APOE4 Allele, Sex, and Dementia Risk in Parkinson's Disease: Lessons From a Longitudinal Cohort.

INTRODUCTION: The effect of APOE4 allele on dementia risk is well established in Alzheimer's disease and Parkinson's disease (PD). However, it is unknown if sex modifies this relationship. We sought to determine the effect of sex on the relationship between APOE4 status and incident cognitive decline in PD. METHODS: Data from the prospectively collected longitudinal National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) and Neuropathology Data Set (NDS) were analyzed. The NACC develops and maintains data from approximately 29 National Institutes of Aging-funded Alzheimer's Disease Research Centers. Further details may be found at the NACC web site (www.alz.washington.edu). The visit at which diagnosis of PD was made was termed the baseline visit. All patients with a PD diagnosis but without dementia at the baseline visit were included in the analyses. RESULTS: Presence of APOE4 allele was associated with higher odds (OR = 7.4; P < .001) of subsequent diagnosis of dementia and with a faster time to developing dementia (P = .04). Those with APOE4 allele were more likely to have neuropathology associated with Alzheimer's disease than those without APOE4 allele. We did not find any difference by sex. There were no differences between Lewy body pathology or neuron loss in the substantia nigra between the 2 groups. Sex was not associated with dementia risk in PD (OR = 0.53, P = .15) or with the time to dementia onset (P = .22). Sex did not modify the relationship between the APOE4 allele and dementia onset in PD patients (P = .12). CONCLUSIONS: APOE4 allele status in PD may be a predictor of cognitive decline in PD but does not appear to be modified by sex.

Dissociation between urate and blood pressure in mice and in people with early Parkinson's disease.

BACKGROUND: Epidemiological, laboratory and clinical studies have established an association between elevated urate and high blood pressure (BP). However, the inference of causality remains controversial. A naturally occurring antioxidant, urate may also be neuroprotective, and urate-elevating treatment with its precursor inosine is currently under clinical development as a potential disease-modifying strategy for Parkinson's disease (PD). METHODS: Our study takes advantage of a recently completed phase II trial evaluating oral inosine in de novo non-disabling early PD with no major cardiovascular and nephrological conditions, and of three lines of genetically engineered mice: urate oxidase (UOx) global knockout (gKO), conditional KO (cKO), and transgenic (Tg) mice with markedly elevated, mildly elevated, and substantially reduced serum urate, respectively, to systematically investigate effects of urate-modifying manipulation on BP. FINDINGS: Among clinical trial participants, change in serum urate but not changes in systolic, diastolic and orthostatic BP differed by treatment group. There was no positive correlation between urate elevations and changes in systolic, diastolic and orthostatic BP ((p = .05 (in inverse direction), 0.30 and 0.63, respectively)). Between UOx gKO, cKO, or Tg mice and their respective wildtype littermates there were no significant differences in systolic or diastolic BP or in their responses to BP-regulating interventions. INTERPRETATION: Our complementary preclinical and human studies of urate modulation in animal models and in generally healthy early PD do not support a hypertensive effect of urate elevation or an association between urate and BP. FUND: U.S. Department of Defense, RJG Foundation, Michael J. Fox Foundation LEAPS program, National Institutes of Health, American Federation for Aging Research, Parkinson's Disease Foundation Advancing Parkinson's Therapies initiative.

Factors associated with falling in early, treated Parkinson's disease: The NET-PD LS1 cohort.

