Nabila Dahodwala

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.

Genetic Influences on Cognitive Decline in Parkinson's Disease

The role of genetic factors in cognitive decline associated with Parkinsons disease (PD) is unclear. We examined whether variations in apolipoprotein E (APOE), microtubule‐associated protein tau (MAPT), or catechol‐O‐methytransferase (COMT) genotypes are associated with cognitive decline in PD. We performed a prospective cohort study of 212 patients with a clinical diagnosis of PD. The primary outcome was change in Mattis Dementia Rating Scale version 2 score. Linear mixed‐effects models and survival analysis were used to test for associations between genotypes and change in cognitive function over time. The ε4 allele of APOE was associated with more rapid decline (loss of 2.9; 95% confidence interval [CI]: 1.7–4.1) of more points per year; P < 0.001) in total score and an increased risk of a ≥10 point drop during the follow‐up period (hazard ratio, 2.8; 95% CI: 1.4–5.4; P = 0.003). MAPT haplotype and COMT genotype were associated with measures of memory and attention, respectively, over the entire follow‐up period, but not with the overall rate of cognitive decline. These results confirm and extend previously described genetic associations with cognitive decline in PD and imply that individual genes may exert effects on specific cognitive domains or at different disease stages. Carrying at least one APOE ε4 allele is associated with more rapid cognitive decline in PD, supporting the idea of a component of shared etiology between PD dementia and Alzheimers disease. Clinically, these results suggest that genotyping can provide information about the risk of future cognitive decline for PD patients.

Sex differences in Parkinson's disease and other movement disorders.

Movement disorders including Parkinsons disease (PD), Huntingtons disease (HD), chorea, tics, and Tourettes syndrome (TS) display sex differences in disease susceptibility, disease pathogenesis, and clinical presentation. PD is more common in males than in females. Epidemiologic studies suggest that exposure to endogenous and exogenous estrogen contributes to these sex differences. There is extensive evidence that estrogen prevents dopaminergic neuron depletion induced by neurotoxins in PD animal models and therefore is neuroprotective. Estrogen may also decrease the efficacy of other neuroprotective substances such as caffeine in females but not males. Sex chromosomes can exert effects independent of sex steroid hormones on the development and maintenance of the dopamine system. As a result of hormone, chromosome and other unknown effects, there are sexual dimorphisms in the basal ganglia, and at the molecular levels in dopaminergic neurons that may lead to distinct mechanisms of pathogenesis in males and females. In this review, we summarize the evidence that estrogen and selective estrogen receptor modulators are neuroprotective in PD and discuss potential mechanisms of action. We also briefly review how sex differences in basal ganglia function and dopaminergic pathways may impact HD, chorea, and tics/Tourettes syndrome. Further understanding of these sex differences may lead to novel therapeutic strategies for prevention and treatment of these diseases.

Longitudinal study of normal cognition in Parkinson disease.

Objective: To report the rates and predictors of progression from normal cognition to either mild cognitive impairment (MCI) or dementia using standardized neuropsychological methods. Methods: A prospective cohort of patients diagnosed with Parkinson disease (PD) and baseline normal cognition was assessed for cognitive decline, performance, and function for a minimum of 2 years, and up to 6. A panel of movement disorders experts classified patients as having normal cognition, MCI, or dementia, with 55/68 (80.9%) of eligible patients seen at year 6. Kaplan-Meier curves and Cox proportional hazard models were used to examine cognitive decline and its predictors. Results: We enrolled 141 patients, who averaged 68.8 years of age, 63% men, who had PD on average for 5 years. The cumulative incidence of cognitive impairment was 8.5% at year 1, increasing to 47.4% by year 6. All incident MCI cases had progressed to dementia by year 5. In a multivariate analysis, predictors of future decline were male sex (p = 0.02), higher Unified Parkinsons Disease Rating Scale motor score (p ≤ 0.001), and worse global cognitive score (p < 0.001). Conclusions: Approximately half of patients with PD with normal cognition at baseline develop cognitive impairment within 6 years and all new MCI cases progress to dementia within 5 years. Our results show that the transition from normal cognition to cognitive impairment, including dementia, occurs frequently and quickly. Certain clinical and cognitive variables may be useful in predicting progression to cognitive impairment in PD.

Racial differences in the diagnosis of Parkinson's disease†

The objective of this cohort study was to determine the incidence of Parkinsons disease (PD) and the effects of race/ethnicity, other demographic characteristics, geography, and healthcare utilization on probability of diagnosis. The authors used the Pennsylvania state Medicaid claims dataset from 1999 to 2003 to identify newly diagnosed cases of PD among the 182,271 Medicaid enrolled adults age 40–65; 319 incident cases of PD were identified. The 4‐year cumulative incidence of PD was 45 per 100,000; 54 per 100,000 among whites, 23 per 100,000 among African‐Americans and 40 per 100,000 among Latinos (P < 0.0001), corresponding to a relative risk (RR) of PD of 0.43 for African‐Americans (P < 0.0001) compared with whites. After adjusting for age, sex, geography, reason for Medicaid eligibility, and average number of visits, African‐Americans were still half as likely to be diagnosed with PD as whites (RR 0.45, P < 0.0001). Older age, more healthcare visits and Medicaid eligibility because of income alone also were significantly associated with PD diagnosis, while male sex was not. Observed racial differences in incidence of PD are not explained by differences in age, sex, income, insurance or healthcare utilization but still may be explained by biological differences or other factors such as education or aging beliefs. Better understanding of the complex biological and social determinants of these disparities is critical to improve PD care.

