Publications by authors named "Andrew Feigin"

68 Publications

Huntington's Disease: New Frontiers in Therapeutics.

Curr Neurol Neurosci Rep 2021 02 14;21(3):10. Epub 2021 Feb 14.

Department of Neurology, The Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders, NYU Langone Health, 222 East 41st Street - 13th Floor, New York, USA.

Purpose Of Review: This article describes and discusses new potential disease-modifying therapies for Huntington's disease that are currently in human clinical trials as well as promising new therapies in preclinical development.

Recent Findings: Multiple potential disease-modifying therapeutics for HD are in active development, including direct DNA/gene therapies, RNA modulation, and therapies targeted at aberrant downstream pathways. The etiology of Huntington's disease (HD) is well-known as an abnormally expanded trinucleotide repeat within the huntingtin gene. However, the pathogenesis downstream of the mutant huntingtin gene is complex, involving multiple toxic pathways, including abnormal protein fragmentation and neuroinflammation. The current treatment of HD focuses largely on symptomatic management. This article discusses new, potential disease-modifying therapies that are currently in human clinical trials and preclinical development.
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http://dx.doi.org/10.1007/s11910-021-01093-3DOI Listing
February 2021

Art therapy for Parkinson's disease.

Parkinsonism Relat Disord 2021 03 23;84:148-154. Epub 2021 Jan 23.

Department of Physiology and Pharmacology, City University of New York Medical School, New York, NY, USA.

Objective: To explore the potential rehabilitative effect of art therapy and its underlying mechanisms in Parkinson's disease (PD).

Methods: Observational study of eighteen patients with PD, followed in a prospective, open-label, exploratory trial. Before and after twenty sessions of art therapy, PD patients were assessed with the UPDRS, Pegboard Test, Timed Up and Go Test (TUG), Beck Depression Inventory (BDI), Modified Fatigue Impact Scale and PROMIS-Self-Efficacy, Montreal Cognitive Assessment, Rey-Osterrieth Complex Figure Test (RCFT), Benton Visual Recognition Test (BVRT), Navon Test, Visual Search, and Stop Signal Task. Eye movements were recorded during the BVRT. Resting-state functional MRI (rs-fMRI) was also performed to assess functional connectivity (FC) changes within the dorsal attention (DAN), executive control (ECN), fronto-occipital (FOC), salience (SAL), primary and secondary visual (V1, V2) brain networks. We also tested fourteen age-matched healthy controls at baseline.

Results: At baseline, PD patients showed abnormal visual-cognitive functions and eye movements. Analyses of rs-fMRI showed increased functional connectivity within DAN and ECN in patients compared to controls. Following art therapy, performance improved on Navon test, eye tracking, and UPDRS scores. Rs-fMRI analysis revealed significantly increased FC levels in brain regions within V1 and V2 networks.

Interpretation: Art therapy improves overall visual-cognitive skills and visual exploration strategies as well as general motor function in patients with PD. The changes in brain connectivity highlight a functional reorganization of visual networks.
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http://dx.doi.org/10.1016/j.parkreldis.2021.01.013DOI Listing
March 2021

Blood-brain barrier permeability in Parkinson's disease patients with and without dyskinesia.

J Neurol 2021 Jun 27;268(6):2246-2255. Epub 2021 Jan 27.

Center for Neurosciences, The Feinstein Institutes for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.

Objective: Recent studies on a rodent model of Parkinson's disease (PD) have raised the possibility of increased blood-brain barrier (BBB) permeability, demonstrated by histology, autoradiography, and positron emission tomography (PET). However, in human PD patients, in vivo evidence of increased BBB permeability is lacking. We examined the hypothesis that levodopa treatment increases BBB permeability in human subjects with PD, particularly in those with levodopa-induced dyskinesia (LID).

Methods: We used rubidium-82 (Rb) and PET to quantify BBB influx in vivo in 19 PD patients, including eight with LID, and 12 age- and sex-matched healthy subjects. All subjects underwent baseline Rb scans. Seventeen chronically levodopa-treated patients were additionally rescanned during intravenous levodopa infusion. Influx rate constant, K, by compartmental modeling or net influx transport, K, by graphical approach could not be estimated reliably. However, V, the "apparent volume of distribution" based on the Rb concentration in brain tissue and blood, was estimated with good stability as a local measure of the volume of distribution.

Results: Rubidium influx into brain tissue was undetectable in PD patients with or without LID, scanned on and off drug. No significant differences in regional V were observed for PD patients with or without LID relative to healthy subjects, except in left thalamus. Moreover, changes in V measured off- and on-levodopa infusion were also not significant for dyskinetic and non-dyskinetic subjects.

Conclusion: Rb PET did not reveal significant changes in BBB permeability in PD patients.
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http://dx.doi.org/10.1007/s00415-021-10411-1DOI Listing
June 2021

Medical, Surgical, and Genetic Treatment of Huntington Disease.

Neurol Clin 2020 05 9;38(2):367-378. Epub 2020 Mar 9.

NYU Langone Health, Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders, 222 East 41st Street, Floor 13, New York, NY 10017, USA.

Huntington disease, a neurodegenerative disease characterized by progressive motor, behavioral, and cognitive decline, is caused by a CAG trinucleotide repeat expansion in the huntingtin gene on chromosome 4. Current treatments target symptom management because there are no disease-modifying therapies at this time. Investigation of RNA-based and DNA-based treatment strategies are emerging and hold promise of possible future disease-modifying therapy.
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http://dx.doi.org/10.1016/j.ncl.2020.01.010DOI Listing
May 2020

Rapid picture naming in Parkinson's disease using the Mobile Universal Lexicon Evaluation System (MULES).

J Neurol Sci 2020 Mar 9;410:116680. Epub 2020 Jan 9.

