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Parkinsn Current Topics
The latest abstracts by Dr. Mark Stacy on PubMed are here:
Stacy M
1. Prog Neuropsychopharmacol Biol Psychiatry. 2009 Sep 28. [Epub ahead of print]
Responsiveness of motor and nonmotor symptoms of Parkinson disease to
dopaminergic therapy.
Stacy MA, Murck H, Kroenke K.
Division of Neurology, Duke University, 932 Morreene Rd, MS 3333, Durham, NC
27705, United States.
BACKGROUND: The duration of clinical control of motor symptoms of Parkinson
disease (PD) treated with levodopa/carbidopa preparations eventually starts to
shorten, a phenomenon known as end-of-dose "wearing off." The involvement of core
nonmotor symptoms of "wearing off" (depressed mood, pain/aching, anxiety, and
cloudy/slowed thinking) is not well understood. METHODS: A post hoc analysis from
a study to validate the self-rated 9-item, Wearing-Off Questionnaire (WOQ-9),
which was designed to identify motor and nonmotor symptoms of "wearing off" in PD
patients, was performed to compare the frequency and sensitivity of motor and
nonmotor symptoms of "wearing off" from dopaminergic therapy. RESULTS: Analysis
of responses to the WOQ-9 from 216 PD patients found that individual nonmotor
symptoms were reported by 25% to 50% and motor symptoms by 55% to 80% of
patients. Individual nonmotor symptoms improved following the next dose of
dopaminergic therapy in 43% to 53% of the patients who presented with such
symptoms, whereas motor symptoms improved in 48% to 66% of the cases, suggesting
both types of symptoms respond to dopaminergic therapies. CONCLUSION: Nonmotor
symptoms of PD appear sensitive to dopaminergic treatment. These symptoms
resemble those seen with depressive, anxiety, and somatoform disorders suggesting
potential shared mechanisms as well as possible treatment implications.
PMID: 19793544 [PubMed - as supplied by publisher]
2. BMC Med Genet. 2009 Sep 22;10:98.
Genomewide association study for onset age in Parkinson disease.
Latourelle JC, Pankratz N, Dumitriu A, Wilk JB, Goldwurm S, Pezzoli G, Mariani
CB, DeStefano AL, Halter C, Gusella JF, Nichols WC, Myers RH, Foroud T; PROGENI
Investigators, Coordinators and Molecular Genetic Laboratories; GenePD
Investigators, Coordinators and Molecular Genetic Laboratories.
Collaborators: Factor S, Higgins D, Evans S, Shill H, Stacy M, Danielson J,
Marlor L, Williamson K, Jankovic J, Hunter C, Simon D, Ryan P, Scollins L,
Saunders-Pullman R, Boyar K, Costan-Toth C, Ohmann E, Sudarsky L, Joubert C,
Friedman J, Chou K, Fernandez H, Lannon M, Galvez-Jimenez N, Podichetty A,
Thompson K, Lewitt P, DeAngelis M, O'Brien C, Seeberger L, Dingmann C, Judd D,
Marder K, Fraser J, Harris J, Bertoni J, Peterson C, Rezak M, Medalle G,
Chouinard S, Panisset M, Hall J, Poiffaut H, Calabrese V, Roberge P, Wojcieszek
J, Belden J, Jennings D, Marek K, Mendick S, Reich S, Dunlop B, Jog M, Horn C,
Uitti R, Turk M, Ajax T, Mannetter J, Sethi K, Carpenter J, Dill B, Hatch L,
Ligon K, Narayan S, Blindauer K, Abou-Samra K, Petit J, Elmer L, Aiken E, Davis
K, Schell C, Wilson S, Velickovic M, Koller W, Phipps S, Feigin A, Gordon M,
Hamann J, Licari E, Marotta-Kollarus M, Shannon B, Winnick R, Simuni T, Videnovic
A, Kaczmarek A, Williams K, Wolff M, Rao J, Cook M, Fernandez M, Kostyk S, Hubble
J, Campbell A, Reider C, Seward A, Camicioli R, Carter J, Nutt J, Andrews P,
Morehouse S, Stone C, Mendis T, Grimes D, Alcorn-Costa C, Gray P, Haas K,
Vendette J, Sutton J, Hutchinson B, Young J, Rajput A, Rajput A, Klassen L,
Shirley T, Manyam B, Simpson P, Whetteckey J, Wulbrecht B, Truong D, Pathak M,
Frei K, Luong N, Tra T, Tran A, Vo J, Lang A, Kleiner-Fisman G, Nieves A,
Johnston L, So J, Podskalny G, Giffin L, Atchison P, Allen C, Martin W, Wieler M,
Suchowersky O, Klimek M, Hermanowicz N, Niswonger S, Shults C, Fontaine D,
Aminoff M, Christine C, Diminno M, Hevezi J, Dalvi A, Kang U, Richman J, Uy S,
Young J, Dalvi A, Sahay A, Gartner M, Schwieterman D, Hall D, Leehey M, Culver S,
Derian T, Demarcaida T, Thurlow S, Rodnitzky R, Dobson J, Lyons K, Pahwa R, Gales
T, Thomas S, Shulman L, Reich S, Weiner W, Dustin K, Lyons K, Singer C, Koller W,
Weiner W, Zelaya L, Tuite P, Hagen V, Rolandelli S, Schacherer R, Kosowicz J,
Gordon P, Werner J, Serrano C, Roque S, Kurlan R, Berry D, Gardiner I, Hauser R,
Sanchez-Ramos J, Zesiewicz T, Delgado H, Price K, Rodriguez P, Wolfrath S,
Pfeiffer R, Davis L, Pfeiffer B, Dewey R, Hayward B, Johnson A, Meacham M, Estes
B, Walker F, Hunt V, O'Neill C, Racette B, Good L, Rundle M, Pauciulo MW, Marek
DK, Elsaesser VE, Lew M, Suchowersky O, Furtado S, Klein C, Golbe L, Mark MH,
Growdon J, Huggins N, Wooten GF, Watts R, Guttman M, Racette B, Perlmutter J,
Marlor L, Shill H, Singer C, Saint-Hilaire MH, Massood T, Baker K, Itin I, Ahmed
A, Litvan I, Nicholson G, Corbett A, Nance M, Drasby E, Isaacson S, Burn D,
Chinnery P, Pramstaller P, Al-hinti J, Moller A, Ostergaard K, Sherman S,
Roxburgh R, Snow B, Slevin J, Cambi F, McDonald ME, Sun M, Mysore L, Anderson MA,
Lucente D, Williamson S, Nagle MW, Brandler B.
Boston University School of Medicine, Boston, MA, USA. jlatoure@bu.edu
BACKGROUND: Age at onset in Parkinson disease (PD) is a highly heritable
quantitative trait for which a significant genetic influence is supported by
multiple segregation analyses. Because genes associated with onset age may
represent invaluable therapeutic targets to delay the disease, we sought to
identify such genetic modifiers using a genomewide association study in familial
PD. There have been previous genomewide association studies (GWAS) to identify
genes influencing PD susceptibility, but this is the first to identify genes
contributing to the variation in onset age. METHODS: Initial analyses were
performed using genotypes generated with the Illumina HumanCNV370Duo array in a
sample of 857 unrelated, familial PD cases. Subsequently, a meta-analysis of
imputed SNPs was performed combining the familial PD data with that from a
previous GWAS of 440 idiopathic PD cases. The SNPs from the meta-analysis with
the lowest p-values and consistency in the direction of effect for onset age were
then genotyped in a replication sample of 747 idiopathic PD cases from the
Parkinson Institute Biobank of Milan, Italy. RESULTS: Meta-analysis across the
three studies detected consistent association (p < 1 x 10(-5)) with five SNPs,
none of which reached genomewide significance. On chromosome 11, the SNP with the
lowest p-value (rs10767971; p = 5.4 x 10(-7)) lies between the genes QSER1 and
PRRG4. Near the PARK3 linkage region on chromosome 2p13, association was observed
with a SNP (rs7577851; p = 8.7 x 10(-6)) which lies in an intron of the AAK1
gene. This gene is closely related to GAK, identified as a possible PD
susceptibility gene in the GWAS of the familial PD cases. CONCLUSION: Taken
together, these results suggest an influence of genes involved in endocytosis and
lysosomal sorting in PD pathogenesis.
