagnosed cases every year.
The estimated cost of PD to society is $27 billion per year. Based on United
States Census Bureau projections, it is estimated that the frequency of PD will
increase fourfold by the year 2040, making it an even larger burden on patients,
their families and society.

PMID: 11052214 [PubMed - indexed for MEDLINE]

121. Brain Res. 2000 Sep 22;877(2):379-81.

TorsinA accumulation in Lewy bodies in sporadic Parkinson's disease.

Shashidharan P, Good PF, Hsu A, Perl DP, Brin MF, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy
Place, New York, NY 10029, USA. pullani.shashi@mssm.edu

Parkinson's disease (PD) is a neurodegnerative disorder that is pathologically
characterized by the presence of Lewy bodies in the brain. We show that Lewy
bodies in PD are strongly immunoreactive for torsinA, the protein product of the
DYT1 gene, which is associated with primary generalized dystonia. In the
substantia nigra, torsinA immunoreactivity is localized to the periphery of Lewy
bodies, whereas, in cortical Lewy bodies it is uniformly distributed. The
significance of this finding is unknown, but may implicate torsinA in neuronal
dysfunction that occurs in PD as well as in primary dystonia.

PMID: 10986355 [PubMed - indexed for MEDLINE]

122. Neuropsychiatry Neuropsychol Behav Neurol. 2000 Jul;13(3):204-19.

A program for neuropsychological investigation of deep brain stimulation (PNIDBS)
in movement disorder patients: development, feasibility, and preliminary data.

Morrison CE, Borod JC, Brin MF, Raskin SA, Germano IM, Weisz DJ, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, and Queens College and
The Graduate Center of the City University of New York, New York, USA.
ChrisEMorrison@juno.com

OBJECTIVE: This technical report and feasibility study propose a standardized
method for collecting neuropsychological data in patients undergoing the deep
brain stimulation (DBS) procedure. BACKGROUND: Programs for standardizing motor
data collected in studies investigating surgical therapies for Parkinson disease
are already widely used (e.g., Core Assessment Program for Intracerebral
Transplantations). The development and rationale for the proposed Program for
Neuropsychological Investigation of Deep Brain Stimulation (PNIDBS) are outlined,
and support for the feasibility of these methodologies is provided via
preliminary data. METHOD: The PNIDBS includes a core battery of
neuropsychological tests that assesses a wide range of cognitive functions
(attention, language, visuospatial, memory, and executive) as well as depression.
Using the PNIDBS, three Parkinson disease and two dystonia patients were
evaluated at baseline and after surgery, once with stimulation off and once with
stimulation on. RESULTS: Patients with severe motor disabilities were able to
complete the PNIDBS. These preliminary data suggest that the DBS procedure as a
whole had a minimal impact on cognitive functioning in most patients studied.
There was also some evidence that the one patient who showed cognitive decline
after the DBS procedure had demographic and clinical characteristics that may
have put him at risk for this decline. CONCLUSIONS: The procedures in the PNIDBS
were systematically developed and are feasible to execute. The relatively brief
core battery has multiple versions and can be supplemented to meet individual
investigator needs. By evaluating the components of the DBS procedure (electrode
placement and stimulation), the PNIDBS can address clinical questions regarding
the cognitive effects of the DBS procedure as well as investigate basic
scientific issues regarding how different cognitive functions are affected when
subcortical-prefrontal circuits are manipulated by the DBS procedure.

PMID: 10910093 [PubMed - indexed for MEDLINE]

123. Mov Disord. 2000 May;15(3):485-9.

Time course of loss of clinical benefit following withdrawal of
levodopa/carbidopa and bromocriptine in early Parkinson' s disease.

Hauser RA, Koller WC, Hubble JP, Malapira T, Busenbark K, Olanow CW.

Parkinson's Disease and Movement Disorders Center, University of South Florida,
Tampa 33606, USA.

Putative neuroprotective agents for Parkinson's disease can be assessed in
untreated patients using progression of clinical disability as an index of
disease progression. To avoid the confound associated with symptomatic therapy,
progression of the underlying disease can be assessed by evaluating the
progression of clinical disability from an untreated baseline to a final visit
following wash-out of symptomatic medication. In this type of analysis it is
critical to use a washout of sufficient duration to ensure elimination of
symptomatic effects. To assess the time course of resolution of symptomatic
effects, we evaluated 31 patients at days 1, 8, and 15 following discontinuation
of levodopa/carbidopa and bromocriptine. Mean total Unified Parkinson's Disease
Rating Scale scores (+/- standard error) increased (worsened) by 7.4+/-1.5 from
day 1 to day 15 (p <0.0001), 4.5+/-1.2 from day 1 to day 8 (p = 0.0009), and
2.9+/-1.0 from day 8 to day 15 (p = 0.01). We conclude that a wash-out of at
least 2 weeks is required to eliminate the symptomatic effects of
levodopa/carbidopa and bromocriptine in patients with early Parkinson's disease.

PMID: 10830413 [PubMed - indexed for MEDLINE]

124. Ann Neurol. 2000 Apr;47(4 Suppl 1):S167-76; discussion S176-8.

Preventing levodopa-induced dyskinesias.

Olanow CW, Obeso JA.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.

The precise cause of levodopa-induced dyskinesias is unknown. Current evidence
indicates that dyskinesias develop in response to pulsatile stimulation of
striatal dopamine receptors. The half-life of the dopaminergic agent employed and
disease severity are thought to affect the occurrence of pulsatile stimulation.
Dyskinesias are not seen or are attenuated with continuous delivery of levodopa
or short-acting agonists, or with the use of long-acting agonists. In advanced
disease, there are fewer striatal dopamine terminals and reduced buffering
capacity; fluctuations in plasma levodopa concentration are more likely to cause
fluctuations in striatal dopamine concentration and pulsatile stimulation of
dopamine receptors. Pulsatile stimulation is thought to induce postsynaptic gene
and protein changes that result in alterations in the patterns of neuronal
communication, with the emergence of dyskinetic movements. Thus, strategies
preventing pulsatile stimulation may prevent the development of dyskinesias.
These could include the use of dopaminergic agents with a relatively long
half-life, neuroprotective therapies that prevent the loss of dopamine neurons,
and transplantation strategies or trophic factors that increase the number of
dopamine terminals capable of buffering fluctuations in striatal dopamine.
Alternatively, approaches that interfere with or compensate for postsynaptic
molecular and neurophysiologic changes that ensue in downstream neurons might
provide antidyskinetic benefits.

PMID: 10762145 [PubMed - indexed for MEDLINE]

125. Ann Neurol. 2000 Apr;47(4 Suppl 1):S22-32; discussion S32-4.

Pathophysiology of levodopa-induced dyskinesias in Parkinson's disease: problems
with the current model.

Obeso JA, Rodriguez-Oroz MC, Rodriguez M, DeLong MR, Olanow CW.

Department of Neurology and Neurosurgery, Clínica Universitaria and Medical
School, University of Navarra, Pamplona, Spain.

The anatomical and physiological basis of levodopa-induced dyskinesias (LIDs) in
patients with Parkinson's disease (PD) is reviewed in the light of the current
model for the organization of the basal ganglia. This model, which was developed
in the late 1980s, works relatively well in explaining the motor features of PD
but, for example, it does not account for why tremor, rigidity, bradykinesia,
gait dysfunction and postural instability present to differing degrees in
different patients, and may respond differently to levodopa treatment or surgical
procedures. Recent information suggests that LIDs develop as a consequence of
pulsatile stimulation of dopamine receptors, with consequent dysregulation of
genes and proteins in downstream neurons resulting in changes in neuronal firing
patterns. A modified model of the basal ganglia in PD patients with LID is
proposed, which incorporates more recent clinical and experimental data.

PMID: 10762129 [PubMed - indexed for MEDLINE]

126. Mov Disord. 2000 Mar;15(2):212-5.

Waking up to sleep episodes in Parkinson's disease.

Olanow CW, Schapira AH, Roth T.

Department of Neurology, Mount Sinai School of Medicine, New York, New York, USA.

PMID: 10752568 [PubMed - indexed for MEDLINE]

127. J Neurol Neurosurg Psychiatry. 2000 Apr;68(4):526-31.

Progressive dementia and gait disorder in a 78 year old woman.

Tagliati M, Perl DP, Drayer B, Olanow CW.

Department of Neurology, The Mount Sinai Medical Center, NY, USA.
mtagliat@bethisraelny.org

Comment in:
J Neurol Neurosurg Psychiatry. 2000 Nov;69(5):702.

PMCID: 1736868
PMID: 10727496 [PubMed - indexed for MEDLINE]

128. Arch Neurol. 2000 Feb;57(2):263-7.

Tolcapone and hepatotoxic effects. Tasmar Advisory Panel.

Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.

Four patients with Parkinson disease have recently been described in whom severe
hepatic dysfunction developed in association with tolcapone therapy. These
reports led to the introduction of a "black box" warning and more intensive
monitoring requirements in the United States. A review of these cases and all
clinical trials indicates that liver dysfunction did not develop in any patient
who had received monitoring of liver function according to the original
prescribing information. Virtually all instances of liver enzyme abnormality and
clinical liver dysfunction occurred within 6 months of initiating treatment. To
assess the current role of tolcapone therapy in Parkinson disease, a panel of
neurologists and hepatologists was convened. Consensus was reached with respect
to the following: (1) Tolcapone is an effective agent in the treatment of
patients with fluctuating Parkinson disease. (2) The risk of developing
irreversible liver injury is negligible with appropriate monitoring. (3) It may
be possible to reduce the frequency of monitoring after 6 months of treatment.
(4) The requirement that tolcapone be withdrawn if liver enzymes are elevated
above the upper limit of normal on a single occasion is unnecessarily
restrictive. It was concluded that tolcapone, when used as an adjunct to
levodopa, is an effective anti-parkinsonian agent and that less frequent
monitoring after 6 months, with an action limit of 2 to 3 times the upper limit
of normal, is sufficient to ensure safety in patients who are deriving benefit
from the drug.

PMID: 10681087 [PubMed - indexed for MEDLINE]

129. Brain Res. 2000 Jan 24;853(2):197-206.

Immunohistochemical localization and distribution of torsinA in normal human and
rat brain.

Shashidharan P, Kramer BC, Walker RH, Olanow CW, Brin MF.

Department of Neurology, Box 1137, Mount Sinai School of Medicine, One Gustave L.
Levy Place, New York, NY, USA. pullani.shashi@mssm.edu

Dystonia is a disease of basal ganglia function, the pathophysiology of which is
poorly understood. Primary torsion dystonia is one of the most severe types of
inherited dystonia and can be transmitted in an autosomal dominant manner.
Recently, one mutation causing this disorder was localized to a gene on
chromosome 9q34, designated DYT1, which encodes for a novel protein termed
torsinA. The role of this protein in cellular function, in either normal or
dystonic individuals is not known. We have developed a polyclonal antibody to
torsinA and report its localization and distribution in normal human and rat
brain. We demonstrate that torsinA is widely expressed in brain and peripheral
tissues. Immunohistochemical studies of normal human and rat brain reveal the
presence of torsinA in the dopaminergic neurons of the substantia nigra pars
compacta (SNc), in addition to many other regions, including neocortex,
hippocampus, and cerebellum. Labeling is restricted to neurons, as shown by
double-immunofluorescence microscopy, and is present in both nuclei and
cytoplasm. An ATP-binding property for torsinA has been suggested by its homology
to ATP-binding proteins; this was confirmed by enrichment of torsinA in
ATP-agarose affinity-purified fractions from tissue homogenates. An understanding
of the role of torsinA in cellular function and the impact of the mutation
(deletion of a glutamic acid at residue 303) is likely to provide insights into
the etiopathogenesis of primary dystonia.

PMID: 10640617 [PubMed - indexed for MEDLINE]

130. Neurology. 2000 Jan 11;54(1):274; author reply 276-7.

Falling asleep at the wheel: motor vehicle mishaps in people taking pramipexole
and ropinirole.

Olanow CW, Schapira AH, Roth T.

Comment on:
Neurology. 1999 Jun 10;52(9):1908-10.

PMID: 10636179 [PubMed - indexed for MEDLINE]

131. N Engl J Med. 1999 Sep 23;341(13):988-92.

Use of placebo surgery in controlled trials of a cellular-based therapy for
Parkinson's disease.

Freeman TB, Vawter DE, Leaverton PE, Godbold JH, Hauser RA, Goetz CG, Olanow CW.

University of South Florida, Tampa 33606, USA.

Comment in:
N Engl J Med. 2000 Feb 3;342(5):353; author reply 354-5.

PMID: 10498497 [PubMed - indexed for MEDLINE]

132. Mov Disord. 1999;14 Suppl 1:69-73.

Dyskinesias assessment workshop: reports from the working groups.

Melamed E, Olanow CW, Nutt JG, Lang AE.

The Beilinson Medical Center, Tel Aviv University, Petah Tiqva, Israel.

PMID: 10493407 [PubMed - indexed for MEDLINE]

133. J Neurochem. 1999 Jul;73(1):112-9.

Glial cells mediate toxicity in glutathione-depleted mesencephalic cultures.

Mytilineou C, Kokotos Leonardi ET, Kramer BC, Jamindar T, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, New York
10029, USA.

We have examined the role of glial cells in the toxicity that results from
inhibition of reduced glutathione (GSH) synthesis by L-buthionine sulfoximine
(BSO) in mesencephalic cell cultures. We show that GSH depletion, to levels that
cause total cell loss in cultures containing neurons and glial cells, has no
effect on cell viability in enriched neuronal cultures. An increase in the
plating cell density sensitizes glia-containing cultures to GSH depletion-induced
toxicity. This suggests that cell death in this model is the consequence of
events that are induced by GSH depletion and are mediated by glial cells. The
antioxidant ascorbic acid and the lipoxygenase (LOX) inhibitor
nordihydroguaiaretic acid (1-10 microM) provide full protection from BSO
toxicity, indicating that arachidonic acid metabolism through the LOX pathway and
the generation of reactive oxygen species play a role in the loss of cell
viability. In contrast, inhibition of nitric oxide (NO) synthase affords only
partial protection from BSO toxicity, suggesting that increased NO production
cannot entirely account for cell death in this model. Our data provide evidence
that GSH depletion in the presence of glial cells leads to neuronal degeneration
that can be prevented by inhibition of LOX. This may have relevance to the
pathogenesis of Parkinson's disease, where glial activation and depletion of GSH
have been found in the substantia nigra pars compacta.

