Anwar Ahmed

Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial.

IMPORTANCE Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD). OBJECTIVE To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial. DESIGN, SETTING, AND PARTICIPANTS The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled. INTERVENTIONS Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month. MAIN OUTCOMES AND MEASURES The prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability. CONCLUSIONS AND RELEVANCE Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00833690.

The Gly2019Ser Mutation in LRRK2 is not Fully Penetrant in Familial Parkinson's Disease: The GenePD Study

BackgroundWe report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinsons disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD.MethodsA sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample.ResultsThirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families.ConclusionLifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.

Effects of STN DBS for Parkinson's disease on restless legs syndrome and other sleep-related measures.

Restless legs syndrome (RLS) and other sleep abnormalities are common in Parkinsons Disease (PD). We prospectively examined sleep measures in PD patients undergoing subthalamic nucleus (STN) deep brain stimulation (DBS). An RLS questionnaire, Epworth Sleepiness Scale (ESS), and Parkinsons Disease Sleep Scale (PDSS) were administered through telephone interviews preoperatively and postoperatively. Seventeen patients were included. Mean preoperative and 4 weeks postoperative ESS scores were 11.6 and 6.4 respectively (p < 0.001) and PDSS scores were 94.2 and 122.9 respectively (p < 0.001). The improvement was sustained at 6 months. Six patients were diagnosed with RLS preoperatively. Mean preoperative International Restless Legs Syndrome Study Group rating scale score was 23.0. Mean 4 week and 6 month postoperative IRLSSG rating scale scores were 14.8 and 13.8 respectively, significantly improved compared to preoperative scores (p = 0.027 and p = 0.037 respectively). No patients developed new-onset RLS postoperatively. STN DBS improves daytime sleepiness, sleep quality, and RLS.

Tracking motor impairments in the progression of Huntington's disease

The Unified Huntingtons Disease Rating Scale is used to characterize motor impairments and establish motor diagnosis. Little is known about the timing of diagnostic confidence level categories and the trajectory of motor impairments during the prodromal phase. Goals of this study were to estimate the timing of categories, model the prodromal trajectory of motor impairments, estimate the rate of motor impairment change by category, and provide required sample size estimates for a test of efficacy in clinical trials. In total, 1010 gene‐expanded participants from the Neurobiological Predictors of Huntingtons Disease (PREDICT‐HD) trial were analyzed. Accelerated failure time models were used to predict the timing of categories. Linear mixed effects regression was used to model the longitudinal motor trajectories. Age and length of gene expansion were incorporated into all models. The timing of categories varied significantly by gene expansion, with faster progression associated with greater expansion. For the median expansion, the third diagnostic confidence level category was estimated to have a first occurrence 1.5 years before diagnosis, and the second and first categories were estimated to occur 6.75 years and 19.75 years before diagnosis, respectively. Motor impairments displayed a nonlinear prodromal course. The motor impairment rate of change increased as the diagnostic confidence level increased, with added acceleration for higher progression scores. Motor items can detect changes in motor impairments before diagnosis. Given a sufficiently high progression score, there is evidence that the diagnostic confidence level can be used for prodromal staging. Implications for Huntingtons disease research and the planning of clinical trials of efficacy are discussed.

Cortical and motor responses to acute forced exercise in Parkinson's disease

INTRODUCTION Studies in animal models of Parkinsons disease (PD) have suggested that the rate of exercise performance is important in treatment efficacy and neuroprotection. In humans with PD, lower-extremity forced-exercise (FE) produced global improvements in motor symptoms based on clinical ratings and biomechanical measures of upper extremity function. METHODS fMRI was used to compare the underlying changes in brain activity in PD patients following the administration of anti-parkinsonian medication and following a session of FE. RESULTS Nine individuals with PD completed fMRI scans under each condition: off anti-PD medication, on anti-PD medication, and off medication + FE. Unified Parkinsons Disease Rating Motor Scale scores improved by 50% in the FE condition compared to the off-medication condition. The pattern of fMRI activation after FE was similar to that seen with anti-PD medication. Direct comparison of the fMRI activation patterns showed high correlation between FE and anti-PD medication. CONCLUSION These findings suggest that medication and FE likely utilize the same pathways to produce symptomatic relief in individuals with PD.

