Our previous work has demonstrated that quantitative in vivo magnetic resonance imaging (MRI) techniques can identify structural and functional alterations within the medial temporal lobe (MIL) in individuals with mild cognitive impairment (MCI), who manifest clinical symptoms of AD prior to dementia. Compared to cognitively intact persons of similar age, persons with MCI demonstrate abnormalities in both MIL function and structure. For example, changes in hippocampal activation may precede (and possibly initially serve a compensatory role for) hippocampal atrophy (which correlates with AD neuropathology). Yet the specificity of these changes to particular MIL subregions is not yet clear, primarily due to limitations in the resolution of imaging techniques. Histological investigations suggest that aging is associated with changes in the dentate gyrus and subiculum, while AD affects the entorhinal cortex and cornu ammonis (CA) hippocampal fields. Recent advances in MRI methods have begun to produce in vivo data of unprecedented resolution (e.g., 500 micrometer resolution-at least twice the resolution of typical research scans), enabling the development of novel methods for the in vivo visualization and quantification of MRI data from MIL subregions. We propose to use these novel high-resolution in vivo MRI methods to investigate the specificity of memory- related functional and structural substrates within MIL subregions in cognitively intact older individuals and in those with MCI, including very mildly symptomatic individuals who do not yet have significant memory impairment (""""""""preMCI""""""""). The primary goal of this research is to determine whether MTL-subregion-specific functional changes can be found in PreMCI before structural changes are detected. Since histologic studies indicate that distinct cellular and pathologic changes within MIL subregions are present in AD and not in normal aging, high-resolution imaging data may enable more precise differentiation of individuals with mild age-related memory changes vs. those with the earliest clinical signs of AD. In addition, high-resolution MIL imaging could begin to bridge the gap between in vivo and histologic data. Ultimately, we hope that these tools will enable earlier identification of minimally symptomatic individuals with AD-related brain changes who could be enrolled in clinical trials of drugs to slow the progression of this devastating disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Hsiao, John
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Bickart, Kevin C; Brickhouse, Michael; Negreira, Alyson et al. (2014) Atrophy in distinct corticolimbic networks in frontotemporal dementia relates to social impairments measured using the Social Impairment Rating Scale. J Neurol Neurosurg Psychiatry 85:438-448
Wolk, David A; Mancuso, Lauren; Kliot, Daria et al. (2013) Familiarity-based memory as an early cognitive marker of preclinical and prodromal AD. Neuropsychologia 51:1094-102
Quiroz, Yakeel T; Stern, Chantal E; Reiman, Eric M et al. (2013) Cortical atrophy in presymptomatic Alzheimer's disease presenilin 1 mutation carriers. J Neurol Neurosurg Psychiatry 84:556-61
Das, Sandhitsu R; Pluta, John; Mancuso, Lauren et al. (2013) Increased functional connectivity within medial temporal lobe in mild cognitive impairment. Hippocampus 23:1-6
Modirrousta, Mandana; Price, Bruce H; Dickerson, Bradford C (2013) Neuropsychiatric symptoms in primary progressive aphasia: phenomenology, pathophysiology, and approach to assessment and treatment. Neurodegener Dis Manag 3:133-146
Greve, Douglas N; Van der Haegen, Lise; Cai, Qing et al. (2013) A surface-based analysis of language lateralization and cortical asymmetry. J Cogn Neurosci 25:1477-92
Bakkour, Akram; Morris, John C; Wolk, David A et al. (2013) The effects of aging and Alzheimer's disease on cerebral cortical anatomy: specificity and differential relationships with cognition. Neuroimage 76:332-44
Domoto-Reilly, Kimiko; Sapolsky, Daisy; Brickhouse, Michael et al. (2012) Naming impairment in Alzheimer's disease is associated with left anterior temporal lobe atrophy. Neuroimage 63:348-55
Bickart, Kevin C; Hollenbeck, Mark C; Barrett, Lisa Feldman et al. (2012) Intrinsic amygdala-cortical functional connectivity predicts social network size in humans. J Neurosci 32:14729-41
Dickerson, Bradford C; Wolk, David A; Alzheimer's Disease Neuroimaging Initiative (2012) MRI cortical thickness biomarker predicts AD-like CSF and cognitive decline in normal adults. Neurology 78:84-90

Showing the most recent 10 out of 40 publications