Movement Disorder Highlights From the 57th Annual AAN Meeting
Four studies expand the understanding of the role of the LRRK2 gene in Parkinson's disease (PD). The clinical features of PD caused by LRRK2 mutations are typical for late-onset PD, according to 2 reports from different populations. The G2019S mutation is especially common among North Africans. And the first molecular characterization of the lrrk2 protein suggests that 2 mutations in 2 different domains have 2 different effects on the function of the protein.
Parkinson's Disease Related to the Basque Dardarin Mutation
Marti Masso JF, Paisan Ruiz C, Simon J, et al
S17.002
Clinical features were determined for 35 PD patients with LRRK2 mutations, including 22 from 4 previously identified families, 9 patients in 7 new families, and 4 sporadic patients. All had the R1396G mutation. Mean age at onset was 63 years, with unilateral rest tremor of the lower leg the most common presenting symptom. Of 33 treated with levodopa, all had a good response with typical motor complications after several years of treatment.
The Clinical Features and Frequency of LRRK2 Associated Parkinson's Disease in Central Norway
Aasly JO, Toft M, Fernandez-Mata I, et al
S17.003, A148
Of 435 PD patients referred to a single hospital in central Norway, 9 (2%) were heterozygous for the G2019S mutation. The same mutation was found in 10 of 26 first-degree relatives and in 0 of 724 unrelated, unaffected controls. In 2 cases, no family history was reported or found. Mean age of onset was 57, with tremor or bradykinesia as the most common presenting symptom. All patients were levodopa-responsive, and dyskinesias were common.
The G2019S LRRK2 Mutation in Autosomal Dominant European and North African Parkinson's Disease Is Frequent and Its Penetrance Is Age-Dependent
Lesage S, Ibanez P, Lohmann E, et al
LBS.003
Analysis of 200 index cases of autosomal dominant PD revealed that among North Africans, 41% were associated with LRRK2 mutation, while among Europeans, the frequency was 2.8%.
Molecular Characterization of LRRK2, the Gene Responsible for Autosomal Dominant PARK8
Taylor JP, Lincoln S, Pielsticker L, Farrer MJ
P02.037, A88
Two identified mutations in LRRK2 appear to have different effects on the lrrk2 protein, according to this report. LRRK2 was expressed in cell lines and localized by a fluorescent tag. Protein from the R1441C mutant formed cytoplasmic inclusions. Homology modeling of the Roc domain that bears this mutation suggested it is responsible for interacting with other proteins. Protein from the G2019S mutant formed no inclusions and appeared to be distributed normally. Homology modeling of the MAPKKK domain bearing this mutation suggests that the mutation may lead to overactivity of the kinase function.
Discordant Sibling Analysis Confirms the Association of UCHL1 With Parkinson's Disease
Maraganore DM, Facheris M, Lesnick TG, et al
P01.102, A58
The S18Y variant of UCHL1 is inversely associated with risk of PD, according to this study. Genotyping was performed in 496 case-control pairs (496 PD cases, 434 unaffected sibling controls, 62 unaffected unrelated controls where no sibling was available). The S18Y variant was significantly less common in cases than in controls (odds ratio [OR] = .18; P = .004), a relationship that remained significant even when previously published cases and unrelated controls were excluded. The authors note, "The UCHL1 S18Y variant encodes a UCHL1 protein that is unable to form dimers, thus favoring the degradation of alpha-synuclein via the ubiquitin-proteasome pathway."
Mitochondrial ND5 Mutations in Idiopathic Parkinson's Disease
Parker WD, Parks JK
P02.042, A89
A mitochondrial complex I mutation is more common in PD cases than in controls, according to this report. Mitochondrial DNA from 8 idiopathic PD cases and 8 age-matched controls was amplified and sequenced prospectively. Missense mutations in the gene for the ND5 subunit of complex I were found in all PD cases and only 1 control. The mutations were found in 1% to 8% of mitochondrial chromosomes in affected individuals. The authors note that very high abundance of 2 of the identified mutations has been previously associated with early-onset neurodegenerative diseases.
Molecular Study of Parkin in 300 Patients With Early Onset Parkinson's Disease
Garavaglia B, Ghezzi D, Marelli E, et al
P02.036, A88
Among 300 patients with early-onset PD (278 sporadic, 22 familial), 47 parkin-positive patients were identified: 22 homozygous, 15 compound heterozygous, and 10 with only 1 mutation (as confirmed by quantitative reverse-transcriptase polymerase chain reaction [RT-PCR]). Among sporadic cases, 38 (14%) had mutations, with greater frequency among younger patients. The authors state, "The frequency of a single heterozygous mutation in our cohort of positive patients (21.3%) reinforces the hypothesis of a haplo-insufficiency and/or a dominant negative allele mechanism of certain mutations in the parkin gene."
