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 #
5P01NS044233-08
Application #
8330337
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
2012-08-01
Budget End
2013-07-31
Support Year
8
Fiscal Year
2012
Total Cost
$1,109,757
Indirect Cost
$215,498
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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

Showing the most recent 10 out of 108 publications