Comprehensive assessment of TDP-43 neuropathology data in the National Alzheimer's Coordinating Center database

Abstract

TDP-43 proteinopathy is a salient neuropathologic feature in a subset of frontotemporal lobar degeneration (FTLD-TDP), in amyotrophic lateral sclerosis (ALS-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and is associated with hippocampal sclerosis of aging (HS-A). We examined TDP-43-related pathology data in the National Alzheimer's Coordinating Center (NACC) in two parts: (I) availability of assessments, and (II) associations with clinical diagnoses and other neuropathologies in those with all TDP-43 measures available. Part I: Of 4326 participants with neuropathology data collected using forms that included TDP-43 assessments, data availability was highest for HS-A (97%) and ALS (94%), followed by FTLD-TDP (83%). Regional TDP-43 pathologic assessment was available for 77% of participants, with hippocampus the most common region. Availability for the TDP-43-related measures increased over time, and was higher in centers with high proportions of participants with clinical FTLD. Part II: In 2142 participants with all TDP-43-related assessments available, 27% of participants had LATE-NC, whereas ALS-TDP or FTLD-TDP (ALS/FTLD-TDP) was present in 9% of participants, and 2% of participants had TDP-43 related to other pathologies ("Other TDP-43"). HS-A was present in 14% of participants, of whom 55% had LATE-NC, 20% ASL/FTLD-TDP, 3% Other TDP-43, and 23% no TDP-43. LATE-NC, ALS/FTLD-TDP, and Other TDP-43, were each associated with higher odds of dementia, HS-A, and hippocampal atrophy, compared to those without TDP-43 pathology. LATE-NC was associated with higher odds for Alzheimer's disease (AD) clinical diagnosis, AD neuropathologic change (ADNC), Lewy bodies, arteriolosclerosis, and cortical atrophy. ALS/FTLD-TDP was associated with higher odds of clinical diagnoses of primary progressive aphasia and behavioral-variant frontotemporal dementia, and cortical/frontotemporal lobar atrophy. When using NACC data for TDP-43-related analyses, researchers should carefully consider the incomplete availability of the different regional TDP-43 assessments, the high frequency of participants with ALS/FTLD-TDP, and the presence of other forms of TDP-43 pathology.

Keywords: Alzheimer’s disease; Amyotrophic lateral sclerosis; Dementia; Frontotemporal lobar degeneration; Hippocampal sclerosis of aging; Limbic predominant age-related TDP-43 encephalopathy neuropathologic change; National Alzheimer’s coordinating center; TDP-43.

Fig. 1

Flow diagrams for a the inclusion/exclusion of participants b assigning of TDP-43 categories and c LATE-NC stages. Numbers are shown as: N (percentage of previous) for (a) and N (percentage of total) in (b, c). NP neuropathology. Path. Pathology, ALS/FTLD-TDP amyotrophic lateral sclerosis or frontotemporal lobar degeneration with TDP-43 pathology, LATE-NC limbic-predominant age-related TDP-43 encephalopathy neuropathologic change, EC/ITC entorhinal cortex/inferior temporal cortex

Fig. 2

Availability of TDP-43 related pathology measures in NACC database by year of death of participant. NACC National Alzheimer’s Coordinating Center, HS-A hippocampal sclerosis of aging, FTLD-TDP frontotemporal lobar degeneration with TDP-43 pathology, ALS amyotrophic lateral sclerosis, Reg. regional, Amyg. amygdala, Hipp. hippocampus, EC/ITC entorhinal cortex/inferior temporal cortex, NeoC. neocortex, SC spinal cord

Fig. 3

Availability of TDP-43 related pathology measures in National Alzheimer’s Coordinating Center (NACC) participants. a Venn diagram of availability across the various TDP-43 pathology measures in participants with version 10 + pathology forms (N = 4319). b Venn diagram of availability of TDP-43 assessment by region in participants with at least one regional assessment available (N = 3324). NACC National Alzheimer’s Coordinating Center, HS-A hippocampal sclerosis of aging, FTLD-TDP frontotemporal lobar degeneration with TDP-43 pathology, ALS amyotrophic lateral sclerosis, Reg. regional, Amyg. amygdala, Hipp. hippocampus, EC/ITC entorhinal cortex/inferior temporal cortex, NeoC. neocortex

Fig. 4

Venn diagrams for presence of regional TDP-43 inclusions by pathological category ALS/FTLD-TDP (a), LATE-NC (b), and Other TDP-43 (c). ALS/FTLD-TDP amyotrophic lateral sclerosis or frontotemporal lobar degeneration with TDP-43 pathology, LATE-NC limbic-predominant age-related TDP-43 encephalopathy neuropathologic change, Amyg. amygdala, Hipp. hippocampus, EC/ITC entorhinal cortex/inferior temporal cortex, NeoC. neocortex

Fig. 5

Odds ratios for various clinical diagnoses and other neuropathologic changes with regards to TDP-43 categories, ALS/FTLD-TDP, LATE-NC, and Other TDP-43, compared to those without TDP-43. Logistic regressions adjusted for age at death, sex, education, and interval between last visit and death. Dots represent odds ratios and error bars represent 95% confidence intervals. LATE-NC limbic-predominant age-related TDP-43 encephalopathy neuropathologic change, ALS/FTLD-TDP amyotrophic lateral sclerosis or frontotemporal lobar degeneration with TDP-43 pathology, AD Alzheimer’s disease, PPA primary progressive aphasia, bvFTD behavioral variant of frontotemporal dementia, HS-A hippocampal sclerosis of aging, ADNC Alzheimer’s disease neuropathologic change, CAA cerebral amyloid angiopathy

Fig. 6

Proportional Euler diagrams depicting co-occurrence of ALS/FTLD-TDP, LATE-NC, Alzheimer’s disease neuropathologic change (ADNC), and Lewy bodies (LB), in overall cohort excluding participants with “Other TDP-43” or without ADNC or LB ratings (N = 2057). ALS/FTLD-TDP amyotrophic lateral sclerosis or frontotemporal lobar degeneration with TDP-43 pathology, LATE-NC limbic-predominant age-related TDP-43 encephalopathy neuropathologic change, ADNC Alzheimer’s disease neuropathologic change, LB Lewy bodies