The Mayo Clinic Cohort Study of Personality and Aging: Results for Parkinson's Disease
Bower JH, Grossardt BR, Maraganore DM, et al
S39.004, A282-283
The presence of an anxious personality is associated with development of PD later in life, according to this study. Among more than 7000 subjects who completed the Minnesota Multiphasic Personality Inventory in the 1960s, medical record follow-up identified 68 cases of PD. Cases were age- and sex-matched with up to 5 controls within the same cohort. Subjects who scored within the top quartile on psychasthenia (a measure of anxiety) were approximately twice as likely to develop PD over the next 40 years as those in lower quartiles. No association was found for depression, social introversion, or optimism. "It remains unclear whether anxiety is a risk factor for PD, an early manifestation of PD, or linked to PD via common risk factors or a common genetic predisposition," the authors state.
The Mayo Clinic Cohort Study of Oophorectomy and Aging: Results for Parkinsonism and Parkinson's Disease
Rocca WA, Grossardt BR, Bower JH, et al
S39.005, A283
Bilateral oophorectomy increases the risk of parkinsonism and PD, according to this study. Medical record follow-up identified 1202 women who underwent bilateral oophorectomy and 1283 who underwent unilateral oophorectomy between 1950 and 1987. Compared with age-matched subjects from the same area, women receiving bilateral, but not unilateral, oophorectomy had twice the risk of developing parkinsonism or PD. "Bilateral oophorectomy is the major cause of reduced endogenous estrogen during fertile life," the authors note, and suggest this is the likely reason for the association.
Nonsteroidal Antiinflammatory Drugs and the Risk of Parkinson's Disease
Chen H, Jacobs E, Schwarzschild M, et al
P05.073, A311
Ibuprofen reduces the risk of developing PD, according to this study. Incident cases of PD were identified from more than 146,000 participants in the American Cancer Society's Cancer Prevention Study II Nutrition Cohort. PD risk was lower (relative risk = 0.65) for ibuprofen users vs nonusers, unaffected by age, sex, or smoking. No effect was found for acetaminophen, aspirin, or other nonsteroidal anti-inflammatory drugs (NSAIDs).
Cocaine Abuse Triggers Abnormal Expression of Alpha-Synuclein Expression in DA Cell Bodies and Terminals
Mash DC, Qin Y, Ouyang Q, et al
P06.053, A355
Postmortem analysis of substantia nigra and striatum from 10 cocaine abusers showed that alpha-synuclein levels were elevated 3-fold compared with age-matched controls (P = .01). No elevation was seen in the anterior caudate nucleus. Dopamine uptake was elevated 2-fold in the ventrolateral and ventromedial putamen in cocaine abusers, as determined by assays on synaptosomal fractions. The authors conclude, "These observations suggest that alpha-synuclein expression may play a role in dopamine-mediated adaptive mechanisms in the striatum from cocaine abusers," possibly placing abusers at increased risk for PD.
The Effects of Expiratory Muscle Strength Training on Pharyngeal Swallowing in Patients With Idiopathic Parkinson's Disease
Sapienza CM, Rosenbek JC, Musson ND, Okun M
S47.008, A397
A simple breathing exercise program improves swallowing efficiency in people with PD, according to this study. Ten PD patients (mean Hoehn and Yahr stage 2.6) underwent a 4-week home-based training program to develop expiratory muscle strength. Patients exerted sustained expiratory pressure while attempting to exhale through a valve set to open only at near-maximal expiratory pressure, adjusted for each patient. This exercise develops the suprahyoid muscles, which promote efficient swallowing. Training resulted in a 50% improvement in mouth expiratory pressure, and increased swallowing efficiency with less retention of food at the laryngeal opening after swallowing. "This program may have the long-term potential for reducing the life-threatening risk of aspiration pneumonia," according to the authors.
The Evolution of Disability in Parkinson's Disease
Shulman LM, Gruber-Baldini AL, Anderson KE, et al
S47.002
Evaluation of 388 PD patients (mean age, 66 years; 6.5 years since diagnosis) with the Unified Parkinson Disease Rating Scale (UPDRS) and the Older Americans Resources and Services Scale ADL and Instrumental ADL (IADL) sections revealed that loss of independence in ADLs occurred first for walking, dressing, and getting in and out of bed, and last for eating and toileting. Loss of IADLs occurred first for housework, traveling, and shopping, and last for using the telephone, taking medicines independently, and handling money. "Gait impairment is the leading edge of disability in PD," the authors conclude, because it heralds the loss of many gait-dependent activities.
Long-term Follow-up of Patients With Scans Without Evidence of Dopaminergic Deficit (SWEDD) in the ELLDOPA Study
Marek KL, Jennings DL, Seibyl JP
S34.004, A274
Scans Without Evidence of Dopaminergic Deficit (SWEDD) patients probably do not have PD, according to this study. Subjects from the Early versus Late Levodopa (ELLDOPA) study whose baseline and end-of-study scans showed no evidence of dopaminergic deficit were followed for up to 4 years. Of the 142 patients in the ELLDOPA study, 21 were defined as SWEDD patients. Normal scans were obtained for 19 of 19 at 9 months, 17 of 17 at 18 months, 12 of 12 at 36 months, and 10 of 10 at 48 months. In blinded evaluations by 5 movement disorders experts reviewing video of UPDRS "off-state" examinations, 3 or more evaluators doubted the diagnosis of PD in the majority of cases. "The balance of evidence suggests that ELLDOPA subjects with SWEDD do not have PD," the authors conclude. "Dopaminergic imaging at baseline should be considered as an inclusion criterion in future studies evaluation early Parkinson's disease patients." A previous E-MOVE report on the ELLDOPA study is archived at http://www.mdvu.org/emove/article.asp?ID=516 .