PMID: 10386961 [PubMed - indexed for MEDLINE]

134. Annu Rev Neurosci. 1999;22:123-44.

Etiology and pathogenesis of Parkinson's disease.

Olanow CW, Tatton WG.

Department of Neurology, Mount Sinai Medical Center, New York, New York 10029,
USA.

Parkinson's disease (PD) is an age-related neurodegenerative disorder that
affects approximately 1 million persons in the United States. It is characterized
by resting tremor, rigidity, bradykinesia or slowness, gait disturbance, and
postural instability. Pathological features include degeneration of dopaminergic
neurons in the substantia nigra pars compacta coupled with intracytoplasmic
inclusions known as Lewy bodies. Neurodegeneration and Lewy bodies can also be
found in the locus ceruleus, nucleus basalis, hypothalamus, cerebral cortex,
cranial nerve motor nuclei, and central and peripheral components of the
autonomic nervous system. Current treatment consists of a dopamine replacement
strategy using primarily the dopamine precursor levodopa. While levodopa provides
benefit to virtually all PD patients, after 5-10 years of treatment the majority
of patients develop adverse events in the form of dyskinesia (involuntary
movements) and fluctuations in motor response. Further, disease progression is
associated with the development of dementia, autonomic dysfunction, and postural
instability, which do not respond to levodopa therapy. Accordingly, research
efforts have been directed toward understanding the etiology and pathogenesis of
PD in the hope of developing a more effective therapy that will slow or halt the
natural progression of PD. This paper reviews recent advances.

PMID: 10202534 [PubMed - indexed for MEDLINE]

135. Mov Disord. 1999 Mar;14(2):262-8.

Parkinsonism associated with Sjögren's syndrome: three cases and a review of the
literature.

Walker RH, Spiera H, Brin MF, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, New York
10029, USA.

Sjögren's syndrome (SS) is a common multisystem autoimmune disorder. As with
other autoimmune disorders such as systemic lupus erythematosus (SLE), SS has
been associated with a wide range of neurologic abnormalities. Parkinsonism has
been reported previously in five SS patients. We present three additional cases
of SS with parkinsonism.

PMID: 10091620 [PubMed - indexed for MEDLINE]

136. Biochim Biophys Acta. 1999 Feb 9;1410(2):195-213.

Apoptosis in neurodegenerative diseases: the role of mitochondria.

Tatton WG, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, 1 Gustave Levy Place,
Annenberg 14-94, New York, NY 10029, USA.

Comment in:
Biochim Biophys Acta. 1999 Feb 9;1410(2):99-102.

Nerve cell death is the central feature of the human neurodegenerative diseases.
It has long been thought that nerve cell death in these disorders occurs by way
of necrosis, a process characterized by massive transmembrane ion currents,
compromise of mitochondrial ATP production, and the formation of high levels of
reactive oxygen species combining to induce rapid disruption of organelles, cell
swelling, and plasma membrane rupture with a secondary inflammatory response.
Nuclear DNA is relatively preserved. Recent evidence now indicates that the
process of apoptosis rather than necrosis primarily contributes to nerve cell
death in neurodegeneration. This has opened up new avenues for understanding the
pathogenesis of neurodegeneration and may lead to new and more effective
therapeutic approaches to these diseases.

PMID: 10076027 [PubMed - indexed for MEDLINE]

137. Arch Neurol. 1999 Feb;56(2):179-87.

Long-term evaluation of bilateral fetal nigral transplantation in Parkinson
disease.

Hauser RA, Freeman TB, Snow BJ, Nauert M, Gauger L, Kordower JH, Olanow CW.

Department of Neurology, University of South Florida, Tampa 33606, USA.

BACKGROUND: Parkinson disease (PD) is associated with a progressive loss of
nigrostriatal dopamine neurons. Medication therapy provides adequate control of
symptoms for several years, but long-term treatment is complicated by progressive
disability and the development of motor fluctuations and dyskinesias. In animal
models of PD, fetal nigral transplants have been shown to survive grafting into
the striatum, provide extensive striatal reinnervation, and improve motor
function. In patients with PD, cell survival and clinical benefit have been
observed following fetal nigral grafting, but results have been inconsistent.
OBJECTIVE: To evaluate the safety and efficacy of bilateral fetal nigral
transplantation into the postcommissural putamen in patients with advanced PD
complicated by motor fluctuations and dyskinesias. PATIENTS AND METHODS: Six
patients with advanced PD underwent bilateral fetal nigral transplantation. Each
patient received solid grafts derived from donors aged 6 1/2 to 9 weeks after
conception stereotactically implanted into the postcommissural putamen using 3 to
4 donors per side. Cyclosporine was administered for approximately 6 months to
provide immune suppression. Clinical evaluations included the Unified Parkinson's
Disease Rating Scale (UPDRS), Schwab-England Activities of Daily Living Scale,
and timed tests of motor function conducted during both the "off' and "on" states
at baseline and at 1, 3, 6, 9, 12, 18, and 24 months following transplantation.
Percentage of time off and percentage of time on with and without dyskinesia were
recorded at half-hour intervals using home diaries during the week prior to each
evaluation. 18F-fluorodopa positron emission tomographic scans were performed at
baseline, and at 6 months and 1 year following transplantation. RESULTS: Patients
have been followed up for a mean+/-SD of 20.5+/-5.5 months. Complications related
to surgery were mild and transient. Activities of daily living, motor, and total
(activities of daily living plus motor) UPDRS scores during the off state
improved significantly (P<.05, Wilcoxon signed rank test) at final visit in
comparison with baseline. Mean total UPDRS off score improved 32%, and each
patient experienced at least a 19% improvement. Mean percentage of time on
without dyskinesia during the waking day improved from 22% to 60% (P<.05). Mean
putamenal fluorodopa uptake on positron emission tomography increased
significantly at 6 and 12 months in comparison with baseline (P<.001, 2-tailed t
test). This increase correlated with clinical improvement. Two patients died 18
months after transplantation from causes unrelated to the surgical procedure. In
both cases, histopathological examination showed robust survival of tyrosine
hydroxylase immunoreactive cells and abundant reinnervation of the
postcommissural putamen. CONCLUSIONS: Fetal nigral tissue can be transplanted
into the postcommissural putamen bilaterally in patients with advanced PD safely
and with little morbidity. In this open-label pilot study we observed consistent
long-term clinical benefit and increased fluorodopa uptake on positron emission
tomography. Clinical improvement appears to be related to the survival and
function of transplanted fetal tissue.

PMID: 10025423 [PubMed - indexed for MEDLINE]

138. Neurology. 1998 Oct;51(4):1057-62.

A multicenter trial of ropinirole as adjunct treatment for Parkinson's disease.
Ropinirole Study Group.

Lieberman A, Olanow CW, Sethi K, Swanson P, Waters CH, Fahn S, Hurtig H, Yahr M.

Barrow Neurological Institute, Phoenix, AZ 85013-4496, USA.

Erratum in:
Neurology 1999 Jan 15;52(2):435.

Comment in:
Neurology. 1999 Aug 11;53(3):658.

OBJECTIVE: To evaluate the nonergot dopamine agonist ropinirole as an adjunct to
L-dopa in a randomized, double-blind trial in PD patients with motor
fluctuations. BACKGROUND: L-dopa in the treatment of PD is associated with motor
fluctuations, dyskinesia, and other adverse effects. The use of dopamine agonists
in the treatment of PD delays recourse to L-dopa and thus delays the possibility
of adverse effect onset. METHODS: Ropinirole (n = 95) or placebo (n = 54) was
added to L-dopa, and L-dopa was then reduced in a planned manner during the
6-month trial. RESULTS: A significantly greater number of ropinirole patients
were able to achieve a 20% or greater reduction in both L-dopa dose and in
percent time spent "off" compared with placebo (35.0% versus 13.0%; p = 0.003).
The mean daily L-dopa dose was reduced significantly with ropinirole treatment
(242 mg versus 51 mg; p < 0.001) as was the percent awake time spent "off" (11.7%
versus 5.1%; p = 0.039). There was no difference in the percent of patients who
withdrew because of adverse effects (15.8% on ropinirole versus 16.7% on
placebo). CONCLUSIONS: Ropinirole permits a reduction in L-dopa dose with
enhanced clinical benefit for PD patients with motor fluctuations.

PMID: 9781529 [PubMed - indexed for MEDLINE]

139. Ann Neurol. 1998 Sep;44(3 Suppl 1):S189-96.

The causes of Parkinson's disease are being unraveled and rational
neuroprotective therapy is close to reality.

Marsden CD, Olanow CW.

Institute of Neurology, London, United Kingdom.

There has been significant progress in our knowledge of the cause, the
pathogenesis, and the nature of the mechanism of cell death in Parkinson's
disease (PD). Mutations in single genes have now been shown to be able to cause
PD but likely only account for a small number of cases. Alternatively, there is
evidence that environmental factors play a large role in the majority of cases of
sporadic PD. Most likely, genetic factors predispose patients to develop PD if
combined with other gene mutations or environmental toxins. Interest has thus
focused on factors that contribute to the pathogenesis of neurodegeneration and
the mechanism of cell death in an attempt to design a neuroprotective therapy.
Oxidant stress, mitochondrial dysfunction, excitotoxicity with excess nitric
oxide formation, and glia and inflammatory processes are all thought to
contribute to the cell death process and agents that interfere with these events
may be neuroprotective. It is now generally held that the final culmination of
these events is the induction of apoptosis in nigral dopaminergic neurons and
this too offers opportunities for providing neuroprotection. A rational argument
can be made for investigating a large number of different approaches or
combination of approaches in the hope of developing a meaningful neuroprotective
therapy, using clinically relevant indices and neuroimaging markers of nigral
dopaminergic neurons. It is evident that conventional approaches to trials that
utilize large numbers of patients in search of small incremental effects are
costly and time consuming. As such, it will be virtually impossible to test all
of the potentially valuable neuroprotective agents that are now at hand, let
alone those that will likely soon emerge. We suggest that it may be more
profitable to test a large number of agents in a small number of selected
patients in search of a more robust neuroprotective effect. In this way, we will
reduce the risk of missing a powerful neuroprotective treatment with a treatment
that might not otherwise have been studied because of a lack of time, money, or
patients.

PMID: 9749592 [PubMed - indexed for MEDLINE]

140. Ann Neurol. 1998 Sep;44(3 Suppl 1):S175-88.

Subthalamic nucleus-mediated excitotoxicity in Parkinson's disease: a target for
neuroprotection.

Rodriguez MC, Obeso JA, Olanow CW.

Department of Neurology and Neurosurgery, HOSPITEN, Medical School, Universidad
de La Laguna, Tenerife, Spain.

Dopamine deficiency causes disinhibition and overactivity of the subthalamic
nucleus (STN). Output neurons from the STN are excitatory and use glutamate as a
neurotransmitter. They project to the external and internal segments of the
globus pallidum (GPe and GPi), the substantia nigra pars reticulata (SNr), and
the pedunculopontine nucleus (PPN). In addition, STN neurons provide excitatory
innervation to dopaminergic (DA) neurons in the substantia nigra pars compacta
(SNc) that contain glutamate receptors. Stimulation of the STN induces bursting
activity in SNc dopaminergic neurons. This raises the possibility that the
disinhibition of STN neurons that occurs as a result of a dopamine lesion might
induce excitotoxic damage in target structures, including the SNc. In addition,
the reduction in complex I activity found in the nigra in Parkinson's disease
(PD) may cause mitochondrial dysfunction and make SNc dopaminergic neurons
vulnerable to even physiologic concentrations of glutamate. We postulate that the
dopamine loss that occurs in PD produces augmented STN activity which, in turn,
causes further damage to vulnerable dopaminergic neurons, thereby creating a
scenario for an increasing cycle of neuronal loss in the SNc. In addition, STN
overactivity could, in theory, cause damage to the GPi, SNr, and PPN and thereby
account for the development of parkinsonian features that do not respond to
levodopa in patients with advanced disease. This hypothesis suggests that
pharmacologic or surgical therapies that reduce STN neuronal overactivity or
block glutamate receptors in the SNc and other target structures might be
neuroprotective and might slow or halt the progression of neurodegeneration in
PD.

PMID: 9749591 [PubMed - indexed for MEDLINE]

141. Ann Neurol. 1998 Sep;44(3 Suppl 1):S167-74.

Dopamine agonists and neuroprotection in Parkinson's disease.

Olanow CW, Jenner P, Brooks D.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.

There is increasing interest in the potential of dopamine agonists to provide a
neuroprotective effect and to alter the natural course of levodopa-treated
Parkinson's disease (PD). Theoretically, such a protective effect might derive
from (a) a levodopa sparing effect, (b) stimulation dopamine autoreceptors
resulting in decreased dopamine synthesis, release, and turnover, (c) direct
anti-oxidant effects, and (d) restoration of dopaminergic tone to the
dopamine-denervated brain so as to restore inhibition to the subthalamic nucleus
and thereby diminish STN-mediated excitotoxicity. Preclinical studies have
demonstrated that dopamine agonists reduce dopamine formation in comparison to
levodopa, protect cultured dopaminergic neurons from a variety of toxins
including levodopa, and protect dopaminergic neurons from toxins and age-related
degeneration in some rodent models of parkinsonism. Based on these findings,
several clinical trials have been initiated in patients with early PD to test the
effect of dopamine agonists on clinical and neuroimaging markers of disease
progression.

PMID: 9749590 [PubMed - indexed for MEDLINE]

142. Ann Neurol. 1998 Sep;44(3 Suppl 1):S142-8.

A fluorescent double-labeling method to detect and confirm apoptotic nuclei in
Parkinson's disease.

Tatton NA, Maclean-Fraser A, Tatton WG, Perl DP, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.

