The relationship between past medical histories (PMH) and dementia-related neuropathologies is not well understood. Using the National Alzheimer's Coordinating Center (NACC) database, we explored the relationship between patient-reported PMH and various vascular and degenerative neuropathologies. We examined the following PMH: transient ischemic attack (TIA), stroke, traumatic brain injury, seizures, hypertension, cardiovascular events, hypercholesterolemia, B12 deficiency, diabetes mellitus, and thyroid disease. We dichotomized the following neuropathologies: atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy (CAA), Alzheimer disease neuropathology (ADNP), Lewy bodies (LB), hippocampal sclerosis, frontotemporal lobar degeneration (FTLD), and TAR DNA-binding protein-43 (TDP-43). Separate logistic regression models assessed the relationship between the outcome of individual neuropathologies and all PMHs. Additional logistic regressions were stratified by sex to further examine these associations. Hypertension history was associated with an increased likelihood of atherosclerosis (OR = 1.7) and arteriolosclerosis (OR = 1.3), but decreased odds of ADNP (OR = 0.81), CAA (OR = 0.79), and LB (OR = 0.78). History of TIA was associated with an increased likelihood of atherosclerosis (OR = 1.3) and arteriolosclerosis (OR = 1.4) and lower odds of ADNP (OR = 0.72). Seizure history was associated with an increased likelihood of ADNP (OR = 1.9) and lower odds of FTLD (OR = 0.49). Hypertension history was associated with a greater likelihood of vascular pathologies yet a lower likelihood of ADNP and other neurodegenerative pathologies.

The oldest-old, those 85 years and older, are the fastest growing segment of the population and present with the highest prevalence of dementia. Given the importance of neuroimaging measures to understand aging and dementia, the objective of this study was to review neuroimaging studies performed in oldest-old participants. We used PubMed, Google Scholar, and Web of Science search engines to identify in vivo CT, MRI, and PET neuroimaging studies either performed in the oldest-old or that addressed the oldest-old as a distinct group in analyses. We identified 60 studies and summarized the main group characteristics and findings. Generally, oldest-old participants presented with greater atrophy compared to younger old participants, with most studies reporting a relatively stable constant decline in brain volumes over time. Oldest-old participants with greater global atrophy and atrophy in key brain structures such as the medial temporal lobe were more likely to have dementia or cognitive impairment. The oldest-old presented with a high burden of white matter lesions, which were associated with various lifestyle factors and some cognitive measures. Amyloid burden as assessed by PET, while high in the oldest-old compared to younger age groups, was still predictive of transition from normal to impaired cognition, especially when other adverse neuroimaging measures (atrophy and white matter lesions) were also present. While this review highlights past neuroimaging research in the oldest-old, it also highlights the dearth of studies in this important population. It is imperative to perform more neuroimaging studies in the oldest-old to better understand aging and dementia.

Background: Limbic predominant age related TDP-43 encephalopathy (LATE) is a newly proposed term to denote the contribution of transactive response DNA-binding pro-tein of 43 kDa (TDP-43) pathology to dementia at older age. The aim of this work was to study the role of LATE in cognitive impairment and its risk factors in the oldest old (those ≥ 90years old). Methods: 240 participants of The 90+ Study with comprehensive clinical, neuropsychology, and neuropathology data were included. Dementia status, clinical syndrome, and impaired cognitive domains were determined at multidisciplinary post-mortem case conferences blind to autopsy data. Alzheimer’s disease neuropathology (ADNP) was defined as CERAD neuritic plaque score≥2 and Braak neuro-fibrillary tangle stage≥5. We defined LATE as those with at least amygdala and hippocampal TDP-43 pathology (stage>2). We explored the association of LATE and of ADNP with cognition measures by logistic regression ana-lyses adjusting for age, sex, and education. We separately explored the association between medical histories (as potential risk factors) and LATE and ADNP as outcomes adjusting for the above covariates.

