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Principal Investigator  
Principal Investigator's Name: Jeffrey Phillips
Institution: Penn FTD Center, University of Pennsylvania
Department: Neurology
Country:
Proposed Analysis: I propose to use imaging and clinical data from the ADNI study in hypothesis-driven and exploratory analyses of the anatomical progression of amnestic and non-amnestic variants of Alzheimer's disease (AD). This project is supported by a 3-year Alzheimer's Association Research Fellowship. The objective of this study is to test the hypothesis that atypical, non-amnestic presentations of Alzheimer's disease (i.e., with impairments in language, visuospatial, or executive function) are characterized by a distinct anatomical origin of disease and a divergent pattern of disease spread than in typical, amnestic AD. ADNI study data will be used to supplement the typical AD and normal control cohorts. Specific aims of this project are as follows: Aim 1: MRI staging of typical and atypical AD. Aim 1 will use a novel MRI staging method, patterned on our autopsy staging studies, to contrast disease spread in typical, amnestic AD and atypical, non-amnestic AD. While MRI staging in typical AD will recapitulate traditional Braak staging, atypical AD is expected to have a neocortical disease origin with later spread to MTL and hippocampus, consistent with its non-amnestic presentation and characteristic deficits in language, visuospatial function, executive/social function. Aim 2: Longitudinal analysis of neuropsychological change in atypical AD. Aim 2 will validate Aim 1 by comparing longitudinal change in MRI measures and cognitive/behavioral domains for each non-amnestic phenotype, including language (logopenic-variant primary progressive aphasia, lvPPA), visuospatial function (posterior cortical atrophy and corticobasal syndrome, PCA/CBS), and executive/social function (clinical diagnosis of frontal-variant AD, fvAD). Relative to amnestic AD, we predict lvPPA will have a left perisylvian origin associated with faster language decline; PCA/CBS, an occipito-parietal origin associated with faster visuospatial decline; and fvAD, a prefrontal origin associated with steeper executive/social decline. Aim 3: Connectomic analysis of typical and atypical disease networks. Aim 3 will apply graph-theoretical techniques to investigate brain connectivity differences in early- and late-stage patients within disease networks identified by the Aim 1 staging analysis. We predict that spreading disease will be better predicted by local connection strength (measured by GM covariance and WM tract integrity) than by metabolically active hubs (measured by betweenness centrality), consistent with a local-connectivity model of disease spread.
Additional Investigators