In situ end-labeling (ISEL) has become a widely used method to determine whether
cells die via apoptosis by detecting double-stranded DNA breaks that are the
result of endonuclease digestion. The enzyme terminal deoxynucleotidyl
transferase can be used to label the digested 3'-OH ends of DNA with biotin-,
digoxigenin-, or fluorescent probe-conjugated nucleotides. However, both
single-stranded and double-stranded DNA breaks can be labeled by this method and
therefore ISEL cannot unequivocally demonstrate apoptosis when used alone. We
have developed a fluorescent double-labeling method using ISEL combined with the
cyanine dye YOYO-1 that binds to DNA. When combined with confocal laser
microscopy and deconvolution analysis, YOYO-1 can demonstrate the presence or
absence of nuclear chromatin condensation and thus confirm that ISEL-positive
nuclei are indeed apoptotic. Preliminary findings indicate that dopaminergic
neurons in the substantia nigra compacta die via apoptosis in Parkinson's
disease.

PMID: 9749586 [PubMed - indexed for MEDLINE]

143. Ann Neurol. 1998 Sep;44(3 Suppl 1):S72-84.

Understanding cell death in Parkinson's disease.

Jenner P, Olanow CW.

Neurodegenerative Disease Research Centre, Pharmacology Group, King's College,
London, United Kingdom.

Current concepts of the cause of Parkinson's disease (PD) suggest a role for both
genetic and environmental influences. Common to a variety of potential causes of
nigral cell degeneration in PD is the involvement of oxidative stress. Postmortem
analysis shows increased levels of iron, decreased complex I activity, and a
decrease in reduced glutathione (GSH) levels. The decrease in GSH levels may be a
particularly important component of the cascade of events leading to cell death
because it occurs in the presymptomatic stage of PD and may directly induce
nigral cell degeneration or render neurons susceptible to the actions of toxins.
There is evidence suggesting that oxidative stress might originate in glial cells
rather than in neurons, and alterations in glial function may be an important
contributor to the pathologic process that occurs in PD. Oxidative damage occurs
in the brain in PD, as shown by increased lipid peroxidation and DNA damage in
the substantia nigra. Increased protein oxidation is also apparent, but this
occurs in many areas of the brain and raises the specter of a more widespread
pathologic process occurring in PD to which the substantia nigra is particularly
vulnerable. The inability of the substantia nigra to handle damaged or mutant
(eg, alpha-synuclein) proteins may lead to their aggregation and deposition and
to the formation of Lewy bodies. Indeed, Lewy bodies stain for both
alpha-synuclein and nitrated proteins. Current evidence enables us to hypothesize
that a failure to process structurally modified proteins in regions of the brain
exhibiting oxidative stress is a cause of both familial and sporadic PD.

PMID: 9749577 [PubMed - indexed for MEDLINE]

144. Ann Neurol. 1998 Sep;44(3 Suppl 1):S19-31.

Alzheimer's disease and Parkinson's disease: distinct entities or extremes of a
spectrum of neurodegeneration?

Perl DP, Olanow CW, Calne D.

Department of Pathology [Neuropathology], Mount Sinai Medical Center, New York,
NY, USA.

Alzheimer's disease (AD) and Parkinson's disease (PD) are generally considered to
be separate and distinct disease entities. However, a considerable amount of
evidence demonstrates that these disorders share common clinical and
neuropathologic features and that overlap between the two conditions is
extensive. For example, a significant percentage of AD patients exhibit
extrapyramidal features, and many PD patients develop dementia. Similarly, at
autopsy many AD patients not only exhibit the neuropathologic features of that
disorder but also exhibit nigral pathology, including Lewy bodies. The vast
majority of demented PD patients show widespread neurofibrillary tangles and
senile plaques as well as Lewy body formation and nigral degeneration. The extent
of such overlap is far greater than one would anticipate by chance alone. We
argue that such overlap reflects a common pathogenic mechanism for the
neurodegeneration encountered within specific vulnerable neuronal populations.
Furthermore, we suggest that the current nosologic approach, which attempts to
separate AD from PD, fails to properly deal with the issue of overlap and that a
new classification of the neurodegenerative disorders should be considered.

PMID: 9749570 [PubMed - indexed for MEDLINE]

145. Neurology. 1998 Sep;51(3):825-30.

Effect of selegiline on mortality in patients with Parkinson's disease: a
meta-analysis.

Olanow CW, Myllylä VV, Sotaniemi KA, Larsen JP, Pålhagen S, Przuntek H, Heinonen
EH, Kilkku O, Lammintausta R, Mäki-Ikola O, Rinne UK.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.

Comment in:
Neurology. 2001 Jul 24;57(2):369; author reply 369-70.

INTRODUCTION: The Parkinson's Disease Research Group of the United Kingdom
(PDRG-UK) reported increased mortality in PD patients treated with levodopa plus
selegiline compared with those treated with levodopa alone. METHODS: We performed
a meta-analysis on five long-term, prospective, randomized trials of selegiline
in patients with untreated PD. Included in the analysis were four randomized,
double-blind, placebo-controlled studies and one randomized, double-blind,
placebo-controlled study of 2 years' duration followed by long-term, open
follow-up. RESULTS: The mean duration of follow-up was 4.1 +/- 1.8 years. There
were 14 deaths in 297 selegiline-treated patients (4.7%) and 17 deaths in 292
non-selegiline-treated patients (5.8%). The hazard ratio for mortality was 1.02
(95% CI 0.44 to 2.37; p = 0.96). An analysis restricted to patients receiving
only levodopa with or without selegiline noted 11 deaths in 257
levodopa/selegiline-treated patients (4.3%) and 11 deaths in 254 patients treated
with levodopa alone (4.3%). The hazard ratio was 1.06 (95% CI 0.44 to 2.55; p =
0.90). Death rate per 1,000 patient years was 11.4 in the selegiline group and
14.2 in the nonselegiline group. Kaplan-Meier survival curves reflecting pooled
survival data showed no significant difference in duration of survival. The
hazard ratio was 0.84 (95% CI 0.41 to 1.70; p = 0.63) for selegiline- versus
non-selegiline-treated patients and 1.05 (95% CI 0.46 to 2.43; p = 0.91) for
selegiline/levodopa- versus levodopa-treated patients. CONCLUSION: These results
contrast with those of the PDRG-UK study and demonstrate no increase in mortality
associated with selegiline treatment whether or not patients also received
levodopa.

PMID: 9748034 [PubMed - indexed for MEDLINE]

146. Mov Disord. 1998 May;13(3):383-93.

Fetal nigral grafts survive and mediate clinical benefit in a patient with
Parkinson's disease.

Kordower JH, Freeman TB, Chen EY, Mufson EJ, Sanberg PR, Hauser RA, Snow B,
Olanow CW.

Research Center for Brain Repair and Department of Neurological Sciences, Rush
Presbyterian Medical Center, Chicago, Illinois 60612, USA.

We have previously demonstrated that fetal nigral grafts can survive, reinnervate
the striatum, and mediate clinically relevant recovery in a patient with
Parkinson's disease (PD). Most previous autopsy cases have failed to identify
meaningful numbers of viable grafted cells suggesting that differences in
critical transplant variables determine graft viability. The present study
evaluated the structural and functional correlates of fetal nigral
transplantation in a second PD patient who received fetal nigral grafts according
to our previously published transplant protocol. A 61-year-old woman with severe
PD received bilateral fetal nigral grafts to the postcommissural putamen from
seven donor fetuses (four right side and three left side) aged 6.5-9 weeks
postconception. This patient died 19 months after surgery from a cause unrelated
to the transplant surgery. Her postoperative clinical course was characterized by
improved motor and activities of daily living scores during "off time," reduced
"off time," and increased "on" time without dyskinesia. Positron emission
tomography (PET) scans revealed a bilateral and progressive increase in
fluorodopa (FD) uptake within the grafted putamen. Postmortem examination of the
right hemisphere revealed large oval-shaped grafts containing more than 138,000
tyrosine-hydroxylase-immunoreactive (TH-ir) neurons. Grafted cells formed a
seamless border with the host and provided dense TH-ir innervation to 78% of the
host postcommissural putamen. Graft-mediated sprouting of host fibers was not
observed. These data provide essential confirmation that, under appropriate
transplant conditions, grafted nigral neurons can survive, reinnervate the host
striatum, and provide clinical benefit to PD patients. These findings also
support the concept that improved motor function and striatal FD uptake on PET
after nigral grafting in PD are the result of the viability of grafted neurons
and graft-derived reinnervation of the host striatum.

PMID: 9613726 [PubMed - indexed for MEDLINE]

147. Mov Disord. 1998;13 Suppl 1:88-95.

Neuropathology of fetal nigral grafts in patients with Parkinson's disease.

Kordower JH, Freeman TB, Olanow CW.

Research Center for Brain Repair and Department of Neurological Sciences,
Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA.

PMID: 9613724 [PubMed - indexed for MEDLINE]

148. Mov Disord. 1998;13 Suppl 1:55-8.

Current status of selegiline as a neuroprotective agent in Parkinson's disease.

Olanow CW, Mytilineou C, Tatton W.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.

PMID: 9613720 [PubMed - indexed for MEDLINE]

149. J Neuropathol Exp Neurol. 1998 Apr;57(4):338-42.

Protein nitration in Parkinson's disease.

Good PF, Hsu A, Werner P, Perl DP, Olanow CW.

Department of Pathology and the Fishberg Research Center for Neurobiology, The
Mount Sinai School of Medicine, New York City, New York 10029-6574, USA.

Oxidative stress has been proposed as a pathogenetic mechanism in Parkinson's
disease (PD). One mechanism of oxidative cellular injury is the nitration of
protein tyrosine residues, mediated by peroxynitrite, a reaction product of
nitric oxide and superoxide radicals. We demonstrate here the presence of
nitrotyrosine immunoreactivity in Lewy bodies within melanized neurons and in
amorphous deposits associated with intact and degenerating neurons. The core of
the Lewy body was frequently intensely immunolabeled, while the rim was lightly
labeled or unlabeled. This likely reflects the fact that tyrosine residues of
neurofilament proteins are primarily localized to Lewy body cores, and suggests
that nitrotyrosine is present in neurofilament protein itself. Although these
observations are as yet unable to provide a definitive link between oxidative
stress and neuronal dysfunction, they demonstrate that oxidative stress has
occurred within the vulnerable neurons of PD, leaving a permanent marker of
oxidative modification of neuronal proteins within the target cells of
neurodegeneration. In addition, these observations provide a potential link
between excitotoxicity and oxidative stress within the vulnerable neurons of PD
and represent a pathogenetic mechanism in common with the 2 other major
age-related neurodegenerative diseases, Alzheimer disease and amyotrophic lateral
sclerosis.

PMID: 9600227 [PubMed - indexed for MEDLINE]

150. Neurology. 1998 Mar;50(3 Suppl 3):S1-57.

An algorithm (decision tree) for the management of Parkinson's disease: treatment
guidelines. American Academy of Neurology.

Olanow CW, Koller WC.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.

PMID: 9524552 [PubMed - indexed for MEDLINE]

151. J Pharmacol Exp Ther. 1998 Feb;284(2):700-6.

Deprenyl and desmethylselegiline protect mesencephalic neurons from toxicity
induced by glutathione depletion.

Mytilineou C, Leonardi EK, Radcliffe P, Heinonen EH, Han SK, Werner P, Cohen G,
Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, New York
10029, USA.

Oxidative stress is thought to play an important role in the pathogenesis of
Parkinson's disease (PD). Glutathione (GSH), a major cellular antioxidant, is
decreased in the substantia nigra pars compacta of PD patients. The aim of the
present study was to investigate whether deprenyl and its desmethyl metabolite,
putative neuroprotective agents in the treatment of PD, could protect cultured
rat mesencephalic neurons from cell death caused by GSH depletion due to
treatment with L-buthionine-(S,R)-sulfoximine (BSO). BSO (10 microM) caused
extensive cell death after 48 hr, as demonstrated by disruption of cellular
integrity and release of lactate dehydrogenase into the culture medium. Both
deprenyl and desmethylselegiline, at concentrations of 5 and 50 microM,
significantly protected dopaminergic neurons from toxicity without preventing the
BSO-induced loss in GSH. Protection was not associated with monoamine oxidase
type B inhibition in that pargyline, a potent MAO inhibitor, was ineffective and
pretreatment with pargyline did not prevent the protective effects of deprenyl.
Protection was not associated with inhibition of dopamine uptake by deprenyl
because the dopamine uptake inhibitor mazindol did not diminish BSO toxicity. The
antioxidant ascorbic acid (200 microM) also protected against BSO-induced cell
death, suggesting that oxidative events were involved. This study demonstrates
that deprenyl and its desmethyl metabolite can diminish cell death associated
with GSH depletion.

PMID: 9454817 [PubMed - indexed for MEDLINE]

152. Cell Transplant. 1997 Nov-Dec;6(6):553-6.

Infectious issues in human fetal neural transplantation.

Holt DA, Nauert GM, Othberg AI, Randall TS, Willing AE, Widen RH, Hauser RA,
Sanberg PR, Olanow CW, Freeman TB.

University of South Florida, Division of Infectious Diseases, Tampa General
Hospital, FL 33606, USA.

PMID: 9440864 [PubMed - indexed for MEDLINE]

153. Biol Trace Elem Res. 1997 Sep;58(3):177-95.

Intranigral iron infusion in the rat. Acute elevations in nigral lipid
peroxidation and striatal dopaminergic markers with ensuing nigral degeneration.

Sengstock GJ, Zawia NH, Olanow CW, Dunn AJ, Arendash GW.

Department of Biology, University of South Florida Tampa 33620, USA.

Iron is known to induce lipid peroxidation and recent evidence indicates that
both iron and lipid peroxidation are elevated in the substantia nigra in
Parkinson's disease (PD). To test whether excess intranigral iron induces lipid
peroxidation, we infused an iron citrate solution (0.63 nmol in 0.25 microL) into
the rat substantia nigra and measured nigral thiobarbituric acid reactive
products at 1-h, 1-d, 1-wk, and 1-mo postinfusion. In a separate group of
iron-infused animals, histologic analysis within the substantia nigra through
1-mo postinfusion was accomplished by thionine- and iron-staining, with
concurrent assessment of striatal neurochemical markers. Concentrations of nigral
thiobarbituric acid reactive products were significantly elevated at 1 h and 1 d
in iron-infused animals compared to vehicle-infused and unoperated animals, with
a return to control values by 1 wk. Similarly, striatal dopamine turnover was
acutely elevated, suggesting damage to dopaminergic neurons, which was confirmed
histologically. Although iron-staining within the iron diffusionary area was
increased through the postinfusion month, there was an apparent progression of
the cellular character of staining from predominantly neuronal to reactive glial
and finally to oligodendroglial by 1 mo postinfusion. This progression of
cellular iron-staining may indicate a shifting of infused iron to a more bound
unreactive form, thus explaining only an acute elevation in lipid peroxidation
through 1 d following intranigral iron infusion. The data indicate that damage to
nigral neurons induced by iron infusion is transciently associated with a marker
of oxidative damage and supports the possibility that iron-induced oxidative
stress contributes to the pathogenesis of PD.

