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.
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.
|Singer, Wolfgang; Berini, Sarah E; Sandroni, Paola et al. (2017) Pure autonomic failure: Predictors of conversion to clinical CNS involvement. Neurology 88:1129-1136|
|Valera, Elvira; Spencer, Brian; Mott, Jennifer et al. (2017) MicroRNA-101 Modulates Autophagy and Oligodendroglial Alpha-Synuclein Accumulation in Multiple System Atrophy. Front Mol Neurosci 10:329|
|Coon, Elizabeth A; Low, Phillip A (2017) Pure autonomic failure without alpha-synuclein pathology: an evolving understanding of a heterogeneous disease. Clin Auton Res 27:67-68|
|Valera, Elvira; Spencer, Brian; Fields, Jerel A et al. (2017) Combination of alpha-synuclein immunotherapy with anti-inflammatory treatment in a transgenic mouse model of multiple system atrophy. Acta Neuropathol Commun 5:2|
|Spencer, Brian; Valera, Elvira; Rockenstein, Edward et al. (2017) Anti-?-synuclein immunotherapy reduces ?-synuclein propagation in the axon and degeneration in a combined viral vector and transgenic model of synucleinopathy. Acta Neuropathol Commun 5:7|
|Coon, Elizabeth A; Fealey, Robert D; Sletten, David M et al. (2017) Anhidrosis in multiple system atrophy involves pre- and postganglionic sudomotor dysfunction. Mov Disord 32:397-404|
|Coon, Elizabeth A; Ahlskog, J Eric; Silber, Michael H et al. (2017) Do selective serotonin reuptake inhibitors improve survival in multiple system atrophy? Parkinsonism Relat Disord :|
|Spencer, Brian; Kim, Changyoun; Gonzalez, Tania et al. (2016) ?-Synuclein interferes with the ESCRT-III complex contributing to the pathogenesis of Lewy body disease. Hum Mol Genet 25:1100-15|
|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|
|Spencer, Brian; Williams, Stephanie; Rockenstein, Edward et al. (2016) ?-synuclein conformational antibodies fused to penetratin are effective in models of Lewy body disease. Ann Clin Transl Neurol 3:588-606|
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