Clinical, anatomic, and pathologic spread of semantic language impairment in the type c variant of frontotemporal lobar degeneration due to TDP-43 (TDP-c)

The National Institute on Aging awarded Northwestern University $148,614 under the Aging Research program (CFDA 93.866) on February 15, 2026, to conduct longitudinal research characterizing the clinical, anatomic, and pathologic relationships underlying semantic language impairment in the Type C variant of frontotemporal lobar degeneration due to TDP-43 (TDP-C).

The research examines semantic primary progressive aphasia (PPA-S), a dementia syndrome marked by decline in word knowledge and atrophy of the anterior temporal lobe in the left language hemisphere. Nearly 90 percent of PPA-S cases show TDP-C pathology at autopsy. The study will use longitudinal neuropsychological testing to identify the anatomic signature of semantic language impairment progression in PPA-S due to TDP-C, hypothesizing that progression is defined by progressive atrophy along the temporal lobe of the left language hemisphere. The research aims to clarify relationships between clinical symptoms, brain atrophy patterns, and underlying pathological substrates, examining anatomic language networks, mechanisms of neurotoxicity, and principles of selective vulnerability in this disease model.

Work is performed in Illinois. The award runs through January 31, 2029. Northwestern University's Sponsored Research Division administers the grant as the parent recipient organization.

Abstract

Neurodegenerative diseases are currently defined by the clinical symptoms observed antemortem (i.e., dementia syndrome), patterns of anatomic atrophy, and cellular and molecular pathology confirmed postmortem. A key challenge in this field is the fact that a single dementia syndrome can be caused by multiple pathologies, and the same pathology can manifest as multiple dementia syndromes. The "type c" variant of frontotemporal lobar degeneration due to TDP (TDP-c) pathology is unique. TDP-c shows a strong affinity for the anterior temporal lobe (ATL), a brain region critical for word knowledge. TDP-c also has an uncommonly tight coupling with semantic primary progressive aphasia (PPA-s), a dementia syndrome defined by initial decline primarily in semantic (i.e., word knowledge) abilities and atrophy of the ATL in the left language hemisphere; nearly 90% of PPA-s cases show TDP-c at death. The association of selective ATL atrophy, TDP- c pathology, and semantic language impairment in PPA-s offers an ideal paradigm to examine anatomic language networks, mechanisms of neurotoxicity, and principles of selective vulnerability. A central hypothesis is that atrophy patterns in PPA-s mirror underlying neurodegenerative changes due to TDP-c, leading to dysfunction in neurocognitive networks critical for semantics. The proposed research will characterize and clarify relationships between clinical symptoms, atrophy, and underlying pathological substrates in PPA-s due to TDP- c. Aim 1 of this study focuses on identifying the anatomic signature unique to semantic language impairment progression seen in PPA-s due to TDP-c. IT is hypothesized that this progression is defined by progressive atrophy along the temporal lobe of the left language hemisphere. Longitudinal neuropsychological testing will categorize TDP-c individuals into discrete stages of semantic language impairment. Volume loss will be assessed using voxel-based morphometry, comparing whole brain volume and specific regions of interest (rois) along the temporal lobe in TDP-c participants to a cognitively healthy group at and between impairment stages. The goal of aim 2 is to examine the clinicopathologic relationship between antemortem patterns of atrophy and postmortem pathologic markers in the temporal lobe in PPA-s. IT is expected that regional and hemispheric densities of markers will mirror the aphasic phenotype and atrophy pattern in PPA-s. Using whole hemisphere sections, pathologic inclusions, neuronal and synaptic integrity, and neuroinflammatory (microglia) markers will be quantified in bilateral rois used in aim 1 using unbiased stereology and digital pathology methods. This project will occur within the northwestern university alzheimer's disease research center, a multidisciplinary, international PPA referral center that holds the world's largest cohort of TDP-c participants with extensive longitudinal clinical, neuroimaging, and neuropathologic data. The public health impact of this study is significant, as studies of TDP-c have the potential to address questions about dysfunction due to neurodegenerative pathology and inform future development of disease-specific biomarkers and therapeutic targets.