Burton L. Scott

Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease.

Glial cell line–derived neurotrophic factor (GDNF) exerts potent trophic influence on midbrain dopaminergic neurons. This randomized controlled clinical trial was designed to confirm initial clinical benefits observed in a small, open‐label trial using intraputamenal (Ipu) infusion of recombinant human GDNF (liatermin).

Mitochondrial Polymorphisms Significantly Reduce the Risk of Parkinson Disease

Mitochondrial (mt) impairment, particularly within complex I of the electron transport system, has been implicated in the pathogenesis of Parkinson disease (PD). More than half of mitochondrially encoded polypeptides form part of the reduced nicotinamide adenine dinucleotide dehydrogenase (NADH) complex I enzyme. To test the hypothesis that mtDNA variation contributes to PD expression, we genotyped 10 single-nucleotide polymorphisms (SNPs) that define the European mtDNA haplogroups in 609 white patients with PD and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.34-0.91; P=.02) or K (OR 0.52; 95% CI 0.30-0.90; P=.02) demonstrated a significant decrease in risk of PD versus individuals carrying the most common haplogroup, H. Furthermore, a specific SNP that defines these two haplogroups, 10398G, is strongly associated with this protective effect (OR 0.53; 95% CI 0.39-0.73; P=.0001). SNP 10398G causes a nonconservative amino acid change from threonine to alanine within the NADH dehydrogenase 3 (ND3) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men (OR 0.43; 95% CI 0.27-0.71; P=.0009). In addition, SNP 9055A of ATP6 demonstrated a protective effect for women (OR 0.45; 95% CI 0.22-0.93; P=.03). Our results suggest that ND3 is an important factor in PD susceptibility among white individuals and could help explain the role of complex I in PD expression.

Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease.

Parkinson disease (PD) is a chronic neurodegenerative disorder with a cumulative prevalence of greater than one per thousand. To date three independent genome‐wide association studies (GWAS) have investigated the genetic susceptibility to PD. These studies implicated several genes as PD risk loci with strong, but not genome‐wide significant, associations.

Age at onset in two common neurodegenerative diseases is genetically controlled.

To identify genes influencing age at onset (AAO) in two common neurodegenerative diseases, a genomic screen was performed for AAO in families with Alzheimer disease (AD; n=449) and Parkinson disease (PD; n=174). Heritabilities between 40%--60% were found in both the AD and PD data sets. For PD, significant evidence for linkage to AAO was found on chromosome 1p (LOD = 3.41). For AD, the AAO effect of APOE (LOD = 3.28) was confirmed. In addition, evidence for AAO linkage on chromosomes 6 and 10 was identified independently in both the AD and PD data sets. Subsequent unified analyses of these regions identified a single peak on chromosome 10q between D10S1239 and D10S1237, with a maximum LOD score of 2.62. These data suggest that a common gene affects AAO in these two common complex neurodegenerative diseases.

Parkin mutations and susceptibility alleles in late-onset Parkinson's disease

Parkin, an E2‐dependent ubiquitin protein ligase, carries pathogenic mutations in patients with autosomal recessive juvenile parkinsonism, but its role in the late‐onset form of Parkinsons disease (PD) is not firmly established. Previously, we detected linkage of idiopathic PD to the region on chromosome 6 containing the Parkin gene (D6S305, logarithm of odds score, 5.47) in families with at least one subject with age at onset (AAO) younger than 40 years. Mutation analysis of the Parkin gene in the 174 multiplex families from the genomic screen and 133 additional PD families identified mutations in 18% of early‐onset and 2% of late‐onset families (5% of total families screened). The AAO of patients with Parkin mutations ranged from 12 to 71 years. Excluding exon 7 mutations, the mean AAO of patients with Parkin mutations was 31.5 years. However, mutations in exon 7, the first RING finger (Cys253Trp, Arg256Cys, Arg275Trp, and Asp280Asn) were observed primarily in heterozygous PD patients with a much later AAO (mean AAO, 49.2 years) but were not found in controls in this study or several previous reports (920 chromosomes). These findings suggest that mutations in Parkin contribute to the common form of PD and that heterozygous mutations, especially those lying in exon 7, act as susceptibility alleles for late‐onset form of Parkinson disease. Ann Neurol 2003

Pesticide exposure and risk of Parkinson's disease: a family-based case-control study.

BackgroundPesticides and correlated lifestyle factors (e.g., exposure to well-water and farming) are repeatedly reported risk factors for Parkinsons disease (PD), but few family-based studies have examined these relationships.MethodsUsing 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.ResultsOverall, 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 ≤ 0.013). Associations of direct pesticide application did not vary by sex but were modified by family history of PD, as significant associations were restricted to individuals with no family history. When classifying pesticides by functional type, both insecticides and herbicides were found to significantly increase risk of PD. Two specific insecticide classes, organochlorines and organophosphorus compounds, were significantly associated with PD. Consuming well-water and living/working on a farm were not associated with PD.ConclusionThese data corroborate positive associations of broadly defined pesticide exposure with PD in families, particularly for sporadic PD. These data also implicate a few specific classes of pesticides in PD and thus emphasize the need to consider a more narrow definition of pesticides in future studies.