Departments of Neurology, New York University School of Medicine, New York, NY, USA; Departments of Population Health, New York University School of Medicine, New York, NY, USA; Departments of Ophthalmology, New York University School of Medicine, New York, NY, USA. Electronic address:

Objective: The Mobile Universal Lexicon Evaluation System (MULES) is a test of rapid picture naming that captures extensive brain networks, including cognitive, language and afferent/efferent visual pathways. MULES performance is slower in concussion and multiple sclerosis, conditions in which vision dysfunction is common. Visual aspects captured by the MULES may be impaired in Parkinson's disease (PD) including color discrimination, object recognition, visual processing speed, and convergence. The purpose of this study was to compare MULES time scores for a cohort of PD patients with those for a control group of participants of similar age. We also sought to examine learning effects for the MULES by comparing scores for two consecutive trials within the patient and control groups.

Methods: MULES consists of 54 colored pictures (fruits, animals, random objects). The test was administered in a cohort of PD patients and in a group of similar aged controls. Wilcoxon rank-sum tests were used to determine statistical significance for differences in MULES time scores between PD patients and controls. Spearman rank-correlation coefficients were calculated to examine the relation between MULES time scores and PD motor symptom severity (UPDRS). Learning effects were assessed using Wilcoxon rank-sum tests.

Results: Among 51 patients with PD (median age 70 years, range 52-82) and 20 disease-free control participants (median age 67 years, range 51-90), MULES scores were significantly slower (worse performance) in PD patients (median 63.2 s, range 37.3-296.3) vs. controls (median 53.9 s, range 37.5-128.6, P = .03, Wilcoxon rank-sum test). Slower MULES times were associated with increased motor symptom severity as measured by the Unified Parkinson's Disease Rating Scale, Section III (r = 0.37, P = .02). Learning effects were greater among patients with PD (median improvement of 14.8 s between two MULES trials) compared to controls (median 7.4 s, P = .004).

Conclusion: The MULES is a complex test of rapid picture naming that captures numerous brain pathways including an extensive visual network. MULES performance is slower in patients with PD and our study suggests an association with the degree of motor impairment. Future studies will determine the relation of MULES time scores to other modalities that test visual function and structure in PD.
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http://dx.doi.org/10.1016/j.jns.2020.116680DOI Listing
March 2020

Urodynamic Mechanisms Underlying Overactive Bladder Symptoms in Patients With Parkinson Disease.

Int Neurourol J 2019 Sep 30;23(3):211-218. Epub 2019 Sep 30.

Department of Urology, New York University School of Medicine, New York, NY, USA.

Purpose: To assess the urodynamic findings in patients with Parkinson disease (PD) with overactive bladder symptoms.

Methods: We performed a retrospective chart review of all PD patients who were seen in an outpatient clinic for lower urinary tract symptoms (LUTS) between 2010 and 2017 in a single-institution. Only patients who complained of overactive bladder (OAB) symptoms and underwent a video-urodynamic study for these symptoms were included. We excluded patients with neurological disorders other than PD and patients with voiding LUTS but without OAB symptoms.

Results: We included 42 patients (29 men, 13 women, 74.5±8.1 years old). Seven patients (16.7%) had a postvoid residual (PVR) bladder volume >100 mL and only one reported incomplete bladder emptying. Detrusor overactivity (DO) was found in all 42 patients (100%) and was terminal in 19 (45.2%) and phasic in 22 patients (52.4%). Eighteen patients had detrusor underactivity (DU) (42.3%). Later age of PD diagnosis was the only parameter associated with DU (P=0.02). Patients with bladder outlet obstruction (BOO) were younger than patients without BOO (70.1 years vs. 76.5 years, P=0.004), had later first sensation of bladder filling (173.5 mL vs. 120.3 mL, P=0.02) and first involuntary detrusor contraction (226.4 mL vs. 130.4 mL, P=0.009).

Conclusion: DO is almost universal in all patients with PD complaining of OAB symptoms (97.1%). However, a significant percentage of patients also had BOO (36.8%), DU (47%), and increased PVR (16.7%) indicating that neurogenic DO may not be the only cause of OAB symptoms in PD patients.
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http://dx.doi.org/10.5213/inj.1938086.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790817PMC
September 2019

Tele-monitored tDCS rehabilitation: feasibility, challenges and future perspectives in Parkinson's disease.

J Neuroeng Rehabil 2019 01 31;16(1):20. Epub 2019 Jan 31.

The Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders, Department of Neurology, NYU School of Medicine, 222 East 41st Street, New York, NY, 10017, USA.

Transcranial direct current stimulation (tDCS) is a modality of non-invasive brain stimulation involving the application of low amplitude direct current via surface electrodes on the scalp. tDCS has been studied in healthy populations and in multiple brain disorders and has the potential to be a treatment for several neuropsychiatric conditions by virtue of its capability of influencing cognitive, motor and behavioral processes. tDCS is a generally safe technique when performed within standardized protocols in research or clinical settings. Furthermore, tDCS portability, high acceptability and user-friendly interface makes it highly appealing for telemedicine practices. The term "telemedicine" refers to the procedures, educational strategies, and care services that are remotely administered by means of different communication technologies, with the final goal of increasing access to care for individuals and for improving public health. The use of telemedicine combined with tDCS protocols is increasing, although the safety of this approach in different clinical settings awaits further assessment. While "do-it-yourself" tDCS should be discouraged due to the unknown risk of adverse events, the implementation of tele-monitored tDCS (tele-tDCS) within standardized frameworks ensuring safety, tolerability, and reproducibility may allow this technology to reach larger clinical populations and bypass some of the common barriers preventing access to health services and clinical trials. This review will discuss the current evidence supporting the feasibility of tele-tDCS paradigms and their therapeutic potential, with particular emphasis on the implications for patients with Parkinson's disease.
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http://dx.doi.org/10.1186/s12984-019-0481-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357497PMC
January 2019

Gene therapy reduces Parkinson's disease symptoms by reorganizing functional brain connectivity.

Sci Transl Med 2018 11;10(469)

Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, NY 10030, USA.