PMCID: 2758866
PMID: 19772629 [PubMed - indexed for MEDLINE]
3. J Neurol. 2009 Aug;256 Suppl 3:293-8.
Non-motor symptoms in Parkinson's disease.
Park A, Stacy M.
Department of Neurology, The Ohio State University, Columbus, OH, USA.
Parkinson's disease is a hypokinetic movement disorder with cardinal motor
features of bradykinesia, resting tremor and rigidity. However, non-motor
symptoms, such as cognitive, neuropsychiatric, sleep, autonomic and sensory
disturbances are gaining increasing attention. These non-motor symptoms may be
intrinsic to the disease pathology or may be results of treatment with
dopaminergic agents. Given that most, if not all, patients with Parkinson's
disease will experience non-motor symptoms, it is important to be sensitive to
these phenomena, especially since some non-motor signs may precede motor
impairment. Treatment may include interventions independent of traditional,
dopaminergic anti-Parkinson therapy or may be tailored to increase or reduce
dopamine responsiveness of the symptom.
PMID: 19711119 [PubMed - in process]
4. Neurology. 2009 Jul 28;73(4):279-86.
Parkin dosage mutations have greater pathogenicity in familial PD than simple
sequence mutations.
Pankratz N, Kissell DK, Pauciulo MW, Halter CA, Rudolph A, Pfeiffer RF, Marder
KS, Foroud T, Nichols WC; Parkinson Study Group-PROGENI Investigators.
Collaborators: Pfeiffer RF, Marshall F, Oakes D, Rudolph A, Shinaman A, Marder K,
Conneally PM, Foroud T, Halter C, Lyons K, Siemers E, Elmers L, Hermanowicz N,
Factor S, Higgins D, Evans S, Shill H, Stacy M, Danielson J, Marlor L, Williamson
K, Jankovic J, Hunter C, Simon D, Ryan P, Scollins L, Saunders-Pullman R, Boyar
K, Costan-Toth C, Ohmann E, Sudarsky L, Joubert C, Friedman J, Chou K, Fernandez
H, Lannon M, Galvez-Jimenez N, Podichetty A, Thompson K, Lewitt P, DeAngelis M,
O'Brien C, Seeberger L, Dingmann C, Judd D, Marder K, Fraser J, Harris J, Bertoni
J, Peterson C, Rezak M, Medalle G, Chouinard S, Panisset M, Hall J, Poiffaut H,
Calabrese V, Roberge P, Wojcieszek J, Belden J, Jennings D, Marek K, Mendick S,
Reich S, Dunlop B, Jog M, Horn C, Uitti R, Turk M, Ajax T, Mannetter J, Sethi K,
Carpenter J, Dill B, Hatch L, Ligon K, Narayan S, Blindauer K, Abou-Samra K,
Petit J, Elmer L, Aiken E, Davis K, Schell C, Wilson S, Velickovic M, Koller W,
Phipps S, Feigin A, MGordon M, Hamann J, Licari E, Marotta-Kollarus M, Shannon B,
Winnick R, Simuni T, Videnovic A, Kaczmarek A, Williams K, Wolff M, Rao J, Cook
M, Fernandez M, Kostyk S, Hubble J, Campbell A, Reider C, Seward A, Camicioli R,
Carter J, Nutt J, Andrews P, Morehouse S, Stone C, Mendis T, Grimes D,
Alcorn-Costa C, Gray P, Haas K, Vendette J, Young J, Rajput A, Klassen L, Shirley
T, Manyam B, Simpson P, Whetteckey J, Wulbrecht B, Truong D, Pathak M, Frei K,
Luong N, Tra T, Tran A, Vo J, Lang A, Kleiner-Fisman G, Nieves A, Johnston L, So
J, Podskalny G, Giffin L, Atchison P, Allen C, Martin W, Wieler M, Klimek M,
Hermanowicz N, Niswonger S, Shults C, Fontaine D, Aminoff M, Christine C, Diminno
M, Hevezi J, Dalvi A, Kang U, Richman R, Uy S, Young J, Sahay A, Gartner M,
Schwieterman D, Hall D, Leehey M, Culver S, Derian T, Demarcaida T, Thurlow S,
Rodnitzky R, Dobson J, Pahwa R, Gales T, Thomas S, Shulman L, Reich S, Weiner W,
Dustin K, Singer C, Zelaya L, Tuite P, Hagen V, Rolandelli S, Schacherer R,
Kosowicz J, Gordon P, Werner J, Serrano C, Roque S, Kurlan R, Berry D, Gardiner
I, Hauser R, Sanchez-Ramos J, Zesiewicz T, Delgado H, Price K, Rodriguez P,
Wolfrath S, Pfeiffer R, Davis L, Pfeiffer B, Dewey R, Hayward B, Johnson A,
Meacham M, Estes B, Walker F, Hunt V, O'Neill C, Racette B, Good L, Rundle M,
Watts A, Wang A, Ross T, Bennett S, Kamp D, Julian-Baros E, Daigneault S, Doolan
R.
Medical and Molecular Genetics, Indiana University, School of Medicine,
Hereditary Genomics Division, 410 W. 10th St., MI-4000, Indianapolis, IN 46202,
USA. tforoud@iupui.edu
OBJECTIVE: Mutations in both alleles of parkin have been shown to result in
Parkinson disease (PD). However, it is unclear whether haploinsufficiency
(presence of a mutation in only 1 of the 2 parkin alleles) increases the risk for
PD. METHODS: We performed comprehensive dosage and sequence analysis of all 12
exons of parkin in a sample of 520 independent patients with familial PD and 263
controls. We evaluated whether presence of a single parkin mutation, either a
sequence (point mutation or small insertion/deletion) or dosage (whole exon
deletion or duplication) mutation, was found at increased frequency in cases as
compared with controls. We then compared the clinical characteristics of cases
with 0, 1, or 2 parkin mutations. RESULTS: We identified 55 independent patients
with PD with at least 1 parkin mutation and 9 controls with a single sequence
mutation. Cases and controls had a similar frequency of single sequence mutations
(3.1% vs 3.4%, p = 0.83); however, the cases had a significantly higher rate of
dosage mutations (2.6% vs 0%, p = 0.009). Cases with a single dosage mutation
were more likely to have an earlier age at onset (50% with onset at < or =45
years) compared with those with no parkin mutations (10%, p = 0.00002); this was
not true for cases with only a single sequence mutation (25% with onset at < or
=45 years, p = 0.06). CONCLUSIONS: Parkin haploinsufficiency, specifically for a
dosage mutation rather than a point mutation or small insertion/deletion, is a
risk factor for familial PD and may be associated with earlier age at onset.
PMCID: 2715211
PMID: 19636047 [PubMed - indexed for MEDLINE]
5. Neuropsychiatr Dis Treat. 2009;5:33-6. Epub 2009 Apr 8.
Update on ropinirole in the treatment of Parkinson's disease.
Shill HA, Stacy M.
Sun Health Research Institute, Sun City, AZ, USA; Duke University and Medical
Center, Durham, NC, USA.
Ropinirole is a dopamine agonist, approved for use to treat symptoms of early and
advanced Parkinson's disease, is now available in a 24-hour formulation in
addition to the immediate release version. This review discusses the mode of
action of ropinirole and compares the pharmacokinetics of both formulations.
Pivotal studies leading to the approval of both preparations are reviewed in
terms of efficacy, dose range and side effects. Patient factors such as
compliance are discussed in terms of the place for ropinirole in the
armamentarium of Parkinson's disease therapies.
PMCID: 2695212
PMID: 19557097 [PubMed - in process]
6. Neurol Clin. 2009 Aug;27(3):605-31, v.
Medical treatment of Parkinson disease.
Stacy M.
Division of Neurology, Department of Medicine, Duke University Medical Center,
Durham, NC 27705, USA. stacy002@mc.duke.edu
The cardinal characteristics of Parkinson disease (PD) include resting tremor,
rigidity, and bradykinesia. Patients may also develop autonomic dysfunction,
cognitive changes, psychiatric symptoms, sensory complaints, and sleep
disturbances. The treatment of motor and non-motor symptoms of Parkinson disease
is addressed in this article.
