Cortical and subcortical pathological burden and neuronal loss in an autopsy series of FTLD-TDP-type C

Abstract

Abstract The TDP-43 type C pathologic form of frontotemporal lobar degeneration (FTLD-TDP-type C) is characterized by the presence of immunoreactive TDP-43 short and long dystrophic neurites (DNs), neuronal cytoplasmic inclusions (NCIs), neuronal loss and gliosis (NL/G), and the absence of neuronal intranuclear inclusions (NIIs). FTLD-TDP-type C cases are commonly associated with the semantic variant of primary progressive aphasia (PPA-S) or behavioral variant frontotemporal dementia (bvFTD). Here, we provide detailed characterization of regional distributions of pathologic TDP-43 and NL/G in cortical and subcortical regions in 10 FTLD-TDP-type C cases and investigate the relationship between inclusions and NL/G. Specimens were obtained from the first 10 FTLD-TDP-type C cases accessioned from the Northwestern Alzheimer’s Disease Research Center (PPA-S, N = 7; bvFTD, N = 3). A total of 42 cortical (majority bilateral) and subcortical regions were immunostained with a phosphorylated TDP-43 antibody and/or stained with hematoxylin-eosin. Regions were evaluated for atrophy, and for long DNs, short DNs, NCIs, and NL/G using a semiquantitative 5-point scale. We calculated a “neuron-to-inclusion” score (TDP-C mean score—NL/G mean score) for each region per case to assess the relationship between TDP-type C inclusions and NL/G. PPA cases demonstrated leftward asymmetry of cortical atrophy consistent with the aphasic phenotype. We also observed abundant inclusions and neurodegeneration in both cortical and subcortical regions, with certain subcortical regions emerging as particularly vulnerable to DNs (e.g. amygdala, caudate, and putamen). Interestingly, linear mixed models showed that regions with lowest type C pathology had high neuronal dropout, and conversely, regions with abundant pathology displayed relatively preserved neuronal densities (p < 0.05). This inverse relationship between the extent of TDP-positive inclusions and neuronal loss may reflect a process whereby inclusions disappear as their associated neurons are lost. Together, these findings offer insight into the putative substrates of neurodegeneration in unique dementia syndromes.