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Purpose: To assess the repeatability of peripapillary OCT angiography (OCTA) in those with Alzheimer disease (AD), mild cognitive impairment (MCI), Parkinson disease (PD), or normal cognition. Design: Cross-sectional. Participants: Patients with a clinical diagnosis of AD, MCI, PD, or normal cognition were imaged. Those with glaucoma, diabetes mellitus, vitreoretinal pathology, and poor-quality images were excluded. Methods: Each eligible eye of each participant underwent 2 OCTA 4.5 × 4.5-mm peripapillary scans in a single session using a Zeiss Cirrus HD-OCT 5000 with AngioPlex (Carl Zeiss Meditec). The Zeiss software (v11.0.0.29946) quantified measures of perfusion in the radial peripapillary capillary (RPC) plexus in 4 sectors (superior, nasal, inferior, temporal). The average of these sectors was calculated and reported. Main Outcome Measures: Radial peripapillary capillary plexus perfusion was quantified using 2 parameters: capillary perfusion density (CPD) and capillary flux index (CFI). Intraclass correlation coefficients (ICCs) were used to quantify repeatability. For subjects who had both eyes included, the average values of each scan pair were used to assess interocular symmetry of CPD and CFI. Results: Of 374 eyes, 46 were from participants who had AD, 85 were from participants who had MCI, 87 were from participants who had PD, and 156 were from participants who had normal cognition. Capillary perfusion density ICC in AD = 0.88 (95% confidence interval [CI], 0.79–0.93), MCI = 0.95 (0.92–0.96), PD = 0.91 (0.87–0.94), and controls = 0.90 (0.87–0.93). Capillary flux index ICC in AD = 0.82 (0.70–0.90), MCI = 0.87 (0.80–0.91), PD = 0.91 (0.87–0.94) and controls = 0.85 (0.79–0.89). There were no significant differences in interocular variation in average CPD and CFI in AD, MCI, or PD (all P > 0.05). Isolated interocular sectoral CPD differences were noted in AD (nasal, P = 0.049; temporal, P = 0.024), PD (nasal, P = 0.036), and controls (nasal, P = 0.016). Interocular differences in CFI in the superior sector in MCI (P = 0.028) and in average CFI for controls (P = 0.035) were observed. Conclusions: Peripapillary OCTA repeatability in AD, MCI, and PD is good-excellent and similar to those with normal cognition. Insignificant interocular asymmetry in peripapillary OCTA suggests neurodegeneration may proceed uniformly; future studies may reveal the appropriateness of single-eye imaging.

IMPORTANCE: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. OBJECTIVE: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. DESIGN, PARTICIPANTS, AND SETTING: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (

Importance Noninvasive retinal imaging may detect structural changes associated with Parkinson disease (PD) and may represent a novel biomarker for disease detection. Objective To characterize alterations in the structure and microvasculature of the retina and choroid in eyes of individuals with PD and compare them with eyes of age- and sex-matched cognitively healthy control individuals using optical coherence tomography (OCT) and OCT angiography (OCTA). Design, Setting, and Participants This cross-sectional study was conducted at the Duke Neurological Disorders Clinic in Durham, North Carolina. Individuals aged 50 years or older with a diagnosis of PD were eligible for inclusion and underwent an evaluation and diagnosis confirmation before enrollment. Control individuals aged 50 years or older and without subjective cognitive dysfunction, a history of tremor, or evidence of motor dysfunction consistent with parkinsonism were solicited from the clinic or the Duke Alzheimer’s Disease Prevention Registry. Individuals with diabetes, glaucoma, retinal pathology, other dementias, and corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity worse than 20/40 Snellen were excluded. Data were analyzed between January 1, 2020, and March 30, 2020. Exposures All participants underwent OCT and OCTA imaging. Main Outcomes and Measures Generalized estimating equation analysis was used to characterize the association between imaging parameters and PD diagnosis. Superficial capillary plexus vessel density (VD) and perfusion density (PFD) were assessed within the ETDRS 6 × 6-mm circle, 6 × 6-mm inner ring, and 6 × 6-mm outer ring, as was the foveal avascular zone area. Peripapillary retinal nerve fiber layer thickness, macular ganglion cell–inner plexiform layer thickness, central subfield thickness, subfoveal choroidal thickness, total choroidal area, luminal area, and choroidal vascularity index (CVI) were measured. Results A total of 124 eyes of 69 participants with PD (39 men [56.5%]; mean [SD] age, 71.7 [7.0] years) and 248 eyes of 137 control participants (77 men [56.2%]; mean [SD] age, 70.9 [6.7] years) were analyzed. In the 6 × 6-mm ETDRS circle, VD (β coefficient = 0.37; 95% CI, 0.04-0.71;P = .03) and PFD (β coefficient = 0.009; 95% CI, 0.0003-0.018;P = .04) were lower in eyes of participants with PD. In the inner ring of the 6 × 6-mm ETDRS circle, VD (β coefficient = 0.61; 95% CI, 0.20-1.02;P = .003) and PFD (β coefficient = 0.015; 95% CI, 0.005-0.026;P = .004) were lower in eyes of participants with PD. Total choroidal area (β coefficient = –1.74 units2; 95% CI, −3.12 to −0.37 units2;P = .01) and luminal area (β coefficient = –1.02 units2; 95% CI, −1.86 to −0.18 units2;P = .02) were greater, but CVI was lower (β coefficient = 0.5%; 95% CI, 0.2%-0.8%;P Conclusions and Relevance This study found that individuals with PD had decreased retinal VD and PFD as well as choroidal structural changes compared with age- and sex-matched control participants. Given the observed population differences in these noninvasive retinal biomarkers, further research into their clinical utility in PD is needed.