Comprehensive, Multidisciplinary Deep Brain Stimulation Screening for Parkinson Patients: No Room for “Short Cuts”

Careful, often cumbersome, screening is a fundamental part of DBS evaluation in Parkinsons disease (PD). It often involves a brain MRI, neuropsychological testing, neurological, surgical, and psychiatric evaluation, and “ON/OFF” motor testing. Given that DBS has now been a standard treatment for advanced PD, with clinicians’ improved comfort and confidence in screening and referring patients for DBS, we wondered whether we can now streamline our lengthy evaluation process. We reviewed all PD patients evaluated for DBS at our center between 2006 and 2011 and analyzed the reasons for exclusion and for dropping out despite passing the screening process. A total of 223 PD patients who underwent DBS evaluation had complete charting. Only 131 (58.7%) patients were successfully implanted. Sixty‐one (27.3%) patients were excluded after screening because of significant cognitive decline (32.7%), early disease with room for medication adjustment (29.5%), behavioral dysfunction (21.3%), suspected secondary parkinsonism or atypical parkinsonism syndrome (13.1%), PD, but with poor levodopa response (11.4%), unrealistic goals (9.8%), PD with predominant axial symptoms (6.5%), significant comorbidities (6.5%), or abnormal brain imaging (3.2%). In addition, 31 (13.9%) patients were cleared for surgery, but either chose not have it (18 patients), were lost to follow‐up (12 patients), or were denied by medical insurance (1 patient). Through careful screening, a significant percentage of surgical candidates continue to be identified as less suitable because of a variety of reasons. This underscores the continued need for a comprehensive, multidisciplinary screening process.

Dopamine Transporter (DaT) Scan Utilization in a Movement Disorder Center

The aim of this work was to describe utilization patterns of dopamine transporter (DaT) scan and its influence on patient management at a single movement disorders center. DaT scan helps differentiate between neurodegenerative from non‐neurodegenerative parkinsonism and essential tremor (ET). It has been recently approved in the United States in 2011.

Is 6 months of neuroleptic withdrawal sufficient to distinguish drug-induced parkinsonism from Parkinson's disease?

ABSTRACT Background: Drug-induced parkinsonism (DIP) is the second commonest cause of akinetic-rigid syndrome in the western world. Differentiating DIP from Parkinsons disease (PD) may be a challenge to clinicians. One of the factors distinguishing DIP from PD is that discontinuation of the neuroleptic agent in DIP should relieve the symptoms of parkinsonism. The majority of the literature uses the 6-month timeframe between the neuroleptic withdrawal and resolution of the symptoms of parkinsonism. Methods: We report two cases of DIP wherein the symptoms of parkinsonism persisted more than 6-months from withdrawal of the dopamine receptor blocking agent (DRBA) and the results of their ioflupane iodine-123 (DaT) single-photon emission computed tomography (SPECT) scan. DaT scan is a newly approved radiopharmaceutical in the United States indicated for striatal dopamine transporter visualization to assist in the evaluation of adult patients with suspected parkinsonian syndromes. Results: The first case is a patient who developed parkinsonism from risperidone, while the second case developed parkinsonism from metoclopramide. In both cases, parkinsonism persisted 6 months after discontinuation of the DRBA, therefore DaT scan was obtained, showing normal striatal dopamine transporter uptake. Nine months after the discontinuation of the DRBA, parkinsonism was significantly improved in both patients but not completely resolved. Conclusion: Our two cases illustrate the possibility of persistent parkinsonism beyond 6–9 months from the time of neuroleptic withdrawal without evidence of presynaptic dopaminergic neuronal loss that would be suggestive of conversion to PD. We recommend that the official recommendation of the minimum time of neuroleptic withdrawal be modified to at least 1 year before entertaining the diagnosis of PD conversion in patients with exposure to DRBAs.

