This study of patients with multiple system atrophy (MSA) will test the following hypotheses: (1) prospective longitudinal investigation will demonstrate that the phenotypic class at onset predicts the course of the disease.;(2) postganglionic sympathetic cardiac denervation occurs with disease progression in a subgroup of patients who have rapidly progressive autonomic dysfunction irrespective of the rate of change in parkinsonian or cerebellar symptoms;and (3) owing to its ability to inhibit formation of a-synuclein fibrils and disaggregate fibrils already formed, Rifampicin will delay progression or reverse neurological and autonomic abnormalities in MSA. Prospective natural history studies of 175 patients with probable MSA in 12 different sites in the US initiated during the previous funding cycle will be continued and augmented by 100 subjects recruited at the earlier stage of possible MSA, and in equal numbers from the University of Michigan and the Mayo Medical Center sites. Regular, detailed clinical appraisals, including autonomic and neurologic function, will be augmented by postmortem examination of subjects to verify diagnosis. Post-ganglionic sympathetic cardiac innervation will be evaluated every 2 years in 20 newly recruited subjects with possible MSA and 20 normal control subjects with approximately equal distributions of age and gender. Studies will utilize clinical evaluation, [13NJNH3 and [11C]hydroxylephedrlne with positron emission tomography (PET) to evaluate cardiac perfusion and innervation. All subjects will be followed prospectively to postmortem. Projects 1 and 4 will undertake a double-blind placebo controlled clinical trial to determine whether Rifampicin will retard or reverse the progression of neurologic and autonomic disorders in MSA. Preliminary studies suggest that results will robust, as current data already indicate: (1) accurate diagnosis in 28 of 29 cases studied at autopsy;(2) clinical observations suggesting a strong association of phenotypic class with subsequent course;and (3) cardiac denervation In a substantial proportion of late-stage MSA subjects. These studies will generate novel information about the natural history of MSA and reveal methods of predicting differences in progression that need to be understood for case selection in future clinical trials.

Public Health Relevance

MSA is a progressive neurodegenerative disease with a variable clinical course thought to affect only the central nervous system with no disease-modifying treatment available. This project will determine whether the type of onset predicts the later course;demonstrate peripheral (autonomic) nervous system involvement and explore the stage it begins;and develop a clinical trial for a disease-modifying treatment 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)
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Mayo Clinic, Rochester
United States
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Loavenbruck, A; Iturrino, J; Singer, W et al. (2015) Disturbances of gastrointestinal transit and autonomic functions in postural orthostatic tachycardia syndrome. Neurogastroenterol Motil 27:92-8
Piccione, Ezequiel A; Sletten, David M; Staff, Nathan P et al. (2015) Autonomic system and amyotrophic lateral sclerosis. Muscle Nerve 51:676-9
Low, Phillip A; Robertson, David; Gilman, Sid et al. (2014) Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 13:268-75
Wada, Naoki; Singer, Wolfgang; Gehrking, Tonette L et al. (2014) Determination of vagal baroreflex sensitivity in normal subjects. Muscle Nerve 50:535-40
Valera, Elvira; Ubhi, Kiren; Mante, Michael et al. (2014) Antidepressants reduce neuroinflammatory responses and astroglial alpha-synuclein accumulation in a transgenic mouse model of multiple system atrophy. Glia 62:317-37
Ubhi, Kiren; Rockenstein, Edward; Kragh, Christine et al. (2014) Widespread microRNA dysregulation in multiple system atrophy - disease-related alteration in miR-96. Eur J Neurosci 39:1026-41
Overk, Cassia R; Masliah, Eliezer (2014) Pathogenesis of synaptic degeneration in Alzheimer's disease and Lewy body disease. Biochem Pharmacol 88:508-16
Figueroa, Juan J; Bott-Kitslaar, Darlene M; Mercado, Joaquin A et al. (2014) Decreased orthostatic adrenergic reactivity in non-dipping postural tachycardia syndrome. Auton Neurosci 185:107-11
Mandler, Markus; Valera, Elvira; Rockenstein, Edward et al. (2014) Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials. Acta Neuropathol 127:861-79
May, Verena E L; Ettle, Benjamin; Poehler, Anne-Maria et al. (2014) ?-Synuclein impairs oligodendrocyte progenitor maturation in multiple system atrophy. Neurobiol Aging 35:2357-68

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