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Walker L.C.,Emory University | Diamond M.I.,Washington University in St. Louis | Duff K.E.,Columbia University | Hyman B.T.,MassGeneral Institute for Neurodegenerative Disease
JAMA Neurology | Year: 2013

A growing body of data indicates that the propagation of pathogenic protein aggregates across neural systems, and hence the disruption of function of those neural systems, might be mediated by misfolded protein seeds that are released and taken up by anatomically connected neurons. If so, blocking this process may help arrest the progression of disease. In light of the growing spectrum of disorders involving the accumulation and spread of misfolded proteins, efforts to detect pathogenic protein aggregates and impede their movement between cells could change how we diagnose and treat neurodegenerative diseases. © 2013 American Medical Association. All rights reserved.

Gomperts S.N.,MassGeneral Institute for Neurodegenerative Disease
Current Neurology and Neuroscience Reports | Year: 2014

Cognitive impairment and dementia are significant sequelae of Parkinson disease (PD) and comprise a key feature of dementia with Lewy bodies (DLB), a disease with similar clinical and neuropathological features. Multiple independent causes have been implicated in PD dementia (PDD) and DLB, among them the accumulation of β-amyloid, a neuropathological hallmark of Alzheimer disease. Over the last decade, PET imaging has emerged as a viable method to measure amyloid burden in the human brain and relate it to neurodegenerative diseases. This article reviews what amyloid imaging has taught us about PDD and DLB. Current data suggest that brain amyloid deposition tends to be more marked in DLB, yet contributes to cognitive impairment in both DLB and PD. These results are broadly consistent with neuropathology and CSF studies. β-Amyloid may interact synergistically with other pathological processes in PD and DLB to contribute to cognitive impairment. © 2014 Springer Science+Business Media.

Hung A.Y.,Massachusetts General Hospital | Schwarzschild M.A.,Massachusetts General Hospital | Schwarzschild M.A.,MassGeneral Institute for Neurodegenerative Disease
Neurotherapeutics | Year: 2014

Dopamine depletion resulting from degeneration of nigrostriatal dopaminergic neurons is the primary neurochemical basis of the motor symptoms of Parkinson's disease (PD). While dopaminergic replacement strategies are effective in ameliorating these symptoms early in the disease process, more advanced stages of PD are associated with the development of treatment-related motor complications and dopamine-resistant symptoms. Other neurotransmitter and neuromodulator systems are expressed in the basal ganglia and contribute to the extrapyramidal refinement of motor function. Furthermore, neuropathological studies suggest that they are also affected by the neurodegenerative process. These non-dopaminergic systems provide potential targets for treatment of motor fluctuations, levodopa-induced dyskinesias, and difficulty with gait and balance. This review summarizes recent advances in the clinical development of novel pharmacological approaches for treatment of PD motor symptoms. Although the non-dopaminergic pipeline has been slow to yield new drugs, further development will likely result in improved treatments for PD symptoms that are induced by or resistant to dopamine replacement. © 2013 The American Society for Experimental NeuroTherapeutics, Inc.

Chen J.,University of Wyoming | Marks E.,University of Wyoming | Lai B.,Argonne National Laboratory | Zhang Z.,University of Wyoming | And 7 more authors.
PLoS ONE | Year: 2013

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine-encoding CAG expansion in the huntingtin gene. Iron accumulates in the brains of HD patients and mouse disease models. However, the cellular and subcellular sites of iron accumulation, as well as significance to disease progression are not well understood. We used independent approaches to investigate the location of brain iron accumulation. In R6/2 HD mouse brain, synchotron x-ray fluorescence analysis revealed iron accumulation as discrete puncta in the perinuclear cytoplasm of striatal neurons. Further, perfusion Turnbull's staining for ferrous iron (II) combined with transmission electron microscope ultra-structural analysis revealed increased staining in membrane bound peri-nuclear vesicles in R6/2 HD striatal neurons. Analysis of iron homeostatic proteins in R6/2 HD mice revealed decreased levels of the iron response proteins (IRPs 1 and 2) and accordingly decreased expression of iron uptake transferrin receptor (TfR) and increased levels of neuronal iron export protein ferroportin (FPN). Finally, we show that intra-ventricular delivery of the iron chelator deferoxamine results in an improvement of the motor phenotype in R6/2 HD mice. Our data supports accumulation of redox-active ferrous iron in the endocytic/ lysosomal compartment in mouse HD neurons. Expression changes of IRPs, TfR and FPN are consistent with a compensatory response to an increased intra-neuronal labile iron pool leading to increased susceptibility to iron-associated oxidative stress. These findings, together with protection by deferoxamine, support a potentiating role of neuronal iron accumulation in HD. © 2013 Chen et al.

Schwarzschild M.A.,MassGeneral Institute for Neurodegenerative Disease
JAMA Neurology | Year: 2014

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. MAINOUTCOMESAND 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 © Copyright 2014 American Medical Association. All rights reserved.

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