ASYMMETRIC NEURODEGENERATION AND LANGUAGE IN PRIMARY PROGRESSIVE APHASIA

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PROJECT SUMMARY / ABSTRACT Primary Progressive Aphasia (PPA) is a dementia of language that emerges on a background of preserved memory. It can be caused by multiple neuropathologic entities, including Alzheimer's disease (AD) and frontotemporal lobar degenerations (FTLD). The one core feature of all PPA variants is the selective and asymmetric neurodegeneration of the language-dominant (usually left) hemisphere. For the past 15 years, the Northwestern PPA Program has enrolled patients for biennial cognitive evaluation, multimodal imaging, and genetic characterization. Biofluids on all patients and brain tissue from those who have come to autopsy have been banked, curated, and shared with the National Alzheimer's Coordinating Center (NACC) and the National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD). This cohort represents what is arguably the world's largest registry of deeply phenotyped PPA patients. During the next cycle of this project, PPA groups will be stratified by neuropathology rather than clinical variant. The three interactive specific aims are to characterize neuropathology-specific fingerprints of asymmetry through multimodal imaging; to identify neuropathology-specific correlates of neurosynaptic disruption, inflammatory markers, gene expression, and their hemispheric asymmetry; and to explore molecular signatures of selective left hemisphere susceptibility and memory resilience through genetic analyses. We will continue prospective enrollment into existing and new projects and develop research methodology for single-subject rather than group studies so that individual differences in brain organization can be taken into account. An overarching theme will be the clinicopathology of asymmetry, which is the single universal core feature of PPA, and which offers a unique setting for investigating the mechanisms of selective vulnerability. The innovative aspects include access to a uniformly investigated unique PPA cohort, availability of autopsy tissue from both hemispheres so that asymmetry can be quantitated, graph theory approaches to network architecture, genetic explorations of asymmetric hemispheric vulnerability, and development of personalized single-subject mapping of the diseased language network. The Northwestern PPA Research Program has made key contributions to research on the neurobiology and cognitive characteristics of PPA by showing that the same syndrome (e.g., PPA) can be caused by multiple neuropathologic entities, that a single disease (e.g., AD) can cause multiple syndromes, and that clinical manifestations are determined by network anatomy rather than molecular pathology. Through this work PPA has become a paradigmatic entity for establishing principles of pathophysiologic heterogeneity in dementia. The aims in this proposal will help to shed additional light on the anatomical tropisms of neurodegenerative diseases, the foundations of hemispheric asymmetry in neurodegeneration, the internal architecture of the language network, and the mechanisms that mediate the resilience of memory function in PPA with AD neuropathology.