PMID: 19555824 [PubMed - indexed for MEDLINE]
7. Mov Disord. 2009 Aug 15;24(11):1561-70.
Impulsive and compulsive behaviors in Parkinson's disease.
Evans AH, Strafella AP, Weintraub D, Stacy M.
Department of Neurology, Royal Melbourne Hospital, University of Melbourne,
Parkville, Australia. Andrew.Evans@mh.org.au
Antiparkinson therapy can be the primary cause of a range of nonmotor symptoms
that include a set of complex disinhibitory psychomotor pathologies and are
linked by their repetitive, reward or incentive-based natures. These behaviors
relate to aberrant or excessive dopamine receptor stimulation and encompass
impulse control disorders (ICDs), punding, and the dopamine dysregulation
syndrome (DDS). Common ICDs include pathological gambling, hypersexuality,
compulsive eating, and compulsive buying. This review focuses on the
phenomenology, epidemiology, and methods to identify and rate these disorders.
The management of dopaminergic drug-related compulsive behaviors is discussed in
the light of the current understanding of the neurobiological substrate of these
disorders. 2009 Movement Disorder Society.
PMID: 19526584 [PubMed - in process]
8. Neurology. 2009 Jun 2;72(22):1886-92. Epub 2009 Mar 11.
Variation in GIGYF2 is not associated with Parkinson disease.
Nichols WC, Kissell DK, Pankratz N, Pauciulo MW, Elsaesser VE, Clark KA, Halter
CA, Rudolph A, Wojcieszek J, Pfeiffer RF, Foroud T; Parkinson Study Group-PROGENI
Investigators.
Collaborators: Pfeiffer RF, Marshall F, Oakes D, Rudolph A, Shinaman A, Marder K,
Conneally PM, Foroud T, Halter C, Lyons K, Siemers E, Elmers L, Hermanowicz N,
Factor S, Higgins D, Evans S, Shill H, Stacy M, Danielson J, Marlor L, Williamson
K, Jankovic J, Hunter C, Simon D, Ryan P, Scollins L, Saunders-Pullman R, Boyar
K, Costan-Toth C, Ohmann E, Sudarsky L, Joubert C, Friedman J, Chou K, Fernandez
H, Lannon M, Galvez-Jimenez N, Podichetty A, Thompson K, Lewitt P, DeAngelis M,
O'Brien C, Seeberger L, Dingmann C, Judd D, Fraser J, Harris J, Bertoni J,
Peterson C, Rezak M, Medalle G, Chouinard S, Panisset M, Hall J, Poiffaut H,
Calabrese V, Roberge P, Wojcieszek J, Belden J, Jennings D, Marek K, Mendick S,
Reich S, Dunlop B, Jog M, Horn C, Uitti R, Turk M, Ajax T, Mannetter J, Sethi K,
Carpenter J, Dill B, Hatch L, Ligon K, Narayan S, Blindauer K, Abou-Samra K,
Petit J, Elmer L, Aiken E, Davis K, Schell C, Wilson S, Velickovic M, Koller W,
Phipps S, Feigin A, Gordon M, Hamann J, Licari E, Marotta-Kollarus M, Shannon B,
Winnick R, Simuni T, Videnovic A, Kaczmarek A, Williams K, Wolff M, Rao J, Cook
M, Fernandez M, Kostyk S, Hubble J, Campbell A, Reider C, Seward A, Camicioli R,
Carter J, Nutt J, Andrews P, Morehouse S, Stone C, Mendis T, Grimes D,
Alcorn-Costa C, Gray P, Haas K, Vendette J, Sutton J, Hutchinson B, Young J,
Rajput A, Rajput A, Klassen L, Shirley T, Manyam B, Simpson P, Whetteckey J,
Wulbrecht B, Truong D, Pathak M, Frei K, Luong N, Tra T, Tran A, Vo J, Lang A,
Kleiner-Fisman G, Nieves A, Johnston L, So J, Podskalny G, Giffin L, Atchison P,
Allen C, Martin W, Wieler M, Suchowersky O, Klimek M, Niswonger S, Shults C,
Fontaine D, Aminoff M, Christine C, Diminno M, Hevezi J, Dalvi A, Kang U, Richman
J, Uy S, Young J, Dalvi A, Sahay A, Gartner M, Schwieterman D, Hall D, Leehey M,
Culver S, Derian T, Demarcaida T, Thurlow S, Rodnitzky R, Dobson J, Pahwa R,
Gales T, Thomas S, Shulman L, Reich S, Weiner W, Dustin K, Lyons K, Singer C,
Koller W, Weiner W, Zelaya L, Tuite P, Hagen V, Rolandelli S, Schacherer R,
Kosowicz J, Gordon P, Werner J, Serrano C, Roque S, Kurlan R, Berry D, Gardiner
I, Hauser R, Sanchez-Ramos J, Zesiewicz T, Delgado H, Price K, Rodriguez P,
Wolfrath S, Davis L, Pfeiffer B, Dewey R, Hayward B, Johnson A, Meacham M, Estes
B, Walker F, Hunt V, O'Neill C, Racette B, Good L, Rundle M, Watts A, Wang A,
Ross T, Bennett S, Kamp D, Julian-Baros E, Daigneault S, Doolan R.
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333
Burnet Avenue, Cincinnati, OH 45229, USA. bill.nichols@cchmc.org
Comment in:
Neurology. 2009 Jun 2;72(22):1882-3.
OBJECTIVE: A recent study reported that mutations in a gene on chromosome
2q36-37, GIGYF2, result in Parkinson disease (PD). We have previously reported
linkage to this chromosomal region in a sample of multiplex PD families, with the
strongest evidence of linkage obtained using the subset of the sample having the
strongest family history of disease and meeting the strictest diagnostic
criteria. We have tested whether mutations in GIGYF2 may account for the
previously observed linkage finding. METHODS: We sequenced the GIGYF2 coding
region in 96 unrelated patients with PD used in our original study that
contributed to the chromosome 2q36-37 linkage signal. Subsequently, we genotyped
the entire sample of 566 multiplex PD kindreds as well as 1,447 controls to test
whether variants in GIGYF2 are causative or increase susceptibility for PD.
RESULTS: We detected three novel variants as well as one of the previously
reported seven variants in a total of five multiple PD families; however, there
was no consistent evidence that these variants segregated with PD in these
families. We also did not find a significant increase in risk for PD among those
inheriting variants in GIGYF2 (p = 0.28). CONCLUSIONS: We believe that variation
in a gene other than GIGYF2 accounts for the previously reported linkage finding
on chromosome 2q36-37.
PMCID: 2690967
PMID: 19279319 [PubMed - indexed for MEDLINE]
9. Mov Disord. 2009 Apr 30;24(6):926-8.
Motor learning in essential tremor.
Shill HA, De La Vega FJ, Samanta J, Stacy M.
Cleo Roberts Center for Clinical Research, Sun Health Research Institute, Sun
City, AZ 85351, USA. holly.shill@sunhealth.org
Classical conditioning is abnormal in patients with cerebellar degeneration.
Pathological studies have recently demonstrated the finding of Purkinje cell loss
in a subset of essential tremor (ET). We studied 10 subjects with long duration
ET using a blink reflex conditioning paradigm and compared them with nine
controls. A 55.6% reduction in motor learning was seen in the first block of
stimulation and this finding persisted across all subsequent trials. We conclude
that motor learning is significantly abnormal in subjects with advanced ET and
likely reflects pathological involvement of the cerebellum. (c) 2009 Movement
Disorder Society.
PMID: 19243062 [PubMed - indexed for MEDLINE]
10. Expert Rev Neurother. 2008 Dec;8(12):1829-39.
What's in the pipeline for the treatment of Parkinson's disease?
Sommer DB, Stacy MA.
Movement Disorders Center, Duke University Medical Center, DUMC Box 3333, Durham,
NC 27710, USA. david.sommer@duke.edu
Parkinson's disease (PD) is a common, debilitating neurodegenerative disorder
that creates a significant burden for patients, family members and society at
large. Major unmet needs include effective therapies that could favorably modify
the underlying pathogenetic processes in PD, and better control of motor and
nonmotor symptoms in advanced-stage disease. This review examines the current
state of development of potential PD therapies, including dopaminergic therapies,
modulators of adenosine and glutamate receptors, cell-based therapies, genetic
therapies and device-based therapies. In addition, research into potential
neuroprotective agents and pipeline therapies for nonmotor symptoms of PD are
summarized.