Long-term Benefits of Rivastigmine in Dementia Associated With Parkinson's Disease: An Open-label Extension Study
Poewe W, EXPRESS Study Group
P02.096, A105
Rivastigmine improves cognitive performance in PD patients for up to 48 weeks, according to this study.
PD patients with dementia were randomly assigned to receive placebo or rivastigmine at 3-12 mg/day for 24 weeks. Patients completing the trial were offered open-label treatment with rivastigmine for an additional 24 weeks. Of 541 who were enrolled in the double-blind trial, 433 completed it; 334 entered the open-label extension; and 273 completed that. By the end of the double-blind phase, rivastigmine-treated patients had improved by 3.5 points (15%) over baseline on the Alzheimer's Disease Assessment Scale-cognitive subscale, while placebo-treated patients declined by .5 points. During the open-label phase, patients originally receiving rivastigmine declined to 2.0 points above baseline, and patients originally receiving placebo improved to 2.0 points above baseline. Adverse events were predominantly cholinergic, and included nausea (19% of patients), vomiting (11%), tremor (7%), falls (5%), confusion (5%), and hallucinations (5%). Supported by Novartis Neuroscience
Cholinergic Denervation Is Associated With More Severe Depression in Parkinson's Disease
Bohnen I, Kaufer DI, Ivanco LS, et al
P04.057, A222
Age-matched controls (n = 14) and PD patients with (n = 10) and without (n = 13) dementia underwent acetylcholinesterase positron emission tomographic (PET) imaging and testing for depression with the Cornell depression rating scale. Parkinson's disease dementia (PDD) patients had higher depression ratings compared with both nondemented PD patients and controls (scores were 10.2, 5.9, and 2.7, respectively). Acetylcholinesterase hydrolysis rates were inversely correlated with depression scores (P = .001). "These data indicate that cortical cholinergic denervation is associated with more severe depressive symptomatology in PD and worsens with the development of dementia," according to the authors.
Onset and Severity of Levodopa-Induced Dyskinesias in Parkinson's Disease Patients in Olmstead County, Minnesota, 1976-1990
Van Gerpen JA, Kumar N, Bower JH, Ahlskog JE
P04.095, A233
Medical records were reviewed for 126 incident PD cases with onset from 1976 to 1990. Median age of onset was 68.6 years, with treatment onset at 71.1 years. The probability of levodopa-induced dyskinesias of any severity was 30% after 5 years of treatment and 59% after 10 years. Risk of dyskinesias sufficiently severe enough to require treatment adjustment was 17% and 43% at those time points. Risk of dyskinesias whose control undermined control of parkinsonism was 12% at 10 years. These figures are "substantially less than previously has been reported, perhaps reflecting a more typical age distribution of Parkinson's disease," the authors state.
Effect of STNDBS on Quality of Life in Parkinson's Disease Depends Upon Time of Assessment!
Gronchi-Perrin A, Violier S, Combremont P, et al
P05.144, A331-332
Subthalamic nucleus deep brain stimulation (STN DBS) improves quality of life (QOL), but patient assessment of the degree of improvement is compromised by a retrospective overestimate of their preoperative QOL, according to this study.
Fourteen PD patients completed QOL assessments preoperatively and 6 months postoperatively. At the 6-month assessment, they were also asked to assess preoperative QOL. Postoperative PDQ-39 scores improved by 28% over preoperative. However, postoperative assessment of preoperative function underestimated disability by 16%; when this estimate was used instead of the actual preoperative assessment, surgery offered no significant benefit. "Such discrepancy should be taken into account in the interpretation of auto-evaluative questionnaires not only in studies, but also in the daily care of each patient," the authors conclude.
Essential Tremor Is Associated With an Increased Risk of Dementia in a Community-Based Longitudinal Study
Benito-Leon J, Bermejo-Pareja F, Louis ED
P04.163, A253-254
A door-to-door survey of 4880 elderly people in central Spain in 1994-1995 revealed 240 essential tremor (ET) patients. Follow-up after a mean of 3.2 years indicated that 3.5% of 3541 non-ET subjects had developed dementia, while 7.4% of 202 ET patients had (relative risk 2.17, 95% confidence interval [CI] 1.27-3.72; P = .005). The increased risk remained significant after adjusting for sex, age, and education.
