Neurocognitive speed associates with frontotemporal lobar degeneration TDP-43 subtypes

Frontotemporal lobar degeneration (FTLD) is pathologically heterogeneous with the TAR DNA binding protein 43 kDa (TDP-43) proteinopathy the most common substrate. Previous work has identified atrophy patterns across TDP-43 subtypes with Type A showing greater frontotemporal and parietal atrophy, Type C predominantly anterior temporal, and Type B predominantly posterior frontal. Despite neuroanatomical correlates of involvement, neuropsychological findings have been inconsistent. The current study utilized broader neurocognitive domains based on aggregated neuropsychological measures to distinguish between subtypes. We hypothesized that patterns of neurocognitive domain impairments would predict FTLD–TDP subtype. Fifty-one patients, aged 38–87, were identified post mortem with pathologically confirmed FTLD with TDP-43. Participants were classified into subtypes A, B, or C. Patients had completed neuropsychological assessments as part of their clinical evaluation. Six cognitive domains were created: Language; Cognitive Speed; Memory; Learning; Visuoperception; and Fluency. Binary logistic regression was conducted. All but three patients could be classified as FTLD–TDP Types A, B, or C: 26 as Type A; nine as Type B; and 13 as Type C. Cognitive Speed scores were associated with Types A and C (p < 0.001 and p = 0.003, respectively). Impaired performances on the Trail Making Test differentiated Types A and C. Worse Boston Naming Test and Logical Memory (Immediate) (p < 0.05) scores also increased the likelihood of Type C phenotype. Findings suggest Cognitive Speed associates with TDP-43 subtypes. Type C also demonstrated language-specific involvement. Differences between TDP-43 subtypes further supports the notion of differences in pathophysiology or topography across these types.