PMID: 9403131 [PubMed - indexed for MEDLINE]

154. Ann Neurol. 1997 Sep;42(3):292-9.

High-frequency unilateral thalamic stimulation in the treatment of essential and
parkinsonian tremor.

Koller W, Pahwa R, Busenbark K, Hubble J, Wilkinson S, Lang A, Tuite P, Sime E,
Lazano A, Hauser R, Malapira T, Smith D, Tarsy D, Miyawaki E, Norregaard T,
Kormos T, Olanow CW.

Department of Neurology, University of Kansas Medical Center, Kansas City
66160-7314, USA.

Pharmacologic treatment for essential tremor and the tremor of Parkinson's
disease is often inadequate. Stereotaxic surgery, such as thalamotomy, can
effectively reduce tremors. We performed a multicenter trial of unilateral
high-frequency stimulation of the ventral intermedius nucleus of the thalamus in
29 patients with essential tremor and 24 patients with Parkinson's disease, using
a blinded assessment at 3 months after surgery to compare clinical rating of
tremor with stimulation ON with stimulation OFF and baseline and a 1-year
follow-up. Six patients were not implanted because of lack of intraoperative
tremor suppression (2 patients), hemorrhage (2 patients), withdrawal of consent
(1 patient), and persistent microthalamotomy effect (1 patient). A significant
reduction in both essential and parkinsonian tremor occurred contralaterally with
stimulation. Patients reported a significant reduction in disability. Measures of
function were significantly improved in patients with essential tremor.
Complications related to surgery in implanted patients were few. Stimulation was
commonly associated with transient paresthesias. Other adverse effects were mild
and well tolerated. Efficacy was not reduced at 1 year. Chronic high-frequency
stimulation is safe and highly effective in ameliorating essential and
parkinsonian tremor.

PMID: 9307249 [PubMed - indexed for MEDLINE]

155. Neurology. 1997 Jul;49(1 Suppl 1):S26-33.

Attempts to obtain neuroprotection in Parkinson's disease.

Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.

It is suggested that oxidant stress is a contributing factor in the pathogenesis
of Parkinson's disease (PD). Oxidant stress may contribute to cell death in PD
because oxidative metabolism of dopamine has the potential to yield highly
reactive and cytotoxic free radicals. Evidence for this hypothesis includes: (1)
increased dopamine turnover with increased hydrogen peroxide formation; (2)
decreased glutathione availability; and (3) increased reactive iron in the brains
of patients with PD. Antioxidant therapies might be neuroprotective and could
slow the clinical progression of the disease whereas metabolites of levodopa
therapy may accelerate the rate of neuronal degeneration. Laboratory studies
demonstrate that both selegiline and dopamine agonists can provide
neuroprotective benefits. Selegiline-treated patients require less levodopa and
have a delay in the progression of parkinsonian signs and symptoms. Dopamine
agonists provide antiparkinson benefits and also diminish the need for levodopa.

PMID: 9222272 [PubMed - indexed for MEDLINE]

156. Transplant Proc. 1997 Jun;29(4):1925.

Toward the use of surgical placebo-controlled trials.

Freeman TB, Vawter D, Goetz CG, Leaverton PE, Hauser RA, Sanberg PR, Godbold JH,
Olanow CW.

University of South Florida, Division of Neurosurgery, Tampa 33606, USA.

PMID: 9193457 [PubMed - indexed for MEDLINE]

157. Neurology. 1997 Jun;48(6):1737-8.

Treatment with fetal allografts.

Kordower JH, Freeman TB, Bakay RA, Goetz CG, Olanow CW.

Comment on:
Neurology. 1996 May;46(5):1219-25.

PMID: 9191805 [PubMed - indexed for MEDLINE]

158. Cell Transplant. 1997 May-Jun;6(3):213-9.

Fetal grafting for Parkinson's disease: expression of immune markers in two
patients with functional fetal nigral implants.

Kordower JH, Styren S, Clarke M, DeKosky ST, Olanow CW, Freeman TB.

Research Center for Brain Repair and Department of Neurological Sciences, Rush
Presbyterian St.-Lukes Medical Center, Chicago, IL 60612, USA.

In a number of centers throughout the world, fetal nigral transplantation is
being performed for the treatment of Parkinson's disease (PD). Clinical results
have been inconsistent. One parameter that differs among transplant studies is
the degree and manner by which patients are immunosuppressed following
transplantation. Indeed, the role of the immune system following fetal grafting
in humans is not well understood. Recently, two patients from our open label
trial that received fetal nigral implants have come to autopsy. These patients
were immunosuppressed with cyclosporin for 6 mo posttransplantation and survived
for a total of 18 mo postgrafting. Robust survival of grafted dopamine-containing
cells was observed in both cases. Immunostaining for HLA-DR revealed a dense
collection of cells within grafts from both cases. HLA-DR staining was rarely
observed within the host including nongrafted regions of the striatum. A more
detailed analysis of immune markers was performed in Case 2. Numerous pan
macrophages, T-cells, and B-cells were observed within graft sites located in the
postcommissural putamen. In contrast, staining for these immune cells was not
observed within the ungrafted anterior putamen. These findings suggest that even
in healthy appearing functional nigral implants, grafts are invaded by host
immune cells that could compromise their long-term viability and function.
Alternatively, immune cells are known to secrete trophic factors, which may
ultimately favor graft survival and function. Further work is needed to
understand the role of the immune system in fetal grafting.

PMID: 9171154 [PubMed - indexed for MEDLINE]

159. Exp Neurol. 1997 Mar;144(1):41-6.

Dopaminergic transplants in patients with Parkinson's disease: neuroanatomical
correlates of clinical recovery.

Kordower JH, Goetz CG, Freeman TB, Olanow CW.

Department of Neurological Sciences, Rush Presbyterian Medical Center, Chicago,
Illinois 60612, USA.

For the past 15 years, patients with Parkinson's disease have participated in
clinical trials evaluating the efficacy of intrastriatal dopamine transplants.
Principally, two donor tissues have been employed, the chromaffin cells of the
adrenal medulla and fetal ventral mesencephalon. The clinical response following
each type of transplant has been variable. In general, the magnitude and the
duration of the clinical response is greater with fetal dopaminergic neurons than
with adrenal medullary grafts. Postmortem studies of patients receiving adrenal
medullary grafts or fetal nigral implants provide a neuroanatomical framework for
the clinical response. Adrenal grafts survive poorly following implantation into
the striatum, but they are capable of inducing sprouting of host-derived fibers
within a the caudate nucleus. In contrast, robust survival of fetal nigral
implants can be achieved within the human brain which can provide extensive
reinnervation to the parkinsonian striatum. These findings are strikingly similar
to what has been seen in rodent and nonhuman primate models of PD. This paper
describes the neuroanatomical correlates of dopamine brain grafting in humans and
elucidates the pattern of changes seen in dopaminergic systems which are
associated with clinical benefit.

PMID: 9126150 [PubMed - indexed for MEDLINE]

160. Adv Neurol. 1997;74:249-69.

Neural transplantation as a therapy for Parkinson's disease.

Olanow CW, Freeman TB, Kordower JH.

Department of Neurology, Mount Sinai Hospital, New York, New York 10029, USA.

PMID: 9348419 [PubMed - indexed for MEDLINE]

161. J Neurochem. 1997 Jan;68(1):434-6.

L-(-)-desmethylselegiline, a metabolite of selegiline [L-(-)-deprenyl], protects
mesencephalic dopamine neurons from excitotoxicity in vitro.

Mytilineou C, Radcliffe PM, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, New York
10029, USA.

Selegiline [L-(-)-deprenyl], a monoamine oxidase B inhibitor, has been used in
the treatment of Parkinson's disease as a putative neuroprotective agent.
Selegiline is metabolized rapidly in the gastrointestinal tract and liver to
desmethylselegiline (DMS) and methamphetamine. We have previously shown that
selegiline protects dopamine neurons in mesencephalic cultures from toxicity
resulting from activation of glutamate receptors. In the present study we
examined whether DMS has similar neuroprotective effects. Our data show that DMS
protects dopamine neurons from N-methyl-D-aspartate receptor-mediated excitotoxic
damage. The efficacy of DMS is greater than that of selegiline, as it can cause
protection at lower concentrations and provide significantly greater levels of
protection at the same concentrations. Our results suggest that DMS might be the
active compound responsible for the neuroprotective properties of selegiline.

PMID: 8978757 [PubMed - indexed for MEDLINE]

162. J Neurochem. 1997 Jan;68(1):33-9.

L-deprenyl protects mesencephalic dopamine neurons from glutamate
receptor-mediated toxicity in vitro.

Mytilineou C, Radcliffe P, Leonardi EK, Werner P, Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, New York
10029, USA.

L-Deprenyl is a relatively selective inhibitor of monoamine oxidase (MAO)-B that
delays the emergence of disability and the progression of signs and symptoms of
Parkinson's disease. Experimentally, deprenyl has also been shown to prevent
neuronal cell death in various models through a mechanism that is independent of
MAO-B inhibition. We examined the effect of deprenyl on cultured mesencephalic
dopamine neurons subjected to daily changes of feeding medium, an experimental
paradigm that causes neuronal death associated with activation of the NMDA
subtype of glutamate receptors. Both deprenyl (0.5-50 microM) and the NMDA
receptor blocker MK-801 (10 microM) protected dopamine neurons from damage caused
by medium changes. The nonselective MAO inhibitor pargyline (0.5-50 microM) was
not protective, indicating that protection by deprenyl was not due to MAO
inhibition. Deprenyl (50 microM) also protected dopamine neurons from delayed
neurotoxicity caused by exposure to NMDA. Because deprenyl had no inhibitory
effect on NMDA receptor binding, it is likely that deprenyl protects from events
occurring downstream from activation of glutamate receptors. As excitotoxic
injury has been implicated in neurodegeneration, it is possible that deprenyl
exerts its beneficial effects in Parkinson's disease by suppressing excitotoxic
damage.

PMID: 8978707 [PubMed - indexed for MEDLINE]

163. Ann Neurol. 1996 Dec;40(6):841-5.

Selegiline and mortality in Parkinson's disease.

Olanow CW, Fahn S, Langston JW, Godbold J.

Department of Neurology, Mount Sinai Medical Center, New York, NY 10029, USA.

Comment in:
Ann Neurol. 1997 Feb;41(2):282-3.

PMID: 9007088 [PubMed - indexed for MEDLINE]

164. Neurology. 1996 Dec;47(6 Suppl 3):S210-6.

Selegiline: current perspectives on issues related to neuroprotection and
mortality.

Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.

PMID: 8959990 [PubMed - indexed for MEDLINE]

165. Neurology. 1996 Dec;47(6 Suppl 3):S161-70.

Oxidative stress and the pathogenesis of Parkinson's disease.

Jenner P, Olanow CW.

Neurodegenerative Diseases Research Centre, King's College London, UK.

Current concepts of the pathogenesis of Parkinson's disease (PD) center on the
formation of reactive oxygen species and the onset of oxidative stress leading to
oxidative damage to substantia nigra pars compacta. Extensive postmortem studies
have provided evidence to support the involvement of oxidative stress in the
pathogenesis of PD; in particular, these include alterations in brain iron
content, impaired mitochondrial function, alterations in the antioxidant
protective systems (most notably superoxide dismutase [SOD] and reduced
glutathione [GSH]), and evidence of oxidative damage to lipids, proteins, and
DNA. Iron can induce oxidative stress, and intranigral injections have been shown
to induce a model of progressive parkinsonism. A loss of GSH is associated with
incidental Lewy body disease and may represent the earliest biochemical marker of
nigral cell loss. GSH depletion alone may not result in damage to nigral neurons
but may increase susceptibility to subsequent toxic or free radical exposure. The
nature of the free radical species responsible for cell death in PD remains
unknown, but there is evidence of involvement of hydroxyl radical (OH.),
peroxynitrite, and nitric oxide. Indeed, OH. and peroxynitrite formation may be
critically dependent on nitric oxide formation. Central to many of the processes
involved in oxidative stress and oxidative damage in PD are the actions of
monoamine oxidase-B (MAO-B). MAO-B is essential for the activation of
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to 1-methyl-4-phenylpyridinium ion,
for a component of the enzymatic conversion of dopamine to hydrogen peroxide
(H2O2), and for the activation of other potential toxins such as isoquinolines
and beta-carbolines. Thus, the inhibition of MAO-B by drugs such as selegiline
may protect against activation of some toxins and free radicals formed from the
MAO-B oxidation of dopamine. In addition, selegiline may act through a mechanism
unrelated to MAO-B to increase neurotrophic factor activity and upregulate
molecules such as glutathione, SOD, catalase, and BCL-2 protein, which protect
against oxidant stress and apoptosis. Consequently, selegiline may be
advantageous in the long-term treatment of PD.

PMID: 8959985 [PubMed - indexed for MEDLINE]

166. J Neuroimaging. 1996 Oct;6(4):222-6.

Magnetic resonance imaging of corticobasal degeneration.

Hauser RA, Murtaugh FR, Akhter K, Gold M, Olanow CW.

Department of Neurology University of South Florida, Tampa, USA.