Olfaction Is Normal in Essential Tremor and Can Be Used to Distinguish It From Parkinson's Disease
Shah M, Findley L, Muhammed N, Hawkes C
S27.001, A261
Two forms of smell tests were administered to 59 ET patients, 65 PD patients, and 74 controls. Tests used were the 40-odorant University of Pennsylvania Smell Identification Test (UPSIT) and olfactory-evoked potentials (OEP) in response to hydrogen sulfide. Mean UPSIT scores were 33 for controls, 32 for ET patients, and 18 for PD patients. OEP values were normal in all but 4 ET patients (which included at least 1 patient who didn't receive testing). Forty percent of PD patients had no recordable OEP, and the remainder had significantly prolonged latency with normal amplitude. "A normosmic patient with tremor is more likely to have ET than PD," the authors conclude.
DYT-1 and Dopamine-Responsive Dystonia and Pregnancy
Shanker VL, Bressman SB, Raymond D, et al
S07.005, A130
Complications of pregnancy were assessed by self-administered questionnaire in 17 women with dopamine-responsive dystonia (DRD; 45 pregnancies), 16 women with DYT1 dystonia (39 pregnancies), and 24 unaffected spouses of men with dystonia (66 pregnancies). First-trimester miscarriage rate was highest among DYT1 women (31% vs 16% for DRD and 12% for unaffected spouses, P = .057). The rate for cesarean section was lower in women with dystonia than unaffected women. No women with dystonia experienced premature rupture of membranes.
Electrophysiologic Evaluation of Yips-Affected and Unaffected Golfers: Evidence for a Task-Specific Dystonia
Adler CH, Crews D, Hentz JG, et al
P06.146, A381
Twenty age- and handicapped-matched golfers, 10 with and 10 without the yips, were examined with surface electromyography (EMG) at rest, during handwriting, holding a putter, and while putting. The yips is the inability to complete a golf stroke, typically during putting or chipping, that occurs in golfers and worsens with anxiety. No abnormal EMG was observed during any activity except active putting. Upon putting, 5 of 10 yips-affected and 0 of 10 unaffected golfers had co-contraction of the wrist flexor/extensors 200 ms prior to contact of ball and putter. "The presence of co-contraction, the electrophysiologic hallmark of task-specific dystonias such as writer's cramp and musician's cramp, during putting in 50% of the yips-affected and none of the yips-unaffected golfers would support the yips possibly being a focal dystonia," the authors conclude.
CSF Iron Status Relates to the Age of Symptom Onset for Restless Legs Syndrome
Early CJ, Gamaldo C, Allen R
S04.001, A26
Levels of iron were analyzed in 15 patients with early-onset restless legs syndrome (RLS) and 15 with late-onset RLS without iron deficiency and not taking iron medications. Early-onset patients had slightly worse Johns Hopkins RLS symptoms scores (2.0 vs 1.5). Early-onset patients had significantly lower cerebrospinal fluid (CSF) ferritin (2.1 vs 2.8 mcg/L; P < .005) and slightly higher CSF transferrin than late-onset patients. For all patients, age at symptom onset correlated with CSF ferritin and CSF transferrin, driven primarily by high correlation among the subgroup of early-onset patients, with no significant correlation among the subgroup of late-onset patients. The authors suggest that central nervous system (CNS) ferritin "may provide a measure of the degree of CNS pathology producing RLS, further supporting a causal relation between compromised CNS iron status and RLS."
Preliminary Study of the Natural History of the Fragile X Associated Tremor/Ataxia Syndrome (FXTAS)
Leehey MA, Hall D, Rice C, et al
P02.053, A93
Medical records were reviewed for 37 FXTAS patients (35 males, 2 females) with average disease duration of 10 years. Average age of onset was 60 years, with the most common initial symptom either tremor (54%) or gait ataxia (24%). Median time to first falling was 4 years, initial cognitive dysfunction 6 years, inability to walk independently 9 years, and inability to perform most ADLs 9.5 years.
Toxin Neutralizing Antibody Formation With Botulinum Neurotoxin Type A (BoNT A) Treatment in Neuromuscular Disorders
Yablon SA, Daggett S, Brin MF
Serum antibodies to botulinum neurotoxin type A (BoNT-A) were determined in 880 analyzable samples from 929 patients, enrolled in clinical trials of BoNT-A for cervical dystonia, spasticity, and headache. Five samples (.6%) had neutralizing antibodies: 4 from CD patients, treated for up to 24 months with a maximum exposure of 4210 units, and 1 from a spasticity patient, who had no initial clinical response to treatment.
Treatment of Pediatric Hyperkinetic Movement Disorders With Tetrabenazine (TBZ)
Jain S, Greene PE, Frucht SJ
S57.003, A419
Tetrabenazine (TBZ) is effective in a wide variety of pediatric movement disorders, according to this study. Retrospective chart review was performed for 30 pediatric patients receiving TBZ for chorea (17), tics (10), and dystonia (3). Diagnoses included Tourette's syndrome, cerebral palsy, Sydenhams chorea, posthypoxic injury, Leigh's disease, and others. Twenty-eight had tried and failed other medications. TBZ significantly reduced excess movements in 22 patients. Sedation, behavioral changes, and depression were significant side effects, and caused discontinuation in 9 patients. Parkinsonism occurred in 1 patient, and tardive dyskinesia in none.
