The candidate, Gad A. Marshall, M.D., is resubmitting an application for a Mentored Patient-Oriented Research Career Development Award (K23). The candidate has developed an integrated research/educational plan that will lead to advanced knowledge in neuroimaging and clinical research design. The candidate will attend classes and tutorials in biostatistics, research design, epidemiology, ethics, and neuroimaging. This multidisciplinary training, along with the experience of being the principal investigator of a large neuroimaging in aging study, will facilitate the development of the candidate into an independent clinical investigator who is an academic neurologist and dementia expert, experienced in the use of neuroimaging in clinical research, with an emphasis on developing and testing new treatments for early Alzheimer's disease (AD). AD and its potential precursor stage, amnestic mild cognitive impairment (MCI), are nearing epidemic proportions. Early neuropsychiatric symptoms, such as apathy, are particularly troublesome to caregivers of patients with AD and MCI. Apathy is associated with executive dysfunction and has been localized to the frontal regions. We propose to demonstrate a connection between apathy, executive dysfunction, in vivo cortical amyloid deposition assessed by positron emission tomography (PET) using Pittsburgh Compound B (PIB), and frontal and parietal hypometabolism assessed by 18F-fluorodeoxyglocuse (FDG) PET, in amnestic MCI and AD. We propose a 36 month prospective follow-up study of 80 subjects with normal cognition (n=20), amnestic MCI (n=40) and mild AD (n=20), ages 55 to 90, who will undergo brain PIB PET, FDG PET, and magnetic resonance imaging (MRI) at baseline. They will then be followed longitudinally for 36 months. Clinical assessments will be performed at baseline and every 12 months to determine disease progression. Clinical evaluation will consist of tests of overall cognitive function, global function, functional assessments, behavioral assessments focusing on apathy, and neuropsychological tests focusing on executive function. We hypothesize that although fibrillar amyloid deposition may occur early in prefrontal and medial parietal regions, it will be hypometabolism in these regions that best correlates with apathy and executive dysfunction. Greater frontal and parietal PIB retention and lower frontal and parietal FDG metabolism, in combination with apathy and executive dysfunction, will lead to impairment in instrumental activities of daily living (IADLs), and rapid progression to clinical AD.

Public Health Relevance

Earlier detection and treatment of AD, at the stage of MCI, is vital. Many potentially disease-modifying agents targeting amyloid pathology are in early phase clinical trials of AD. MCI pathology is variable and must be better characterized to become the target of such trials. This proposal provides a unique opportunity to explore the convergence of the clinically significant elements of apathy and executive dysfunction with frontal and parietal hypometabolism and amyloid burden, early in the disease course, in order to better characterize MCI.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Mentored Patient-Oriented Research Career Development Award (K23)
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National Institute on Aging Initial Review Group (NIA)
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Hsiao, John
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Brigham and Women's Hospital
United States
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Marshall, Gad A; Zoller, Amy S; Kelly, Kathleen E et al. (2014) Everyday cognition scale items that best discriminate between and predict progression from clinically normal to mild cognitive impairment. Curr Alzheimer Res 11:853-61
Roy, Kamolika; Pepin, Lesley C; Philiossaint, Marlie et al. (2014) Regional fluorodeoxyglucose metabolism and instrumental activities of daily living across the Alzheimer's disease spectrum. J Alzheimers Dis 42:291-300
Zoller, Amy S; Gaal, Ildiko M; Royer, Christine A et al. (2014) SIST-M-IR activities of daily living items that best discriminate clinically normal elderly from those with mild cognitive impairment. Curr Alzheimer Res 11:785-91
Donovan, Nancy J; Amariglio, Rebecca E; Zoller, Amy S et al. (2014) Subjective cognitive concerns and neuropsychiatric predictors of progression to the early clinical stages of Alzheimer disease. Am J Geriatr Psychiatry 22:1642-51
Marshall, Gad A; Lorius, Natacha; Locascio, Joseph J et al. (2014) Regional cortical thinning and cerebrospinal biomarkers predict worsening daily functioning across the Alzheimer's disease spectrum. J Alzheimers Dis 41:719-28
Becker, J Alex; Hedden, Trey; Carmasin, Jeremy et al. (2011) Amyloid-? associated cortical thinning in clinically normal elderly. Ann Neurol 69:1032-42
Marshall, Gad A; Rentz, Dorene M; Frey, Meghan T et al. (2011) Executive function and instrumental activities of daily living in mild cognitive impairment and Alzheimer's disease. Alzheimers Dement 7:300-8
Marshall, Gad A; Olson, Lauren E; Frey, Meghan T et al. (2011) Instrumental activities of daily living impairment is associated with increased amyloid burden. Dement Geriatr Cogn Disord 31:443-50