Program Director/Principal Investigator (Last, First, Middle): Rosas, Herminia Diana Abstract: The most important goal of experimental therapeutics for symptomatic Huntington's disease (HD) is to develop disease-modifying (neuroprotective) therapies able to slow progression. Rapidly advancing basic and translational research has identified numerous potential targets for neuroprotection and treatments based on them are creating an expanding pipeline for clinical trials. However, clinical trials are not close to keeping up with compounds for which there is already some rationale, as well as likelihood of safety and tolerability, and the gap is quickly widening. The development and use of biomarkers in clinical trials for HD have profound potential to increase the rate and accuracy with which compounds, and by implication their targets, can be assessed. Since HD is fundamentally a progressive neurodegenerative disease, neuro-imaging measures hold great promise as direct measures of disease progression that may also provide the necessary sensitivity and specificity to help assess disease modification in Phase II and Phase III clinical trials. During the current funding period, we used state-of-the-art neuro-imaging tools to show that regional brain atrophy in HD is early and progressive, and corresponds to clinical features, including the TFC. We also used these tools as a pharmacodynamic biomarker in a pilot study of high-dose Creatine, a leading candidate neuroprotective agent, in HD subjects. We found that high dose Creatine slowed brain atrophy, reduced measures of oxidative stress, and may have slowed cognitive decline. We are seeking to validate our neuro-imaging tools in a funded placebo-controlled, double-blind Phase III clinical trial of high-dose creatine as a biomarker of disease progression. Should Creatine slow progression and slow brain atrophy, it will be a crucial step in demonstrating the value of neuro-imaging as a pharmacodynamic biomarker of disease modification. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

Public Health Relevance

Herminia Diana Rosas Narrative: If Creatine slows the clinical progression of HD as measured by the TFC, we will learn how well neuro-imaging measures perform as pharmacodynamic biomarkers;it will set the stage for neuro-imaging as a useful indicator of potential neuroprotective efficacy in Phase II studies;it will be a first step towards eventually qualifying neuro-imaging as a potential secondary or surrogate endpoint in Phase III studies. Even without efficacy, we will learn how regional brain involvement underlies the complex symptomatology and course of HD PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042861-09
Application #
8260536
Study Section
Special Emphasis Panel (ZRG1-BDCN-M (92))
Program Officer
Sutherland, Margaret L
Project Start
2001-08-15
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
9
Fiscal Year
2012
Total Cost
$723,903
Indirect Cost
$312,431
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Coutinho, Artur Martins; Coutu, Jean-Philippe; Lindemer, Emily Rose et al. (2017) Differential associations between systemic markers of disease and cortical thickness in healthy middle-aged and older adults. Neuroimage 146:19-27
Coutu, Jean-Philippe; Goldblatt, Alison; Rosas, H Diana et al. (2016) White Matter Changes are Associated with Ventricular Expansion in Aging, Mild Cognitive Impairment, and Alzheimer's Disease. J Alzheimers Dis 49:329-42
Konukoglu, Ender; Coutu, Jean-Philippe; Salat, David H et al. (2016) Multivariate statistical analysis of diffusion imaging parameters using partial least squares: Application to white matter variations in Alzheimer's disease. Neuroimage 134:573-586
Lee, S-H; Coutu, J-P; Wilkens, P et al. (2015) Tract-based analysis of white matter degeneration in Alzheimer's disease. Neuroscience 301:79-89
Rosas, Herminia D; Doros, Gheorghe; Bhasin, Swati et al. (2015) A systems-level ""misunderstanding"": the plasma metabolome in Huntington's disease. Ann Clin Transl Neurol 2:756-68
Ryu, Seon Young; Coutu, Jean-Philippe; Rosas, H Diana et al. (2014) Effects of insulin resistance on white matter microstructure in middle-aged and older adults. Neurology 82:1862-70
Sabuncu, Mert R; Bernal-Rusiel, Jorge L; Reuter, Martin et al. (2014) Event time analysis of longitudinal neuroimage data. Neuroimage 97:9-18
Adriaanse, Sofie M; van Dijk, Koene R A; Ossenkoppele, Rik et al. (2014) The effect of amyloid pathology and glucose metabolism on cortical volume loss over time in Alzheimer's disease. Eur J Nucl Med Mol Imaging 41:1190-8
Rosas, Herminia D; Doros, Gheorghe; Gevorkian, Sona et al. (2014) PRECREST: a phase II prevention and biomarker trial of creatine in at-risk Huntington disease. Neurology 82:850-7
Biffi, Alessandro; Sabuncu, Mert R; Desikan, Rahul S et al. (2014) Genetic variation of oxidative phosphorylation genes in stroke and Alzheimer's disease. Neurobiol Aging 35:1956.e1-8

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