Four studies expand the understanding of the role of the LRRK2 gene in Parkinson's disease (PD). The clinical features of PD caused by LRRK2 mutations are typical for late-onset PD, according to 2 reports from different populations. The G2019S mutation is especially common among North Africans. And the first molecular characterization of the lrrk2 protein suggests that 2 mutations in 2 different domains have 2 different effects on the function of the protein.
Parkinson's Disease Related to the Basque Dardarin Mutation
Marti Masso JF, Paisan Ruiz C, Simon J, et al
S17.002
Clinical features were determined for 35 PD patients with LRRK2 mutations, including 22 from 4 previously identified families, 9 patients in 7 new families, and 4 sporadic patients. All had the R1396G mutation. Mean age at onset was 63 years, with unilateral rest tremor of the lower leg the most common presenting symptom. Of 33 treated with levodopa, all had a good response with typical motor complications after several years of treatment.
The Clinical Features and Frequency of LRRK2 Associated Parkinson's Disease in Central Norway
Aasly JO, Toft M, Fernandez-Mata I, et al
S17.003, A148
Of 435 PD patients referred to a single hospital in central Norway, 9 (2%) were heterozygous for the G2019S mutation. The same mutation was found in 10 of 26 first-degree relatives and in 0 of 724 unrelated, unaffected controls. In 2 cases, no family history was reported or found. Mean age of onset was 57, with tremor or bradykinesia as the most common presenting symptom. All patients were levodopa-responsive, and dyskinesias were common.
The G2019S LRRK2 Mutation in Autosomal Dominant European and North African Parkinson's Disease Is Frequent and Its Penetrance Is Age-Dependent
Lesage S, Ibanez P, Lohmann E, et al
LBS.003
Analysis of 200 index cases of autosomal dominant PD revealed that among North Africans, 41% were associated with LRRK2 mutation, while among Europeans, the frequency was 2.8%.
Molecular Characterization of LRRK2, the Gene Responsible for Autosomal Dominant PARK8
Taylor JP, Lincoln S, Pielsticker L, Farrer MJ
P02.037, A88
Two identified mutations in LRRK2 appear to have different effects on the lrrk2 protein, according to this report. LRRK2 was expressed in cell lines and localized by a fluorescent tag. Protein from the R1441C mutant formed cytoplasmic inclusions. Homology modeling of the Roc domain that bears this mutation suggested it is responsible for interacting with other proteins. Protein from the G2019S mutant formed no inclusions and appeared to be distributed normally. Homology modeling of the MAPKKK domain bearing this mutation suggests that the mutation may lead to overactivity of the kinase function.
Discordant Sibling Analysis Confirms the Association of UCHL1 With Parkinson's Disease
Maraganore DM, Facheris M, Lesnick TG, et al
P01.102, A58
The S18Y variant of UCHL1 is inversely associated with risk of PD, according to this study. Genotyping was performed in 496 case-control pairs (496 PD cases, 434 unaffected sibling controls, 62 unaffected unrelated controls where no sibling was available). The S18Y variant was significantly less common in cases than in controls (odds ratio [OR] = .18; P = .004), a relationship that remained significant even when previously published cases and unrelated controls were excluded. The authors note, "The UCHL1 S18Y variant encodes a UCHL1 protein that is unable to form dimers, thus favoring the degradation of alpha-synuclein via the ubiquitin-proteasome pathway."
Mitochondrial ND5 Mutations in Idiopathic Parkinson's Disease
Parker WD, Parks JK
P02.042, A89
A mitochondrial complex I mutation is more common in PD cases than in controls, according to this report. Mitochondrial DNA from 8 idiopathic PD cases and 8 age-matched controls was amplified and sequenced prospectively. Missense mutations in the gene for the ND5 subunit of complex I were found in all PD cases and only 1 control. The mutations were found in 1% to 8% of mitochondrial chromosomes in affected individuals. The authors note that very high abundance of 2 of the identified mutations has been previously associated with early-onset neurodegenerative diseases.
Molecular Study of Parkin in 300 Patients With Early Onset Parkinson's Disease
Garavaglia B, Ghezzi D, Marelli E, et al
P02.036, A88
Among 300 patients with early-onset PD (278 sporadic, 22 familial), 47 parkin-positive patients were identified: 22 homozygous, 15 compound heterozygous, and 10 with only 1 mutation (as confirmed by quantitative reverse-transcriptase polymerase chain reaction [RT-PCR]). Among sporadic cases, 38 (14%) had mutations, with greater frequency among younger patients. The authors state, "The frequency of a single heterozygous mutation in our cohort of positive patients (21.3%) reinforces the hypothesis of a haplo-insufficiency and/or a dominant negative allele mechanism of certain mutations in the parkin gene."