To compare radial peripapillary capillary (RPC) plexus vascular parameters and retinal nerve fiber layer (RNFL) thickness between those with Parkinson's disease (PD) and controls.Prospective, cross-sectional study.A total of 151 eyes of 81 PD participants and 514 eyes of 266 controls.Participants underwent OCT angiography (OCTA) imaging using the Zeiss Cirrus HD-5000 AngioPlex (Carl Zeiss AG). Capillary perfusion density (CPD) and capillary flux index (CFI) were assessed using a 4.5 × 4.5-mm peripapillary scan, and RNFL thickness was assessed using a 200 × 200-μm optic nerve cube OCT scan. Hoehn and Yahr clinical staging for PD was determined by an experienced movement disorders specialist. Generalized estimating equations adjusted for age and sex were used for analysis.Differences in RNFL thickness, CPD, and CFI as assessed using multivariable generalized estimating equations between individuals with PD and controls.After adjustment for age and sex, average CPD (0.446% ± 0.018% vs. 0.439% ± 0.017%, P0.001) and CFI (0.434 ± 0.031 vs. 0.426 ± 0.036, P = 0.008) were significantly higher in PD eyes. Average RNFL thickness was similar between groups (PD 89.71 ± 10.45 μm vs. control 88.20 ± 10.33 μm, P = 0.19). Significant correlations between Hoehn and Yahr stage and OCTA parameters were not observed. The OCTA parameters were not significantly different between eyes of the same patient.Increased peripapillary microvascular density and flux were detected in a large cohort of individuals with PD compared with controls after adjusting for age and sex; however, RNFL thickness was similar between groups. Peripapillary OCTA parameters may not correlate with the severity of PD. OCTA may serve as a noninvasive method to identify novel biomarkers for the early diagnosis of PD; as such, this methodology deserves further investigation.

Parkinson's Disease (PD) leads to poor quality of life and caregiver burden. Mindfulness-based stress reduction (MBSR) may improve these symptoms. We assessed the impact of a 9-week MBSR course on people with PD (PwP) and their care partners (CPs).Participants completed questionnaires at screening, at the end of the course, and at 3-month follow-up: Parkinson's Disease Quality-39 (PDQ-39, PD only), Zarit Burden Inventory (ZBI, CP only) and Mindful Attention Awareness Scale (MAAS, both). The primary outcome measure was change in PDQ-39 (for PwP) or ZBI (for CP). Patient-reported scales were analyzed quantitatively; qualitative data on perceived effectiveness was collected.53.8% PwP and 100% CPs completed the course. Among PwP, there was a significant reduction in MAAS(p 0.001) and in PDQ-39 (p = 0.008). CPs experienced an increase in MAAS (p = 0.02) but no change in ZBI (p = 0.239). Qualitatively, both PwP and CPs expressed satisfaction with the course.MBSR improves mindful awareness in CPs and improves health-related quality of life in PwP.

