Amygdalar and hippocampal volume loss in limbic-predominant age-related TDP-43 encephalopathy.

Limbic-predominant age-related TAR-DNA binding protein (TDP-43) encephalopathy neuropathological change (LATE-NC) refers to the aberrant accumulation of TDP-43 in the brains of aging individuals either in isolation or in combination with neurodegenerative disease. LATE-NC is most commonly found in the amygdala and hippocampus and is associated with progressive amnestic decline in individuals with a neurodegenerative disease. Since LATE-NC can only be diagnosed post-mortem, there is a need for pathology-validated neuroimaging biomarkers for LATE-NC. In the current study we assessed MRI-measured amygdalar and hippocampal volume in brain donors with Alzheimer's disease or Lewy Body diseases with and without co-occurring LATE-NC pathology. Post-mortem in-situ 3D-T1 3T-MRI data were collected for 51 cases (27 Alzheimer's disease and 24 Lewy Body Disease) of whom 17 had post-mortem confirmed LATE-NC and 34 were non-LATE-NC (matched on age, sex, and neurodegenerative disease). Amygdalar and hippocampal volumes were calculated using FreeSurfer. Within-subject amygdalar and hippocampal tissue sections were immunostained for TDP-43 (pTDP-43), phosphorylated tau (AT8), amyloid-β (4G8) and α-synuclein (pSer129). Positive cell density (TDP-43 and α-synuclein) and area percentage immunoreactivity (p-tau and amyloid-β) outcome measures were quantified using QuPath. Group differences between LATE-NC and non-LATE-NC donors were assessed with univariate analyses and correlations were assessed with linear regression models, all adjusting for intracranial volume and post-mortem delay and if applicable for primary pathology. Brain donors with LATE-NC showed significantly lower amygdalar (-26%, p=.014) and hippocampal (-19%, p=.003) volumes than non-LATE-NC brain donors, even when correcting for regional phosphorylated tau, amyloid-β and α-synuclein burden. These group differences remained significant in the Alzheimer's disease group (amygdala -24%, p=.028; hippocampus -21%, p=.002), but in the Lewy body diseases group only the amygdala was smaller in LATE-NC donors compared to non-LATE-NC donors (18%, p=.030). These results suggest that severity of TDP-43 burden plays a role in amygdala and hippocampus atrophy on MRI, even when correcting for effects of primary pathology. This study proposes that exceptionally low amygdalar and hippocampal volumes could indicate LATE-NC and that this may serve as a potential biomarker for in-vivo studies.