Background and objectives

Limbic predominant age-related TAR DNA binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) is a prevalent degenerative pathology in the oldest-old who are the fastest-growing segment of our population with the highest rates of dementia. We aimed to determine the relationship between LATE-NC and cognitive impairment and to identify its potential risk factors by studying its relationship with common past medical histories in an oldest-old cohort.

Methods

Participants from The 90+ Study with longitudinal evaluations and autopsy data were included. Dementia status and impairment in 5 main cognitive domains were determined at postmortem conferences leveraging all clinical and neuropsychological data blind to neuropathologic diagnosis. Medical history information was obtained from patients and their informants. LATE-NC and Alzheimer disease neuropathologic change (ADNC) were considered present in those with TDP-43 pathology in the hippocampus and/or neocortex and those with high likelihood of ADNC according to NIA-AA guidelines, respectively. We examined the association of degenerative pathologies with cognitive outcomes and multiple comparisons-adjusted relationship of medical history variables with LATE-NC and ADNC using logistic regressions adjusted for age at death, sex, and education.

Results

Three hundred twenty-eight participants were included in this study. LATE-NC was present in 32% of the participants. It had a significant association with the presence of dementia (OR 2.8, 95% CI 1.7-4.6) and impairment in memory (OR 3.0, 95% CI 1.8-5.1), language (OR 2.6, 95% CI 1.6-4.3), and orientation (OR 3.5, 95% CI 2.1-5.9). The association with impaired orientation was unique to LATE-NC, and the strength and significance of the other associations were comparable to ADNC. Furthermore, we found that history of osteoarthritis (OR 0.37, adjusted 95% CI 0.21-0.66) and hypertension (OR 0.52, adjusted 95% CI 0.28-0.98) were associated with a reduced likelihood of LATE-NC, but not ADNC.

Discussion

Our results suggest that LATE-NC is a prevalent degenerative pathology in the oldest-old and has significant associations with dementia and impairment in cognitive domains with magnitudes that are comparable to ADNC. We also found that past medical histories of hypertension and osteoarthritis were associated with a lower likelihood of LATE-NC. This might help identify upstream mechanisms leading to this important pathology.

Recent work from our research group has shown that dementia is strongly associated with hippocampal atrophy from in-vivo MRI even after accounting for degenerative neuropathologies. We sought to confirm this finding using ratings of hippocampal atrophy at autopsy and examining their relationship with dementia while also accounting for relevant degenerative neuropathologies. We used data from the National Alzheimer's Coordinating Center (NACC) neuropathology dataset (09/2005-05/2020). Our outcome measure was hippocampal atrophy severity assessed as part of gross findings at autopsy (NPGRHA variable, graded none/mild/moderate/severe). Inclusion criteria were availability of hippocampal atrophy rating, clinical assessment within a year before death, and death at age 65 years or older. For our independent variables we used dementia status and the following dichotomized neuropathologies: Alzheimer's disease neuropathological change (ADNC, high), hippocampal sclerosis (HS), limbic-transitional or neocortical Lewy Bodies (LB), cerebral amyloid angiopathy (CAA, moderate/severe), atherosclerosis (moderate/severe), gross infarcts, microinfarcts, and micro/macro-hemorrhages. We also examined a subset of the participants that had TAR DNA-binding protein 43 (TDP-43) assessed in the hippocampus, and due to the high correlation with HS, we excluded HS from these analyses. Ordinal logistic regressions were used for individual models of the variables of interest as well as for joint models which included dementia and all neuropathologies. All models were adjusted for age at death, sex, years of education, and months from last clinical assessment to death. We report odds ratios (OR). Table-1 summarizes participant characteristics across hippocampal atrophy ratings (N=1148). In the ordinal logistic regressions dementia was the strongest predictor of hippocampal atrophy (OR=6.6 in individual, 3.8 in joint model), followed by HS (OR=4.3 in individual, 3.2 in joint model), then ADNC (OR=3.9 in individual, 2.4 in joint model, Figure-1A,B). Results remained consistent for the TDP-43 subset analysis (N=717, 27% TDP-43 positive in the hippocampus, TDP-43 OR=1.9 for joint model, Figure-1C). In both individual and joint ordinal logistic regressions, dementia was the variable most strongly associated with hippocampal atrophy at autopsy, followed by hippocampal sclerosis, and then ADNC and TDP-43. Therefore, dementia is a significant and strong predictor of hippocampal atrophy, above and beyond common degenerative neuropathologies.