Gene therapy is emerging as a promising approach for treating neurological disorders, including Parkinson's disease (PD). A phase 2 clinical trial showed that delivering glutamic acid decarboxylase () into the subthalamic nucleus (STN) of patients with PD had therapeutic effects. To determine the mechanism underlying this response, we analyzed metabolic imaging data from patients who received gene therapy and those randomized to sham surgery, all of whom had been scanned preoperatively and at 6 and 12 months after surgery. Those who received gene therapy developed a unique treatment-dependent polysynaptic brain circuit that we termed as the -related pattern (GADRP), which reflected the formation of new polysynaptic functional pathways linking the STN to motor cortical regions. Patients in both the treatment group and the sham group expressed the previously reported placebo network (the sham surgery-related pattern or SSRP) when blinded to the treatment received. However, only the appearance of the GADRP correlated with clinical improvement in the gene therapy-treated subjects. Treatment-induced brain circuits can thus be useful in clinical trials for isolating true treatment responses and providing insight into their underlying biological mechanisms.
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http://dx.doi.org/10.1126/scitranslmed.aau0713DOI Listing
November 2018

Mirabegron in patients with Parkinson disease and overactive bladder symptoms: A retrospective cohort.

Parkinsonism Relat Disord 2018 12 20;57:22-26. Epub 2018 Jul 20.

Department of Urology, New York University School of Medicine, New York, USA.

Introduction: This study aimed to assess the outcomes of mirabegron for the treatment of overactive bladder (OAB) symptoms in patients with Parkinson disease (PD).

Methods: A retrospective study was conducted including patients with PD who received mirabegron 50 mg once daily for OAB symptoms between 2012 and 2017. The primary endpoint was clinical success defined as any improvement in overactive bladder symptoms self-assessed by the patients 6 weeks after mirabegron initiation. Secondary endpoints included number of pads per day, number of nocturia episodes and adverse events.

Results: Fifty patients (mean 74 years old) were included. Before being treated with mirabegron, 56% had failed prior anticholinergic therapy. After 6 weeks of mirabegron 50 mg, five patients (11.4%) had a complete resolution of their OAB symptoms; 25 patients (50%) reported improvement, 23 (46%) reported no change and 2(4%) reported worsening of their OAB symptoms. The number of pads per day decreased from 1.5 to 0.9 (p = 0.01) and so did the number of nocturia episodes (from 3 to 2.6/night; p = 0.02). Only 2 adverse events were reported during mirabegron treatment (4%): one dizziness and one diaphoresis, that disappeared after mirabegron discontinuation. After a median follow-up of 19 months, 23 patients (46%) persisted on mirabegron. Persistence rates were 51.5%, 44.6% and 36.4% at 1, 2 and 3 years respectively.

Conclusion: Mirabegron has an excellent safety profile and appears to be an effective treatment for overactive bladder symptoms in patients with PD. Further prospective randomized trials are needed to properly assess mirabegron in PD patients.
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http://dx.doi.org/10.1016/j.parkreldis.2018.07.005DOI Listing
December 2018

Outcomes of intradetrusor onabotulinum toxin A injection in patients with Parkinson's disease.

Neurourol Urodyn 2018 11 16;37(8):2669-2677. Epub 2018 May 16.

Department of Urology, New York University School of Medicine, New York, New York.

Objective: To assess the safety and efficacy of intradetrusor onabotulinum toxin A injections for the treatment of overactive bladder (OAB) in patients with Parkinson's disease (PD).

Methods: All PD patients who underwent intradetrusor injections of onabotulinum toxin A (BoNT-A) for storage symptoms between 2010 and 2017 were included in a retrospective study. A 100 U dose of BoNT-A (Botox®, Allergan Irvine, CA) was used for the first injection in all patients. The primary endpoint was clinical success defined as any subjective improvement in OAB symptoms self-assessed by the patients 4 weeks after the injections.

Results: Out of 24 patients analyzed, 19 reported improvement of their OAB symptoms 4 weeks after the first injection (79.2%) with complete resolution of urgency urinary incontinence in seven patients (29.1%; P < 0.001). The average post-void residual (PVR) increased significantly after the first injection from 17.6 to 125.3 mL (P < 0.001). Three of the patients had to start clean intermittent catheterization (CIC) after the first injection (12.5%). Out of 49 injections in total, only five caused incomplete bladder emptying requiring the use of CIC (10.2%). Higher pre-injection PVR was significantly associated with both a lower chance of symptomatic improvement (P = 0.04) and a higher risk of incomplete bladder emptying with institution of CIC (P = 0.047).

Conclusion: Intradetrusor injections of BoNT-A 100 U appeared as a safe and effective option in PD patients with OAB symptoms and a low PVR before the injection. Higher preoperative PVR was the strongest predictor of both treatment failure and postoperative urinary retention requiring CIC.
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http://dx.doi.org/10.1002/nau.23717DOI Listing
November 2018

Biomarkers for atypical Parkinsonism: Some progress, but much work remains.

Parkinsonism Relat Disord 2018 03;48:1-2

University of Pennsylvania Perelman School of Medicine, 330 South 9th Street, Philadelphia, PA, 19107, USA.

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http://dx.doi.org/10.1016/j.parkreldis.2018.02.025DOI Listing
March 2018

Increased putamen hypercapnic vasoreactivity in levodopa-induced dyskinesia.

JCI Insight 2017 10 19;2(20). Epub 2017 Oct 19.

Center for Neurosciences, Feinstein Institute for Medical Research, Manhasset, New York, USA.