The Mayo Clinic Cohort Study of Personality and Aging: Results for Parkinson's Disease
Bower JH, Grossardt BR, Maraganore DM, et al
S39.004, A282-283
The presence of an anxious personality is associated with development of PD later in life, according to this study. Among more than 7000 subjects who completed the Minnesota Multiphasic Personality Inventory in the 1960s, medical record follow-up identified 68 cases of PD. Cases were age- and sex-matched with up to 5 controls within the same cohort. Subjects who scored within the top quartile on psychasthenia (a measure of anxiety) were approximately twice as likely to develop PD over the next 40 years as those in lower quartiles. No association was found for depression, social introversion, or optimism. "It remains unclear whether anxiety is a risk factor for PD, an early manifestation of PD, or linked to PD via common risk factors or a common genetic predisposition," the authors state.
The Mayo Clinic Cohort Study of Oophorectomy and Aging: Results for Parkinsonism and Parkinson's Disease
Rocca WA, Grossardt BR, Bower JH, et al
S39.005, A283
Bilateral oophorectomy increases the risk of parkinsonism and PD, according to this study. Medical record follow-up identified 1202 women who underwent bilateral oophorectomy and 1283 who underwent unilateral oophorectomy between 1950 and 1987. Compared with age-matched subjects from the same area, women receiving bilateral, but not unilateral, oophorectomy had twice the risk of developing parkinsonism or PD. "Bilateral oophorectomy is the major cause of reduced endogenous estrogen during fertile life," the authors note, and suggest this is the likely reason for the association.
Nonsteroidal Antiinflammatory Drugs and the Risk of Parkinson's Disease
Chen H, Jacobs E, Schwarzschild M, et al
P05.073, A311
Ibuprofen reduces the risk of developing PD, according to this study. Incident cases of PD were identified from more than 146,000 participants in the American Cancer Society's Cancer Prevention Study II Nutrition Cohort. PD risk was lower (relative risk = 0.65) for ibuprofen users vs nonusers, unaffected by age, sex, or smoking. No effect was found for acetaminophen, aspirin, or other nonsteroidal anti-inflammatory drugs (NSAIDs).
Cocaine Abuse Triggers Abnormal Expression of Alpha-Synuclein Expression in DA Cell Bodies and Terminals
Mash DC, Qin Y, Ouyang Q, et al
P06.053, A355
Postmortem analysis of substantia nigra and striatum from 10 cocaine abusers showed that alpha-synuclein levels were elevated 3-fold compared with age-matched controls (P = .01). No elevation was seen in the anterior caudate nucleus. Dopamine uptake was elevated 2-fold in the ventrolateral and ventromedial putamen in cocaine abusers, as determined by assays on synaptosomal fractions. The authors conclude, "These observations suggest that alpha-synuclein expression may play a role in dopamine-mediated adaptive mechanisms in the striatum from cocaine abusers," possibly placing abusers at increased risk for PD.
The Effects of Expiratory Muscle Strength Training on Pharyngeal Swallowing in Patients With Idiopathic Parkinson's Disease
Sapienza CM, Rosenbek JC, Musson ND, Okun M
S47.008, A397
A simple breathing exercise program improves swallowing efficiency in people with PD, according to this study. Ten PD patients (mean Hoehn and Yahr stage 2.6) underwent a 4-week home-based training program to develop expiratory muscle strength. Patients exerted sustained expiratory pressure while attempting to exhale through a valve set to open only at near-maximal expiratory pressure, adjusted for each patient. This exercise develops the suprahyoid muscles, which promote efficient swallowing. Training resulted in a 50% improvement in mouth expiratory pressure, and increased swallowing efficiency with less retention of food at the laryngeal opening after swallowing. "This program may have the long-term potential for reducing the life-threatening risk of aspiration pneumonia," according to the authors.
The Evolution of Disability in Parkinson's Disease
Shulman LM, Gruber-Baldini AL, Anderson KE, et al
S47.002
Evaluation of 388 PD patients (mean age, 66 years; 6.5 years since diagnosis) with the Unified Parkinson Disease Rating Scale (UPDRS) and the Older Americans Resources and Services Scale ADL and Instrumental ADL (IADL) sections revealed that loss of independence in ADLs occurred first for walking, dressing, and getting in and out of bed, and last for eating and toileting. Loss of IADLs occurred first for housework, traveling, and shopping, and last for using the telephone, taking medicines independently, and handling money. "Gait impairment is the leading edge of disability in PD," the authors conclude, because it heralds the loss of many gait-dependent activities.
Long-term Follow-up of Patients With Scans Without Evidence of Dopaminergic Deficit (SWEDD) in the ELLDOPA Study
Marek KL, Jennings DL, Seibyl JP
S34.004, A274
Scans Without Evidence of Dopaminergic Deficit (SWEDD) patients probably do not have PD, according to this study. Subjects from the Early versus Late Levodopa (ELLDOPA) study whose baseline and end-of-study scans showed no evidence of dopaminergic deficit were followed for up to 4 years. Of the 142 patients in the ELLDOPA study, 21 were defined as SWEDD patients. Normal scans were obtained for 19 of 19 at 9 months, 17 of 17 at 18 months, 12 of 12 at 36 months, and 10 of 10 at 48 months. In blinded evaluations by 5 movement disorders experts reviewing video of UPDRS "off-state" examinations, 3 or more evaluators doubted the diagnosis of PD in the majority of cases. "The balance of evidence suggests that ELLDOPA subjects with SWEDD do not have PD," the authors conclude. "Dopaminergic imaging at baseline should be considered as an inclusion criterion in future studies evaluation early Parkinson's disease patients." A previous E-MOVE report on the ELLDOPA study is archived at http://www.mdvu.org/emove/article.asp?ID=516 .