Predictors of Functional and Quality of Life Outcomes following Deep Brain Stimulation Surgery in Parkinson’s Disease Patients: Disease, Patient, and Surgical Factors

Objective The primary objective was to evaluate predictors of quality of life (QOL) and functional outcomes following deep brain stimulation (DBS) in Parkinsons disease (PD) patients. The secondary objective was to identify predictors of global improvement. Methods PD patients who underwent DBS at our Center from 2006 to 2011 were evaluated by chart review and email/phone survey. Postoperative UPDRS II and EQ-5D were analyzed using simple linear regression adjusting for preoperative score. For global outcomes, we utilized the Patient Global Impression of Change Scale (PGIS) and the Clinician Global Impression of Change Scale (CGIS). Results There were 130 patients in the dataset. Preoperative and postoperative UPDRS II and EQ-5D were available for 45 patients, PGIS for 67 patients, and CGIS for 116 patients. Patients with falls/postural instability had 6-month functional scores and 1-year QOL scores that were significantly worse than patients without falls/postural instability. For every 1-point increase in preoperative UPDRS III and for every 1-unit increase in body mass index (BMI), the 6-month functional scores significantly worsened. Patients with tremors, without dyskinesia, and without gait-freezing were more likely to have “much” or “very much” improved CGIS. Conclusions Presence of postural instability, high BMI, and worse baseline motor scores were the greatest predictors of poorer functional and QOL outcomes after DBS.

Reply to Comment on: Dopamine Transporter (DaT) Scan Utilization in a Movement Disorder Center

Thank you very much for your interest in our study. Different methods for interpreting dopamine transporter (DaT) scans have been described. Our radiologist uses visual assessment for DaT scan interpretation. Although there are reports that quantitative or semiquantitative methods have better accuracy than visual assessment, there are also several reports suggesting comparable accuracy for visual assessment and semiquantitative assessment. Our radiologist classified DaT scan results using the Benamer system (i.e., Grade 1, 2, and 3 for all abnormal scans); however, in our, study we simply combined all abnormal scans regardless of their class or grade. Morphological imaging, such as computed tomography and magnetic resonance imaging of the brain, were not routinely evaluated when reading DaT scans. However, in certain cases, when an atypical pattern of decreased uptake is noted (such as a concern for structural lesions), then morphological images were obtained and compared. Lewy body dementia (LBD) was included as a prescan clinical diagnosis of neurodegenerative parkinsonism in our study. Our center does not routinely use DaT scans to assist in the diagnosis of LBD. However, in our study, 1 patient was suspected of having idiopathic Parkinson’s disease (PD) versus LBD versus another form of dementia, such as Alzheimer’s disease or frontotemporal lobe dementia. The scan for that patient turned out to be abnormal, and the patient was started on carbidopa/levodopa. Tolosa et al. described the possibility that 3 different clinical outcomes can be encountered in patients with drug-induced parkinsonism: (1) full and long-lasting recovery of drug-induced parkinsonism with no subsequent development of PD, (2) persistence and eventual worsening of parkinsonism after discontinuation of the offending drug (drug-induced parkinsonism unmasks PD), and (3) full remission of drug-induced parkinsonism after withdrawal of the offending drug with later reappearance of parkinsonism (drug-induced parkinsonism antedates PD). Rajput et al. reported 2 patients with drug-induced parkinsonism who had completely recovered after stopping the offending drugs and had histopathology findings of Lewy bodies similar to those observed in idiopathic PD. These findings underscore the complexity of the problem. Clearly, further studies involving larger numbers of patients with clinicopathological correlation are needed to determine the sensitivity and specificity of DaT scans.