Conversion Between Mini-Mental State Examination, Montreal Cognitive Assessment, and Dementia Rating Scale-2 Scores in Parkinson’s Disease

Cognitive impairment is one of the earliest, most common, and most disabling non‐motor symptoms in Parkinsons disease (PD). Thus, routine screening of global cognitive abilities is important for the optimal management of PD patients. Few global cognitive screening instruments have been developed for or validated in PD patients. The Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Dementia Rating Scale‐2 (DRS‐2) have been used extensively for cognitive screening in both clinical and research settings. Determining how to convert the scores between instruments would facilitate the longitudinal assessment of cognition in clinical settings and the comparison and synthesis of cognitive data in multicenter and longitudinal cohort studies. The primary aim of this study was to apply a simple and reliable algorithm for the conversion of MoCA to MMSE scores in PD patients. A secondary aim was to apply this algorithm for the conversion of DRS‐2 to both MMSE and MoCA scores. The cognitive performance of a convenience sample of 360 patients with idiopathic PD was assessed by at least two of these cognitive screening instruments. We then developed conversion scores between the MMSE, MoCA, and DRS‐2 using equipercentile equating and log‐linear smoothing. The conversion score tables reported here enable direct and easy comparison of three routinely used cognitive screening assessments in PD patients.

Treatment Disparities in Parkinson’s Disease

We sought to identify racial disparities in the treatment of Parkinsons disease (PD). We identified 307 incident PD cases using Pennsylvania State Medicaid claims, and extracted claims for medications, physical therapy, and healthcare visits for the 6 months after diagnosis. After controlling for age, sex, and geography, African‐Americans were four times less likely than whites to receive any PD treatment (odds ratio, 0.24; 95% confidence interval, 0.09–0.64), especially indicated medications. In a group with the same healthcare insurance, disparities in PD treatment exist. Physician and community awareness of these racial differences in PD treatment is the first step in addressing healthcare disparities. Ann Neurol 2009;66:142–145

Questionnaire‐based diagnosis of REM sleep behavior disorder in Parkinson's disease

Rapid eye movement (REM) sleep behavior disorder (RBD) is present in around 40% of Parkinsons disease (PD) patients. Definitive diagnosis requires a polysomnogram, but that is costly, time intensive, and not practical for large‐scale studies. Therefore, we assessed using a questionnaire‐based diagnostic approach.

Analysis of the treatment of neuromyelitis optica

BACKGROUND Treatment options for neuromyelitis optica (NMO) are currently based on small retrospective case series and open label studies, ranging from 10 to 103 patients. OBJECTIVE To compare the efficacy and tolerability of azathioprine, cyclophosphamide, mycophenolate, and rituximab in patients with neuromyelitis optica. METHODS This is a retrospective chart review and telephone follow-up study of 71 patients with NMO or NMO spectrum disorder, 54 of whom were treated with the study drugs. We compared adverse events, annualized relapse rates and expanded disability status scales before and after treatment. RESULTS The median ARR decreased from 1.17 to 0.25 on rituximab (P<0.01), 0.92 to 0.56 on azathioprine (P=0.475), 1.06 to 0.39 on mycophenolate (P<0.05) and 1.30 to 0.92 on cyclophosphamide (P=0.746). When compared directly to azathioprine, rituximab significantly reduced relapse rates (P=0.021). The median EDSS decreased from 7 to 5 on rituximab (P<0.01) and 7 to 6 on azathioprine (P<0.01), and did not change significantly on mycophenolate (4 to 5; P=0.463) or cyclophosphamide (6.5 to 6.5; P=0.881). Twenty-five percent of patients noted adverse events on rituximab, 36% on azathioprine, 36% on mycophenolate, and 80% on cyclophosphamide. CONCLUSION Rituximab significantly reduces relapse rates and improves disability while maintaining comparable tolerability to other immunosuppressive treatments for NMO.

Surface EMG activity during REM sleep in Parkinson's disease correlates with disease severity

OBJECTIVES Over 40% of individuals with Parkinsons disease (PD) have rapid eye movement sleep behavior disorder (RBD). This is associated with excessive sustained (tonic) or intermittent (phasic) muscle activity instead of the muscle atonia normally seen during REM sleep. We examined characteristics of manually-quantitated surface EMG activity in PD to ascertain whether the extent of muscle activity during REM sleep is associated with specific clinical features and measures of disease severity. METHODS In a convenience sample of outpatients with idiopathic PD, REM sleep behavior disorder was diagnosed based on clinical history and polysomnogram, and severity was measured using the RBD sleep questionnaire. Surface EMG activity in the mentalis, extensor muscle group of the forearms, and anterior tibialis was manually quantitated. Percentage of REM time with excessive tonic or phasic muscle activity was calculated and compared across PD and RBD characteristics. RESULTS Among 65 patients, 31 had confirmed RBD. In univariate analyses, higher amounts of surface EMG activity were associated with longer PD disease duration (srho = 0.34; p = 0.006) and greater disease severity (p < 0.001). In a multivariate regression model, surface EMG activity was significantly associated with RBD severity (p < 0.001) after adjustment for age, PD disease duration, PD severity and co-morbid sleep abnormalities. CONCLUSION Surface EMG activity during REM sleep was associated with severity of both PD and RBD. This measure may be useful as a PD biomarker and, if confirmed, may aid in determining which PD patients warrant treatment for their dream enactment to reduce risk of injury.