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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS044233-07
Application #
8142001
Study Section
Special Emphasis Panel (ZNS1-SRB-E (33))
Program Officer
Sieber, Beth-Anne
Project Start
2002-07-01
Project End
2015-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
7
Fiscal Year
2011
Total Cost
$1,144,456
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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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