Brain atrophy is associated with degenerative neuropathologies and the clinical status of dementia. Whether dementia is associated with atrophy independent of neuropathologies is not known. In this study, we examined the pattern of atrophy associated with dementia while accounting for the most common dementia-related neuropathologies. We used data from National Alzheimer's Coordinating Center (n = 129) and Alzheimer's Disease Neuroimaging Initiative (n = 47) participants with suitable in vivo 3D-T₁w MRI and autopsy data. We determined dementia status at the visit closest to MRI. We examined the following dichotomized neuropathological variables: Alzheimer's disease neuropathology, hippocampal sclerosis, Lewy bodies, cerebral amyloid angiopathy and atherosclerosis. Voxel-based morphometry identified areas associated with dementia after accounting for neuropathologies. Identified regions of interest were further analysed. We used multiple linear regression models adjusted for neuropathologies and demographic variables. We also examined models with dementia and Clinical Dementia Rating sum of the boxes as the outcome and explored the potential mediating effect of medial temporal lobe structure volumes on the relationship between pathology and cognition. We found strong associations for dementia with volumes of the hippocampus, amygdala and parahippocampus (semi-partial correlations ≥ 0.28, P < 0.0001 for all regions in National Alzheimer's Coordinating Center; semi-partial correlations ≥ 0.35, P ≤ 0.01 for hippocampus and parahippocampus in Alzheimer's Disease Neuroimaging Initiative). Dementia status accounted for more unique variance in atrophy in these structures (∼8%) compared with neuropathological variables; the only exception was hippocampal sclerosis which accounted for more variance in hippocampal atrophy (10%). We also found that the volumes of the medial temporal lobe structures contributed towards explaining the variance in Clinical Dementia Rating sum of the boxes (ranging from 5% to 9%) independent of neuropathologies and partially mediated the association between Alzheimer's disease neuropathology and cognition. Even after accounting for the most common neuropathologies, dementia still had among the strongest associations with atrophy of medial temporal lobe structures. This suggests that atrophy of the medial temporal lobe is most related to the clinical status of dementia rather than Alzheimer's disease or other neuropathologies, with the potential exception of hippocampal sclerosis.

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.

Background

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a clinicopathological construct proposed to facilitate studying TDP-43 pathology in older individuals.

Objective

Our aim was to describe clinical and cognitive characteristics of LATE-NC without Alzheimer's disease neuropathologic change (ADNC) and Lewy body (LB) and to compare this with ADNC and primary age related tauopathy (PART).

Methods

In 364 autopsies of the oldest old of The 90+ Study, we identified those with LATE-NC without ADNC and LB. Control groups were participants with ADNC and PART.

Results

Of 31% of participants who had LATE-NC, only 5 (1.4%) had LATE-NC without ADNC and LB, all of whom had tau. These participants had a gradual and progressive cognitive decline. Four (80%) had dementia at death, a rate that was higher than ADNC (50%) and PART (21.7%). Mean duration of cognitive impairment was twice as long in LATE-NC without ADNC and LB (6.2 years) compared to ADNC (2.9 years) and PART (3 years). LATE-NC without ADNC and LB group had a higher prevalence of syncope, depression, and extrapyramidal signs than the ADNC and PART groups.

Conclusions

Despite the high prevalence of LATE-NC, LATE-NC without ADNC and LB was rare in this large oldest-old cohort, highlighting the very high prevalence of multiple pathologic changes in the oldest old. Slowly progressive cognitive decline, ubiquitous memory impairment, history of syncope and depression, and extrapyramidal signs were prominent features among our LATE-NC without ADNC and LB group.