Long-term Benefits of Rivastigmine in Dementia Associated With Parkinson's Disease: An Open-label Extension Study
Poewe W, EXPRESS Study Group
P02.096, A105
Rivastigmine improves cognitive performance in PD patients for up to 48 weeks, according to this study.
PD patients with dementia were randomly assigned to receive placebo or rivastigmine at 3-12 mg/day for 24 weeks. Patients completing the trial were offered open-label treatment with rivastigmine for an additional 24 weeks. Of 541 who were enrolled in the double-blind trial, 433 completed it; 334 entered the open-label extension; and 273 completed that. By the end of the double-blind phase, rivastigmine-treated patients had improved by 3.5 points (15%) over baseline on the Alzheimer's Disease Assessment Scale-cognitive subscale, while placebo-treated patients declined by .5 points. During the open-label phase, patients originally receiving rivastigmine declined to 2.0 points above baseline, and patients originally receiving placebo improved to 2.0 points above baseline. Adverse events were predominantly cholinergic, and included nausea (19% of patients), vomiting (11%), tremor (7%), falls (5%), confusion (5%), and hallucinations (5%). Supported by Novartis Neuroscience
Cholinergic Denervation Is Associated With More Severe Depression in Parkinson's Disease
Bohnen I, Kaufer DI, Ivanco LS, et al
P04.057, A222
Age-matched controls (n = 14) and PD patients with (n = 10) and without (n = 13) dementia underwent acetylcholinesterase positron emission tomographic (PET) imaging and testing for depression with the Cornell depression rating scale. Parkinson's disease dementia (PDD) patients had higher depression ratings compared with both nondemented PD patients and controls (scores were 10.2, 5.9, and 2.7, respectively). Acetylcholinesterase hydrolysis rates were inversely correlated with depression scores (P = .001). "These data indicate that cortical cholinergic denervation is associated with more severe depressive symptomatology in PD and worsens with the development of dementia," according to the authors.
Onset and Severity of Levodopa-Induced Dyskinesias in Parkinson's Disease Patients in Olmstead County, Minnesota, 1976-1990
Van Gerpen JA, Kumar N, Bower JH, Ahlskog JE
P04.095, A233
Medical records were reviewed for 126 incident PD cases with onset from 1976 to 1990. Median age of onset was 68.6 years, with treatment onset at 71.1 years. The probability of levodopa-induced dyskinesias of any severity was 30% after 5 years of treatment and 59% after 10 years. Risk of dyskinesias sufficiently severe enough to require treatment adjustment was 17% and 43% at those time points. Risk of dyskinesias whose control undermined control of parkinsonism was 12% at 10 years. These figures are "substantially less than previously has been reported, perhaps reflecting a more typical age distribution of Parkinson's disease," the authors state.
Effect of STNDBS on Quality of Life in Parkinson's Disease Depends Upon Time of Assessment!
Gronchi-Perrin A, Violier S, Combremont P, et al
P05.144, A331-332
Subthalamic nucleus deep brain stimulation (STN DBS) improves quality of life (QOL), but patient assessment of the degree of improvement is compromised by a retrospective overestimate of their preoperative QOL, according to this study.
Fourteen PD patients completed QOL assessments preoperatively and 6 months postoperatively. At the 6-month assessment, they were also asked to assess preoperative QOL. Postoperative PDQ-39 scores improved by 28% over preoperative. However, postoperative assessment of preoperative function underestimated disability by 16%; when this estimate was used instead of the actual preoperative assessment, surgery offered no significant benefit. "Such discrepancy should be taken into account in the interpretation of auto-evaluative questionnaires not only in studies, but also in the daily care of each patient," the authors conclude.
Essential Tremor Is Associated With an Increased Risk of Dementia in a Community-Based Longitudinal Study
Benito-Leon J, Bermejo-Pareja F, Louis ED
P04.163, A253-254
A door-to-door survey of 4880 elderly people in central Spain in 1994-1995 revealed 240 essential tremor (ET) patients. Follow-up after a mean of 3.2 years indicated that 3.5% of 3541 non-ET subjects had developed dementia, while 7.4% of 202 ET patients had (relative risk 2.17, 95% confidence interval [CI] 1.27-3.72; P = .005). The increased risk remained significant after adjusting for sex, age, and education.
