Anatomic, Pathologic, and Molecular Signatures of FTLD-TDP type C - ABSTRACT. Neurodegenerative diseases can have common, uncommon, and idiosyncratic manifestations. In contrast, frontotemporal lobar degeneration with transactive response DNA-binding protein type C (TDP-C) shows a consistent and prolonged predilection for the anterior temporal lobe, a region critical for word comprehension on the left-sided hemisphere and non-verbal semantics (e.g., object recognition, contextualization of conduct) on the right. During the past 15 years, the Northwestern Primary Progressive Aphasia (PPA) Research Program has recruited one of the world’s largest cohorts of TDP-C cases. Each case has been deeply-phenotyped and longitudinally imaged and 25 have come to autopsy. In the course of these investigations, we have made important discoveries that have led to a theoretical overview of TDP-C, its distinctions from other forms of FTLD- TDP, its remarkable affinity for the anterior temporal lobe, and its impact on the fundamental process of language comprehension. These studies have raised new questions about TDP-C neuropathology. The current proposal aims to expand on these discoveries in ways that go beyond PPA by encompassing other clinical manifestations of TDP-C, their corresponding hemispheric asymmetry patterns, their distinctive impact on local cortical circuitry, and their relationship to the molecular fingerprints of the anterior temporal lobe. This proposal will benefit from synergies with the overall PPA program and the Northwestern ADRC and will, in turn, enrich both programs. The proposal revolves around three aims. Aim 1 will investigate the neuropathological concordance of TDP-C neuropathology with the asymmetric atrophy patterns seen in PPA versus other major neurobehavioral syndromes, each with a distinct pattern of asymmetric progression. Aim 2 will focus on the microcircuitry of these concordance patterns, namely the impact on inhibitory neurons and the laminar distribution of neurosynaptic perturbations. Aim 3 will address the transcriptomic patterns that potentially earmark the anterior temporal lobe for special vulnerability to TDP-C in each syndrome, each with different asymmetries of vulnerability. Although TDP-C is a relatively rare disease it offers unprecedented opportunities for understanding the general biologic mechanisms of selective vulnerability in neurodegenerative disease. An additional consequential outcome would be to discover druggable protein targets that interfere with the destructive effect of TDP-C on the anterior temporal lobes.