Delayed-onset progressive movement disorders after static brain lesions

Article abstract-We studied 53 patients (64% females) with static brain lesions who developed progressive movement disorders. Of these, 50 (94%) had dystonia, 17 (32%) tremor, eight (15%) parkinsonism, seven (13%) myoclonus, and three (6%) chorea. The precipitating insults included perinatal hypoxia/ischemia in 22 (42%), stroke in 12 (23%), head injury in eight (15%), encephalitis in eight (15%), and carbon monoxide poisoning, kernicterus, and radiation necrosis in one patient (2%) each. Among the 30 patients with initial insult occurring at age 2 years or younger (Infant group), distribution of dystonia at follow-up was focal in three (10%), segmental in eight (27%), unilateral in 10 (33%), and generalized in nine (30%). The mean latency between the original injury and onset of movement disorder was 25.5 +/- 16.7 years. Among the nine patients who developed dystonia after an insult occurring between ages 6 and 17 (Childhood group), the distribution of dystonia at follow-up was segmental in two (22%) and unilateral in seven (78%); the mean latency of dystonia onset was 4.9 +/- 7.8 years. Of the 14 patients in the Adult group (injury at age 25 or older), 11 developed dystonia, two developed parkinsonism, and one had carbon monoxide encephalopathy and parkinsonism. The distribution of dystonia in the 11 patients at follow-up was segmental in three (27%) and unilateral in eight (73%). The mean latency of movement disorder onset in the 14 patients of the Adult group was 2.5 +/- 4.9 years. No individuals in the Childhood or Adult groups became left-hand dominant; by comparison, nine of the 30 individuals in the Infant group became left-handed. In conclusion, brain injury at a young age is associated with a longer latency to onset of subsequent movement disorder, a greater tendency to development of generalized dystonia, and a greater probability of altered handedness. These tendencies may result from differences in age-related neuroplasticity. NEUROLOGY 1996;46: 68-74

Ropinirole 24-hour prolonged release and ropinirole immediate release in early Parkinson's disease: a randomized, double-blind, non-inferiority crossover study

ABSTRACT Objective: This study compares once-daily ropinirole 24-h prolonged release and three-times-daily ropinirole immediate release in patients with early Parkinsons disease. Methods: This multicentre, double-blind, non-inferiority crossover study involved 161 patients randomized to one of four formulation sequences: (1) immediate release–immediate release–prolonged release; (2) immediate release–prolonged release–prolonged release; (3) prolonged release–prolonged release–immediate release; (4) prolonged release–immediate release–immediate release. During a 12-week dose-titration period, ropinirole immediate release was titrated according to the approved labelling; titration of ropinirole 24-h prolonged release started at a higher dose and was more rapid. Patients then entered three consecutive, flexible-dose, 8-week maintenance periods. At the end of the first maintenance period, half of the patients in each formulation group switched to the same or closest dose of the alternative formulation; remaining patients switched at the end of the second maintenance period. Results: At the end of titration, before the first dose switch, there were substantial reductions in mean Unified Parkinsons Disease Rating Scale (UPDRS) motor scores. During maintenance periods, both groups showed similar efficacy on the UPDRS motor score. Overall mean (standard error) change from period baseline was −0.1 (0.28) for ropinirole 24-h prolonged release, and 0.6 (0.30) for ropinirole immediate release (adjusted mean treatment difference −0.7; 95% confidence interval [CI]: −1.51, 0.10; p = 0.0842). The upper limit of the 95% CI was less than the predefined threshold of 3 points for non-inferiority. Ropinirole 24-h prolonged release was well-tolerated when titrated more rapidly than ropinirole immediate release; overnight switching between formulations was also well-tolerated. Study limitations included complexity of the non-inferiority study design and the forced dose-titration schedule. Conclusion: Ropinirole 24-h prolonged release was effective and well-tolerated in patients with early Parkinsons disease.

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial

IMPORTANCE Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. OBJECTIVE To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. DESIGN, SETTING, AND PARTICIPANTS Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. INTERVENTIONS Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. MAIN OUTCOMES AND MEASURES Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form- physical functioning subscale score (SF-36), and the change in the Berg Balance Test. RESULTS Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was -2.5 units (95% CI, -3.7 to -1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, -0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. CONCLUSIONS AND RELEVANCE Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01795859.

Family-based case-control study of cigarette smoking and Parkinson disease

Objective: To determine whether people with Parkinson disease (PD) are less likely to report a history of cigarette smoking than their unaffected siblings. Background: Previous studies reported that individuals with PD are half as likely to have smoked as those unaffected by PD. Other studies reported that smoking modified the risk of PD due to polymorphisms in the MAO-B and nNOS genes. Thus, genetic studies of PD should consider confounding or interaction with smoking history as well. The authors have collected detailed smoking histories on a family-based case-control sample ascertained for genetic studies of PD. Methods: In a matched case-control study of 140 sibships, individuals with PD (n = 143) were compared to sibling controls (n = 168). Cigarette smoking history was collected by a structured telephone interview. Conditional logistic regression was used to examine the relationship between smoking and PD while controlling for confounding by age and sex. Results: Ever smoking, current smoking, and increasing duration (in years), dose (in packs/day), and intensity (in pack-years) of smoking were significantly inversely associated with PD (p < 0.05). The association was not modified by sex, age at onset, or recency of exposure. Conclusions: Consistent with previous studies, individuals with Parkinson disease are significantly less likely to have smoked regularly than their unaffected siblings. This association was detected even though discordant sibling pairs are more likely to be overmatched for environmental exposures than unmatched case and control groups.