Importance There is a critical need for careful and independent validation of reported symptomatic efficacy and dopaminergic biomarker changes induced by nilotinib in Parkinson disease (PD). Objectives To assess safety and tolerability of nilotinib in participants with moderately advanced PD. Secondary and exploratory objectives were to assess its affect on PD disability, pharmacokinetics, cerebrospinal fluid (CSF) penetration, and biomarkers. Design, Setting, and Participants This was a 6-month, multicenter, randomized parallel-group, double-blind, placebo-controlled trial. Recruitment was from November 20, 2017, to December 28, 2018, and follow-up ended on September 9, 2019. The study was conducted at 25 US sites. The study approached 173 patients, of whom 48 declined, 125 were screened, and 76 who received a stable regimen of PD medications were enrolled (39% screen failure). Interventions Participants were randomized 1:1:1 to placebo, 150-mg nilotinib, or 300-mg nilotinib once daily orally for 6 months, followed by 2-month off-drug evaluation. Main Outcomes and Measures The primary outcomes were safety and tolerability. The tolerability end point was defined as the ability to complete the study while receiving the assigned dose. An active arm was considered tolerable if the percentage of participants meeting the tolerability end point for that group was not significantly lower than the percentage observed in the placebo group. Secondary outcomes included change in PD disability (Movement Disorder Society Unified Parkinson’s Disease Rating Scale [MDS-UPDRS], Part II OFF/ON). Exploratory outcomes included serum and CSF pharmacokinetic profile, and CSF dopaminergic biomarkers. Results At baseline, mean (SD) participants’ age was 64.6 (7.5) years, 52 were male (68%), mean (SD) disease duration was 9.9 years (4.7), MDS-UPDRS Part 1-3 OFF score was 66.4 (19.3), ON score was 48.4 (16.2), and Montreal Cognitive Assessment score was 27.1 (2.2). The number of participants who completed the study receiving the assigned dose were 21 (84%), 19 (76%), and 20 (77%) in the placebo, 150-mg, and 300-mg arms, respectively. Both active doses had acceptable safety profile. The most common reasons for drug suspension were asymptomatic, dose-dependent elevations of amylase, and/or lipase. Nilotinib, 150 mg and 300 mg, exhibited worse MDS-UPDRS-3 ON scores compared with placebo, achieving significance for nilotinib, 300 mg, at month 1 (P Conclusions and Relevance While we demonstrated acceptable safety and tolerability of nilotinib in our cohort, the low CSF exposure and lack of biomarkers effect combined with the efficacy data trending in the negative direction indicate that nilotinib should not be further tested in PD. Trial Registration ClinicalTrials.gov Identifier:NCT03205488

Background Essential tremor is a neurological condition characterized by tremor during voluntary movement. To date, 3 loci linked to familial essential tremor have been identified. Methods We examined 48 essential tremor patients in 5 large essential tremor pedigrees in our data set for genetic linkage using an Affymetrix Axiom array. Linkage analysis was performed using an affecteds-only dominant model in SIMWALK2. To incorporate all genotype information, GERMLINE was used to identify genome segments shared identical-by-descent in pairs of affecteds. Exome sequencing was performed in pedigrees showing evidence of linkage. Results For one family, chromosomes 5 and 18 showed genome-wide significant linkage to essential tremor. Shared segment analysis excluded the 18p11 candidate region and reduced the 5q35 region by 1 megabase. Exome sequencing did not identify a potential causative variant in this region. Conclusion A locus on chromosome 5 is linked to essential tremor. Further research is needed to identify a causative variant. © 2016 International Parkinson and Movement Disorder Society

Summary Background A systematic assessment of potential disease-modifying compounds for Parkinson's disease concluded that pioglitazone could hold promise for the treatment of patients with this disease. We assessed the effect of pioglitazone on the progression of Parkinson's disease in a multicentre, double-blind, placebo-controlled, futility clinical trial. Methods Participants with the diagnosis of early Parkinson's disease on a stable regimen of 1 mg/day rasagiline or 10 mg/day selegiline were randomly assigned (1:1:1) to 15 mg/day pioglitazone, 45 mg/day pioglitazone, or placebo. Investigators were masked to the treatment assignment. Only the statistical centre and the central pharmacy knew the treatment name associated with the randomisation number. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score between the baseline and 44 weeks, analysed by intention to treat. The primary null hypothesis for each dose group was that the mean change in UPDRS was 3 points less than the mean change in the placebo group. The alternative hypothesis (of futility) was that pioglitazone is not meaningfully different from placebo. We rejected the null if there was significant evidence of futility at the one-sided alpha level of 0·10. The study is registered at ClinicalTrials.gov , number NCT01280123 . Findings 210 patients from 35 sites in the USA were enrolled between May 10, 2011, and July 31, 2013. The primary analysis included 72 patients in the 15 mg group, 67 in the 45 mg group, and 71 in the placebo group. The mean total UPDRS change at 44 weeks was 4·42 (95% CI 2·55–6·28) for 15 mg pioglitazone, 5·13 (95% CI 3·17–7·08) for 45 mg pioglitazone, and 6·25 (95% CI 4·35–8·15) for placebo (higher change scores are worse). The mean difference between the 15 mg and placebo groups was −1·83 (80% CI −3·56 to −0·10) and the null hypothesis could not be rejected (p=0·19). The mean difference between the 45 mg and placebo groups was −1·12 (80% CI −2·93 to 0·69) and the null hypothesis was rejected in favour of futility (p=0·09). Planned sensitivity analyses of the primary outcome, using last value carried forward (LVCF) to handle missing data and using the completers' only sample, suggested that the 15 mg dose is also futile (p=0·09 for LVCF, p=0·09 for completers) but failed to reject the null hypothesis for the 45 mg dose (p=0·12 for LVCF, p=0·19 for completers). Six serious adverse events occurred in the 15 mg group, nine in the 45 mg group, and three in the placebo group; none were thought to be definitely or probably related to the study interventions. Interpretation These findings suggest that pioglitazone at the doses studied here is unlikely to modify progression in early Parkinson's disease. Further study of pioglitazone in a larger trial in patients with Parkinson's disease is not recommended. Funding National Institute of Neurological Disorders and Stroke.