PMID: 19086879 [PubMed - indexed for MEDLINE]
11. Mov Disord. 2009 Mar 15;24(4):564-73.
Long-term outcome of early versus delayed rasagiline treatment in early
Parkinson's disease.
Hauser RA, Lew MF, Hurtig HI, Ondo WG, Wojcieszek J, Fitzer-Attas CJ; TEMPO
Open-label Study Group.
Collaborators: Marshall F, Gardiner IF, Pearson N, Berry D, Shannon K, Jaglin JA,
Ondo W, Hunter C, Anderson CR, LeWitt PA, Kaminski P, Miller D, DeAngelis M,
Miyasaki J, So J, Johnston L, Tanner C, Stewart T, Tagg L, Everett S, Germain G,
Welsh M, McCollister M, Mann LL, Singer C, Koller WC, Weiner WJ, Bateman D,
Mendis T, Moterson M, Alcorn-Costa C, Haas K, Gray P, Mohtat D, Mendis N,
Sutherland L, Hurtig H, Lloyd M, Mathews M, Gauger L, Dyches P, Newcomb C, Hubble
J, Betcher K, Weeks CC, Kostyk S, Rajput AH, Gerow M, Klassen L, Ewanishin M,
Golbe LI, Patterson V, Caputo D, Seuffert P, Pahwa R, Gales T, Jenkins LJ,
Parsons A, Crader S, Wellinghoff JN, Coe S, Lew MF, Armstrong C, Kawai C,
Hawthorne KB, Gelles K, Lu X, Schuman SW, Cooper C, Marek K, Fussell B, Caplan K,
Barnabei E, Karen Stavris K, Sethi KD, Carpenter JG, Osborne J Jr, Narayan S,
Ligon KM, Molho E, Evans S, Nash J, Brown D, Stacy M, Williamson K, Novak P,
Feldman RG, Thomas C, Martin W, King P, McInnes G, Caouette S, Wojcieszek J,
Belden J, Feigin A, Ayan J, Shannon B, Adler CH, Newman S, Radam T, Schear M,
Santoni N, Wortzel S, Satou N, Tuite P, Rolandelli S, Lowery J, Ebbitt BJ,
Baranauskas A, Aminoff MJ, DiMinno M, Roth J, Borst T, Hevezi J, Deloa C, Tam T,
Lopez A, Bertoni JM, Skrypnik LI, Peterson C, Gordon MF, Winnick R, Parness S,
Hamann J, Calabrese V, Roberge P, Atchison PR, Allen CW, Rolli S, Kang UJ,
Richman J, Uy S.
Parkinsons's Disease and Movement Disorders Center, University of South Florida,
5 Tampa General Circle, Tampa, FL 33606, USA. rhauser@health.usf.edu
The purpose of this study to compare the long-term clinical outcome of early
versus delayed rasagiline treatment in early Parkinson's disease (PD). Subjects
(N = 404) were randomly assigned to initial treatment with rasagiline
(early-start group) or placebo for 6 months followed by rasagiline (delayed-start
group) in the TEMPO study. Subjects who chose to participate in an open-label
extension (N = 306) continued to receive rasagiline as well as other PD
medications as needed. Average (+/-SD) duration in the study was 3.6 +/- 2.1
years; 177 subjects received rasagiline for > or =5.0 years. Over the entire
6.5-year follow-up period, the adjusted mean difference in change from baseline
in total UPDRS scores was 2.5 units (SE 1.1; P = 0.021) or 16% (SE 5.7; P =
0.006) in favor of the early-start versus delayed-start rasagiline group.
Although the interaction between treatment and time was significant, values for
the early-start group were better than the delayed-start group across all time
points. Significantly less worsening (percent change) in total UPDRS scores was
observed in the early-start group at the time points 0.5, 1.5, 2.0, 3.0, 4.5,
5.0, and 5.5 years (P < 0.05). Compared to delayed start, early initiation of
rasagiline provided long-term clinical benefit, even in the face of treatment
with other dopaminergic agents. This might reflect enduring benefits due to
neuroprotection or effects on compensatory mechanisms in early PD.
PMID: 19086083 [PubMed - indexed for MEDLINE]
12. Clin Neurol Neurosurg. 2009 Apr;111(3):303-6. Epub 2008 Dec 10.
Myoclonus and tremor response to thalamic deep brain stimulation parameters in a
patient with inherited myoclonus-dystonia syndrome.
Kuncel AM, Turner DA, Ozelius LJ, Greene PE, Grill WM, Stacy MA.
Department of Biomedical Engineering, Duke University, Box 90281, Durham, NC
27708, United States. alexis.kuncel@duke.edu
We present a 74-year-old woman with inherited myoclonus-dystonia, with
predominant myoclonus and a novel mutation in the epsilon-sarcoglycan gene. The
patient reports a life-long history of rapid, jerking movements, most severe in
the upper extremities as well as a postural and action tremor. Bilateral deep
brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus was
performed, and the patient demonstrated moderate clinical improvement in
myoclonus. We studied the effects on myoclonus and tremor of varying DBS
frequency and amplitude. The frequency tuning curve for myoclonus was similar to
that of tremor, suggesting similar mechanisms by which DBS alleviates both
disorders.
PMID: 19081669 [PubMed - indexed for MEDLINE]
13. Neurology. 2009 Jan 27;72(4):310-6. Epub 2008 Nov 5.
Mutations in GBA are associated with familial Parkinson disease susceptibility
and age at onset.
Nichols WC, Pankratz N, Marek DK, Pauciulo MW, Elsaesser VE, Halter CA, Rudolph
A, Wojcieszek J, Pfeiffer RF, Foroud T; Parkinson Study Group-PROGENI
Investigators.
Collaborators: Pfeiffer RF, Marshall F, Oakes D, Rudolph A, Shinaman A, Marder K,
Conneally PM, Foroud T, Halter C, Lyons K, Siemers E, Elmers L, Hermanowicz N,
Factor S, Higgins D, Evans S, Shill H, Stacy M, Danielson J, Marlor L, Williamson
K, Jankovic J, Hunter C, Simon D, Ryan P, Scollins L, Saunders-Pullman R, Boyar
K, Costan-Toth C, Ohmann E, Sudarsky L, Joubert C, Friedman J, Chou K, Fernandez
H, Lannon M, Galvez-Jimenez N, Podichetty A, Lewitt P, DeAngelis M, O'Brien C,
Seeberger L, Dingmann C, Judd D, Marder K, Fraser J, Harris J, Bertoni J,
Peterson C, Rezak M, Medalle G, Chouinard S, Panisset M, Hall J, Poiffaut H,
Calabrese V, Roberge P, Wojcieszek J, Belden J, Halter C, Jennings D, Marek K,
Mendick S, Reich S, Dunlop B, Jog M, Horn C, Rao J, Cook M, Uitti R, Turk M, Ajax
T, Mannetter J, Panisset M, Hall J, Sethi K, Carpenter J, Dill B, Ligon K,
Narayan S, Woodward L, Blindauer K, Abou-Samra K, Petit J, Elmer L, Aiken E,
Davis K, Schell C, Wilson S, Velickovic M, Koller W, Phipps S, Feigin A, Gordon
M, Hamann J, Licari E, Marotta-Kollarus M, Shannon B, Winnick R, Simuni T,
Kaczmarek A, Williams K, Wolff M, Rao J, Cook M, Hubble J, Kostyk S, Campbell A,
Reider C, Seward A, Nutt J, Camicioli R, Carter J, Andrews P, Morehouse S, Stone
C, Mendis T, Alcorn-Costa C, Grimes D, Gray P, Haas K, Vendette J, Sutton J,
Hutchinson B, Young J, Rajput A, Klassen L, Shirley T, Manyam B, Simpson P,
Whetteckey J, Wulbrecht B, Truong D, Pathak M, Luong N, Tra T, Tran A, Vo J, Lang
A, Johnston L, Kleiner-Fisman G, Nieves A, So J, Podskalny G, Giffin L, Atchison
P, Allen C, Martin W, Wieler M, Suchowersky O, Klimek M, Hermanowicz N, Niswonger
S, Shults C, Fontaine D, Aminoff M, Christine C, Diminno M, Hevezi J, Dalvi A,
Kang U, Richman J, Uy S, Young J, Dalvi A, Gartner M, Sahay A, Schwieterman D,
Wolthoff B, Hall D, Leehey M, Culver S, Derian T, Demarcaida T, Belber S,
Rodnitzky R, Dobson J, Pahwa R, Lyons K, Gales T, Thomas S, Shulman L, Reich S,
Weiner W, Dustin K, Singer C, Koller W, Lyons K, Weiner W, Zelaya L, Tuite P,
Hagen V, Kosowicz J, Rolandelli S, Schacherer R, Gordon P, Werner J, Serrano C,
Roque S, Kurlan R, Berry D, Gardiner I, Hauser R, Sanchez-Ramos J, Zesiewicz T,
Delgado H, Price K, Rodriguez P, Wolfrath S, Davis L, Pfeiffer B, Dewey R, Estes
B, Hayward B, Johnson A, Meacham M, Walker F, Hunt V, O'Neill C, Racette B, Good
L, Rundle M.