BACKGROUND: Recognizing the factors associated with falling in Parkinson's disease (PD) would improve identification of at-risk individuals. OBJECTIVE: To examine frequency of falling and baseline characteristics associated with falling in PD using the National Institute of Neurological Disorders and Stroke (NINDS) Exploratory Trials in PD Long-term Study-1 (NET-PD LS-1) dataset. METHODS: The LS-1 database included 1741 early treated PD subjects (median 4year follow-up). Baseline characteristics were tested for a univariate association with post-baseline falling during the trial. Significant variables were included in a multivariable logistic regression model. A separate analysis using a negative binomial model investigated baseline factors on fall rate. RESULTS: 728 subjects (42%) fell during the trial, including at baseline. A baseline history of falls was the factor most associated with post-baseline falling. Men had lower odds of post-baseline falling compared to women, but for men, the probability of a post-baseline fall increased with age such that after age 70, men and women had similar odds of falling. Other baseline factors associated with a post-baseline fall and increased fall rate included the Unified PD Rating Scale (UPDRS) Activities of Daily Living (ADL) score, total functional capacity (TFC), baseline ambulatory capacity score and dopamine agonist monotherapy. CONCLUSION: Falls are common in early treated PD. The biggest risk factor for falls in PD remains a history of falling. Measures of functional ability (UPDRS ADL, TFC) and ambulatory capacity are novel clinical risk factors needing further study. A significant age by sex interaction may help to explain why age has been an inconsistent risk factor for falls in PD.

Sweat Gland Denervation in Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS).

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a newly recognized disorder characterized by cerebellar ataxia, nonlength-dependent sensory impairment, and bilateral vestibular loss. Sudomotor dysfunction has been described in CANVAS; however, the underlying pathology is not well characterized. To describe novel histopathological features of this syndrome, 2 siblings are presented who had CANVAS with unique findings of sweat gland denervation. Skin biopsy testing was performed to assess sudomotor structure and revealed markedly reduced sweat gland nerve fiber density below the 2.5th percentile in both patients. These histopathological findings suggest that postganglionic sudomotor dysfunction is an additional feature of CANVAS.

Longer Duration of MAO-B Inhibitor Exposure is Associated with Less Clinical Decline in Parkinson's Disease: An Analysis of NET-PD LS1.

BACKGROUND: Monoamine oxidase type B (MAO-B) inhibitors exhibit neuroprotective effects in preclinical models of PD but clinical trials have failed to convincingly demonstrate disease modifying benefits in PD patients. OBJECTIVE: To perform a secondary analysis of NET-PD LS1 to determine if longer duration of MAO-B inhibitor exposure was associated with less clinical decline. METHODS: The primary outcome measure was the Global Outcome (GO), comprised of 5 measures: change from baseline in the Schwab and England (ADL) scale, the 39-item Parkinson's Disease Questionnaire (PDQ-39), the UPDRS Ambulatory Capacity Scale, the Symbol Digit Modalities Test, and the most recent Modified Rankin Scale. A linear mixed model was used to explore the association between the cumulative duration of MAO-B inhibitor exposure and the GO, adjusting for necessary factors and confounders. Associations between MAO-B inhibitor exposure and each of the five GO components were then studied individually. RESULTS: 1616 participants comprised the analytic sample. Mean observation was 4.1 (SD = 1.4) years, and 784 (48.5%) participants received an MAO-B inhibitor. The regression coefficient of cumulative duration of MAO-B inhibitor exposure (in years) on the GO was - 0.0064 (SE = 0.002, p = 0.001). Significant associations between duration of MAO-B inhibitor exposure and less progression were observed for ADL (p < 0.001), Ambulatory Capacity (p < 0.001), and the Rankin (p = 0.002). CONCLUSIONS: Our analysis identified a significant association between longer duration of MAO-B inhibitor exposure and less clinical decline. These findings support the possibility that MAO-B inhibitors slow clinical disease progression and suggest that a definitive prospective trial should be considered.

Clinicopathological Correlates in a PRNP P102L Mutation Carrier with Rapidly Progressing Parkinsonism-dystonia.