Corticobasal degeneration (CBD) is an adult-onset, progressive parkinsonian
syndrome with strikingly asymmetrical features, and signs and symptoms referable
to both cerebral cortex and basal ganglia. Although once considered rare, it is
now recognized with increasing frequency during life. Eight patients with
clinically diagnosed CBD and 8 age- and sex-matched patients with Parkinson's
disease underwent high-field-strength magnetic resonance imaging (MRI) of the
brain. MRIs were graded by a blinded neuroradiologist using a semiquantitative
(0-3) scale. MRI of patients with CBD revealed significantly greater T2-weighted
signal hypointensity in the putamena and globi pallidi, and ventricular
enlargement. When specifically sought, asymmetrical cortical atrophy was
identified in 5 of 8 CBD patients. Increased T2-weighted lenticular signal
hypointensity, ventricular enlargement, and asymmetrical cortical atrophy are
supportive MRI findings of CBD.

PMID: 8903073 [PubMed - indexed for MEDLINE]

167. Ann Neurol. 1996 Sep;40(3):341-3.

GPi pallidotomy--have we made a dent in Parkinson's disease?

Olanow CW.

Comment on:
Ann Neurol. 1996 Sep;40(3):355-66.

PMID: 8797522 [PubMed - indexed for MEDLINE]

168. Am J Pathol. 1996 Jul;149(1):21-8.

Evidence of neuronal oxidative damage in Alzheimer's disease.

Good PF, Werner P, Hsu A, Olanow CW, Perl DP.

Department of Pathology, Mount Sinai School of Medicine, New York, New York, USA.

Oxidative stress has been proposed as a pathogenetic mechanism in Alzheimer's
disease. One mechanism of oxidative damage is the nitration of tyrosine residues
in proteins, mediated by peroxynitrite breakdown. Peroxynitrite, a reaction
product of nitric oxide and superoxide radicals, has been implicated in
N-methyl-D-aspartate receptor-mediated excitotoxic damage. Reported evidence of
oxidative stress in Alzheimer's disease includes increased iron, alterations in
protective enzymes, and markers of oxidative damage to proteins and lipids. In
this report, we demonstrate the presence of nitrotyrosine in neurofibrillary
tangles of Alzheimer's disease. Nitrotyrosine was not detected in controls
lacking neurofibrillary tangles. Immunolabeling was demonstrated to be specific
nitrotyrosine in a series of control experiments. These observations link
oxidative stress with a key pathological lesion of Alzheimer's disease, the
neurofibrillary tangle, and demonstrate a pathogenetic mechanism in common with
the other major neurodegenerative diseases of aging, Parkinson's disease and
amyotrophic lateral sclerosis. These findings further implicate nitric oxide
expression and excitotoxicity in the pathogenesis of cell death in Alzheimer's
disease.

PMCID: 1865248
PMID: 8686745 [PubMed - indexed for MEDLINE]

169. J Comp Neurol. 1996 Jun 24;370(2):203-30.

Functional fetal nigral grafts in a patient with Parkinson's disease:
chemoanatomic, ultrastructural, and metabolic studies.

Kordower JH, Rosenstein JM, Collier TJ, Burke MA, Chen EY, Li JM, Martel L, Levey
AE, Mufson EJ, Freeman TB, Olanow CW.

Research Center for Brain Repair, Rush Presbyterian Medical Center, Chicago,
Illinois 60612, USA.

A patient with Parkinson's disease received bilateral fetal human nigral implants
from six donors aged 6.5 to 9 weeks post-conception. Eighteen months following a
post-operative clinical course characterized by marked improvement in clinical
function, this patient died from events unrelated to the grafting procedure.
Post-mortem histological analyses revealed the presence of viable grafts in all
12 implant sites, each containing a heterogeneous population of neurons and glia.
Approximately 210,146 implanted tyrosine hydroxylase-immunoreactive (TH-ir)
neurons were found. A greater number of TH-ir grafted neurons were observed in
the right (128,162) than the left (81,905) putamen. Grafted TH-ir neurons were
organized in an organotypic fashion. These cells provided extensive TH-ir and
dopamine transporter-ir innervation to the host striatum which occurred in a
patch-matrix fashion. Quantitative evaluations revealed that fetal nigral grafts
reinnervated 53% and 28% of the post-commissural putamen on the right and left
side, respectively. Grafts on the left side innervated a lesser area of the
striatum, but optical density measurements were similar on both sides. There was
no evidence that the implants induced sprouting of host TH-ir systems. Electron
microscopic analyses revealed axo-dendritic and occasional axo-axonic synapses
between graft and host. In contrast, axo-somatic synapses were not observed. In
situ hybridization for TH mRNA revealed intensely hybridized grafted neurons
which far exceeded TH mRNA expression within residual host nigral cells. In
addition, gamma-amino butyric acid (GABA)-ergic neurons were observed within the
graft that formed a dense local neuropil which was confined to the implant site.
Serotonergic neurons were not observed within the graft. Cytochrome oxidase
activity was increased bilaterally within the grafted post-commissural putamen,
suggesting increased metabolic activity. In this regard, a doubling of cytochrome
oxidase activity was observed within the grafted post-commissural putamen
bilaterally relative to the non-grafted anterior putamen. The grafts were
hypovascular relative to the surrounding striatum and host substantia nigra.
Blood vessels within the graft stained intensely for GLUT-1, suggesting that this
marker of blood--brain barrier function is present within human nigral
allografts. Taken together, these data indicate that fetal nigral neurons can
survive transplantation, functionally reinnervate the host putamen, establish
synaptic contacts with host neurons, and sustain many of the morphological and
functional characteristics of normal nigral neurons following grafting into a
patient with PD.

PMID: 8808731 [PubMed - indexed for MEDLINE]

170. Can J Neurol Sci. 1996 May;23(2):95-8.

Blood manganese correlates with brain magnetic resonance imaging changes in
patients with liver disease.

Hauser RA, Zesiewicz TA, Martinez C, Rosemurgy AS, Olanow CW.

Department of Neurology, University of South Florida, Tampa, USA.

BACKGROUND: Chronic liver failure is associated with high signal abnormalities in
the basal ganglia on T1-weighted magnetic resonance imaging of the brain. These
abnormalities are strikingly similar to those seen following manganese
intoxication. As dietary manganese is normally cleared by the liver, we
hypothesize that hepatic dysfunction could lead to manganese overload and account
for the MRI abnormalities seen in patients with chronic liver disease. METHODS:
We measured blood manganese concentrations in eleven patients with biopsy-proven
hepatic cirrhosis and eleven healthy age and sex-matched controls. We also
performed semi-quantitative measures of T1 signal abnormalities on MRI in the
patients with chronic liver disease. RESULTS: Patients with cirrhosis had
significantly higher blood manganese concentrations (20.6 +/- 10.2 mcg/L) than
controls (7.2 +/- 2.7, p = .0013). In addition, semi-quantitative scores of
T1-weighted signal hyperintensity on MRI correlated with blood manganese
concentration in patients with cirrhosis (r = .65, p = .029). CONCLUSIONS: These
findings demonstrate that chronic liver disease is associated with manganese
overload and suggest that manganese is responsible for the T1-weighted signal
hyperintensity seen on MRI of patients with liver disease. As manganese
intoxication is known to cause parkinsonism and an encephalopathy similar to
those which occur with chronic liver disease, it is possible that manganese
toxicity contributes to the development of these symptoms in liver damaged
patients and that therapies which prevent or reduce manganese overload may have
clinical benefit.

PMID: 8738919 [PubMed - indexed for MEDLINE]

171. BMJ. 1996 Mar 16;312(7032):702-3; author reply 704-5.

Effect of adding selegeline to levodopa in early, mild Parkinson's disease.
Patients taking selegeline may have received more levodopa than necessary.

Olanow CW, Godbold JH, Koller W.

Comment on:
BMJ. 1995 Dec 16;311(7020):1602-7.

PMCID: 2350527
PMID: 8597746 [PubMed - indexed for MEDLINE]

172. JAMA. 1996 Mar 6;275(9):716-22.

A 61-year-old man with Parkinson's disease.

Olanow CW.

Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.

Comment in:
JAMA. 1996 Jul 10;276(2):103-4; author reply 104. JAMA. 1996 Jul 10;276(2):104. JAMA. 1996 Oct 9;276(14):1171.

PMID: 8594271 [PubMed - indexed for MEDLINE]

173. Trends Neurosci. 1996 Mar;19(3):102-9.

Fetal nigral transplantation as a therapy for Parkinson's disease.

Olanow CW, Kordower JH, Freeman TB.

Dept. of Neurology, Mount Sinai School of Medicine, New York, USA.

Fetal nigral grafts have been demonstrated to survive, secrete dopamine, form
synaptic connections with host neurons, and reverse behavioral disturbances in
experimental models of parkinsonism. These findings suggest that fetal nigral
grafting may be a useful therapy for patients with Parkinson's disease (PD).
Recent preliminary clinical trials of transplantation in PD have shown increased
striatal fluorodopa uptake (measured using positron emission tomography) and
clinical benefit in some patients. An autopsy study of one patient who had
received fetal nigral transplants demonstrated robust graft survival and striatal
reinnervation, with no evidence of host-derived sprouting or immune rejection.
The development of a successful clinical transplantation program depends on a
careful consideration of the transplantation variables and the related long-term
risks and benefits to the patients.

PMID: 9054056 [PubMed - indexed for MEDLINE]

174. Neurology. 1996 Feb;46(2):492-8.

Manganese intoxication in the rhesus monkey: a clinical, imaging, pathologic, and
biochemical study.

Olanow CW, Good PF, Shinotoh H, Hewitt KA, Vingerhoets F, Snow BJ, Beal MF, Calne
DB, Perl DP.

Department of Neurology, Mount Sinai Medical Center, New York, NY 10029, USA.

We gave three adult rhesus monkeys seven IV injections of manganese chloride at
approximately 1-week intervals. We evaluated neurologic status by serial clinical
examinations and performed a levodopa test if the animal developed features of
basal ganglia dysfunction. After the animals were killed, we performed
neuropathologic, neurochemical, and laser microprobe mass analysis (LAMMA)
studies. Two of three animals developed a parkinsonian syndrome characterized by
bradykinesia, rigidity, and facial grimacing suggestive of dystonia but not
tremor. Neither animal responded to levodopa. Autopsy demonstrated gliosis
primarily confined to the globus pallidus (GP) and the substantia nigra pars
reticularis (SNr). We detected focal mineral deposits throughout the GP and SNr,
particularly in a perivascular distribution. LAMMA studies noted that mineral
deposits were primarily comprised of iron and aluminum. The severity of
pathologic change correlated with the degree of clinical dysfunction. These
studies demonstrate that, in contrast to Parkinson's disease (PD) and
MPTP-induced parkinsonism, manganese primarily damages the GP and SNr and
relatively spares the nigrostriatal dopaminergic system. Further, the results
suggest that Mn-induced parkinsonism can be differentiated from PD and
MPTP-induced parkinsonism by the clinical syndrome and response to levodopa. The
accumulation of iron and aluminum suggests that iron/aluminum-induced oxidant
stress may contribute to the damage associated with Mn toxicity.

PMID: 8614520 [PubMed - indexed for MEDLINE]

175. J Neural Transm Suppl. 1996;48:75-84.

Deprenyl in the treatment of Parkinson's disease: clinical effects and
speculations on mechanism of action.

Olanow CW.

Mount Sinai School of Medicine, New York, NY, USA.

Selegiline is a relatively selective inhibitor of monoamine oxidase type B that
has been used in Parkinson's disease as an adjunct to levodopa and as putative
neuroprotective therapy. Clinical trials demonstrate that selegiline slows the
rate of disease progression and delays the appearance of disability necessitating
levodopa. However, confounding symptomatic effects have made it difficult to
ascertain the presence of any direct neuroprotective effect. Laboratory studies
demonstrate that selegiline protects dopaminergic neurons through a mechanism
that does not involve MAO-B inhibition. Recent studies suggest that
neuroprotection in laboratory models may be related to the capacity of selegiline
to up-regulate a series of anti-oxidant and anti-apoptotic molecules which
promote cell survival. Further delineation of the precise mechanism whereby
selegiline induces this effect may permit for the development of enhanced
neuroprotective benefits in PD patients.

PMID: 8988463 [PubMed - indexed for MEDLINE]

176. Acta Neuropathol. 1996;91(4):351-9.

Hyperphosphorylated tau proteins differentiate corticobasal degeneration and
Pick's disease.

Buée Scherrer V, Hof PR, Buée L, Leveugle B, Vermersch P, Perl DP, Olanow CW,
Delacourte A.

INSERM U422, Lille, France.

In neurodegenerative disorders, hyperphosphorylated tau proteins aggregate into
abnormal filaments. In the present study, tau protein alterations were studied in
one corticobasal degeneration and seven Pick's disease cases using specific
immunological probes. The typical lesions of corticobasal degeneration and Pick's
disease were revealed by immunohistochemistry, including the presence of Pick
bodies and achromatic swollen neurons, neuritic alterations, and neurofibrillary
tangles. Tau-immunoreactive glial tangles were also observed. By immunoblotting,
the case of corticobasal degeneration was characterized by the tau profile
previously reported to occur in progressive supranuclear palsy with an intense
labeling of the two tau 64 and 69 bands, while tau 55 was not visualized. In
Pick's disease cases with Pick bodies and neurofibrillary tangles, a tau triplet
similar to that encountered in Alzheimer's disease (tau 55, 64 and 69) was
detected. Furthermore, a particular tau profile was found in four Pick's disease
cases showing only Pick bodies and no neurofibrillary tangles. In these cases,
tau 55 and 64 were strongly immunoreactive, whereas tau 69 was almost unlabeled.
These differences are likely to be related to particular pools of tau isoforms
present within the degenerating neurons. Since there is a great diversity of
neurodegenerative disorders with substantial clinical and neuropathological
overlap, the electrophoretic profile of tau proteins could represent a useful
marker for the type of neurodegeneration.

PMID: 8928611 [PubMed - indexed for MEDLINE]

177. Ann Neurol. 1995 Nov;38(5):771-7.

The effect of deprenyl and levodopa on the progression of Parkinson's disease.

Olanow CW, Hauser RA, Gauger L, Malapira T, Koller W, Hubble J, Bushenbark K,
Lilienfeld D, Esterlitz J.

Department of Neurology, Mount Sinai Medical Center, New York, NY 10029, USA.

Comment in:
Ann Neurol. 1997 Jun;41(6):833-4.

