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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Vannini, Patrizia; Hanseeuw, Bernard; Munro, Catherine E et al. (2017) Anosognosia for memory deficits in mild cognitive impairment: Insight into the neural mechanism using functional and molecular imaging. Neuroimage Clin 15:408-414
Hsu, David; Marshall, Gad A (2017) Primary and Secondary Prevention Trials in Alzheimer Disease: Looking Back, Moving Forward. Curr Alzheimer Res 14:426-440
Marshall, Gad A; Aghjayan, Sarah L; Dekhtyar, Maria et al. (2017) Activities of daily living measured by the Harvard Automated Phone Task track with cognitive decline over time in non-demented elderly. J Prev Alzheimers Dis 4:81-86
Mormino, Elizabeth C; Papp, Kathryn V; Rentz, Dorene M et al. (2016) Heterogeneity in Suspected Non-Alzheimer Disease Pathophysiology Among Clinically Normal Older Individuals. JAMA Neurol 73:1185-1191
Hsu, David C; Mormino, Elizabeth C; Schultz, Aaron P et al. (2016) Lower Late-Life Body-Mass Index is Associated with Higher Cortical Amyloid Burden in Clinically Normal Elderly. J Alzheimers Dis 53:1097-105
Growdon, Matthew E; Schultz, Aaron P; Dagley, Alexander S et al. (2015) Odor identification and Alzheimer disease biomarkers in clinically normal elderly. Neurology 84:2153-60
Marshall, Gad A; Zoller, Amy S; Lorius, Natacha et al. (2015) Functional Activities Questionnaire Items that Best Discriminate and Predict Progression from Clinically Normal to Mild Cognitive Impairment. Curr Alzheimer Res 12:493-502
Lorius, Natacha; Locascio, Joseph J; Rentz, Dorene M et al. (2015) Vascular disease and risk factors are associated with cognitive decline in the alzheimer disease spectrum. Alzheimer Dis Assoc Disord 29:18-25
Huijbers, Willem; Mormino, Elizabeth C; Schultz, Aaron P et al. (2015) Amyloid-? deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression. Brain 138:1023-35
Sperling, R A; Amariglio, R E; Marshall, G A et al. (2015) Establishing Clinical Relevance in Preclinical Alzheimer's Disease. J Prev Alzheimers Dis 2:85-87

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