Associate Division of Human Genetics, Cincinnati Children's Hospital Medical
Center, Cincinnati, OH 45229, USA. bill.nichols@cchmc.org
Comment in:
Neurology. 2009 Oct 27;73(17):1424-5, author reply 1425-6.
OBJECTIVE: To characterize sequence variation within the glucocerebrosidase (GBA)
gene in a select subset of our sample of patients with familial Parkinson disease
(PD) and then to test in our full sample whether these sequence variants
increased the risk for PD and were associated with an earlier onset of disease.
METHODS: We performed a comprehensive study of all GBA exons in one patient with
PD from each of 96 PD families, selected based on the family-specific lod scores
at the GBA locus. Identified GBA variants were subsequently screened in all 1325
PD cases from 566 multiplex PD families and in 359 controls. RESULTS: Nine
different GBA variants, five previously reported, were identified in 21 of the 96
PD cases sequenced. Screening for these variants in the full sample identified
161 variant carriers (12.2%) in 99 different PD families. An unbiased estimate of
the frequency of the five previously reported GBA variants in the familial PD
sample was 12.6% and in the control sample was 5.3% (odds ratio 2.6; 95%
confidence interval 1.5-4.4). Presence of a GBA variant was associated with an
earlier age at onset (p = 0.0001). On average, those patients carrying a GBA
variant had onset with PD 6.04 years earlier than those without a GBA variant.
CONCLUSIONS: This study suggests that GBA is a susceptibility gene for familial
Parkinson disease (PD) and patients with GBA variants have an earlier age at
onset than patients with PD without GBA variants.
PMCID: 2677501
PMID: 18987351 [PubMed - indexed for MEDLINE]
14. Hum Genet. 2009 Jan;124(6):593-605. Epub 2008 Nov 6.
Genomewide association study for susceptibility genes contributing to familial
Parkinson disease.
Pankratz N, Wilk JB, Latourelle JC, DeStefano AL, Halter C, Pugh EW, Doheny KF,
Gusella JF, Nichols WC, Foroud T, Myers RH; PSG-PROGENI and GenePD Investigators,
Coordinators and Molecular Genetic Laboratories.
Collaborators: Factor S, Higgins D, Evans S, Shill H, Stacy M, Danielson J,
Marlor L, Williamson K, Jankovic J, Hunter C, Simon D, Ryan P, Scollins L,
Saunders-Pullman R, Boyar K, Costan-Toth C, Ohmann E, Sudarsky L, Joubert C,
Friedman J, Chou K, Fernandez H, Lannon L, Galvez-Jimenez N, Podichetty A,
Thompson K, Lewitt P, DeAngelis M, O'Brien C, Seeberger L, Dingmann C, Judd D,
Marder K, Fraser J, Harris J, Bertoni J, Peterson C, Rezak M, Medalle G,
Chouinard S, Panisset M, Hall J, PoiVaut H, Calabrese V, Roberge P, Wojcieszek J,
Belden J, Jennings D, Marek K, Mendick S, Reich S, Dunlop B, Jog M, Horn C, Uitti
R, Turk M, Ajax T, Mannetter J, Sethi K, Carpenter J, Dill B, Hatch L, Ligon K,
Narayan S, Blindauer K, Abou-Samra K, Petit J, Elmer L, Aiken E, Davis K, Schell
C, Wilson S, Velickovic M, Koller W, Phipps S, Feigin A, Gordon M, Hamann J,
Licari E, Marotta-Kollarus M, Shannon B, Winnick R, Simuni T, Videnovic A,
Kaczmarek A, Williams K, WolV M, Rao J, Cook M, Fernandez M, Kostyk S, Hubble J,
Campbell A, Reider C, Seward A, Camicioli R, Carter J, Nutt J, Andrews P,
Morehouse S, Stone C, Mendis T, Grimes D, Alcorn-Costa C, Gray P, Haas K,
Vendette J, Sutton J, Hutchinson B, Young J, Rajput A, Rajput A, Klassen L,
Shirley T, Manyam B, Simpson P, Whetteckey J, Wulbrecht B, Truong D, Pathak M,
Frei K, Luong N, Tra T, Tran A, Vo J, Lang A, Kleiner-Fisman G, Nieves A,
Johnston L, So J, Podskalny G, Giffin L, Atchison P, Allen C, Martin W, Wieler M,
Suchowersky O, Klimek M, Hermanowicz N, Niswonger S, Shults C, Fontaine D, AminoV
M, Christine C, Diminno M, Hevezi J, Dalvi A, Kang U, Richman J, Uy S, Young J,
Dalvi A, Sahay A, Gartner M, Hall D, Leehey M, Culver S, Derian T, Demarcaida T,
Thurlow S, Rodnitzky R, Dobson J, Lyons K, Pahwa R, Gales T, Thomas S, Shulman L,
Reich S, Weiner W, Dustin K, Lyons K, Singer C, Koller W, Weiner W, Zelaya L,
Tuite P, Hagen V, Rolandelli S, Schacherer R, Kosowicz J, Gordon P, Werner J,
Serrano C, Roque S, Kurlan R, Berry D, Gardiner I, Hauser R, Sanchez-Ramos J,
Zesiewicz T, Delgado H, Price K, Rodriguez P, Wolfrath S, Pfeiffer R, Davis L,
Pfeiffer B, Dewey R, Hayward B, Johnson A, Meacham M, Estes B, Walker F, Hunt V,
O'Neill C, Racette B, Good L, Rundle M, Nichols WC, Pauciulo MW, Marek DK,
Elsaesser VE, Lew M, Suchowersky O, Klein C, Golbe L, Mark MH, Growdon J, Huggins
N, Wooten GF, Watts R, Guttman M, Racette B, Perlmutter J, Marlor L, Shill H,
Singer C, Goldwurm S, Pezzoli G, Saint-Hilaire MH, Massood T, Baker K, Itin I,
Litvan I, Nicholson G, Corbett A, Nance M, Drasby E, Isaacson S, Burn D, Chinnery
P, Pramstaller P, Al-hinti J, Moller A, Ostergaard K, Sherman S, Roxburgh R, Snow
B, Slevin J, Cambi F, Gusella JF, McDonald ME, Sun M, Mysore L, Anderson MA,
Lucente D, Williamson S, Nagle MW, Myers RH.
Indiana University School of Medicine, Health Information and Translational
Sciences Building, Indianapolis, IN 46202-3002, USA. npankrat@iupui.edu
Five genes have been identified that contribute to Mendelian forms of Parkinson
disease (PD); however, mutations have been found in fewer than 5% of patients,
suggesting that additional genes contribute to disease risk. Unlike previous
studies that focused primarily on sporadic PD, we have performed the first
genomewide association study (GWAS) in familial PD. Genotyping was performed with
the Illumina HumanCNV370Duo array in 857 familial PD cases and 867 controls. A
logistic model was employed to test for association under additive and recessive
modes of inheritance after adjusting for gender and age. No result met genomewide
significance based on a conservative Bonferroni correction. The strongest
association result was with SNPs in the GAK/DGKQ region on chromosome 4 (additive
model: p = 3.4 x 10(-6); OR = 1.69). Consistent evidence of association was also
observed to the chromosomal regions containing SNCA (additive model: p = 5.5 x
10(-5); OR = 1.35) and MAPT (recessive model: p = 2.0 x 10(-5); OR = 0.56). Both
of these genes have been implicated previously in PD susceptibility; however,
neither was identified in previous GWAS studies of PD. Meta-analysis was
performed using data from a previous case-control GWAS, and yielded improved p
values for several regions, including GAK/DGKQ (additive model: p = 2.5 x 10(-7))
and the MAPT region (recessive model: p = 9.8 x 10(-6); additive model: p = 4.8 x
10(-5)). These data suggest the identification of new susceptibility alleles for
PD in the GAK/DGKQ region, and also provide further support for the role of SNCA
and MAPT in PD susceptibility.