BackgroundRare mutations in genes associated with Mendelian forms of disease are a potential mechanism for sporadic disease. The need to assess the clinical significance of such variants is increasing as personalized medicine and genome sequencing increases.ObjectiveTo evaluate the rate of rare, functional variants in dystonia genes in the general population to improve interpretation of the clinical relevance of potentially pathogenic variants in dystonia cases.MethodsWe performed an “aggregated” collapsing analysis of exome sequence that considered rare coding variants in genes previously associated with dystonia, a rare neurological movement disorder, on 2,372 population controls of European ethnicity. We then performed a pilot study in sporadic dystonia to assess whether there was a substantially greater incidence of individuals with rare variation in dystonia genes.ResultsNearly half of population controls had a rare coding variant when 148 genes associated with a dystonia phenotype were considered. When the subset of genes causing isolated dystonia (14 genes) was evaluated, 3-4% of controls harbored rare qualifying variants. Our pilot study of case exomes was powered to identify a five-fold higher or greater rate of qualifying variants in isolated dystonia genes in sporadic dystonia cases compared to population controls; we did not find such an enrichment.ConclusionsWe provide the first systematic analysis of rare variation in dystonia genes considered collectively. Our findings emphasize the need to consider the overall frequency of variants in rare disease-related genes in the general population when considering their potential role in clinical presentations.

Importance Tetrabenazine is efficacious for chorea control; however, tolerability concerns exist. Deutetrabenazine, a novel molecule that reduces chorea, was well tolerated in a double-blind, placebo-controlled study. Objectives To evaluate the safety and explore the efficacy of conversion from tetrabenazine to deutetrabenazine in patients with chorea associated with Huntington disease (HD). Design, Setting, and Participants In this ongoing, open-label, single-arm study that started on December 21, 2013, 37 patients at 13 Huntington Study Group sites in the United States and Australia who were taking stable doses of tetrabenazine that provided a therapeutic benefit were switched overnight to deutetrabenazine therapy. After week 1, the deutetrabenazine dose was titrated on a weekly basis for optimal chorea control. Interventions Deutetrabenazine administration at a dosage thought to provide comparable systemic exposure to the active metabolites of the prior, stable tetrabenazine regimen. Main Outcomes and Measures Safety measures included adverse events (AEs), clinical laboratory tests, vital signs, electrocardiograms, and validated scales. Changes in the Unified Huntington’s Disease Rating Scale total maximal chorea score and total motor score were efficacy end points. Results Of the 53 patients with HD screened for the study, 37 ambulatory patients with manifest HD (mean [SD] age, 52.4 [11.5] years; 22 [59%] male and 15 [41%] female; 36 white [97.3%]) were enrolled. Deutetrabenazine was generally well tolerated, with low rates of neuropsychiatric AEs. Safety scales did not reveal subclinical toxicity with deutetrabenazine treatment. Rates of dose reduction or suspension attributable to AEs were also low. Chorea control, as measured by the total maximal chorea score, was maintained at week 1 and significantly improved at week 8 (mean [SD] change from baseline, 2.1 [3.2]; P Conclusions and Relevance In patients with chorea, overnight conversion to deutetrabenazine therapy provided a favorable safety profile and effectively maintained chorea control.