In a rodent model of Parkinson's disease (PD), levodopa-induced involuntary movements have been linked to striatal angiogenesis - a process that is difficult to document in living human subjects. Angiogenesis can be accompanied by localized increases in cerebral blood flow (CBF) responses to hypercapnia. We therefore explored the possibility that, in the absence of levodopa, local hypercapnic CBF responses are abnormally increased in PD patients with levodopa-induced dyskinesias (LID) but not in their nondyskinetic (NLID) counterparts. We used H215O PET to scan 24 unmedicated PD subjects (12 LID and 12 NLID) and 12 matched healthy subjects in the rest state under normocapnic and hypercapnic conditions. Hypercapnic CBF responses were compared to corresponding levodopa responses from the same subjects. Group differences in hypercapnic vasoreactivity were significant only in the posterior putamen, with greater CBF responses in LID subjects compared with the other subjects. Hypercapnic and levodopa-mediated CBF responses measured in this region exhibited distinct associations with disease severity: the former correlated with off-state motor disability ratings but not symptom duration, whereas the latter correlated with symptom duration but not motor disability. These are the first in vivo human findings linking LID to microvascular changes in the basal ganglia.
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http://dx.doi.org/10.1172/jci.insight.96411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846717PMC
October 2017

Preface.

Handb Clin Neurol 2017 ;144:ix

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http://dx.doi.org/10.1016/B978-0-12-801893-4.09986-7DOI Listing
September 2018

National randomized controlled trial of virtual house calls for Parkinson disease.

Neurology 2017 Sep 16;89(11):1152-1161. Epub 2017 Aug 16.

From the Department of Biostatistics and Computational Biology (C.A.B.), University of Rochester, NY; National Parkinson Foundation (D.B.B., P.N.S.), Miami, FL; Department of Neurology (K.M.B., E.R.D., I.H.R., H.S.) and The Center for Human Experimental Therapeutics (E.R.D., M.A.A., M.J.E., S.G., H.T.K., R.K., S.S., E.A.S., W.Z.), University of Rochester Medical Center, NY; Division of Geriatric Medicine and Gerontology, Department of Medicine (C.M.B., Z.M., B.D.), Johns Hopkins University School of Medicine, Baltimore, MD; Simone Consulting (R.S.), Sunnyvale, CA; Departments of Neurology and Biostatistics and Epidemiology (A.W.W., M.S., S.R.), University of Pennsylvania Perelman School of Medicine, Philadelphia; University of California San Francisco (N.B.G., M.K., C.M.T., K.D.); Northwest Neurological, PLLC (J. Aldred), Spokane, WA; Oregon Health and Science University (J.C., A. Fraser), Portland; Baylor College of Medicine (J.J.-S., C.H.), Houston, TX; Augusta University (J.C.M., D.M.), GA; Duke Medical Center (P.H., L.G.), Durham, NC; Massachusetts General Hospital (N.I.M., G.B.), Boston; Struthers Parkinson's Center (M.N.), Minneapolis, MN; Beth Israel Deaconess Medical Center (L.C.S.), Boston, MA; University of Miami (C.S., S.V.-P.), FL; Northwestern University (C.Z., N.O.), Evanston, IL; The Feinstein Institute for Medical Research (A. Feigin, J. Ayan), Northwell Health, Manhasset, NY; Medical University of South Carolina (C.V.), Charleston; University of Kansas Medical Center (R.P.), Kansas City; Parkinson's Institute (R.D.), Sunnyvale, CA; Mayo Clinic (A.H.), Rochester, MN; Center for Information Technology Research in the Interest of Society (CITRIS) (S.D.), University of California, Berkeley; Health Informatics Centre (S.S.R.), Karolinska Institute, Stockholm, Sweden; and PatientsLikeMe (P.W.), Derby, UK.

Objective: To determine whether providing remote neurologic care into the homes of people with Parkinson disease (PD) is feasible, beneficial, and valuable.

Methods: In a 1-year randomized controlled trial, we compared usual care to usual care supplemented by 4 virtual visits via video conferencing from a remote specialist into patients' homes. Primary outcome measures were feasibility, as measured by the proportion who completed at least one virtual visit and the proportion of virtual visits completed on time; and efficacy, as measured by the change in the Parkinson's Disease Questionnaire-39, a quality of life scale. Secondary outcomes included quality of care, caregiver burden, and time and travel savings.

Results: A total of 927 individuals indicated interest, 210 were enrolled, and 195 were randomized. Participants had recently seen a specialist (73%) and were largely college-educated (73%) and white (96%). Ninety-five (98% of the intervention group) completed at least one virtual visit, and 91% of 388 virtual visits were completed. Quality of life did not improve in those receiving virtual house calls (0.3 points worse on a 100-point scale; 95% confidence interval [CI] -2.0 to 2.7 points; = 0.78) nor did quality of care or caregiver burden. Each virtual house call saved patients a median of 88 minutes (95% CI 70-120; < 0.0001) and 38 miles per visit (95% CI 36-56; < 0.0001).

Conclusions: Providing remote neurologic care directly into the homes of people with PD was feasible and was neither more nor less efficacious than usual in-person care. Virtual house calls generated great interest and provided substantial convenience.

Clinicaltrialsgov Identifier: NCT02038959.

Classification Of Evidence: This study provides Class III evidence that for patients with PD, virtual house calls from a neurologist are feasible and do not significantly change quality of life compared to in-person visits. The study is rated Class III because it was not possible to mask patients to visit type.
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http://dx.doi.org/10.1212/WNL.0000000000004357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595275PMC
September 2017

Restless legs syndrome: Losing sleep over the placebo response.

Authors:
Andrew Feigin

Neurology 2017 06 10;88(23):2160-2161. Epub 2017 May 10.

From the Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, NY.

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http://dx.doi.org/10.1212/WNL.0000000000004018DOI Listing
June 2017

Long-term follow-up of a randomized AAV2- gene therapy trial for Parkinson's disease.

JCI Insight 2017 04 6;2(7):e90133. Epub 2017 Apr 6.

Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, USA.

