Patterns of amygdala region pathology in LATE-NC: subtypes that differ with regard to TDP-43 histopathology, genetic risk factors, and comorbid pathologies

Abstract

Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) pathology is a hallmark of limbic-predominant age-related TDP-43 encephalopathy (LATE). The amygdala is affected early in the evolution of LATE neuropathologic change (LATE-NC), and heterogeneity of LATE-NC in amygdala has previously been observed. However, much remains to be learned about how LATE-NC originates and progresses in the brain. To address this, we assessed TDP-43 and other pathologies in the amygdala region of 184 autopsied subjects (median age = 85 years), blinded to clinical diagnoses, other neuropathologic diagnoses, and risk genotype information. As previously described, LATE-NC was associated with older age at death, cognitive impairment, and the TMEM106B risk allele. Pathologically, LATE-NC was associated with comorbid hippocampal sclerosis (HS), myelin loss, and vascular disease in white matter (WM). Unbiased hierarchical clustering of TDP-43 inclusion morphologies revealed discernable subtypes of LATE-NC with distinct clinical, genetic, and pathologic associations. The most common patterns were: Pattern 1, with lamina II TDP-43 + processes and preinclusion pathology in cortices of the amygdala region, and frequent LATE-NC Stage 3 with HS; Pattern 2, previously described as type-β, with neurofibrillary tangle-like TDP-43 neuronal cytoplasmic inclusions (NCIs), high Alzheimer's disease neuropathologic change (ADNC), frequent APOE ε4, and usually LATE-NC Stage 2; Pattern 3, with round NCIs and thick neurites in amygdala, younger age at death, and often comorbid Lewy body disease; and Pattern 4 (the most common pattern), with tortuous TDP-43 processes in subpial and WM regions, low ADNC, rare HS, and lower dementia probability. TDP-43 pathology with features of patterns 1 and 2 were often comorbid in the same brains. Early and mild TDP-43 pathology was often best described to be localized in the "amygdala region" rather than the amygdala proper. There were also important shared attributes across patterns. For example, all four patterns were associated with the TMEM106B risk allele. Each pattern also demonstrated the potential to progress to higher LATE-NC stages with confluent anatomical and pathological patterns, and to contribute to dementia. Although LATE-NC showed distinct patterns of initiation in amygdala region, there was also apparent shared genetic risk and convergent pathways of clinico-pathological evolution.

Keywords: DLB; GRN; Lewy; Neuropathology; Nondemented; PART; Preclinical; Tauopathy.

Fig. 1

Regions-of-interest (ROIs) in the amygdala region. A schematic of the amygdala region and the associated ROIs is shown, with parahippocampal gyrus, collateral sulcus (cs) and semiannular sulcus (sas) labeled for reference. Study ROIs are in red, bolded font. Although not study ROIs, insula, ventral claustrum, centromedial nuclear group, and basal forebrain components were assessed for pTDP-43 pathology in all cases when present. Schematic created with BioRender

Fig. 2

Key TDP-43 inclusion morphologies in LATE-NC. Six key TDP-43 inclusion morphologies are shown, with paired pTDP (top row) and TDP-43 IHC (bottom row). As shown, both pTDP and TDP-43 IHC can identify these pathologies. The colored circles adjacent to the morphology labels are placed on the Fig. 1 schematic to indicate their most common anatomic position in the amygdala region

Fig. 3

Patterns of TDP-43 pathology in the amygdala region of patients with LATE-NC (N = 107). Unbiased hierarchical clustering was performed in the publicly available program Morpheus (see Methods for detail). The resulting dendrogram is shown, and the TDP-43 morphologies shown to the right (“NFT-like”, “Round NCI”, etc.) are those illustrated in Fig. 2

Fig. 4

LATE-NC ordered by pTDP-43 severity and grouped by LATE-NC stage. This heat map shows the regional distribution of pTDP-43 pathology in six study ROIs in all subjects with LATE-NC, independent of inclusion morphology. Samples are grouped by LATE-NC stage 1 (top), stage 2 (middle) and stage 3 (bottom). Ordering of cases within each stage is based on the average pTDP-43 inclusion density across the ROIs, ordered from low to high. The density of pTDP-43 inclusion pathology is indicated by the bar at the bottom right of the heat map

Fig. 5

A proposed classification scheme for LATE-NC. Hierarchical clustering identified four patterns of LATE-NC (Patterns 1–4), and one group with combined features of Patterns 1 + 2, and the salient pathologic and clinical features are shown in this schematic. Consistent with the earlier work of Josephs et al. (2019), type-β is applied to the cluster-derived Pattern 2 (β). Also as in that earlier study, type-α refers to non-NFT associated TDP-43 pathology, but only to the FTLD-like lamina II pathology with frequent preinclusions (Pattern 1, or α). Schematic created (in part) with BioRender