Background Parkinson's disease (PD) is among the most prevalent neurodegenerative conditions. While motor and non-motor aspects of this disease have been well characterized, no objective biomarker exists to support an accurate clinical diagnosis. However, newer imaging techniques, including [123I]-FP-CIT (DaTSCAN), have demonstrated utility in differentiating between PD and non-neurodegenerative tremor disorders. Objective DaTSCAN has been primarily investigated in situations where diagnostic confusion exists, and in these instances has been shown to significantly impact clinical management. The goal of this pilot study was to evaluate the impact of DaTSCAN on the clinical management of patients with early probable PD, where no diagnostic uncertainty exists. Methods This was a prospective, 54-week, comparative pilot study, in which twenty subjects with de novo PD were randomly assigned to DaTSCAN either immediately upon diagnosis (and again at 6 and 12 months) or delayed to 6 months (and again at 12 months). The primary outcome measure was the frequency of deviation from the initial treatment plan from baseline to 54 weeks between the two groups. Secondary outcomes included motor and non-motor assessments. Results There was no significant difference in the number of treatment changes over the course of the study between the two groups: initial imaging group = 4.2 (SD:2.74) vs. delayed imaging group = 2.3 (SD:2.0, p = 0.11). In addition, there were no group differences in medication requirements, motor performance, or patient expectations of disease. Conclusions In patients with early, probable PD, DaTSCAN contributes no additional impact on clinical management or functional outcomes when added to the diagnostic algorithm.

Dystonia is a brain disorder causing involuntary, often painful movements. Apart from a role for dopamine deficiency in some forms, the cellular mechanisms underlying most dystonias are currently unknown. Here, we discover a role for deficient eIF2α signaling in DYT1 dystonia, a rare inherited generalized form, through a genome-wide RNAi screen. Subsequent experiments including patient-derived cells and a mouse model support both a pathogenic role and therapeutic potential for eIF2α pathway perturbations. We further find genetic and functional evidence supporting similar pathway impairment in patients with sporadic cervical dystonia, due to rare coding variation in the eIF2α effector ATF4/CREB2. Considering also that another dystonia, DYT16, involves a gene upstream of the eIF2α pathway, these results mechanistically link multiple forms of dystonia and put forth a new overall cellular mechanism for dystonia pathogenesis – impairment of eIF2α signaling, a pathway known for its roles in cellular stress responses and synaptic plasticity.

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. In this study, we combined data from two previously published GWAS of Caucasian subjects with our GWAS of 604 cases and 619 controls for a joint analysis with a combined sample size of 1752 cases and 1745 controls. SNPs in SNCA (rs2736990, p-value = 6.7 x 10(-8); genome-wide adjusted p = 0.0109, odds ratio (OR) = 1.29 [95% CI: 1.17-1.42] G vs. A allele, population attributable risk percent (PAR%) = 12%) and the MAPT region (rs11012, p-value = 5.6 x 10(-8); genome-wide adjusted p = 0.0079, OR = 0.70 [95% CI: 0.62-0.79] T vs. C allele, PAR%= 8%) were genome-wide significant. No other SNPs were genome-wide significant in this analysis. This study confirms that SNCA and the MAPT region are major genes whose common variants are influencing risk of PD.

Gilles de la Tourette’s syndrome (GTS) is a neuropsychiatric disorder that often presents with a complex array of motor and phonic tics that persist over the majority of a person’s life. GTS often presents with comorbidities such as attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and mood disorders. Psychosocial sequelae are also common among this population.We present the case of a 49-year-old female with severe, lifelong GTS complicated by OCD, inattention, impulsivity, disinhibition, mood disturbances, generalized anxiety, and pain secondary to motor tics. Habit reversal therapy (HRT) was used with full body relaxation conditioned as a competitive response to target her tics, anxiety, and pain simultaneously. The patient demonstrated significant reduction of symptoms and improvement in psychosocial status within four sessions. She was able to maintain this status at a 3 month follow-up session. Aspects of case conceptualization and therapeutic technique are discussed.

We report 3 cases of impulse control disorders (ICDs) that developed in patients with Parkinson disease treated with the novel dopamine agonist, rotigotine.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.The ICDs in these patients were effectively treated with rotigotine reduction or discontinuation.Rotigotine has the potential for causing ICD, similar to other dopamine agonists.

Objective: To determine if future studies of coenzyme Q10 and GPI-1485 in Parkinson disease (PD) may be warranted. Methods: We conducted a randomized, double-blind, calibrated futility clinical trial of coenzyme Q10 and GPI-1485 in early untreated PD using placebo data from the DATATOP study to establish the futility threshold. Results: The primary outcome measure (change in total Unified Parkinson's Disease Rating Scale scores over 1 year) did not meet the prespecified criteria for futility for either agent. Secondary analyses using calibration controls and other more recent placebo data question the appropriateness of the predetermined definition of futility, and suggest that a more restrictive threshold may be needed. Conclusions: Coenzyme Q10 and GPI-1485 may warrant further study in Parkinson disease, although the data are inconsistent. Additional factors (cost, availability of other agents, more recent data on placebo outcomes, other ongoing trials) should also be considered in the selection of agents for Phase III studies. NEUROLOGY 2007;68:20-28

To determine whether people with Parkinson disease (PD) are less likely to report a history of cigarette smoking than their unaffected siblings.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.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.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 (p0.05). The association was not modified by sex, age at onset, or recency of exposure.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.