We report the 12-month clinical and imaging data on the effects of bilateral delivery of the glutamic acid decarboxylase gene into the subthalamic nuclei (STN) of advanced Parkinson's disease (PD) patients. 45 PD patients were enrolled in a 6-month double-blind randomized trial of bilateral AAV2- delivery into the STN compared with sham surgery and were followed for 12 months in open-label fashion. Subjects were assessed with clinical outcome measures and F-fluorodeoxyglucose (FDG) PET imaging. Improvements under the blind in Unified Parkinson's Disease Rating Scale (UPDRS) motor scores in the AAV2- group compared with the sham group continued at 12 months [time effect: (4,138) = 11.55, < 0.001; group effect: (1,35) = 5.45, < 0.03; repeated-measures ANOVA (RMANOVA)]. Daily duration of levodopa-induced dyskinesias significantly declined at 12 months in the AAV2- group ( = 0.03; post-hoc Bonferroni test), while the sham group was unchanged. Analysis of all FDG PET images over 12 months revealed significant metabolic declines ( < 0.001; statistical parametric mapping RMANOVA) in the thalamus, striatum, and prefrontal, anterior cingulate, and orbitofrontal cortices in the AAV2- group compared with the sham group. Across all time points, changes in regional metabolism differed for the two groups in all areas, with significant declines only in the AAV2- group ( < 0.005; post-hoc Bonferroni tests). Furthermore, baseline metabolism in the prefrontal cortex (PFC) correlated with changes in motor UPDRS scores; the higher the baseline PFC metabolism, the better the clinical outcome. These findings show that clinical benefits after gene therapy with STN AAV2- in PD patients persist at 12 months. ClinicalTrials.gov NCT00643890. Neurologix Inc.
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http://dx.doi.org/10.1172/jci.insight.90133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374069PMC
April 2017

A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease.

Neurology 2017 Jan 2;88(2):152-159. Epub 2016 Dec 2.

From Cooper University Healthcare at Rowan University (A.M.), Camden, NJ; University of Rochester (M.M., K.K., E.A.d.B., K.B., P.C.); Weill Cornell Medical Center (F.B.); Columbia Presbyterian Medical Center (K.M.), New York, NY; Johns Hopkins Medical Center (C.R.), Baltimore, MD; Georgetown University (I.S.), Washington, DC; NINDS (P.G.), Bethesda, MD; Hereditary Neurological Disease Center (W.M.M.), Wichita, KS; The Centre for Movement Disorders (M.G.), Toronto, Canada; Indiana University School of Medicine (J.W.), Indianapolis; Colorado Neurological Institute (R.K.), Englewood; University of Tennessee Health Science Center (M.S.L.), Memphis; London Health Sciences Centre (M.J.), Canada; Massachusetts General Hospital (H.D.R.), Boston; Struthers Parkinson's Center (M.N.), Minneapolis, MN; University of Kansas Medical Center (R.M.D.), Kansas City; Rush University Medical Center (K.M.S.), Chicago, IL; University of Texas Southwestern Medical Center (P.O.), Dallas; University of Michigan (K.C.), Ann Arbor; Wake Forest University (F.W.), Winston-Salem, NC; University of Alberta (W.M.), Edmonton, Canada; University of California Davis (V.L.W.), Sacramento; Westmead Hospital (E. McCusker), Westmead, Australia; Baylor College of Medicine (J.J.), Houston, TX; University of Miami Miller School of Medicine (C.S.), FL; University of South Florida (J.S.-R.), Tampa; Duke University (B.S.), Durham, NC; University of Calgary (O.S.), Canada; Emory University School of Medicine (S.A.F.), Atlanta, GA; Albany Medical College (D.S.H., Eric Molho), NY; University of Cincinnati (F.R.), OH; Mayo Clinic Arizona (J.N.C.), Scottsdale; Butler Hospital (J.H.F.), Providence, RI; Washington University (J.S.P.), St. Louis, MO; Feinstein Institute for Medical Research (A.F.), Manhasset, NY; Georgetown University (K.A.), Washington, DC; University of Florida (R.R., N.R.M.), Gainesville; Johns Hopkins University (R.L.M.), Baltimore, MD; University of Nevada School of Medicine (E.S.F.), Reno; University of British Columbia (L.A.R.), Vancouver, Canada; University of Pittsburgh (V.S.), PA; Ohio State University (S.K.), Columbus; The Cooper University Health System (A.C.), Camden, NJ; Idaho Elks Rehabilitation Hospital (L.S.), Boise, ID; University of Iowa (E.E.), Iowa City; North York General Hospital 1 (S.E.), Toronto, Canada; St. Luke's Hospital (N.D.), Allentown, PA; North York General Hospital 2 (W.L.A.F.), University of Toronto, Canada; Washington Regional Medical Center (A.D.), Fayetteville, AR; Beth-Israel Deaconess Medical Center (S.F.), Boston, MA; NJ Neuroscience Institute (P.H.), Edison; University of California Irvine (N.H.); The University of Alabama at Birmingham (L.S.D.); and Massachusetts General Hospital (M.C.), Harvard Medical School, Boston.

Objective: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD.

Methods: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach.

Results: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study.

Conclusions: These data do not justify use of CoQ as a treatment to slow functional decline in HD.

Clinicaltrialsgov Identifier: NCT00608881.

Classification Of Evidence: This article provides Class I evidence that CoQ does not slow the progressive functional decline of patients with HD.
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http://dx.doi.org/10.1212/WNL.0000000000003478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224719PMC
January 2017

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

JAMA 2016 Jul;316(1):40-50

Boston University Medical Campus, Boston, Massachusetts.

Importance: Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity.

Objective: To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease.

Design, Setting, And Participants: Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites.

Interventions: Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout.

Main Outcomes And Measures: Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form- physical functioning subscale score (SF-36), and the change in the Berg Balance Test.

Results: Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was -2.5 units (95% CI, -3.7 to -1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, -0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia.

Conclusions And Relevance: Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety.

Trial Registration: clinicaltrials.gov Identifier: NCT01795859.
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http://dx.doi.org/10.1001/jama.2016.8655DOI Listing
July 2016

Longitudinal Changes in the Motor Learning-Related Brain Activation Response in Presymptomatic Huntington's Disease.

