Huntington's disease (HD) is a devastating neurodegenerative disease for which there is currently no therapy proven to delay onset or to slow progression of the disease. The development of therapies is slowed by an uncertain understanding of disease mechanisms and by the limited availability of biomarkers which could be used to monitor the effects of therapies in all phases of clinical trials. In this application w propose to use metabolomic approaches to better understand pathophysiology and to discover potential therapeutic targets and biomarkers. We have extensive data demonstrating that HD progressively affects a variety of biochemical pathways in plasma from patients beginning presymptomatically. Small molecules in the tryptophan, tyrosine, purine and redox pathways have particular potential as biomarkers. However, it is uncertain exactly how they reflect peripheral, systemic, or CNS manifestations of HD, information essential to defining their usefulness as markers. To help decipher whether the peripheral metabolomic changes we have observed originate from the brain, the entire body, or only from blood, we propose to use cerebrospinal fluid (CSF) and plasma from the same patients and compare and contrast their metabolomic signatures. We will also compare these results to metabolomic changes in postmortem HD brain. Our goal is to understand the inter-relationships of the plasma and CSF metabolomes and the overlap of these with the brain metabolome and to identify clinically relevant plasma and CSF markers of disease progression or response to therapy.

Public Health Relevance

We have discovered that HD affects a variety of pathways in plasma from patients, particularly tryptophan, tyrosine, purine and redox pathways which have great potential as biomarkers. To help decipher whether the observed peripheral metabolomic changes originate from the brain, the entire body, or only from blood, we propose using cerebrospinal fluid (CSF) and plasma from the same patients to understand the inter- relationships of the plasma and CSF metabolomes and to identify clinically relevant plasma and CSF biomarkers of disease progression or drug response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS087294-01A1
Application #
8824119
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Sutherland, Margaret L
Project Start
2014-09-15
Project End
2016-08-31
Budget Start
2014-09-15
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$217,500
Indirect Cost
$92,500
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199