The pathogenic process responsible for the loss of dopaminergic neurons within the substantia nigra of patients with Parkinson disease (PD) is poorly understood. Current research supports the involvement of fibroblast growth factor (FGF20) in the survival of dopaminergic cells. FGF20 is a neurotrophic factor that is preferentially expressed within the substantia nigra of rat brain. The human homologue has been mapped to 8p21.3-8p22, which is within an area of PD linkage revealed through our published genomic screen. To test whether FGF20 influences risk of PD, we genotyped five single-nucleotide polymorphisms (SNPs) lying within the FGF20 gene, in a large family study. We analyzed our sample (644 families) through use of the pedigree disequilibrium test (PDT), the genotype PDT, the multilocus-genotype PDT, and the family-based association test to assess association between risk of PD and alleles, genotypes, multilocus genotypes, and haplotypes. We discovered a highly significant association of PD with one intronic SNP, rs1989754 (P=.0006), and two SNPs, rs1721100 (P=.02) and ss20399075 (P=.0008), located in the 3′ regulatory region in our overall sample. Furthermore, we detected a haplotype (A-G-C-C-T) that is positively associated with risk of PD (P=.0003), whereas a second haplotype (A-G-G-G-C) was found to be negatively associated with risk of PD (P=.0009). Our results strongly support FGF20 as a risk factor for PD.

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.

The purpose of this study was to derive patient preferences and utilities for outcomes associated with treatment of motor fluctuations, or 'off-time', for patients with Parkinson's disease (PD). Visual analog scale (VAS) and standard gamble (SG) approaches were used with 60 patients to determine patient preferences and utilities for 10 health state descriptions. Health state descriptions were categorized according to two factors: disease severity, and proportion of the day with 'off-time'. There were two representative levels of disease severity, based on Hoehn and Yahr stages 1.5 and 2.5: unilateral disease with no postural instability, and bilateral disease with some postural instability. These severity levels were combined with five levels of 'off-time' per day ranging from none to > 75% of the day. Patients' mean preference or utility for their own current health ranged from 0.65 +/- 0.20 (VAS) to 0.74 +/- 0.22 (SG). Patients assigned the lowest mean values to the health state description for Hoehn and Yahr stage 2.5 with 'off-time' for > 75% of the day (VAS: 0.17 +/- 0.17; SG: 0.49 +/- 0.27). The highest mean values were assigned to Hoehn and Yahr stage 1.5 with no 'off-time' (VAS: 0.83 +/- 0.17; SG: 0.85 +/- 0.18). The results of this study indicated patients with PD would likely seek treatment that would minimize the amount of 'off-time' experienced per day, and that patients were relatively risk averse.

Apolipoprotein E (apoE) is a 34-kDa protein implicated in Alzheimer's disease (AD) that has recently been identified in neuronal cytoplasm. In cultured neurons, the two major isoforms of apoE (E3 and E4) differentially affect neurite extension, microtubule formation, and the ratio of polymerized to depolymerized tubulin. We therefore examined the effects of apoE3 and apoE4 on microtubule assembly in vitro. ApoE3 and apoE4 equally accelerated microtubule polymerization under conditions of slow microtubule assembly. Controls comprising apolipoprotein A1, bovine serum albumin, trypsin inhibitor, and boiled apoE had no effect, demonstrating specificity of the apoE effect. The ability of both apoE isoforms to accelerate microtubule assembly in vitro suggests that isoform-specific differences in neurite extension may result from differences in the uptake, intracytoplasmic transport, or metabolism of these isoforms.

Essential tremor is a neurological condition characterized by tremor during voluntary movement. To date, 3 loci linked to familial essential tremor have been identified.We examined 48 essential tremor patients in 5 large essential tremor pedigrees in our data set for genetic linkage using an Affymetrix Axiom array. Linkage analysis was performed using an affecteds-only dominant model in SIMWALK2. To incorporate all genotype information, GERMLINE was used to identify genome segments shared identical-by-descent in pairs of affecteds. Exome sequencing was performed in pedigrees showing evidence of linkage.For one family, chromosomes 5 and 18 showed genome-wide significant linkage to essential tremor. Shared segment analysis excluded the 18p11 candidate region and reduced the 5q35 region by 1 megabase. Exome sequencing did not identify a potential causative variant in this region.A locus on chromosome 5 is linked to essential tremor. Further research is needed to identify a causative variant. © 2016 International Parkinson and Movement Disorder Society.