PLoS One 2016 18;11(5):e0154742. Epub 2016 May 18.

Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.

Neurocognitive decline, including deficits in motor learning, occurs in the presymptomatic phase of Huntington's disease (HD) and precedes the onset of motor symptoms. Findings from recent neuroimaging studies have linked these deficits to alterations in fronto-striatal and fronto-parietal brain networks. However, little is known about the temporal dynamics of these networks when subjects approach phenoconversion. Here, 10 subjects with presymptomatic HD were scanned with 15O-labeled water at baseline and again 1.5 years later while performing a motor sequence learning task and a kinematically matched control task. Spatial covariance analysis was utilized to characterize patterns of change in learning-related neural activation occurring over time in these individuals. Pattern expression was compared to corresponding values in 10 age-matched healthy control subjects. Spatial covariance analysis revealed significant longitudinal changes in the expression of a specific learning-related activation pattern characterized by increasing activity in the right orbitofrontal cortex, with concurrent reductions in the right medial prefrontal and posterior cingulate regions, the left insula, left precuneus, and left cerebellum. Changes in the expression of this pattern over time correlated with baseline measurements of disease burden and learning performance. The network changes were accompanied by modest improvement in learning performance that took place concurrently in the gene carriers. The presence of increased network activity in the setting of stable task performance is consistent with a discrete compensatory mechanism. The findings suggest that this effect is most pronounced in the late presymptomatic phase of HD, as subjects approach clinical onset.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154742PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871440PMC
July 2017

A Placebo-Controlled Trial of AQW051 in Patients With Moderate to Severe Levodopa-Induced Dyskinesia.

Mov Disord 2016 07 15;31(7):1049-54. Epub 2016 Mar 15.

Novartis Institutes for BioMedical Research, Basel, Switzerland.

Background: This phase 2 randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of the nicotinic acetylcholine receptor α7 agonist AQW051 in patients with Parkinson's disease and levodopa-induced dyskinesia.

Methods: Patients with idiopathic Parkinson's disease and moderate to severe levodopa-induced dyskinesia were randomized to AQW051 10 mg (n = 24), AQW051 50 mg (n = 24), or placebo (n = 23) once daily for 28 days. Coprimary end points were change in Modified Abnormal Involuntary Movement Scale and Unified Parkinson's Disease Rating Scale part III scores. Secondary outcomes included pharmacokinetics.

Results: In total, 67 patients completed the study. AQW051-treated patients experienced no significant improvements in Modified Abnormal Involuntary Movement Scale or Unified Parkinson's Disease Rating Scale part III scores by day 28. AQW051 was well tolerated; the most common adverse events were dyskinesia, fatigue, nausea, and falls.

Conclusions: AQW051 did not significantly reduce dyskinesia or parkinsonian severity. © 2016 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.26569DOI Listing
July 2016

National Randomized Controlled Trial of Virtual House Calls for People with Parkinson's Disease: Interest and Barriers.

Telemed J E Health 2016 07 17;22(7):590-8. Epub 2016 Feb 17.

19 Department of Neurology, Beth Israel Deaconess Medical Center , Boston, Massachusetts.

Background: Delivering specialty care remotely directly into people's homes can enhance access for and improve the healthcare of individuals with chronic conditions. However, evidence supporting this approach is limited.

Materials And Methods: Connect.Parkinson is a randomized comparative effectiveness study that compares usual care of individuals with Parkinson's disease in the community with usual care augmented by virtual house calls with a Parkinson's disease specialist from 1 of 18 centers nationally. Individuals in the intervention arm receive four virtual visits from a Parkinson's disease specialist over 1 year via secure, Web-based videoconferencing directly into their homes. All study activities, including recruitment, enrollment, and assessments, are conducted remotely. Here we report on interest, feasibility, and barriers to enrollment in this ongoing study.

Results: During recruitment, 11,734 individuals visited the study's Web site, and 927 unique individuals submitted electronic interest forms. Two hundred ten individuals from 18 states enrolled in the study from March 2014 to June 2015, and 195 were randomized. Most participants were white (96%) and college educated (73%). Of the randomized participants, 73% had seen a Parkinson's disease specialist within the previous year.

Conclusions: Among individuals with Parkinson's disease, national interest in receiving remote specialty care directly into the home is high. Remote enrollment in this care model is feasible but is likely affected by differential access to the Internet.
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http://dx.doi.org/10.1089/tmj.2015.0191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939367PMC
July 2016

Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS): Implications for Clinical Trials.

JAMA Neurol 2016 Jan;73(1):102-10

Wake Forest University School of Medicine, Winston-Salem, North Carolina.

Importance: Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials.

Objective: To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS).

Design, Setting, And Participants: A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (≥37 repeats) and nonexpansion (<37 repeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013.

Exposure: Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion.

Main Outcomes And Measures: Unified Huntington's Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years.

Results: Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P < .001), cognitive (P < .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P < .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [-0.05 to 0.11]), cognitive (-0.54 [-0.67 to -0.40] vs 0.22 [0.12 to 0.32]), and functional (-0.08 [-0.09 to -0.06] vs -0.01 [-0.02 to 0]) measures compared with those without expansion (P < .001 for all); behavioral domain scores did not diverge significantly between groups.

Conclusions And Relevance: Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion.
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http://dx.doi.org/10.1001/jamaneurol.2015.2736DOI Listing
January 2016

Automated Differential Diagnosis of Early Parkinsonism Using Metabolic Brain Networks: A Validation Study.

J Nucl Med 2016 Jan 8;57(1):60-6. Epub 2015 Oct 8.

Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York

Unlabelled: The differentiation of idiopathic Parkinson disease (IPD) from multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), the most common atypical parkinsonian look-alike syndromes (APS), can be clinically challenging. In these disorders, diagnostic inaccuracy is more frequent early in the clinical course when signs and symptoms are mild. Diagnostic inaccuracy may be particularly relevant in trials of potential disease-modifying agents, which typically involve participants with early clinical manifestations. In an initial study, we developed a probabilistic algorithm to classify subjects with clinical parkinsonism but uncertain diagnosis based on the expression of metabolic covariance patterns for IPD, MSA, and PSP. Classifications based on this algorithm agreed closely with final clinical diagnosis. Nonetheless, blinded prospective validation is required before routine use of the algorithm can be considered.