PMCID: 2627511
PMID: 18985386 [PubMed - indexed for MEDLINE]
15. Clin Neuropharmacol. 2009 Mar-Apr;32(2):59-62.
Impulse control disorders arising in 3 patients treated with rotigotine.
Wingo TS, Evatt M, Scott B, Freeman A, Stacy M.
Emory University School of Medicine, Atlanta, GA, USA.
OBJECTIVE: We report 3 cases of impulse control disorders (ICDs) that developed
in patients with Parkinson disease treated with the novel dopamine agonist,
rotigotine. METHODS: Three patients were identified retrospectively who developed
symptoms of an ICD while taking rotigotine. The ICD symptoms developed at 4, 5,
and 8 years after diagnosis of Parkinson disease in these patients and while they
were taking rotigotine and levodopa. Other drugs included entacapone, amantadine,
and selegiline. The first patient developed symptoms of hypersexuality while
taking rotigotine 18 mg (40-cm2 patch) daily and levodopa 300 mg/d. The second
patient developed pathological gambling while taking rotigotine 22.5 mg (50-cm2
patch) daily and levodopa 300 mg/d. The third patient developed symptoms of
hypersexuality, punding, and pathological gambling, losing more than $100,000
while taking rotigotine 18 mg (40-cm2 patch) and levodopa 400 mg/d. In the first
2 patients, the development of the ICD was temporally associated with an increase
in rotigotine dosage, whereas the third patient experienced a dramatic increase
in his gambling with the addition of rotigotine. Both subjects who developed
pathological gambling had a history of recreational gambling for many years, and
1 of the 2 subjects who developed hypersexuality had a history of cross-dressing
since childhood. RESULT: The ICDs in these patients were effectively treated with
rotigotine reduction or discontinuation. CONCLUSION: Rotigotine has the potential
for causing ICD, similar to other dopamine agonists.
PMID: 18978496 [PubMed - indexed for MEDLINE]
16. Neurology. 2008 Oct 14;71(16):1275-82.
Update on blepharospasm: report from the BEBRF International Workshop.
Hallett M, Evinger C, Jankovic J, Stacy M; BEBRF International Workshop.
Collaborators: Ali M, Berardelli A, Daroff RB, Defazio G, Delong M, Eidelberg D,
Evinger C, Foote K, Hallett M, Hattori N, Jankovic J, Katz B, Nguyen QT, Lehericy
S, Meunier S, Morecraft RJ, Ozelius LJ, Patrinely JR, Peckham E, Perl DP,
Perlmutter JS, Scott AB, Singleton A, Stacy M, Tolosa E, Valente EM, Valls-Solé
J, Wang JJ.
Human Motor Control Section, NINDS, NIH, 10 Center Drive MSC 1428, Bethesda, MD
20892-1428, USA. hallettm@ninds.nih.gov
This review updates understanding and research on blepharospasm, a subtype of
focal dystonia. Topics covered include clinical aspects, pathology,
pathophysiology, animal models, dry eye, photophobia, epidemiology, genetics, and
treatment. Blepharospasm should be differentiated from apraxia of eyelid opening.
New insights into pathology and pathophysiology are derived from different types
of imaging, including magnetic resonance studies. Physiologic studies indicate
increased plasticity and trigeminal sensitization. While botulinum neurotoxin
injections are the mainstay of therapy, other therapies are on the horizon.
PMCID: 2676990
PMID: 18852443 [PubMed - indexed for MEDLINE]
17. Mov Disord. 2008 Nov 15;23(15):2216-23.
Clinical correlates of depressive symptoms in familial Parkinson's disease.
Pankratz N, Marder KS, Halter CA, Rudolph A, Shults CW, Nichols WC, Foroud T;
Parkinson's Study Group-PROGENI Investigators.
Collaborators: Shults C, Marshall F, Oakes D, Rudolph A, Shinaman A, Marder K,
Conneally PM, Foroud T, Halter C, Lyons K, Siemers E, Factor S, Higgins D, Evans
S, Shill H, Stacy M, Danielson J, Marlor L, Williamson K, Jankovic J, Hunter C,
Simon D, Ryan P, Scollins L, Saunders-Pullman R, Boyar K, Ohmann E, Sudarsky L,
Joubert C, Friedman J, Chou K, Fernandez H, Lannon M, Galvez-Jimenez N,
Podichetty A, Lewitt P, DeAngelis M, O'Brien C, Seeberger L, Dingmann C, Judd D,
Marder K, Fraser J, Harris J, Bertoni J, Peterson C, Chouinard S, Panisset M,
Hall J, Poiffaut H, Calabrese V, Roberge P, Wojcieszek J, Belden J, Halter C,
Jennings D, Marek K, Mendick S, Reich S, Dunlop B, Jog M, Horn C, Rao J, Cook M,
Uitti R, Turk M, Ajax T, Mannetter J, Panisset M, Hall J, Sethi K, Carpenter J,
Ligon K, Narayan S, Woodward L, Blindauer K, Petit J, Elmer L, Aiken E, Davis K,
Schell C, Wilson S, Velickovic M, Koller W, Phipps S, Feigin A, Gordon M, Hamann
J, Licari E, Marotta-Kollarus M, Shannon B, Winnick R, Simuni T, Kaczmarek A,
Williams K, Wolff M, Fernandez M, Hubble J, Kostyk S, Campbell A, Reider C,
Camicioli R, Carter J, Andrews P, Morehouse S, Stone C, Mendis T, Grimes D, Gray
P, Haas K, Sutton J, Hutchinson B, Young J, Rajput A, Klassen L, Shirley T,
Manyam B, Simpson P, Whetteckey J, Wulbrecht B, Truong D, Pathak M, Luong N, Tra
T, Tran A, Vo J, Lang A, Kleiner-Fisman G, Nieves A, So J, Podskalny G, Giffin L,
Atchison P, Allen C, Martin W, Wieler M, Suchowersky O, Klimek M, Hermanowicz N,
Niswonger S, Shults C, Fontaine D, Aminoff M, Christine C, Diminno M, Hevezi J,
Dalvi A, Kang U, Richman J, Uy S, Young J, Dalvi A, Sahay A, Schwieterman D,
Leehey M, Culver S, Derian T, Demarcaida T, Belber S, Dobson J, Pahwa R, Lyons K,
Gales T, Thomas S, Shulman L, Reich S, Weiner W, Dustin K, Singer C, Koller W,
Lyons K, Weiner W, Zelaya L, Tuite P, Hagen V, Rolandelli S, Schacherer R, Gordon
P, Werner J, Serrano C, Roque S, Kurlan R, Berry D, Gardiner I, Hauser R,
Sanchez-Ramos J, Zesiewicz T, Delgado H, Price K, Rodriguez P, Pfeiffer R, Davis
L, Pfeiffer B, Dewey R, Hayward B, Meacham M, Walker F, Hunt V, Racette B, Good
L, Rundle M, Oakes D, Watts A, Wang A, Ross T, Bennett S, Kamp D, Julian-Baros E.