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 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

Objective Inducible nitric oxide synthase, a protein product of NOS2A, generates nitric oxide as a defense mechanism, but excessive levels threaten cellular survival. NOS2A is a candidate gene for Parkinson's disease (PD) that potentially interacts with cigarette smoking. We examined NOS2A for association with PD risk and age at onset (AAO) and for interaction with smoking. Methods We genotyped 13 NOS2A single nucleotide polymorphisms (SNPs) in 466 singleton families and in a validation set of 286 multiplex families. We tested allelic and haplotypic association using the association in the presence of linkage test, genotypic associations using the genotype pedigree disequilibrium test, AAO effects using the quantitative transmission disequilibrium test, and interactions using generalized estimating equations. Results Among the pooled earliest onset families, rs2255929 and rs1060826 generated significant allelic (p = 0.000059 and 0.0062, respectively) and genotypic (p = 0.0039 and 0.0014, respectively) associations with risk and AAO (p = 0.00070 and 0.0073, respectively); the two-SNP haplotype generated even stronger association with PD (p = 0.000013). Significant interactions with smoking (p = 0.0015 for rs 2255929 and p < 0.0001 for rs 1060826) were detected in a subset of the families; smoking was inversely associated with PD among risk allele noncarriers, but significance diminished among carriers. Interpretation Our findings support NOS2A as a genetic risk factor in PD, potentially by influencing AAO and by modifying the inverse association between PD and smoking. Ann Neurol 2006

Objective 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). Methods Thirty-four PD patients were randomized 1 to 1 to receive bilateral continuous Ipu infusion of liatermin 15μg/putamen/day or placebo. The primary end point was the change in Unified Parkinson Disease Rating Scale (UPDRS) motor score in the practically defined off condition at 6 months. Secondary end points included other UPDRS scores, motor tests, dyskinesia ratings, patient diaries, and 18F-dopa uptake. Results At 6 months, mean percentage changes in “off” UPDRS motor score were −10.0% and −4.5% in the liatermin and placebo groups, respectively. This treatment difference was not significant (95% confidence interval, −23.0 to 12.0, p = 0.53). Secondary end point results were similar between the groups. A 32.5% treatment difference favoring liatermin in mean 18F-dopa influx constant (p = 0.019) was observed. Serious, device-related adverse events required surgical repositioning of catheters in two patients and removal of devices in another. Neutralizing antiliatermin antibodies were detected in three patients (one on-study and two in the open-label extension). Interpretation Liatermin did not confer the predetermined level of clinical benefit to patients with PD despite increased 18F-dopa uptake. It is uncertain whether technical differences between this trial and positive open-label studies contributed in any way this negative outcome. Ann Neurol 2006

Genomic convergence is a multistep approach that combines gene expression with genomic linkage to identify and prioritize susceptibility genes for complex disease. As a first step, we previously performed linkage analysis on 174 multiplex Parkinson's disease (PD) families, identifying five peaks for PD risk and two for genes affecting age at onset (AAO) in PD [Hauser et al., Hum Mol Genet 2003;12:671–677]. We report here the next step: serial analysis of gene expression [SAGE; Scott et al., JAMA 2001;286:2239–2242] to analyze substantia nigra tissue from three PD patients and two age-matched controls. We find 933 differentially expressed genes (P < 0.05) between PD and controls, but of these, only 50 genes represented by unique SAGE tags map within our previously described PD linkage regions. Furthermore, genes encoded by mitochondrial DNA are expressed 1.5-fold higher in PD patients versus controls, without an increase in the corresponding nuclear-encoded mitochondrial components, suggesting an increase in mtDNA genomes in PD or a disjunction with nuclear expression. The next step in the genomic convergence process will be to screen these 50 high-quality candidate genes for association with PD risk susceptibility and genetic effects on AAO. © 2005 Movement Disorder Society

We describe a 13-year-old boy with Tourette's syndrome (TS) manifested chiefly by severe coprolalia, obsessive compulsive disorder, and attention deficit hyperactivity disorder. He was treated with unilateral injections of botulinum toxin to the vocal cord and experienced marked improvement in coprolalia as well as marked reduction in the premonitory urges associated with the vocal tics and coprolalia. As a result of the improvement, the patient was able to attend school and church and was able to socialize. Botulinum toxin may interfere with a sensory reflex arc required to perpetuate tics and coprolalia in TS, possibly by reducing local build-up of tension or muscle contraction in affected areas.