Parkinsonism-dystonia is rare in carriers of PRNP P102L mutation. Severity and distribution of prion protein (PrP) deposition may influence the clinical presentation. We present such clinic-pathological correlation in a 56-year-old male with a PRNP P102L mutation associated with a phenotype characterized by rapidly progressing parkinsonism-dystonia. The patient was studied clinically (videotaped exams, brain MRIs); molecular genetically (gene sequence analysis); and neuropathologically (histology, immunohistochemistry) during his 7-month disease course. The patient had parkinsonism, apraxia, aphasia, and dystonia, which progressed rapidly. Molecular genetic analysis revealed PRNP P102L mutation carrier status. Brain MRIs revealed progressive global volume loss and T2/FLAIR hyperintensity in neocortex and basal ganglia. Postmortem examination showed neuronal loss, gliosis, spongiform changes, and PrP deposition in the striatum. PrP immunohistochemistry revealed widespread severe PrP deposition in the thalamus and cerebellar cortex. Based on the neuropathological and molecular-genetic analysis, the rapidly progressing parkinsonism-dystonia correlated with nigrostriatal, thalamic, and cerebellar pathology.

Sex Differences in Clinical Features of Early, Treated Parkinson's Disease.

INTRODUCTION: To improve our understanding of sex differences in the clinical characteristics of Parkinson's Disease, we sought to examine differences in the clinical features and disease severity of men and women with early treated Parkinson's Disease (PD) enrolled in a large-scale clinical trial. METHODS: Analysis was performed of baseline data from the National Institutes of Health Exploratory Trials in Parkinson's Disease (NET-PD) Long-term Study-1, a randomized, multi-center, double-blind, placebo-controlled study of 10 grams of oral creatine/day in individuals with early, treated PD. We compared mean age at symptom onset, age at PD diagnosis, and age at randomization between men and women using t-test statistics. Sex differences in clinical features were evaluated, including: symptoms at diagnosis (motor) and symptoms at randomization (motor, non-motor, and daily functioning). RESULTS: 1,741 participants were enrolled (62.5% male). No differences were detected in mean age at PD onset, age at PD diagnosis, age at randomization, motor symptoms, or daily functioning between men and women. Differences in non-motor symptoms were observed, with women demonstrating better performance compared to men on SCOPA-COG (Z = 5.064, p<0.0001) and Symbol Digit Modality measures (Z = 5.221, p<0.0001). CONCLUSIONS: Overall, men and women did not demonstrate differences in clinical motor features early in the course of PD. However, the differences observed in non-motor cognitive symptoms suggests further assessment of the influence of sex on non-motor symptoms in later stages of PD is warranted.

Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial.

IMPORTANCE: There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. OBJECTIVE: To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. DESIGN, SETTING, AND PATIENTS: The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. INTERVENTIONS: Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). MAIN OUTCOMES AND MEASURES: The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes. RESULTS: The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test yielded t1865.8 = -0.75 (2-sided P = .45). There were no detectable differences (P < .01 to partially adjust for multiple comparisons) in adverse and serious adverse events by body system. CONCLUSIONS AND RELEVANCE: Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00449865.

Betting on DBS: Effects of subthalamic nucleus deep brain stimulation on risk taking and decision making in patients with Parkinson's disease.

OBJECTIVE: Concerns persist that deep brain stimulation (DBS) for Parkinson's disease (PD) increases impulsivity or induces excessive reward seeking. We report here the performance of PD patients with implanted subthalamic nucleus electrodes, with stimulation on and off, on 3 laboratory tasks of risk taking and decision making. They are compared with PD patients maintained on medication and healthy participants. METHODS AND RESULTS: In the Game of Dice Task, a test of "risky" decision making, PD patients with or without DBS made highest risk bets more often and ended up with less money than did healthy participants. There was a trend for DBS stimulation to ameliorate this effect. Deal or No-Deal is an "ambiguous" decision-making task that assessed preference for risk (holding on to one's briefcase) over a "sure thing" (accepting the banker's offer). Here, DBS patients were more conservative with stimulation on than with it off. They accepted smaller offers from the banker and won less money in the DBS-on condition. Overall, the 2 PD groups won less money than did healthy participants. The Framing Paradigm assessed willingness to gamble on a fixed (unambiguous) prize depending on whether the reward was "framed" as a loss or a gain. Nonsurgical PD patients tended to be more risk-averse than were healthy participants, whereas DBS patients were more willing to gamble for gains as well as losses both on and off stimulation. CONCLUSIONS: On risky decision-making tasks, DBS patients took more risks than did healthy participants, but stimulation may temper this tendency. In contrast, in an ambiguous-risk situation, DBS patients were more risk-averse (conservative) than were healthy participants, and this tendency was greatest with stimulation.

