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

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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

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-M (92))
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Sutherland, Margaret L
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Massachusetts General Hospital
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Sabuncu, Mert R; Bernal-Rusiel, Jorge L; Reuter, Martin et al. (2014) Event time analysis of longitudinal neuroimage data. Neuroimage 97:9-18
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
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
Coutu, Jean-Philippe; Chen, J Jean; Rosas, H Diana et al. (2014) Non-Gaussian water diffusion in aging white matter. Neurobiol Aging 35:1412-21
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
Chen, J Jean; Rosas, H Diana; Salat, David H (2013) The relationship between cortical blood flow and sub-cortical white-matter health across the adult age span. PLoS One 8:e56733
Chen, J Jean; Salat, David H; Rosas, H Diana (2012) Complex relationships between cerebral blood flow and brain atrophy in early Huntington's disease. Neuroimage 59:1043-51
Chen, J Jean; Rosas, H Diana; Salat, David H (2011) Age-associated reductions in cerebral blood flow are independent from regional atrophy. Neuroimage 55:468-78
Rosas, H Diana; Reuter, Martin; Doros, Gheorghe et al. (2011) A tale of two factors: what determines the rate of progression in Huntington's disease? A longitudinal MRI study. Mov Disord 26:1691-7

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