Methods: We used metabolic imaging to study an independent cohort of 129 parkinsonian subjects with uncertain diagnosis; 77 (60%) had symptoms for 2 y or less at the time of imaging. After imaging, subjects were followed by blinded movement disorders specialists for an average of 2.2 y before final diagnosis was made. When the algorithm was applied to the individual scan data, the probabilities of IPD, MSA, and PSP were computed and used to classify each of the subjects. The resulting image-based classifications were then compared with the final clinical diagnosis.

Results: IPD subjects were distinguished from APS with 94% specificity and 96% positive predictive value (PPV) using the original 2-level logistic classification algorithm. The algorithm achieved 90% specificity and 85% PPV for MSA and 94% specificity and 94% PPV for PSP. The diagnostic accuracy was similarly high (specificity and PPV > 90%) for parkinsonian subjects with short symptom duration. In addition, 25 subjects were classified as level I indeterminate parkinsonism and 4 more subjects as level II indeterminate APS.

Conclusion: Automated pattern-based image classification can improve the diagnostic accuracy in patients with parkinsonism, even at early disease stages.
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http://dx.doi.org/10.2967/jnumed.115.161992DOI Listing
January 2016

A disease-specific metabolic brain network associated with corticobasal degeneration.

Brain 2014 Nov 9;137(Pt 11):3036-46. Epub 2014 Sep 9.

1 Centre for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA

Corticobasal degeneration is an uncommon parkinsonian variant condition that is diagnosed mainly on clinical examination. To facilitate the differential diagnosis of this disorder, we used metabolic brain imaging to characterize a specific network that can be used to discriminate corticobasal degeneration from other atypical parkinsonian syndromes. Ten non-demented patients (eight females/two males; age 73.9 ± 5.7 years) underwent metabolic brain imaging with (18)F-fluorodeoxyglucose positron emission tomography for atypical parkinsonism. These individuals were diagnosed clinically with probable corticobasal degeneration. This diagnosis was confirmed in the three subjects who additionally underwent post-mortem examination. Ten age-matched healthy subjects (five females/five males; age 71.7 ± 6.7 years) served as controls for the imaging studies. Spatial covariance analysis was applied to scan data from the combined group to identify a significant corticobasal degeneration-related metabolic pattern that discriminated (P < 0.001) the patients from the healthy control group. This pattern was characterized by bilateral, asymmetric metabolic reductions involving frontal and parietal cortex, thalamus, and caudate nucleus. These pattern-related changes were greater in magnitude in the cerebral hemisphere opposite the more clinically affected body side. The presence of this corticobasal degeneration-related metabolic topography was confirmed in two independent testing sets of patient and control scans, with elevated pattern expression (P < 0.001) in both disease groups relative to corresponding normal values. We next determined whether prospectively computed expression values for this pattern accurately discriminated corticobasal degeneration from multiple system atrophy and progressive supranuclear palsy (the two most common atypical parkinsonian syndromes) on a single case basis. Based upon this measure, corticobasal degeneration was successfully distinguished from multiple system atrophy (P < 0.001) but not progressive supranuclear palsy, presumably because of the overlap (∼ 24%) that existed between the corticobasal degeneration- and the progressive supranuclear palsy-related metabolic topographies. Nonetheless, excellent discrimination between these disease entities was achieved by computing hemispheric asymmetry scores for the corticobasal degeneration-related pattern on a prospective single scan basis. Indeed, a logistic algorithm based on the asymmetry scores combined with separately computed expression values for a previously validated progressive supranuclear palsy-related pattern provided excellent specificity (corticobasal degeneration: 92.7%; progressive supranuclear palsy: 94.1%) in classifying 58 testing subjects. In conclusion, corticobasal degeneration is associated with a reproducible disease-related metabolic covariance pattern that may help to distinguish this disorder from other atypical parkinsonian syndromes.
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http://dx.doi.org/10.1093/brain/awu256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208467PMC
November 2014

Network modulation following sham surgery in Parkinson's disease.

J Clin Invest 2014 Aug 18;124(8):3656-66. Epub 2014 Jul 18.

Patient responses to placebo and sham effects are a major obstacle to the development of therapies for brain disorders, including Parkinson's disease (PD). Here, we used functional brain imaging and network analysis to study the circuitry underlying placebo effects in PD subjects randomized to sham surgery as part of a double-blind gene therapy trial. Metabolic imaging was performed prior to randomization, then again at 6 and 12 months after sham surgery. In this cohort, the sham response was associated with the expression of a distinct cerebello-limbic circuit. The expression of this network increased consistently in patients blinded to treatment and correlated with independent clinical ratings. Once patients were unblinded, network expression declined toward baseline levels. Analogous network alterations were not seen with open-label levodopa treatment or during disease progression. Furthermore, sham outcomes in blinded patients correlated with baseline network expression, suggesting the potential use of this quantitative measure to identify "sham-susceptible" subjects before randomization. Indeed, Monte Carlo simulations revealed that a priori exclusion of such individuals substantially lowers the number of randomized participants needed to demonstrate treatment efficacy. Individualized subject selection based on a predetermined network criterion may therefore limit the need for sham interventions in future clinical trials.
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http://dx.doi.org/10.1172/JCI75073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109544PMC
August 2014

A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit.

JAMA Neurol 2014 May;71(5):543-52

Columbia University Medical Center, Neurological Institute, New York, New York.

Importance: Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit.

Objective: To examine whether CoQ10 could slow disease progression in early PD.

Design, Setting, And Participants: A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation.

Interventions: The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E.

Main Outcomes And Measures: Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo.

Results: The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo).