We and others have previously detected association of the Tau H1 haplotype on chromosome 17 with risk of idiopathic Parkinson disease (PD). The H1 haplotype appears to have a fundamental importance in neurodegeneration, as multiple studies have shown it is also associated with an increased risk for progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration syndromes, and primary progressive aphasia. Therefore, to divide the H1 haplotype into sub-haplotypes that could be more significantly associated with the risk of developing PD, and to delimit the genes lying in the H1 haplotype, we analyzed 34 single nucleotide polymorphisms (SNPs) spanning over 3.15 megabases in the region containing Tau. These SNPs are located in or flank the corticotropin-releasing hormone receptor 1, presenilin homolog 2, Tau, Saitohin, and KIAA1267 genes. Analysis of linkage disequilibrium (LD) using these 34 SNPs suggests that the H1 haplotype extends over about 1.3 megabases, making it the largest region of LD reported to date. Of the 29 SNPs lying in this region of LD, 5 were identified as “haplotype tagging” SNPs (htSNPs), capturing 96% of the sample’s haplotype diversity. Association analysis with these htSNPs revealed a new H1 sub-haplotype that is significantly associated with PD (P

Background Previously, we detected linkage of idiopathic Parkinson disease (PD) to the region on chromosome 6 that contains the Parkin gene (D6S305; logarithm of odds score, 5.47) in families with at least one individual with age at onset younger than 40 years (families with early-onset disease). Further study demonstrated the presence of Parkin mutations in this data set. However, previous case-control studies have reported conflicting results regarding the role of more common Parkin polymorphisms as susceptibility alleles for idiopathic PD. Objective To investigate the association of 7 previously studied Parkin single-nucleotide polymorphisms (SNPs) throughout the promoter and most of the open reading frame with PD in a large cohort of patients with primarily late-onset PD. Methods One promoter, 3 intronic, and 3 exonic Parkin SNPs were genotyped in 1580 individuals belonging to 397 families, and their association with PD was evaluated using family-based association tests. Results No significant association (P>.05) between PD and any Parkin SNP allele or genotype was detected. Haplotype analysis and stratification by age at onset or family history also failed to produce significant results. Conclusions These results suggest that these common variants of Parkin are not associated with PD in white patients, although Parkin mutations are known to cause early- and late-onset PD.

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 Parkinson's 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.

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.

CONTEXT The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease. OBJECTIVE To investigate whether the tau gene is involved in idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene. MAIN OUTCOME MEASURE Family-based tests of association, calculated using asymptotic distributions. RESULTS Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P =.03; SNP 9i, P =.04; and SNP 11, P =.04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P =.11, and SNP 9iii, P =.87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P =.009) and a negative association with another haplotype (P =.007). Substantial linkage disequilibrium (P

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

To assess associations between Parkinson disease (PD) and putatively protective factors-smoking, caffeine (coffee, tea, and soft drinks), and nonsteroidal anti-inflammatory drugs (aspirin, ibuprofen, and naproxen).Family-based case-control study.Academic medical center clinic.A total of 356 case subjects and 317 family controls who self-reported environmental exposures.Associations between PD and environmental measures (history, status, dosage, duration, and intensity) of smoking, coffee, caffeine, nonsteroidal anti-inflammatory drugs, and non-aspirin nonsteroidal anti-inflammatory drugs were examined using generalized estimating equations with an independent correlation matrix while controlling for age and sex.Individuals with PD were significantly less likely to report ever smoking (odds ratio = 0.56; 95% confidence interval, 0.41-0.78). Additional measures of smoking revealed significant inverse associations with PD (P.05) and trends in odds ratios (P.005). Increasing intensity of coffee drinking was inversely associated with PD (test for trend P = .05). Increasing dosage (trend P = .009) and intensity (trend P = .01) of total caffeine consumption were also inversely associated, with high dosage presenting a significant inverse association for PD (odds ratio = 0.58; 95% confidence interval, 0.34-0.99). There were no significant associations between nonsteroidal anti-inflammatory drugs and PD.Inverse associations of smoking and caffeine were corroborated using families with PD, thus emphasizing smoking and caffeine as important covariates to consider in genetic studies of PD.

ContextThe relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD.ObjectiveTo identify genetic risk factors for idiopathic PD.Design, Setting, and ParticipantsGenetic linkage study conducted 1995-2000 in which a complete genomic screen (n = 344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status.Main Outcome MeasuresLogarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis.ResultsTwo-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients.ConclusionsOur data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD.

Reply from the Authors: We thank Drs. Przedborski, Kostic, and Burke for their interest in our work and appreciate their comments concerning striatal …