The goal of this project is to better define the specific nature of memory loss in patients with Amnestic Mild Cognitive Impairment (a-MCI), a group enriched in patients with early Alzheimer's disease (AD) pathology. This work will aid in discrimination of memory loss due to AD pathology versus that of aging. Dual-process models of memory argue that recognition is subserved by recollection and familiarity. Both are impaired with early AD while only recollection is affected by aging. Little is known about the integrity of these processes in a-MCI. Therefore, recollection and familiarity will be measured by behavioral means in healthy elderly subjects and patients with a-MCI and mild AD. These estimates will then be related to (1) event-related potential (ERP) correlates of these processes and (2) medial temporal and cortical volumes using quantitative MRI techniques. As the earliest pathology of AD involves medial temporal structures, it is hypothesized that behavioral, ERP, and MRI measures will reflect involvement of this region in a-MCI and predict conversion to AD in longitudinal assessment. Specifically, familiarity, a form of memory thought dependent on perirhinal cortex, is expected to be impaired in a-MCI relative to elderly controls. Further, ERP correlates of recollection will differ between healthy aging and a-MCI/AD, reflecting prefrontal dysfunction in the former and hippocampal/entorhinal pathology in the latter. Relation of behavioral estimates of recollection and familiarity with volumetric MRI and ERP will provide further understanding of the anatomic and electrophysiologic bases of these processes and the impact of early AD pathology on them. The training plan for this Career Development Award application will build upon a foundation produced by the candidate's prior work in the study of memory in AD using behavioral and ERP techniques. In addition to enhancing these skills, the candidate will learn a new modality of inquiry, quantitative structural MRI. Training in such a multi-modality approach will allow for the candidate to address scientific questions in a novel and flexible manner as he becomes an independent investigator. Alzheimer's disease is already a tremendous public health burden which is expected to grow dramatically in the next 30 to 40 years. Patients with minimal impairment may benefit the most from potential disease modifying interventions. Thus, the pursuit of tools for early diagnosis, as proposed here, is critical. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
7K23AG028018-04
Application #
7691871
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Hsiao, John
Project Start
2006-09-30
Project End
2011-07-31
Budget Start
2008-11-15
Budget End
2009-07-31
Support Year
4
Fiscal Year
2008
Total Cost
$145,800
Indirect Cost
Name
University of Pennsylvania
Department
Neurology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Xie, Long; Pluta, John B; Das, Sandhitsu R et al. (2017) Multi-template analysis of human perirhinal cortex in brain MRI: Explicitly accounting for anatomical variability. Neuroimage 144:183-202
Wolk, David A; Das, Sandhitsu R; Mueller, Susanne G et al. (2017) Medial temporal lobe subregional morphometry using high resolution MRI in Alzheimer's disease. Neurobiol Aging 49:204-213
Gertje, Eske Christiane; Pluta, John; Das, Sandhitsu et al. (2016) Clinical Application of Automatic Segmentation of Medial Temporal Lobe Subregions in Prodromal and Dementia-Level Alzheimer's Disease. J Alzheimers Dis 54:1027-1037
Wisse, L E M; Kuijf, H J; Honingh, A M et al. (2016) Automated Hippocampal Subfield Segmentation at 7T MRI. AJNR Am J Neuroradiol 37:1050-7
Das, Sandhitsu R; Mancuso, Lauren; Olson, Ingrid R et al. (2016) Short-Term Memory Depends on Dissociable Medial Temporal Lobe Regions in Amnestic Mild Cognitive Impairment. Cereb Cortex 26:2006-17
Yushkevich, Paul A; Pluta, John B; Wang, Hongzhi et al. (2015) Automated volumetry and regional thickness analysis of hippocampal subfields and medial temporal cortical structures in mild cognitive impairment. Hum Brain Mapp 36:258-87
Das, Sandhitsu R; Pluta, John; Mancuso, Lauren et al. (2015) Anterior and posterior MTL networks in aging and MCI. Neurobiol Aging 36 Suppl 1:S141-50, S150.e1
Negash, Selam; Kliot, Daria; Howard, Darlene V et al. (2015) Relationship of contextual cueing and hippocampal volume in amnestic mild cognitive impairment patients and cognitively normal older adults. J Int Neuropsychol Soc 21:285-96
Xie, Long; Pluta, John; Wang, Hongzhi et al. (2014) Automatic clustering and thickness measurement of anatomical variants of the human perirhinal cortex. Med Image Comput Comput Assist Interv 17:81-8
Da, Xiao; Toledo, Jon B; Zee, Jarcy et al. (2014) Integration and relative value of biomarkers for prediction of MCI to AD progression: spatial patterns of brain atrophy, cognitive scores, APOE genotype and CSF biomarkers. Neuroimage Clin 4:164-73

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