Conclusions And Relevance: Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit.

Trial Registration: clinicaltrials.gov Identifier: NCT00740714.
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http://dx.doi.org/10.1001/jamaneurol.2014.131DOI Listing
May 2014

Abnormal metabolic network activity in REM sleep behavior disorder.

Neurology 2014 Feb 22;82(7):620-7. Epub 2014 Jan 22.

From the Center for Neurosciences (F.H., Y.M., C.C.T., A.F., V.D., D.E.), The Feinstein Institute for Medical Research, Manhasset, NY; Center for Advanced Research in Sleep Medicine (J.-F.G., R.B.P., M.V., J.M.), Hôpital du Sacré-Coeur de Montréal; Department of Psychology (J.-F.G., M.V.), Université du Québec à Montréal; Department of Neurology (R.B.P.), Montreal General Hospital; Montreal Neurological Institute (J.-P.S.), McGill University; and Department of Psychiatry (J.M.), University of Montreal, Montréal, Canada.

Objective: To determine whether the Parkinson disease-related covariance pattern (PDRP) expression is abnormally increased in idiopathic REM sleep behavior disorder (RBD) and whether increased baseline activity is associated with greater individual risk of subsequent phenoconversion.

Methods: For this cohort study, we recruited 2 groups of RBD and control subjects. Cohort 1 comprised 10 subjects with RBD (63.5 ± 9.4 years old) and 10 healthy volunteers (62.7 ± 8.6 years old) who underwent resting-state metabolic brain imaging with (18)F-fluorodeoxyglucose PET. Cohort 2 comprised 17 subjects with RBD (68.9 ± 4.8 years old) and 17 healthy volunteers (66.6 ± 6.0 years old) who underwent resting brain perfusion imaging with ethylcysteinate dimer SPECT. The latter group was followed clinically for 4.6 ± 2.5 years by investigators blinded to the imaging results. PDRP expression was measured in both RBD groups and compared with corresponding control values.

Results: PDRP expression was elevated in both groups of subjects with RBD (cohort 1: p < 0.04; cohort 2: p < 0.005). Of the 17 subjects with long-term follow-up, 8 were diagnosed with Parkinson disease or dementia with Lewy bodies; the others did not phenoconvert. For individual subjects with RBD, final phenoconversion status was predicted using a logistical regression model based on PDRP expression and subject age at the time of imaging (r(2) = 0.64, p < 0.0001).

Conclusions: Latent network abnormalities in subjects with idiopathic RBD are associated with a greater likelihood of subsequent phenoconversion to a progressive neurodegenerative syndrome.
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http://dx.doi.org/10.1212/WNL.0000000000000130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963420PMC
February 2014

Expanding the genetics of huntingtonism.

Neurology 2014 Jan 20;82(4):286-7. Epub 2013 Dec 20.

From the Center for Neurosciences (A.F.), The Feinstein Institute for Medical Research, Manhasset, NY; and the Nuffield Department of Clinical Neurosciences (K.T.), University of Oxford, UK.

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http://dx.doi.org/10.1212/WNL.0000000000000067DOI Listing
January 2014

Gene-based therapies in Parkinson's disease.

Neurotherapeutics 2014 Jan;11(1):60-7

Center for Neurosciences, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.

Parkinson's disease (PD) is a progressive neurological disorder characterized primarily by the degeneration of nigrostriatal dopaminergic neurons and diminution of the neurotransmitter dopamine. Though dopamine replacement therapies such as levodopa can improve the symptoms of PD, the benefits may be overshadowed by side effects and the onset of symptoms not responsive to dopaminergic treatments (e.g., autonomic symptoms, gait and balance problems, and cognitive impairment). Furthermore, no therapies have proven to slow the neurodegenerative process. Novel approaches to address these difficult problems, and others, are being sought. Over the last decade, several innovative gene therapies for PD have entered human clinical trials in an effort to address both symptomatic and potential disease-modifying effects. Though the results of these trials have been mixed, the therapies have generally been safe and well-tolerated, suggesting gene therapy may be a viable treatment for PD in the future. This article will review past and current clinical trials of gene therapies for PD. In addition, novel preclinical approaches to gene therapy for PD will be described.
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http://dx.doi.org/10.1007/s13311-013-0233-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899481PMC
January 2014

Metabolic network as a progression biomarker of premanifest Huntington's disease.

J Clin Invest 2013 Sep 29;123(9):4076-88. Epub 2013 Aug 29.

Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.

Background: The evaluation of effective disease-modifying therapies for neurodegenerative disorders relies on objective and accurate measures of progression in at-risk individuals. Here we used a computational approach to identify a functional brain network associated with the progression of preclinical Huntington's disease (HD).

Methods: Twelve premanifest HD mutation carriers were scanned with [18F]-fluorodeoxyglucose PET to measure cerebral metabolic activity at baseline and again at 1.5, 4, and 7 years. At each time point, the subjects were also scanned with [11C]-raclopride PET and structural MRI to measure concurrent declines in caudate/putamen D2 neuroreceptor binding and tissue volume. The rate of metabolic network progression in this cohort was compared with the corresponding estimate obtained in a separate group of 21 premanifest HD carriers who were scanned twice over a 2-year period.

Results: In the original premanifest cohort, network analysis disclosed a significant spatial covariance pattern characterized by progressive changes in striato-thalamic and cortical metabolic activity. In these subjects, network activity increased linearly over 7 years and was not influenced by intercurrent phenoconversion. The rate of network progression was nearly identical when measured in the validation sample. Network activity progressed at approximately twice the rate of single region measurements from the same subjects.

Conclusion: Metabolic network measurements provide a sensitive means of quantitatively evaluating disease progression in premanifest individuals. This approach may be incorporated into clinical trials to assess disease-modifying agents.

Trial Registration: Registration is not required for observational studies.

Funding: NIH (National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering) and CHDI Foundation Inc.
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http://dx.doi.org/10.1172/JCI69411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754266PMC
September 2013