Department of Medical and Molecular Genetics, Indiana University, Indianapolis,
Indiana 46202, USA. npankrat@iupui.edu
Depression is one of the most common nonmotor complications of Parkinson's
disease (PD) and has a major impact on quality of life. Although several clinical
factors have been associated with depression in PD, the relationship between
depression and stage of illness as well as between depression and degree of
disability remains controversial. We have collected clinical data on 1,378 PD
cases from 632 families, using the Unified Parkinson's Disease Rating Scale
(UPDRS) Parts II (activities of daily living) & III (motor), the Mini-Mental
State Exam, the Geriatric Depression Scale (GDS), and the Blessed Functional
Activity Scale (Blessed). Analyses were performed using the 840 individuals with
verified PD and without evidence of cognitive decline. Logistic regression was
used to identify study variables that individually and collectively best
predicted the presence of depressive symptoms (GDS >or= 10). After correcting for
multiple tests, depressive symptoms were significantly associated with Hoehn and
Yahr stage and other clinical measures but not with any genetic variant (parkin,
LRRK2, APOE). The Blessed score, education, presence of a first degree relative
with signs of depression, and UPDRS Part II were found to best predict depressive
symptomatology (R(2) = 0.33; P = 4 x 10(-48)). Contrary to several reports, the
results from this large study indicate that stage of illness, motor impairment,
and functional disability are strongly correlated with depressive symptoms.
PMID: 18785635 [PubMed - indexed for MEDLINE]
18. CNS Spectr. 2008 Aug;13(8):690-8.
Impulse-control disorders in Parkinson's disease.
Ferrara JM, Stacy M.
Baylor College of Medicine, Houston, TX, USA.
Parkinson's disease is a neurodegenerative disorder characterized by
bradykinesia, rigidity, postural instability, and resting tremor. Increasingly,
Parkinson's disease has been associated with a broad spectrum of non-motor
symptoms, such as olfactory loss, sleep disorders, autonomic dysfunction,
cognitive impairment, psychosis, depression, anxiety, and apathy. In addition, a
minority of Parkinson's disease patients develop compulsive behaviors while
receiving dopamine-replacement therapy, including medication hoarding,
pathological gambling, binge eating, hyperlibidinous behavior, compulsive
shopping, and punding. These behaviors may result in psychosocial impairment for
patients and therapeutic challenges for clinicians. This article reviews the
anatomic substrates, behavioral spectrum, associated factors, and potential
treatments for dopamine-replacement therapy-related compulsions in Parkinson's
disease.
PMID: 18704024 [PubMed - indexed for MEDLINE]
19. 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]
20. Neurol Clin. 2008 May;26 Suppl 1:23-42.
Epidemiology, clinical presentation, and diagnosis of cervical dystonia.
Stacy M.
Duke University Medical Center, 932 Morreene Road, Durham, NC 27705, USA.
stacy002@mc.duke.edu
PMID: 18603166 [PubMed - indexed for MEDLINE]
21. Neurology. 2008 Jun 3;70(23):2233-40.
A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson
disease.
Stacy M, Silver D, Mendis T, Sutton J, Mori A, Chaikin P, Sussman NM.
Division of Neurology, Duke University Medical Center, Durham, NC 27705, USA.
mark.stacy@duke.edu
Erratum in:
Neurology. 2008 Sep16;71(12): 953.
BACKGROUND: The safety and efficacy of istradefylline, a selective adenosine
A(2A) receptor antagonist, was evaluated in a 12-week, double-blind study in
levodopa-treated Parkinson disease (PD) subjects with motor complications.
METHODS: Levodopa-treated PD subjects (n = 395) received istradefylline 20 mg/day
(n = 163), istradefylline 60 mg/day (n = 155), or placebo (n = 77) at 40 sites.
The primary efficacy variable was the change in the percentage of time per day
spent in the OFF state. Secondary measurements assessed change in ON time,
Unified Parkinson's Disease Rating Scale, and Clinical Global Impression. Safety
monitoring included clinical laboratory, electrocardiograms, vital signs,
physical/neurologic examinations, and adverse events (AEs). RESULTS: Changes from
baseline to endpoint in the percentage OFF time in the active groups compared
with placebo were -4.35% (95% CI -8.16 to -0.54; p = 0.026) for istradefylline 20
mg/day and -4.49% (95% CI -8.35 to -0.62; p = 0.024) for 60 mg/day; these changes
were significant (analysis of covariance). For total hours, istradefylline
demonstrated mean differences from placebo of -0.64 hours (95% CI -1.30 to 0.01)
for 20 mg/day and -0.77 hours (95% CI -1.44 to -0.11) for 60 mg/day (p = 0.065;
overall treatment effect). Clinical response occurred by the second week and was
maintained throughout the study. Istradefylline was well tolerated. The common
AEs were dyskinesia, nausea, dizziness, and hallucinations. CONCLUSIONS:
Istradefylline demonstrated a significant reduction in the percentage of awake
time per day spent in the OFF state, which resulted in a clinically meaningful
reduction in OFF time, without an increase in ON time with troublesome
dyskinesia, and was well tolerated as adjunctive treatment to levodopa in
Parkinson disease.
PMID: 18519872 [PubMed - indexed for MEDLINE]
22. Arch Neurol. 2008 Jun;65(6):716-23. Epub 2008 Apr 14.
Serum urate as a predictor of clinical and radiographic progression in Parkinson
disease.
Schwarzschild MA, Schwid SR, Marek K, Watts A, Lang AE, Oakes D, Shoulson I,
Ascherio A; Parkinson Study Group PRECEPT Investigators, Hyson C, Gorbold E,
Rudolph A, Kieburtz K, Fahn S, Gauger L, Goetz C, Seibyl J, Forrest M, Ondrasik
J.
Collaborators: Kumar R, Jog M, Horn C, Shannon K, Leehey M, Derian T, Grimes D,
Mortensen M, Tuite P, Hermanowicz N, Niswonger S, Kurlan R, Gardiner I, Miyasaki
J, Johnston L, Tetrud J, Friedman J, Fernandez H, Rodnitzky R, Dobson J, Evidente
V, Lind M, Andrews P, Panisset M, Racette B, Deppen P, Jankovic J, Hunter C,
Molho E, Factor S, Wojcieszek J, Scott B, Subramanian T, Kolb R, Siderowf A,
Hauser R, Savitt J, Gerstenhaber M, Sahay A, Gartner M, Turk M, Rivest J, Wooten
F, Schwarzschild M, Tennis M, Sethi K, Hatch L, Pfeiffer R, Pfeiffer B, Feigin A,
Simuni T, Williams K, Elmer L, deMarcaida A, Thurlow S, Chouinard S, Poiffaut H,
Shill H, Stacy M, Zweig R, Feldt R, Waters C, Pahwa R, Parsons A, Hui J, Wu A,
Camicioli R, King P, Dalvi A, Kang UJ, Reich S, Shulman L, Mark M, Rajput A, Song
D, Bertoni JM, Peterson C, Blindauer K, Petit J, Manyam B, Suchowersky O,
Sudarsky L, Tarsy D, Gordon MF, DiRocco A, Andrzejewski A, Galvez-Jimenez N,
Harik S, Tabbal S.
MassGeneral Institute for Neurodegenerative Disease, Massachusetts General
Hospital, Boston, USA.
Comment in:
Arch Neurol. 2008 Jun;65(6):698-9.
OBJECTIVE: To determine whether concentration of serum urate, a purine metabolite
and potent antioxidant that has been linked to a reduced risk of Parkinson
disease (PD), predicts prognosis in PD.
DESIGN: Prospective study. SETTING: The
Parkinson Research Examination of CEP-1347 Trial (PRECEPT) study, which
investigated the effects of a potential neuroprotectant on rates of PD
progression, was conducted between April 2002 and August 2005 (average follow-up
time 21.4 months). PARTICIPANTS: Eight hundred four subjects with early PD
enrolled in the PRECEPT study.
MAIN OUTCOME MEASURES: The primary study end point
was progression to clinical disability sufficient to warrant dopaminergic
therapy. Cox proportional hazards models were used to estimate the hazard ratio
(HR) of reaching end point according to quintiles of baseline serum urate
concentration, adjusting for sex, age, and other potential covariates. Change in
striatal uptake of iodine I 123-labeled
2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([(123)I]beta-CIT), a marker for
the presynaptic dopamine transporter, was assessed with linear regression for a
subset of 399 subjects.