Olfaction Is Normal in Essential Tremor and Can Be Used to Distinguish It From Parkinson's Disease
Shah M, Findley L, Muhammed N, Hawkes C
S27.001, A261
Two forms of smell tests were administered to 59 ET patients, 65 PD patients, and 74 controls. Tests used were the 40-odorant University of Pennsylvania Smell Identification Test (UPSIT) and olfactory-evoked potentials (OEP) in response to hydrogen sulfide. Mean UPSIT scores were 33 for controls, 32 for ET patients, and 18 for PD patients. OEP values were normal in all but 4 ET patients (which included at least 1 patient who didn't receive testing). Forty percent of PD patients had no recordable OEP, and the remainder had significantly prolonged latency with normal amplitude. "A normosmic patient with tremor is more likely to have ET than PD," the authors conclude.
DYT-1 and Dopamine-Responsive Dystonia and Pregnancy
Shanker VL, Bressman SB, Raymond D, et al
S07.005, A130
Complications of pregnancy were assessed by self-administered questionnaire in 17 women with dopamine-responsive dystonia (DRD; 45 pregnancies), 16 women with DYT1 dystonia (39 pregnancies), and 24 unaffected spouses of men with dystonia (66 pregnancies). First-trimester miscarriage rate was highest among DYT1 women (31% vs 16% for DRD and 12% for unaffected spouses, P = .057). The rate for cesarean section was lower in women with dystonia than unaffected women. No women with dystonia experienced premature rupture of membranes.
Electrophysiologic Evaluation of Yips-Affected and Unaffected Golfers: Evidence for a Task-Specific Dystonia
Adler CH, Crews D, Hentz JG, et al
P06.146, A381
Twenty age- and handicapped-matched golfers, 10 with and 10 without the yips, were examined with surface electromyography (EMG) at rest, during handwriting, holding a putter, and while putting. The yips is the inability to complete a golf stroke, typically during putting or chipping, that occurs in golfers and worsens with anxiety. No abnormal EMG was observed during any activity except active putting. Upon putting, 5 of 10 yips-affected and 0 of 10 unaffected golfers had co-contraction of the wrist flexor/extensors 200 ms prior to contact of ball and putter. "The presence of co-contraction, the electrophysiologic hallmark of task-specific dystonias such as writer's cramp and musician's cramp, during putting in 50% of the yips-affected and none of the yips-unaffected golfers would support the yips possibly being a focal dystonia," the authors conclude.
CSF Iron Status Relates to the Age of Symptom Onset for Restless Legs Syndrome
Early CJ, Gamaldo C, Allen R
S04.001, A26
Levels of iron were analyzed in 15 patients with early-onset restless legs syndrome (RLS) and 15 with late-onset RLS without iron deficiency and not taking iron medications. Early-onset patients had slightly worse Johns Hopkins RLS symptoms scores (2.0 vs 1.5). Early-onset patients had significantly lower cerebrospinal fluid (CSF) ferritin (2.1 vs 2.8 mcg/L; P < .005) and slightly higher CSF transferrin than late-onset patients. For all patients, age at symptom onset correlated with CSF ferritin and CSF transferrin, driven primarily by high correlation among the subgroup of early-onset patients, with no significant correlation among the subgroup of late-onset patients. The authors suggest that central nervous system (CNS) ferritin "may provide a measure of the degree of CNS pathology producing RLS, further supporting a causal relation between compromised CNS iron status and RLS."
Preliminary Study of the Natural History of the Fragile X Associated Tremor/Ataxia Syndrome (FXTAS)
Leehey MA, Hall D, Rice C, et al
P02.053, A93
Medical records were reviewed for 37 FXTAS patients (35 males, 2 females) with average disease duration of 10 years. Average age of onset was 60 years, with the most common initial symptom either tremor (54%) or gait ataxia (24%). Median time to first falling was 4 years, initial cognitive dysfunction 6 years, inability to walk independently 9 years, and inability to perform most ADLs 9.5 years.
Toxin Neutralizing Antibody Formation With Botulinum Neurotoxin Type A (BoNT A) Treatment in Neuromuscular Disorders
Yablon SA, Daggett S, Brin MF
Serum antibodies to botulinum neurotoxin type A (BoNT-A) were determined in 880 analyzable samples from 929 patients, enrolled in clinical trials of BoNT-A for cervical dystonia, spasticity, and headache. Five samples (.6%) had neutralizing antibodies: 4 from CD patients, treated for up to 24 months with a maximum exposure of 4210 units, and 1 from a spasticity patient, who had no initial clinical response to treatment.
Treatment of Pediatric Hyperkinetic Movement Disorders With Tetrabenazine (TBZ)
Jain S, Greene PE, Frucht SJ
S57.003, A419
Tetrabenazine (TBZ) is effective in a wide variety of pediatric movement disorders, according to this study. Retrospective chart review was performed for 30 pediatric patients receiving TBZ for chorea (17), tics (10), and dystonia (3). Diagnoses included Tourette's syndrome, cerebral palsy, Sydenhams chorea, posthypoxic injury, Leigh's disease, and others. Twenty-eight had tried and failed other medications. TBZ significantly reduced excess movements in 22 patients. Sedation, behavioral changes, and depression were significant side effects, and caused discontinuation in 9 patients. Parkinsonism occurred in 1 patient, and tardive dyskinesia in none.
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