This project is focused on the diagnosis, pathophysiology, and treatment of multiple system atrophy (MSA), with a specific autonomic focus. Based on our success in the prior 5 years, we are poised to achieve several unique goals. We have assembled a large cohort in the previous 5 years of patients with MSA and Parkinson's disease (PD), with full autonomic and neurological characterization. We will test the hypothesis that there are certain autonomic predictors of a more rapidly progressive course in MSA. We will evaluate if the severity and distribution of autonomic failure at entry into the study is predictive of a more rapid rate of neurologic progression of MSA and if the increase in autonomic deficit documented at the first return visit, at the end of 1 year, is predictive of the rate of progression of MSA. We will enhance the study by adding 50 patients with eariy MSA. The high ascertainment, including neuropathological confirmation of the diagnosis of MSA will permit us to improve the definition of MSA, using autopsy confirmed cases. We should be able to develop an algorithm for the eariy diagnosis of MSA, at a time when they may be amenable to treatment. We will undertake a double-blind placebo controlled clinical trial on the effect of Rifampicin on progression of neurological and autonomic failure in 100 patients with eariy MSA. The underlying hypothesis is that Rifampicin, because of its ability to inhibit the formation of a-synuclein fibrils and disaggregate fibrils already formed, will delay progression or reverse neurologic and autonomic functions and symptoms in MSA. This study is done in collaboration with Projects 1 and 3. Neurogenic orthostatic hypotension (OH) is an integral component of MSA and treatment is problematic since available treatments will aggravate supine hypertension. In MSA, the hwin problem exists of failure of preganglionic neurotransmission and depletion of postganglionic neurons of its neurotransmitter, norepinephrine. We propose a novel double-blind, placebocontrolled inpatient treatment trial, incorporating strategy that will improve OH without aggravating supine hypertension. This goal is to replete the postganglionic axon with norepinephrine (using its precursor, LDOPS) and improving the safety factor of ganglionic neurotransmission (with pyridostigmine).
Multiple system atrophy is a progressive and fatal disorder. We are undertaking a study that will improve our understanding of the natural history of the disorder and improve diagnosis. We will undertake two treatment trials: the first will test a drug that has the potential to prevent worsening or improve MSA;the second is to evaluate a new approach to treat orthostatic hypotension.
|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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