Multiple system atrophy (MSA) is a progressive and fatal neurologic disorder characterized by autonomic failure, parkinsonism, and/or cerebellar ataxia. Consensus criteria for the diagnosis of MSA have improved certitude of diagnosis but have also deferred diagnosis to a later stage of disease. Treatment trials of MSA have been negative in significant part because the disorder could not be diagnosed with certainty until a late stage of disease. An important goal is therefore to identify early, still evolving MSA at a stage when disease activity can be arrested and meaningful recovery is possible. Our proposal is focused on the development of novel biomarkers that will allow us to identify MSA at such an early stage. Firstly, we shall study MSA following diagnosis at the earliest disease stage currently possible (combining consensus criteria with clinical autonomic testing for diagnosis).In this cohort, we will derive and follow a selected set of biomarkers, including MRI morphometry for neuronal loss and spinal fluid biomarkers for central axonal and neuronal degeneration, to identify biomarkers of early MSA (Specific Aim #1). Our second approach involves pure autonomic failure (PAF), a synucleinopathy characterized by severe, progressive autonomic failure. Most patients with PAF survive for decades without clinical central nervous system involvement, but some patients convert to MSA. In our discovery cohort, we have identified highly predictive clinical indicators of conversion to MSA within a two to three year timeframe. We will apply our biomarker approach to patients predicted to evolve from PAF to MSA (Specific Aim #2), follow patients over time, and compare clinical course and biomarkers with stable PAF. This approach enables us to assess the value of the proposed biomarkers and study MSA at an earlier stage than has previously been possible. We are uniquely situated to undertake these studies since our program has access to a large number of patients with both of these rare conditions. Our Autonomic Disorders database, currently has over 300 patients with PAF and over 600 patients with MSA, comprising subjects we have studied over the last 10 years. The findings from this proposal should result in MSA diagnosis at a much earlier stage than has been previously possible. We posit that insights from this approach might eventually allow us to diagnose MSA at an even earlier evolving or preclinical stage of disease. Randomized clinical trials using a novel set of criteria and biomarkers should stand a greater probability of demonstrating efficacy.
With Specific Aim #3 of this proposal we shall identify pattern and progression of atrophy of selected brain structures using MRI morphometry which is tightly interconnected with the other two aims.

Public Health Relevance

Multiple system atrophy (MSA) is a progressive, fatal neurological condition characterized by autonomic failure, parkinsonism, and/or ataxia. Treatment has been ineffective, in major part because the disease is diagnosed at an advanced stage. We propose a novel approach, using imaging and spinal fluid biomarkers in early MSA and in patients with pure autonomic failure who are evolving into MSA, that should result in recognizing the disease at a much earlier stage, when treatment might be more effective.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Sieber, Beth-Anne
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
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
Weiner, Michael W; Harvey, Danielle; Hayes, Jacqueline et al. (2017) Effects of traumatic brain injury and posttraumatic stress disorder on development of Alzheimer's disease in Vietnam Veterans using the Alzheimer's Disease Neuroimaging Initiative: Preliminary Report. Alzheimers Dement (N Y) 3:177-188
Singer, Wolfgang; Berini, Sarah E; Sandroni, Paola et al. (2017) Pure autonomic failure: Predictors of conversion to clinical CNS involvement. Neurology 88:1129-1136
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; Low, Phillip A (2017) Pure autonomic failure without alpha-synuclein pathology: an evolving understanding of a heterogeneous disease. Clin Auton Res 27:67-68
Cummings, Jeffrey; Aisen, Paul S; DuBois, Bruno et al. (2016) Drug development in Alzheimer's disease: the path to 2025. Alzheimers Res Ther 8:39
Labbé, Catherine; Heckman, Michael G; Lorenzo-Betancor, Oswaldo et al. (2016) MAPT haplotype diversity in multiple system atrophy. Parkinsonism Relat Disord 30:40-5