We have performed a 14-month, prospective, randomized, double-blind,
placebo-controlled study to evaluate the effect of deprenyl and
levodopa/carbidopa (Sinemet) on the progression of signs and symptoms in patients
with mild Parkinson's disease (PD). One hundred one untreated PD patients were
randomly assigned to one of the following four treatment groups: Group I,
deprenyl + Sinemet; Group II, placebo-deprenyl + Sinemet; Group III, deprenyl +
bromocriptine; and Group IV, placebo-deprenyl + bromocriptine. The final visit
was performed at 14 months, i.e., 2 months after withdrawal of deprenyl or its
placebo and 7 days after withdrawal of Sinemet or bromocriptine. Deterioration in
Unified Parkinson's Disease Rating Score (UPDRS) between untreated baseline and
final visits was used as an index of disease progression. Placebo-treated
patients deteriorated by 5.8 +/- 1.4 points, while deprenyl-treated patients
deteriorated by 0.4 +/- 1.3 points (p < 0.001). This effect was sufficiently
powerful that a significant deprenyl effect could be detected in the subgroup of
41 patients randomized to Sinemet (p < 0.01) as well as in the 23 patients who
completed a 14-day washout of Sinemet or bromocriptine (p < 0.05). No difference
in the extent of deterioration was detected in patients randomized to Sinemet
versus bromocriptine. This study demonstrates that deprenyl attenuates
deterioration in UPDRS score in patients with early PD. These findings are not
readily explained by the drug's symptomatic effects and are consistent with the
hypothesis that deprenyl has a neuroprotective effect.

PMID: 7486869 [PubMed - indexed for MEDLINE]

178. Ann Neurol. 1995 Sep;38(3):379-88.

Bilateral fetal nigral transplantation into the postcommissural putamen in
Parkinson's disease.

Freeman TB, Olanow CW, Hauser RA, Nauert GM, Smith DA, Borlongan CV, Sanberg PR,
Holt DA, Kordower JH, Vingerhoets FJ, et al.

Department of Surgery, University of South Florida, Tampa, USA.

We performed fetal nigral transplantations in 4 Parkinson's disease (PD)
patients. Solid grafts were bilaterally implanted into the postcommissural
putamen using 3 to 4 donors per side aged 6 1/2 to 9 weeks postconception.
Transplant deposits were separated by no more than 5 mm in three dimensions.
Cyclosporine was employed for a total of 6 months. Patients were evaluated at
baseline and at 1, 3, and 6 months postoperatively. Striatal 18-fluorodopa uptake
was assessed by positron emission tomography at baseline and at 6 months
postoperatively. The procedure was well tolerated in all patients. One patient
had a clinically asymptomatic superficial cortical hemorrhage along the needle
tract and a second had transient postoperative confusion and hallucinations. All
patients experienced clinically meaningful benefit. Significant improvement (p <
0.05) was detected in total UPDRS score during the "off" state, Schwab-England
disability score during the "off" state, percent "off" time, and percent "on"
time with dyskinesia. Increased striatal fluorodopa uptake was observed
bilaterally in each patient, with mean increases of 53% on the right (p = 0.01)
and 33% on the left (p = 0.08). Our study demonstrated clear and consistent
improvement in clinical features and striatal fluorodopa uptake following fetal
tissue transplantation in patients with advanced PD whose condition was not
improved preoperatively by drug manipulation. These preliminary results are
encouraging and support further studies to evaluate grafting strategies as a
therapy for PD.

PMID: 7668823 [PubMed - indexed for MEDLINE]

179. Mov Disord. 1995 Jul;10(4):527-8.

The core assessment program for intracerebral transplantation.

Lang AE, Benabid AL, Koller WC, Lozano AM, Obeso JA, Olanow CW, Pollak P.

Comment in:
Mov Disord. 1997 Jan;12(1):127-8.

Comment on:
Mov Disord. 1994 Jul;9(4):390-4.

PMID: 7565843 [PubMed - indexed for MEDLINE]

180. Arch Neurol. 1995 Jun;52(6):565-70.

Factors predictive of the need for levodopa therapy in early, untreated
Parkinson's disease. The Parkinson Study Group.

McDermott MP, Jankovic J, Carter J, Fahn S, Gauthier S, Goetz CG, Golbe LI,
Koller W, Lang AE, Olanow CW, et al.

Department of Biostatistics, University of Rochester Medical Center, NY 14642,
USA.

OBJECTIVE: To identify characteristics of patients with early, untreated
Parkinson's disease that are the most important predictors of rapid functional
decline. DESIGN: Prospective observational study of a cohort of 800 patients with
early, untreated Parkinson's disease who were involved in a multicenter,
randomized, double-blind, controlled clinical trial of selegiline hydrochloride
(L-deprenyl) and vitamin E (alpha-tocopherol). PRIMARY OUTCOME VARIABLE: Time
from randomization to the onset of disability that necessitated levodopa therapy
(end point), as judged by the enrolling investigator. METHODS: Stepwise Cox
regression was used in combination with clinical judgment to identify the most
important independent baseline predictors of the primary end point among a host
of variables, including treatment with selegiline and vitamin E, global and
specific clinical measures of disease severity, demographic variables, and
neuropsychological test results. RESULTS: In addition to selegiline treatment and
global disease severity measures, such as the stage according to the criteria of
Hoehn and Yahr, impaired domestic capacity, and the activities of daily living
score, the complex of postural instability/gait difficulty and bradykinesia were
found to be the factors that were most highly associated with the risk of
reaching the end point. CONCLUSIONS: The findings suggest that patients with
Parkinson's disease whose early clinical presentation includes either postural
instability/gait difficulty or bradykinesia are at high risk for rapid functional
decline.

PMID: 7763203 [PubMed - indexed for MEDLINE]

181. Cell Transplant. 1995 Jan-Feb;4(1):141-54.

The influence of donor age on the survival of solid and suspension
intraparenchymal human embryonic nigral grafts.

Freeman TB, Sanberg PR, Nauert GM, Boss BD, Spector D, Olanow CW, Kordower JH.

Division of Neurosurgery, University of South Florida, Tampa 33606, USA.

In many species, graft survival and graft-derived behavioral recovery are
affected by the embryonic donor age. We compared the ability of solid and
suspension grafts of human embryonic mesencephalic dopaminergic (DA) neurons at
different embryonic stages to survive intraparenchymal transplantation into
6-OHDA lesioned immunosuppressed rats. Suspension grafts survived best when donor
age was between postconception (PC) days 34 and 56. Transplants displayed
numerous healthy tyrosine hydroxylase immunoreactive (TH-IR) neurons which sent
extensive neuritic processes into the host striatum. Suspension grafts survived
poorly when donor age was greater than 65 days. Solid implants displayed
comparable viability of TH-IR neurons when donor age was between 44 and 65 days.
No solid grafts contained TH-IR cells when donor tissue was older than 72 days.
The suspension and solid methods of transplantation resulted in comparable
survival of robust grafts, but solid grafts resulted in more intergraft
variability than suspension grafts, particularly among the more marginal
implants. Our results demonstrate that the upper limit for survival of human
embryonic DA suspension grafts correlates well with the period of development of
the human nigrostriatal pathway. The "window" for donor age of solid human
embryonic DA grafts appears to be extended by about 9 days in comparison to
suspension grafts. These data suggest that the upper age limit for grafting human
mesencephalic DA neurons should be PC day 56 for suspension grafts, and PC day 65
for solid implants. Older donors are likely to produce grafts with fewer
surviving DA neurons.

PMID: 7728329 [PubMed - indexed for MEDLINE]

182. Ann Neurol. 1994 Dec;36(6):871-5.

Manganese intoxication and chronic liver failure.

Hauser RA, Zesiewicz TA, Rosemurgy AS, Martinez C, Olanow CW.

Department of Neurology, University of South Florida, Tampa.

Manganese intoxication and chronic liver failure are associated with strikingly
similar clinical, imaging, and pathological abnormalities. As manganese is
primarily cleared by the liver, inadequate elimination of manganese absorbed from
the normal diet may lead to manganese overload in patients with liver disease. We
report a significant elevation of blood manganese concentration in 3 patients
with biopsy-proved hepatic cirrhosis who exhibited neurological dysfunction and
characteristic abnormal signal hyperintensity in the globi pallidi and substantia
nigra on T1-weighted magnetic resonance imaging. We speculate that manganese
accumulation in the brain accounts for the magnetic resonance imaging
abnormalities and contributes to neurological dysfunction in patients with liver
disease.

PMID: 7998773 [PubMed - indexed for MEDLINE]

183. Curr Opin Neurol. 1994 Dec;7(6):548-58.

Metals and free radicals in neurodegeneration.

Olanow CW, Arendash GW.

Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029.

Substantial evidence has accumulated implicating metals and free radicals in the
pathogenesis of the major neurodegenerative disorders (Parkinson's disease,
Alzheimer's disease, and amyotrophic lateral sclerosis). Metal-induced oxidant
stress can damage critical biological molecules and initiate a cascade of events
including mitochondrial dysfunction, excitotoxicity, and a rise in cytosolic free
calcium, leading to cell death. In Parkinson's disease and Alzheimer's disease
there is evidence of oxidative stress in affected brain regions, as indicated by
increased metal accumulation (which promotes free radical formation), decreased
antioxidant levels (which protect against free radical formation), and oxidative
damage. Recently, studies of the familial form of amyotrophic lateral sclerosis
have detected mutations in the gene that encodes superoxide dismutase, which is
one of the body's primary oxidant defense mechanisms. Mice that are transfected
with the human mutant superoxide dismutase gene develop an amyotrophic lateral
sclerosis syndrome. These studies demonstrate that oxidant stress can initiate
the development of a chronic progressive neurodegenerative disorder.

PMID: 7866588 [PubMed - indexed for MEDLINE]

184. Exp Neurol. 1994 Nov;130(1):82-94.

Progressive changes in striatal dopaminergic markers, nigral volume, and
rotational behavior following iron infusion into the rat substantia nigra.

Sengstock GJ, Olanow CW, Dunn AJ, Barone S Jr, Arendash GW.

Department of Biology, University of South Florida, Tampa 33620.

Excess iron (Fe) within the substantia nigra zona compacta (SNc) has been
implicated in the pathogenesis of Parkinson's disease (PD). We recently reported
that intranigral Fe infusion into the rat substantia nigra (SN) induces
dose-dependent SN neurodegeneration and associated reductions in striatal
dopaminergic (DA) markers. The objective of the present study was to determine
whether infused Fe is capable of inducing persistent/progressive
neurodegenerative changes relevant to PD. Following unilateral infusions of
vehicle, 1.25 or 2.10 nmol Fe into the rat SN, SNc neuronal loss, SN volume,
striatal neurochemical markers, and apomorphine-induced rotational behavior were
assessed at 2, 4, and 6 months. Semiquantitative analysis of thionine-stained SNc
neurons demonstrated an initial modest neuronal loss which remained stable
through 6 months postinfusion. Fe-induced SN atrophy was dose-dependent and
progressive through 6 months. Striatal DA and homovanillic acid levels were
progressively decreased at least through 4 months following 1.25 nmol Fe
infusion; both doses of Fe induced significant reductions of both DA markers at 4
months with no recovery evident through 6 months. Apomorphine-induced rotational
behavior progressively increased for both Fe infusion groups through the 6 months
of testing. These data indicate that a single exposure of the SN to a modest
amount of Fe can induce persistent/progressive changes occurring through a number
of months postinfusion and further establishes intranigral Fe infusion as an
animal model for PD.

PMID: 7529713 [PubMed - indexed for MEDLINE]

185. Brain Res. 1994 Oct 10;660(1):8-18.

Degeneration of nigrostriatal dopaminergic neurons increases iron within the
substantia nigra: a histochemical and neurochemical study.

Oestreicher E, Sengstock GJ, Riederer P, Olanow CW, Dunn AJ, Arendash GW.

Department of Psychiatry, University of Wurzburg, Germany.

Parkinson's-diseased (PD) brains have increased levels of iron in the zona
compacta of the substantia nigra (SNc). To determine whether these elevated
nigral iron levels may be caused secondarily by degeneration of nigrostriatal
dopaminergic (NS-DA) neurons, the NS-DA pathway was unilaterally lesioned in rats
through 6-hydroxydopamine (6-OHDA) infusion and nigral iron levels evaluated
three weeks later. A significant increase was observed in both iron concentration
(+35%) and iron content (+33) within the substantia nigra (SN) ipsilateral to
comprehensive 6-OHDA lesions. Moreover, ferric iron staining was dramatically
increased within the SNc following 6-OHDA lesions, primarily due to the
appearance of iron-positive SNc neurons and infiltrating reactive glial cells.
Iron staining in the SN zona reticularis was modestly increased after 6-OHDA
lesions, but staining in the neostriatum and globus pallidus was unaffected.
These results indicate that loss of NS-DA neurons is associated with increased
iron levels in the SN. This suggests that increased nigral iron levels in PD may
be secondary to some neurodegenerative process. Nonetheless, even a secondary
increase in nigral iron levels may be of pathogenic importance in PD because of
iron's ability to catalyze neurotoxic free radical formation and perpetuate
neurodegeneration.

PMID: 7828004 [PubMed - indexed for MEDLINE]

186. J Neuroimaging. 1994 Jul;4(3):146-58.

Magnetic resonance imaging of neurodegenerative diseases.

Hauser RA, Olanow CW.

Department of Neurology, University of South Florida, Tampa.

Magnetic resonance imaging (MRI) has become an important diagnostic tool in the
evaluation of neurodegenerative diseases. Although MRI currently does not yield
sufficient predictive power to provide a diagnosis in most individual cases,
important features have been identified in population studies that help support
or exclude a clinical diagnosis under consideration. In parkinsonian patients,
putamenal signal hypointensity is commonly observed in patients with atypical
parkinsonism. In demented patients, hippocampal atrophy and prolonged T2
relaxation may help identify individuals with Alzheimer's disease. Caudate and
putamenal atrophy are seen in Huntington's disease and may serve as markers of
disease progression.

PMID: 8061383 [PubMed - indexed for MEDLINE]

187. Neurology. 1994 Mar;44(3 Suppl 1):S17-20.

The role of surgery in Parkinson's disease management.

Olanow CW, Marsden CD, Lang AE, Goetz CG.

