MSA is a relentlessly progressive and fatal disease characterized by parkinsonism or cerebellar dysfunction and autonomic failure. This PPG, founded by the late Dr. Cliff Shults, is devoted to studies on the pathogenesis and management of MSA. The success and insights gleaned from the last 5 years has enabled us to consolidate, modify, and improve the competing renewal proposal into 3 tightly integrated Cores and 4 Projects with important and achievable endpoints. We have achieved our original goal of recruiting 175 patients with MSA. Preliminary data has led us to modify Project 1 from an epidemiologic study (which has been completed) to an ongoing prospective study that will identify predictors of outcome. Specifically, Project 1 (Oilman) will test the hypothesis that clinical phenotype at onset and autonomic symptoms are predictive of clinical course. This MSA patient cohort will be expanded to 275 patients, by adding 100 additional patients with milder and earlier MSA. Project 1 will additionally study adrenergic innervation of the heart ([llCjhydroxyephedrine labeling), using high resolution PET scanning of the heart. Project 2 (Benarroch) will undertake a morphometric immunohistochemical study on key neuronal groups in hypothalamus. Dr. Masliah will continue his focus on the molecular pathogenesis of MSA. He has developed a transgenic mouse model that mimics human MSA, with glial-cytoplasmic inclusion (GCI) and neuronal loss. He continues his studies to increase or reverse GCI and behavioral deficits. Dr. Benarroch will apply his morphometric analysis of relevant nuclear groups and GCI to this mouse model. Dr. Low will continue his prospective study of laboratory autonomic indicators of a more progressive course. He will additionally undertake a double-blind placebo controlled study to evaluate a novel approach to improving orthostatic hypotension without worsening supine hypertension. A key large pilot study will focus on a treatment trial of Rifampicin, which could potentially halt progression or reverse the pathogenesis of MSA, based on results from Project 3. The study will be conjointly carried out by Projects 1 and 4 and supported by Core A. These projects will continue to be supported by 3 cores.

Public Health Relevance

Multiple system atrophy (MSA) is a progressive and fatal disease. Its cause is unknown and treatment is unsatisfactory. This Program Project is specifically devoted to MSA and focuses on the improved diagnosis, improved understanding of its natural history, and an understanding of what causes the disease. Preliminary results have resulted in the design of a treatment trial aimed at halting the progression of the disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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Special Emphasis Panel (ZNS1-SRB-E (33))
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Sieber, Beth-Anne
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Mayo Clinic, Rochester
United States
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Loavenbruck, Adam J; Singer, Wolfgang; Mauermann, Michelle L et al. (2016) Transthyretin amyloid neuropathy has earlier neural involvement but better prognosis than primary amyloid counterpart: an answer to the paradox? Ann Neurol 80:401-11
Valera, Elvira; Spencer, Brian; Masliah, Eliezer (2016) Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders. Neurotherapeutics 13:179-89
Labbé, Catherine; Heckman, Michael G; Lorenzo-Betancor, Oswaldo et al. (2016) MAPT haplotype diversity in multiple system atrophy. Parkinsonism Relat Disord 30:40-5
Spencer, Brian; Williams, Stephanie; Rockenstein, Edward et al. (2016) α-synuclein conformational antibodies fused to penetratin are effective in models of Lewy body disease. Ann Clin Transl Neurol 3:588-606
Spencer, Brian; Kim, Changyoun; Gonzalez, Tania et al. (2016) α-Synuclein interferes with the ESCRT-III complex contributing to the pathogenesis of Lewy body disease. Hum Mol Genet 25:1100-15
Valera, Elvira; Masliah, Eliezer (2016) Combination therapies: The next logical Step for the treatment of synucleinopathies? Mov Disord 31:225-34
Valera, Elvira; Masliah, Eliezer (2016) Therapeutic approaches in Parkinson's disease and related disorders. J Neurochem 139 Suppl 1:346-352
Valera, E; Monzio Compagnoni, G; Masliah, E (2016) Review: Novel treatment strategies targeting alpha-synuclein in multiple system atrophy as a model of synucleinopathy. Neuropathol Appl Neurobiol 42:95-106
Mandler, Markus; Valera, Elvira; Rockenstein, Edward et al. (2015) Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy. Mol Neurodegener 10:10
Low, Phillip A; Reich, Stephen G; Jankovic, Joseph et al. (2015) Natural history of multiple system atrophy in the USA: a prospective cohort study. Lancet Neurol 14:710-9

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