No sex differences in use of dopaminergic medication in early Parkinson disease in the US and Canada - baseline findings of a multicenter trial.

BACKGROUND: Sex differences in Parkinson disease clinical features have been reported, but few studies have examined sex influences on use of dopaminergic medication in early Parkinson disease. The objective of this study was to test if there are differences in the type of dopaminergic medication used and levodopa equivalent daily dose between men and women with early Parkinson disease enrolled in a large multicenter study of Creatine as a potential disease modifying therapy - the National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease Long-Term Study-1. METHODS: Baseline data of 1,741 participants from 45 participating sites were analyzed. Participants from the United States and Canada were enrolled within five years of Parkinson Disease diagnosis. Two outcome variables were studied: type of dopaminergic medication used and levodopa equivalent daily dose at baseline in the Long-Term Study-1. Chi-square statistic and linear regression models were used for statistical analysis. RESULTS: There were no statistically significant differences in the frequency of use of different types of dopaminergic medications at baseline between men and women with Parkinson Disease. A small but statistically significant difference was observed in the median unadjusted levodopa equivalent daily dose at baseline between women (300 mg) and men (325 mg), but this was not observed after controlling for disease duration (years since Parkinson disease diagnosis), disease severity (Unified Parkinson's Disease Rating Scale Motor and Activities of Daily Living Scores), and body weight. CONCLUSIONS: In this large multicenter study, we did not observe sex differences in the type and dose of dopaminergic medications used in early Parkinson Disease. Further research is needed to evaluate the influence of male or female sex on use of dopaminergic medication in mid- and late-stage Parkinson Disease.

Dopamine transporter imaging in psychogenic parkinsonism and neurodegenerative parkinsonism with psychogenic overlay: a report of three cases.

BACKGROUND: Differentiating psychogenic parkinsonism from neurodegenerative Parkinson's disease (PD) with psychogenic features is a diagnostic challenge. CASE REPORT: We report a detailed longitudinal clinical description of three cases presenting with suspected psychogenic parkinsonism. Dopamine transporter single-photon emission computed tomography (DAT-SPECT) was used as a supplemental diagnostic study and influenced clinical management. DISCUSSION: DAT-SPECT quantified the integrity of the striatal dopaminergic system in these cases of clinically uncertain parkinsonism and supported clinical decision-making.

Dual treatment of hemichorea-hemiballismus syndrome with tetrabenazine and chemodenervation.

BACKGROUND: Hemichorea-hemiballismus involves unilateral involuntary flailing movements and random jerking movements involving proximal or distal muscles. We describe a case of hemichorea-hemiballismus with dystonia after stroke. Treatment with tetrabenazine and chemodenervation produced beneficial responses. Effective treatment of both hemichorea-hemiballismus and dystonia due to stroke has not been reported. CASE REPORT: A 65-year-old male developed left hemichorea-hemiballismus and dystonia after a right hemisphere stroke. He underwent initial treatment with neuroleptics and anticonvulsants without improvement. Subsequent treatment with tetrabenazine improved the hemichorea-hemiballismus and chemodenervation reduced the dystonia. DISCUSSION: Hemichorea-hemiballismus associated with dystonia can be improved with both tetrabenazine and chemodenervation.

Use of Tetrabenazine in Huntington Disease Patients on Antidepressants or with Advanced Disease: Results from the TETRA-HD Study.

The safety and effectiveness of tetrabenazine in different sub-populations of Huntington disease (HD) is not known. In this study, we evaluated the safety of tetrabenazine in individuals on an antidepressant and its effectiveness in advanced HD. Tetrabenazine was not associated with an increased incidence of depressed mood among those taking antidepressants and was effective at reducing chorea in those with advanced HD.