PMID: 8121577 [PubMed - indexed for MEDLINE]

188. Mov Disord. 1994 Jan;9(1):40-7.

A multicenter double-blind placebo-controlled trial of pergolide as an adjunct to
Sinemet in Parkinson's disease.

Olanow CW, Fahn S, Muenter M, Klawans H, Hurtig H, Stern M, Shoulson I, Kurlan R,
Grimes JD, Jankovic J, et al.

Department of Neurology and Pharmacology, University of South Florida, Tampa.

Three hundred and seventy-six subjects with advanced Parkinson's disease
participated in a prospective, double-blind placebo-controlled study of the
dopamine agonist pergolide mesylate as an adjunct to Sinemet. At 6 months,
patients randomized to pergolide had a statistically significant improvement in
total Parkinson's score, scores of activities of daily living, motor function,
number of "off" hours, Hoehn and Yahr stage, and numerous parameters of
parkinsonian function including bradykinesia, rigidity, gait, and dexterity. This
benefit was obtained with the addition of a mean dose of 2.94 mg of pergolide,
which permitted a 24.7% reduction in dose of levodopa. Adverse reactions were,
for the most part, mild, reversible, and not of major clinical significance. No
significant cardiac or electrocardiographic abnormalities were detected. This
study demonstrates that pergolide mesylate, as an adjunct to levodopa, is an
effective antiparkinsonian agent that provides clinical improvement while
permitting a reduction in levodopa dose.

PMID: 8139604 [PubMed - indexed for MEDLINE]

189. Trends Neurosci. 1993 Nov;16(11):439-44.

A radical hypothesis for neurodegeneration.

Olanow CW.

Dept of Neurology, University of South Florida, Tampa 33606.

Comment in:
Trends Neurosci. 1994 May;17(5):192-4.

Point mutations in the cytosolic Cu/Zn superoxide dismutase (SOD-1) gene have
been detected in association with familial amyotrophic lateral sclerosis (FALS).
SOD clears superoxide radical and is one of the body's principal defense
mechanisms against oxygen toxicity. The finding of SOD variants in FALS is
consistent with the hypothesis that free radicals contribute to the pathogenesis
of FALS, and possibly to the pathogenesis of other neurodegenerative disorders
such as Parkinson's disease, in which there is substantial evidence of oxidant
stress. The implication of free radicals in the pathogenesis of neurodegenerative
disorders raises the possibility that antioxidants might provide neuroprotective
therapy.

PMID: 7507613 [PubMed - indexed for MEDLINE]

190. Mov Disord. 1993 Oct;8(4):512-4.

Orobuccal dyskinesia associated with trihexyphenidyl therapy in a patient with
Parkinson's disease.

Hauser RA, Olanow CW.

Department of Neurology, University of South Florida, Tampa.

Comment in:
Mov Disord. 1994 Nov;9(6):689.

Dyskinesia is a common adverse effect complicating chronic dopaminergic therapy
for Parkinson's disease. Movements are frequently choreic in nature and have been
ascribed to overstimulation of "supersensitive" striatal postsynaptic dopamine
receptors. Anticholinergic medications, despite some clinical efficacy in
Parkinson's disease, have rarely been reported to cause dyskinesia. We report a
patient with Parkinson's disease who developed orobuccal dyskinesia while being
treated with trihexyphenidyl (Artane). Dyskinesia was observed following the
introduction of trihexyphenidyl, resolved with its discontinuation, and
reappeared with its reinstitution. Carbidopa-levodopa (Sinemet) alone did not
cause dyskinesia but augmented dyskinesia associated with trihexyphenidyl.

PMID: 8232363 [PubMed - indexed for MEDLINE]

191. Neurology. 1993 Sep;43(9):1704-8.

The effect of L-dopa infusions with and without phenylalanine challenges in
parkinsonian patients: plasma and ventricular CSF L-dopa levels and clinical
responses.

Woodward WR, Olanow CW, Beckner RM, Hauser RA, Gauger LL, Cedarbaum JM, Nutt JG.

Department of Neurology, Oregon Health Sciences University, Portland 97201-3098.

We monitored the motor response and plasma and ventricular CSF (CSFv)
concentrations of L-dopa during IV infusions of L-dopa in two patients with
advanced Parkinson's disease. Concentrations of L-dopa in CSFv mirrored, but
lagged behind, those in plasma. In the fasting state, the duration, but not the
magnitude, of the motor response was greater with increasing plasma and CSFv
levels of L-dopa. During IV infusions of L-dopa following oral administration of
phenylalanine, a large neutral amino acid that shares a transport system into the
brain with L-dopa, the duration of the motor response was markedly attenuated
despite undiminished CSFv levels of L-dopa. These observations suggest that
either L-dopa entry into CSFv and the brain are differentially affected by
phenylalanine or that phenylalanine affects other steps in the motor response.
These observations demonstrate that, except in the fasting state, L-dopa in CSFv
is not a reliable predictor of motor response.

PMID: 8414016 [PubMed - indexed for MEDLINE]

192. J Neurosci Res. 1993 May 1;35(1):67-82.

Infusion of iron into the rat substantia nigra: nigral pathology and
dose-dependent loss of striatal dopaminergic markers.

Sengstock GJ, Olanow CW, Menzies RA, Dunn AJ, Arendash GW.

Department of Biology, University of South Florida, Tampa 33620.

Iron has recently been suggested to contribute to the pathogenesis of Parkinson's
disease (PD) because of the finding of increased iron levels in the substantia
nigra pars compacta (SNc) above those of control patients. Iron is capable of
catalyzing numerous reactions which could lead to free radical formation and
oxidative damage to DNA, proteins, lipid membranes, and other biological
molecules. Neurodegeneration in the SNc of the PD brain may be a consequence of
increased iron, which promotes these cytotoxic reactions. To test whether excess
iron could play a causative role in the degeneration of nigral neurons, we
infused 1.25-6.3 nmol of iron into the rat substantia nigra (SN) unilaterally
utilizing two different infusion protocols. All infusates were isosmotic and
pH-balanced in a citrate-bicarbonate vehicle. Animals were decapitated at either
1 or 2 months postinfusion. Striatal tissue was assayed for biogenic amines by
HPLC and the remaining brainstem was processed for histological analysis.
Iron-stained coronal sections revealed 1) no left/right staining difference with
vehicle infusion, 2) a dose-dependent iron accumulation in the infused SN that
was restricted to the zona compacta and dorsal-most zona reticularis when the
lowest iron concentration was infused, and 3) a dose-dependent reduction in SN
volume. Thionine-stained sections revealed neuronal loss and accompanying
reactive gliosis within an area that corresponded closely to that of increased
iron staining. These degenerative changes were more extensive in animals infused
via a side-by side vs. a sequential protocol. Neurochemically, there was a highly
significant correlation between the amount of iron infused intranigrally and
magnitude of reductions in striatal DA, DOPAC, and HVA within the ipsilateral
striatum. These data indicate that iron infusion into the SN can cause
degenerative changes within the SN and that these changes can be restricted to
the SNc region when low amounts of iron are infused. The data further support the
hypothesis that iron-induced degeneration may contribute to the pathogenesis of
PD.

PMID: 7685399 [PubMed - indexed for MEDLINE]

193. J Neural Transm Gen Sect. 1993;91(2-3):161-80.

A scientific rationale for protective therapy in Parkinson's disease.

Olanow CW.

Department of Neurology, University of South Florida, Tampa.

The desire to introduce neuroprotective therapy for Parkinson's disease has begun
to focus attention on pathogenetic mechanisms responsible for cell death.
Considerable theory and some evidence have now accumulated to suggest that
factors related to oxidative stress, mitochondrial bioenergetic defects,
excitatory neurotoxicity, calcium cytotoxicity, and trophic factor deficiencies
acting either singularly or in combination may contribute to the development of
cell death in Parkinson's disease. A better understanding of the specific
pathogenetic mechanism involved in cell degeneration might provide a scientific
basis for testing a putative neuroprotective therapy. This chapter reviews the
theory and evidence in support of these different mechanisms and possible
strategies that might provide neuroprotection and interfere with the natural
progression of Parkinson's disease.

PMID: 8512683 [PubMed - indexed for MEDLINE]

194. Adv Neurol. 1993;60:666-71.

MAO-B inhibitors in Parkinson's disease.

Olanow CW.

Department of Neurology, University of South Florida, Tampa 33606.

PMID: 8420207 [PubMed - indexed for MEDLINE]

195. Mov Disord. 1993;8 Suppl 1:S1-7.

A rationale for monoamine oxidase inhibition as neuroprotective therapy for
Parkinson's disease.

Olanow CW.

Department of Neurology, Psychiatry and Pharmacology, University of South
Florida, Tampa.

Neurons in the substantia nigra may be vulnerable to oxidant stress because (a)
the metabolism of dopamine generates peroxides, which, in the presence of iron,
can lead to the formation of the highly reactive hydroxyl free radical; and (b)
neuromelanin within nigral neurons can bind metals such as iron and aluminum and
thereby promote the site-specific formation of free radicals. Postmortem studies
show increased iron, decreased glutathione, and increased lipid peroxidation in
the substantia nigra of patients with Parkinson's disease (PD). Recent studies
also report iron and aluminum accumulation within neuromelanin granules of
patients with PD. These findings suggest that the substantia nigra in the patient
with PD is in a state of oxidant stress and that antioxidant therapy might
protect residual dopamine neurons and slow the natural progression of PD.
Selective inhibitors of monoamine oxidase type B (MAO-B) have been chosen for
study because of their capacity to interfere with the oxidative metabolism of
dopamine and so diminish the likelihood that free radicals will be formed.
Initial studies demonstrate that the MAO-B inhibitor L-deprenyl (selegiline)
delays the development of disability in otherwise untreated patients with early
Parkinson's disease. Although the mechanism responsible for these observations
remains unclear, these results are consistent with the possibility that
L-deprenyl provides neuroprotective effects.

PMID: 8302302 [PubMed - indexed for MEDLINE]

196. Brain Res. 1992 Oct 16;593(2):343-6.

Neuromelanin-containing neurons of the substantia nigra accumulate iron and
aluminum in Parkinson's disease: a LAMMA study.

Good PF, Olanow CW, Perl DP.

Department of Pathology, Mt. Sinai Medical Center, New York, NY 10029.

The Laser Microprobe Mass Analyzer (LAMMA) is a sensitive instrument for
identifying and localizing trace elements in tissue samples. Using LAMMA, we have
examined melanin-containing neurons of the substantia nigra in patients with
Parkinson's disease (PD) and controls. We found that iron significantly
accumulates within neuromelanin granules of patients with PD compared to
controls. Increased aluminum was found in the neuromelanin granules of 2 of 3 PD
cases but in no controls. The accumulation of iron and aluminum, which are known
to promote oxidant stress, may account for the selective degeneration of
neuromelanin-containing neurons in PD.

PMID: 1450944 [PubMed - indexed for MEDLINE]

197. Neurol Clin. 1992 May;10(2):405-20.

Magnetic resonance imaging in parkinsonism.

Olanow CW.

University of South Florida, Tampa.

MRI is a relatively simple, safe, in vivo technique that has proved to be of
great value in differentiating patients with Parkinson's disease from those with
atypical parkinsonism, and it is the first laboratory marker to be able to do so.
By permitting the in vivo detection of increased iron in the nigra and striatum
of patients with parkinsonism, MRI may also have provided a clue into the
mechanism of cell death in neurodegenerative disorders. Finally it is conceivable
that MRI scanning may serve as a screening tool that permits the early
recognition of pathologic iron accumulation before the development of clinical
symptoms. This is reasonable to anticipate for patients with atypical
parkinsonism in whom large quantities of iron appear to accumulate in the putamen
early in the disease. It is possible that with some refinement, abnormalities in
the nigra may be detected on MRI with a higher level of certainty. In an era in
which we may be able to provide neuroprotective therapy, MRI might be an
important technique for defining a population of patients at risk for the
development of Parkinson's disease who might benefit from presymptomatic therapy.

PMID: 1584182 [PubMed - indexed for MEDLINE]

198. Brain Res Bull. 1992 Apr;28(4):645-9.

Iron induces degeneration of nigrostriatal neurons.

Sengstock GJ, Olanow CW, Dunn AJ, Arendash GW.

Department of Biology, University of South Florida, Tampa 33620.

Parkinson's-diseased (PD) brains have been reported to contain increased
quantities of iron within the zona compacta of the substantia nigra (SN). To test
whether excess iron in the SN could cause a PD-like loss of dopaminergic neurons,
various concentrations of iron were infused unilaterally within the SN of adult
male rats. At 1-2 months post-infusion, examination of thionine and iron stained
brain sections from animals infused with low concentration iron revealed: (1)
iron diffusion limited to and concentrated within the infused SN and (2) a
selective degeneration of neurons within zona compacta of SN. Infusion of higher
iron concentrations induced near complete neuronal losses in zona compacta, as
well as neuronal degeneration within zona reticularis and areas immediately
adjacent to the SN. Striatal dopamine and its catabolites dihydroxyphenylacetic
acid (DOPAC) and homovanillic acid (HVA) were reduced in a dose-dependent
fashion, with over 80% depletions observed at the highest iron concentration
infused. These data indicated that neurons within zona compacta of SN are
sensitive to infusions of low iron concentrations. The data support the notion
that iron in zona compacta of the SN could act as an endotoxin in the
pathogenesis of PD.

PMID: 1617450 [PubMed - indexed for MEDLINE]

199. Neurology. 1992 Apr;42(4 Suppl 4):13-26; discussion 41-8.

Does selegiline monotherapy in Parkinson's disease act by symptomatic or
protective mechanisms?

Olanow CW, Calne D.

Department of Neurology, University of South Florida, Tampa 33606.

Selegiline monotherapy has been clearly demonstrated to delay the development of
disability in early, otherwise untreated Parkinson's disease patients. It remains
uncertain, however, whether this benefit is due to protective effects on residual
neurons or to symptomatic effects that mask the detection of underlying
disability. This paper examines the evidence and theory supporting the hypotheses
that selegiline acts by protective or symptomatic mechanisms and considers what
future studies might help clarify these issues.