RESULTS: The adjusted HR of reaching end point declined
with increasing baseline concentrations of urate; subjects in the top quintile
reached the end point at only half the rate of subjects in the bottom quintile
(HR, 0.51; 95% confidence interval [CI], 0.37-0.72; P for trend < .001). This
association was markedly stronger in men (HR, 0.39; 95% CI, 0.26-0.60; P for
trend < .001) than in women (HR, 0.77; 95% CI, 0.39-1.50; P for trend = .33). The
percentage of loss in striatal [(123)I]beta-CIT uptake also improved with
increasing serum urate concentrations (overall P for trend = .002; men, P = .001;
women, P = .43). CONCLUSIONS: These findings identify serum urate as the first
molecular factor directly linked to the progression of typical PD and suggest
that targeting urate or its determinants could be an effective disease-modifying
therapy in PD. Trial Registration clinicaltrials.gov Identifier: NCT00040404.
PMCID: 2574855
PMID: 18413464 [PubMed - indexed for MEDLINE]
23. Clin Neuropharmacol. 2008 Mar-Apr;31(2):120-5.
Optimizing long-term therapy for Parkinson disease: options for
treatment-associated dyskinesia.
Stacy M, Galbreath A.
Division of Neurology, Duke University Medical Center, Durham, NC 27705, USA.
mark.stacy@duke.ed
There is currently no satisfactory treatment for dyskinesia in patients with
Parkinson disease because most antidyskinetic strategies have the effect of
aggravating Parkinsonian symptoms, and most pharmacological strategies for
reducing "off" periods have increased dyskinesia as a treatment complication.
Therefore, physicians and patients often have to balance treatment of its effects
on Parkinsonian symptoms and on dyskinesia. In patients with advanced Parkinson
disease, it is often not possible to induce periods of good mobility without
dyskinesia.
PMID: 18382184 [PubMed - indexed for MEDLINE]
24. BMC Neurol. 2008 Mar 28;8:6.
Pesticide exposure and risk of Parkinson's disease: a family-based case-control
study.
Hancock DB, Martin ER, Mayhew GM, Stajich JM, Jewett R, Stacy MA, Scott BL, Vance
JM, Scott WK.
Center for Human Genetics, Duke University Medical Center, Durham, NC, USA.
dana.hancock@duke.edu
BACKGROUND: Pesticides and correlated lifestyle factors (e.g., exposure to
well-water and farming) are repeatedly reported risk factors for Parkinson's
disease (PD), but few family-based studies have examined these relationships.
METHODS: Using 319 cases and 296 relative and other controls, associations of
direct pesticide application, well-water consumption, and farming
residences/occupations with PD were examined using generalized estimating
equations while controlling for age-at-examination, sex, cigarette smoking, and
caffeine consumption. RESULTS: Overall, individuals with PD were significantly
more likely to report direct pesticide application than their unaffected
relatives (odds ratio = 1.61; 95% confidence interval, 1.13-2.29). Frequency,
duration, and cumulative exposure were also significantly associated with PD in a
dose-response pattern (p
TITLE: Respiratory function in Parkinson's disease. AUTHORS: Shill H; Stacy M AUTHOR AFFILIATION: Barrow Neurological Institute, Phoenix, Arizona, USA. SOURCE: Clin Neurosci 1998;5(2):131-5 CITATION IDS: PMID: 10785839 UI: 20247545 ABSTRACT: This article reviews the spectrum of respiratory dysfunction in Parkinson's disease (PD). It includes the primary effects of PD on the ventilation, response to medications, and pulmonary complications of antiparkinson therapy. Primary pulmonary abnormalities include a restrictive change mainly secondary to chest wall rigidity and upper airway obstruction; both are responsive to dopaminergic modulation. Respiratory dyskinesia, a side effect of levodopa therapy, may produce both restrictive and dyskinetic ventilation. Therapy with ergot derivatives may result in pleuropulmonary fibrosis. Lastly, pulmonary infection as a consequence of disordered respiratory mechanics continues to contribute significantly to morbidity and mortality in PD. 2000/05 2000/16 09:00 -------------------------------------------------------------------------------- TITLE: Pharmacotherapy for advanced Parkinson's disease. AUTHORS: Stacy M AUTHOR AFFILIATION: Muhammad Ali Parkinson Center, Barrow Neurological Institute, Phoenix, Arizona 85213, USA. SOURCE: Pharmacotherapy 2000 Jan;20(1 Pt 2):8S-16S CITATION IDS: PMID: 10641987 UI: 20104973 ABSTRACT: Medical management of Parkinson's disease consists of two strategies. A presynaptic strategy attempts to maintain physiologic synaptic concentrations of dopamine, usually by individualizing delivery of levodopa (or exogenous dopamine) by varying the rate of gastrointestinal absorption or blood-brain barrier passage. A postsynaptic strategy bypasses degenerating nigrostriatal neurons by stimulating striatal neurons directly with dopamine agonists. With advancing disease, motor fluctuations appear, related to physiologic changes that narrow the window of levodopa concentration in which symptoms are under control. Then it becomes necessary to add dopamine agonists to therapy. 2000/01 2000/21 09:00 -------------------------------------------------------------------------------- TITLE: Parkinson's disease: therapeutic choices and timing decisions in patient management [interview by Wayne Kuznar] AUTHORS: Stacy M AUTHOR AFFILIATION: National Parkinson Foundation, Phoenix, AZ, USA. SOURCE: Geriatrics 1999 Oct;54(10):44-9; quiz 50 CITATION IDS: PMID: 10542860 UI: 20010573 ABSTRACT: Parkinson's disease is a progressive neurodegenerative disorder characterized by striatal dopaminergic loss. Carbidopa/levodopa is the most effective drug treatment for disease management. It reduces bradykinesia and rigidity, but is less effective against tremor. Whether carbidopa/levodopa should be used at the time of initial diagnosis or delayed until symptoms become disabling is controversial. A clinical trial is in progress to help resolve this dilemma. As carbidopa/levodopa loses efficacy with continued use, adjunct therapies using catechol-O-methyl-transferase inhibitors or dopamine agonists may be considered. In younger patients exhibiting parkinsonian symptoms, dopamine agonists may be used as first-line therapy. A new, reversible surgical intervention known as deep-brain stimulator placement is being used to control disabling tremor in patients not responding to optimal drug therapy. 1999/10 1999/30 09:00 -------------------------------------------------------------------------------- TITLE: Differential diagnosis of Parkinson's disease and the parkinsonism plus syndromes. AUTHORS: Stacy M; Jankovic J AUTHOR AFFILIATION: Department of Neurology, University of Missouri, School of Medicine, Columbia. SOURCE: Neurol Clin 1992 May;10(2):341-59 CITATION IDS: PMID: 1584178 UI: 92261523 ABSTRACT: Although Parkinson's disease (PD) is thought to represent a specific clinical-pathologic entity, up to 20% of patients diagnosed as having PD will have another disorder at autopsy. Furthermore, pathologic features typically associated with PD can also be observed in patients with other neurodegenerative disorders. This article attempts to point out the difficulties in differentiating PD from progressive supranuclear palsy and other parkinsonism plus syndromes and various causes of parkinsonism associated with cognitive changes. The clinical and pathologic differentiation of these disorders are discussed. These disorders are usually associated with postsynaptic receptor changes and therefore levodopa and dopamine agonists provide limited benefit. 1992/05 1992/01 00:00 --------------------------------------------------------------
------------------ TITLE: Tardive tremor. AUTHORS: Stacy M; Jankovic J AUTHOR AFFILIATION: Department of Neurology, Baylor College of Medicine, Houston, Texas 77030. SOURCE: Mov Disord 1992;7(1):53-7 CITATION IDS: PMID: 1348352 UI: 92212338 ABSTRACT: A variety of hyperkinetic movement disorders has been associated with the use of neuroleptics (dopamine receptor blocking drugs), but tardive tremor has not been previously documented. We describe five patients in whom tremor occurred after chronic treatment with neuroleptics, was aggravated by and persisted after neuroleptic withdrawal, and improved after treatment with the dopamine depleting drug tetrabenazine. This involuntary oscillatory movement, with a frequency range of 3-5 Hz, was most prominent during maintenance of a posture, but was also present at rest and during a goal-directed movement. The tremor was accompanied by other tardive movement disorders, including akathisia, chorea, dystonia, myoclonus, and stereotypy. There was no family history or other explanation for tremor in these patients. We suggest that this hitherto unreported movement disorder is best termed "tardive tremor." 1992/01 1992/01 00:00 Return To Index of Current Parkinson's Topics
