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.
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