PMID: 1584429 [PubMed - indexed for MEDLINE]

200. Can J Neurol Sci. 1992 Feb;19(1 Suppl):108-12.

A rationale for dopamine agonists as primary therapy for Parkinson's disease.

Olanow CW.

Department of Neurology and Pharmacology, University of South Florida, Tampa.

Levodopa is the most potent symptomatic treatment for Parkinson's disease but
adverse reactions are common and the initial response is not maintained. Further
there is recent evidence that suggests that free radicals generated from the
oxidative metabolism of dopamine may contribute to the pathogenesis of
Parkinson's disease. This raises the possibility that levodopa therapy by way of
its conversion to dopamine may promote free radical formation and accelerate the
rate of neuronal damage. Levodopa sparing strategies designed to minimize the
cumulative levodopa dosage employed over the course of the disease seem a
rational way to treat Parkinson patients in face of current information. Such a
strategy would include the use of dopamine agonists as primary symptomatic
therapy, the introduction of levodopa as an adjunct when dopamine agonists can no
longer sufficiently provide satisfactory clinical control and the use of the
lowest dose of levodopa that will provide satisfactory clinical control. In this
way symptomatic control is not compromised on theoretical grounds, but the
cumulative levodopa dose is minimized in an effort to reduce the likelihood of
free radical formation with their potential adverse consequences on disease
progression.

PMID: 1349262 [PubMed - indexed for MEDLINE]

TITLE: Time course of loss of clinical benefit following withdrawal of levodopa/carbidopa and bromocriptine in early Parkinson' s disease [In Process Citation]
AUTHORS: Hauser RA; Koller WC; Hubble JP; Malapira T; Busenbark K; Olanow CW
AUTHOR AFFILIATION: Parkinson's Disease and Movement Disorders Center, University of South Florida, Tampa 33606, USA.
SOURCE: Mov Disord 2000 May;15(3):485-9
[MEDLINE record in process]
CITATION IDS: PMID: 10830413 UI: 20289225
ABSTRACT: Putative neuroprotective agents for Parkinson's disease can be assessed in untreated patients using progression of clinical disability as an index of disease progression. To avoid the confound associated with symptomatic therapy, progression of the underlying disease can be assessed by evaluating the progression of clinical disability from an untreated baseline to a final visit following wash-out of symptomatic medication. In this type of analysis it is critical to use a washout of sufficient duration to ensure elimination of symptomatic effects. To assess the time course of resolution of symptomatic effects, we evaluated 31 patients at days 1, 8, and 15 following discontinuation of levodopa/carbidopa and bromocriptine. Mean total Unified Parkinson's Disease Rating Scale scores (+/- standard error) increased (worsened) by 7.4+/-1.5 from day 1 to day 15 (p <0.0001), 4.5+/-1.2 from day 1 to day 8 (p = 0.0009), and 2.9+/-1.0 from day 8 to day 15 (p = 0.01). We conclude that a wash-out of at least 2 weeks is required to eliminate the symptomatic effects of levodopa/carbidopa and bromocriptine in patients with early Parkinson's disease.

2000/06
2000/01 09:00

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TITLE: Preventing levodopa-induced dyskinesias.
AUTHORS: Olanow CW; Obeso JA
AUTHOR AFFILIATION: Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
SOURCE: Ann Neurol 2000 Apr;47(4 Suppl 1):S167-76; discussion S176-8
CITATION IDS: PMID: 10762145 UI: 20222799
ABSTRACT: The precise cause of levodopa-induced dyskinesias is unknown. Current evidence indicates that dyskinesias develop in response to pulsatile stimulation of striatal dopamine receptors. The half-life of the dopaminergic agent employed and disease severity are thought to affect the occurrence of pulsatile stimulation. Dyskinesias are not seen or are attenuated with continuous delivery of levodopa or short-acting agonists, or with the use of long-acting agonists. In advanced disease, there are fewer striatal dopamine terminals and reduced buffering capacity; fluctuations in plasma levodopa concentration are more likely to cause fluctuations in striatal dopamine concentration and pulsatile stimulation of dopamine receptors. Pulsatile stimulation is thought to induce postsynaptic gene and protein changes that result in alterations in the patterns of neuronal communication, with the emergence of dyskinetic movements. Thus, strategies preventing pulsatile stimulation may prevent the development of dyskinesias. These could include the use of dopaminergic agents with a relatively long half-life, neuroprotective therapies that prevent the loss of dopamine neurons, and transplantation strategies or trophic factors that increase the number of dopamine terminals capable of buffering fluctuations in striatal dopamine. Alternatively, approaches that interfere with or compensate for postsynaptic molecular and neurophysiologic changes that ensue in downstream neurons might provide antidyskinetic benefits.

2000/04
2000/29 09:00

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TITLE: Pathophysiology of levodopa-induced dyskinesias in Parkinson's disease: problems with the current model.
AUTHORS: Obeso JA; Rodriguez-Oroz MC; Rodriguez M; DeLong MR; Olanow CW
AUTHOR AFFILIATION: Department of Neurology and Neurosurgery, Clinica Universitaria and Medical School, University of Navarra, Pamplona, Spain.
SOURCE: Ann Neurol 2000 Apr;47(4 Suppl 1):S22-32; discussion S32-4
CITATION IDS: PMID: 10762129 UI: 20222783
ABSTRACT: The anatomical and physiological basis of levodopa-induced dyskinesias (LIDs) in patients with Parkinson's disease (PD) is reviewed in the light of the current model for the organization of the basal ganglia. This model, which was developed in the late 1980s, works relatively well in explaining the motor features of PD but, for example, it does not account for why tremor, rigidity, bradykinesia, gait dysfunction and postural instability present to differing degrees in different patients, and may respond differently to levodopa treatment or surgical procedures. Recent information suggests that LIDs develop as a consequence of pulsatile stimulation of dopamine receptors, with consequent dysregulation of genes and proteins in downstream neurons resulting in changes in neuronal firing patterns. A modified model of the basal ganglia in PD patients with LID is proposed, which incorporates more recent clinical and experimental data.

2000/04
2000/29 09:00

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TITLE: Tolcapone and hepatotoxic effects. Tasmar Advisory Panel.
AUTHORS: Olanow CW
AUTHOR AFFILIATION: Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
SOURCE: Arch Neurol 2000 Feb;57(2):263-7
CITATION IDS: PMID: 10681087 UI: 20143322
ABSTRACT: Four patients with Parkinson disease have recently been described in whom severe hepatic dysfunction developed in association with tolcapone therapy. These reports led to the introduction of a "black box" warning and more intensive monitoring requirements in the United States. A review of these cases and all clinical trials indicates that liver dysfunction did not develop in any patient who had received monitoring of liver function according to the original prescribing information. Virtually all instances of liver enzyme abnormality and clinical liver dysfunction occurred within 6 months of initiating treatment. To assess the current role of tolcapone therapy in Parkinson disease, a panel of neurologists and hepatologists was convened. Consensus was reached with respect to the following: (1) Tolcapone is an effective agent in the treatment of patients with fluctuating Parkinson disease. (2) The risk of developing irreversible liver injury is negligible with appropriate monitoring. (3) It may be possible to reduce the frequency of monitoring after 6 months of treatment. (4) The requirement that tolcapone be withdrawn if liver enzymes are elevated above the upper limit of normal on a single occasion is unnecessarily restrictive. It was concluded that tolcapone, when used as an adjunct to levodopa, is an effective anti-parkinsonian agent and that less frequent monitoring after 6 months, with an action limit of 2 to 3 times the upper limit of normal, is sufficient to ensure safety in patients who are deriving benefit from the drug.

2000/02
2000/26 09:00

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TITLE: Etiology and pathogenesis of Parkinson's disease.
AUTHORS: Olanow CW; Tatton WG
AUTHOR AFFILIATION: Department of Neurology, Mount Sinai Medical Center, New York, New York 10029, USA.
SOURCE: Annu Rev Neurosci 1999;22:123-44
CITATION IDS: PMID: 10202534 UI: 99218859
ABSTRACT: Parkinson's disease (PD) is an age-related neurodegenerative disorder that affects approximately 1 million persons in the United States. It is characterized by resting tremor, rigidity, bradykinesia or slowness, gait disturbance, and postural instability. Pathological features include degeneration of dopaminergic neurons in the substantia nigra pars compacta coupled with intracytoplasmic inclusions known as Lewy bodies. Neurodegeneration and Lewy bodies can also be found in the locus ceruleus, nucleus basalis, hypothalamus, cerebral cortex, cranial nerve motor nuclei, and central and peripheral components of the autonomic nervous system. Current treatment consists of a dopamine replacement strategy using primarily the dopamine precursor levodopa. While levodopa provides benefit to virtually all PD patients, after 5-10 years of treatment the majority of patients develop adverse events in the form of dyskinesia (involuntary movements) and fluctuations in motor response. Further, disease progression is associated with the development of dementia, autonomic dysfunction, and postural instability, which do not respond to levodopa therapy. Accordingly, research efforts have been directed toward understanding the etiology and pathogenesis of PD in the hope of developing a more effective therapy that will slow or halt the natural progression of PD. This paper reviews recent advances.

1999/04
1999/15 02:01

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TITLE: Long-term evaluation of bilateral fetal nigral transplantation in Parkinson disease.
AUTHORS: Hauser RA; Freeman TB; Snow BJ; Nauert M; Gauger L; Kordower JH; Olanow CW
AUTHOR AFFILIATION: Department of Neurology, University of South Florida, Tampa 33606, USA.
SOURCE: Arch Neurol 1999 Feb;56(2):179-87
CITATION IDS: PMID: 10025423 UI: 99148290
ABSTRACT: BACKGROUND: Parkinson disease (PD) is associated with a progressive loss of nigrostriatal dopamine neurons. Medication therapy provides adequate control of symptoms for several years, but long-term treatment is complicated by progressive disability and the development of motor fluctuations and dyskinesias. In animal models of PD, fetal nigral transplants have been shown to survive grafting into the striatum, provide extensive striatal reinnervation, and improve motor function. In patients with PD, cell survival and clinical benefit have been observed following fetal nigral grafting, but results have been inconsistent.

OBJECTIVE: To evaluate the safety and efficacy of bilateral fetal nigral transplantation into the postcommissural putamen in patients with advanced PD complicated by motor fluctuations and dyskinesias.

PATIENTS AND METHODS: Six patients with advanced PD underwent bilateral fetal nigral transplantation. Each patient received solid grafts derived from donors aged 6 1/2 to 9 weeks after conception stereotactically implanted into the postcommissural putamen using 3 to 4 donors per side. Cyclosporine was administered for approximately 6 months to provide immune suppression. Clinical evaluations included the Unified Parkinson's Disease Rating Scale (UPDRS), Schwab-England Activities of Daily Living Scale, and timed tests of motor function conducted during both the "off' and "on" states at baseline and at 1, 3, 6, 9, 12, 18, and 24 months following transplantation. Percentage of time off and percentage of time on with and without dyskinesia were recorded at half-hour intervals using home diaries during the week prior to each evaluation. 18F-fluorodopa positron emission tomographic scans were performed at baseline, and at 6 months and 1 year following transplantation.

RESULTS: Patients have been followed up for a mean+/-SD of 20.5+/-5.5 months. Complications related to surgery were mild and transient. Activities of daily living, motor, and total (activities of daily living plus motor) UPDRS scores during the off state improved significantly (P<.05, Wilcoxon signed rank test) at final visit in comparison with baseline. Mean total UPDRS off score improved 32%, and each patient experienced at least a 19% improvement. Mean percentage of time on without dyskinesia during the waking day improved from 22% to 60% (P<.05). Mean putamenal fluorodopa uptake on positron emission tomography increased significantly at 6 and 12 months in comparison with baseline (P<.001, 2-tailed t test). This increase correlated with clinical improvement. Two patients died 18 months after transplantation from causes unrelated to the surgical procedure. In both cases, histopathological examination showed robust survival of tyrosine hydroxylase immunoreactive cells and abundant reinnervation of the postcommissural putamen.

CONCLUSIONS: Fetal nigral tissue can be transplanted into the postcommissural putamen bilaterally in patients with advanced PD safely and with little morbidity. In this open-label pilot study we observed consistent long-term clinical benefit and increased fluorodopa uptake on positron emission tomography. Clinical improvement appears to be related to the survival and function of transplanted fetal tissue.

1999/02
1999/20 03:12

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TITLE: A multicenter trial of ropinirole as adjunct treatment for Parkinson's disease. Ropinirole Study Group [published erratum appears in Neurology 1999 Jan 15;52(2):435] [see comments]
AUTHORS: Lieberman A; Olanow CW; Sethi K; Swanson P; Waters CH; Fahn S; Hurtig H; Yahr M
AUTHOR AFFILIATION: Barrow Neurological Institute, Phoenix, AZ 85013-4496, USA.
SOURCE: Neurology 1998 Oct;51(4):1057-62
CITATION IDS: PMID: 9781529 UI: 98452789
COMMENT: Comment in: Neurology 1999 Aug 11;53(3):658
ABSTRACT: OBJECTIVE: To evaluate the nonergot dopamine agonist ropinirole as an adjunct to L-dopa in a randomized, double-blind trial in PD patients with motor fluctuations.

BACKGROUND: L-dopa in the treatment of PD is associated with motor fluctuations, dyskinesia, and other adverse effects. The use of dopamine agonists in the treatment of PD delays recourse to L-dopa and thus delays the possibility of adverse effect onset.

METHODS: Ropinirole (n = 95) or placebo (n = 54) was added to L-dopa, and L-dopa was then reduced in a planned manner during the 6-month trial.

RESULTS: A significantly greater number of ropinirole patients were able to achieve a 20% or greater reduction in both L-dopa dose and in percent time spent "off" compared with placebo (35.0% versus 13.0%; p = 0.003). The mean daily L-dopa dose was reduced significantly with ropinirole treatment (242 mg versus 51 mg; p < 0.001) as was the percent awake time spent "off" (11.7% versus 5.1%; p = 0.039). There was no difference in the percent of patients who withdrew because of adverse effects (15.8% on ropinirole versus 16.7% on placebo). CONCLUSIONS: Ropinirole permits a reduction in L-dopa dose with enhanced clinical benefit for PD patients with motor fluctuations.

1998/10
1998/22 02:02

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