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.
| Rockenstein, Edward; Ostroff, Gary; Dikengil, Fusun et al. (2018) Combined Active Humoral and Cellular Immunization Approaches for the Treatment of Synucleinopathies. J Neurosci 38:1000-1014 |
| Coon, Elizabeth A; Ahlskog, J Eric; Silber, Michael H et al. (2018) Do selective serotonin reuptake inhibitors improve survival in multiple system atrophy? Parkinsonism Relat Disord 48:51-53 |
| Ogaki, Kotaro; Martens, Yuka A; Heckman, Michael G et al. (2018) Multiple system atrophy and apolipoprotein E. Mov Disord 33:647-650 |
| Wenning, Gregor; Trojanowski, John Q; Kaufmann, Horacio et al. (2018) Is multiple system atrophy an infectious disease? Ann Neurol 83:10-12 |
| Cutsforth-Gregory, Jeremy K; McKeon, Andrew; Coon, Elizabeth A et al. (2018) Ganglionic Antibody Level as a Predictor of Severity of Autonomic Failure. Mayo Clin Proc 93:1440-1447 |
| 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 |
| 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 |
| 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 |
| El-Agnaf, Omar; Overk, Cassia; Rockenstein, Edward et al. (2017) Differential effects of immunotherapy with antibodies targeting ?-synuclein oligomers and fibrils in a transgenic model of synucleinopathy. Neurobiol Dis 104:85-96 |
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