Abstract Objective: To highlight the high prevalence of TDP-43 pathology, also known as limbic predominant age related TDP-43 encephalopathy (LATE), and its strong association with dementia in the oldest old. Background: The oldest old are the fastest growing segment of our population with the highest prevalence of dementia. By year 2050, more than 50% of dementia sufferers in the US will belong to this age group. TDP-43 pathology is a frequent but less studied pathology in this age. We describe findings from The 90+ Study, a longitudinal clinical and autopsy study of participants aged 90 years and older, that shows TDP-43 pathology might be as important as Alzheimer’s disease (AD) in this age. Design/Methods: 241 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 multi-disciplinary post-mortem conferences blind to autopsy data. AD neuropathology (ADNP) was defined as CERAD score for neuritic plaques ≥2 and Braak stage for neurofibrillary tangles ≥5. TDP-43 pathology was considered present in those with at least amygdala and hippocampal TDP-43. Logistic regression analyses adjusting for age, sex, and education, explored the association between ADNP, TDP-43, and dementia, clinical diagnosis of AD, and memory impairment. Results: 125 participants (52%) died with dementia (Mean age at death: 98.1, 75% female). Of these, 33% had TDP-43 and 40% had ADNP. TDP-43 was as important a predictor of dementia and clinical diagnosis of AD at death as ADNP (For dementia outcome: TDP-43 OR: 3.0 vs. ADNP OR: 2.6; For clinical AD outcome: TDP OR: 3.5 vs. ADNP OR: 3.4). Both pathologies independently predicted memory impairment (TDP-43 OR: 4.7; ADNP OR: 4.1). Conclusions: Our results suggest TDP-43 pathology is as important as ADNP in people over 90, the age group that will have the greatest number of dementia sufferers.

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.

Background: Alzheimer’s disease pathology (AD) is an important cause of neurodegeneration and brain atrophy. Non-AD mechanisms can also cause neurodegeneration alone or in conjunction with AD. Harboring combination of AD and non-AD pathologies leads to greater cognitive impairment and dementia. Here, we examined the hypothesis that the association of amyloid and tau burden from positron emission tomography (PET) with brain volumes from magnetic resonance imaging (MRI) is weaker in those with dementia compared to those with mild cognitive impairment (MCI) or normal cognition. Method: We used data from participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who had either florbetapir amyloid PET (N=1320) of flortaucipir tau PET (N=833, 535 of whom had both). We examined the association between volumes of brain structures (FreeSurfer-v7) and standardized uptake value ratios (SUVr) for amyloid (summary cortical region, normalized to whole cerebellum) and tau (meta-temporal region, normalized to inferior cerebellar gray matter) separately, using linear regressions adjusting for age, sex, and education. We report results in overall groups and by cognitive status (normal, MCI, dementia). We display semi-partial correlations (sr, thresholded at Puncorrected<0.05), as measures of effect size. Result: Table-1 summarizes participant characteristics. The effect of amyloid on brain volumes was modest in the overall cohort, with associations strongest for inferior/middle temporal, inferior parietal, entorhinal, hippocampus, and amygdala regions (sr∼-0.2, P<0.001 all). In those with dementia, however, there were no distinct associations between amyloid and brain atrophy (Figure-1). For tau, associations in the overall cohort were similarly strongest for inferior/middle temporal, inferior parietal, entorhinal, hippocampus, and amygdala regions (sr∼-0.3, P<0.001 all). In those with dementia, associations remained strong for inferior/middle temporal regions (sr∼-0.3, P<0.001) but tau was not associated with hippocampus volumes (left, sr=-0.05, P=0.6; right, sr=-0.12, P=0.14, Figure-2); this divergence is further highlighted in select regions (inferior temporal and hippocampus) in Figure-3. Conclusion: We found that the relationship between amyloid and tau burden and atrophy was stronger in the overall cohort than in participants with dementia. This was particularly the case for medial temporal lobe structures. The effect of non-AD pathologies on medial temporal lobe atrophy is a potential explanation for the observed results.

Abstract Objective: To test the hypothesis that memory impairment in the oldest old has different neural substrates in those with and without Alzheimer’s pathology Background: Memory impairment is the commonest feature of dementia in the oldest old. Unlike younger age groups, non-Alzheimer’s pathologies, such as hippocampal sclerosis, are a common cause of memory impairment and dementia in the oldest old. Lack of reliable biomarkers has hampered the diagnosis of these important pathologies during life. Design/Methods: 36 participants from The 90+ Study with mild dementia (CDR-total-score=0.5) completed volumetric T1 weighted brain MRI scan and California Verbal Learning Test-Delayed Recall (CVLT-DR) (mean interval=65 days). Volumes of CA1 and CA3 hippocampal subfields and cortical thickness of temporal lobe regions were estimated using freesurfer software. A subset of 27 participants also completed florbetapir amyloid PET scans that were dichotomized (positive/negative) by visual read. Regression analysis, adjusted for age, gender, and education, assessed the association between CVLT-DR as outcome and atrophy pattern. Results: In the whole group (N=36), there was a trend of significant association between CVLT-DR and volume of CA1 subfield (estimate:0.35, p=0.08). No association was found between CVLT-DR and CA3 volume or temporal lobe cortical thicknesses. Restricting the analysis to the amyloid negative group (N=12, MMSE mean=23.4), there was a significant association between CVLT-DR and CA1 volume (estimate:0.45, p=0.04) but no association with CA3 volume or temporal lobe cortical thicknesses. In the amyloid positive group (N=15, MMSE mean=24.1), CVLT-DR was not associated with any of the hippocampal volumes. Rather, there was a positive association between CVLT-DR and cortical thickness of the left fusiform region (estimate:0.4, p=0.04). Conclusions: Our results suggest that memory impairment in the oldest old might be due to atrophy of different brain regions in those with and without Alzheimer’s pathology. This differential atrophy may serve as an imaging biomarker for non-Alzheimer’s pathologies such as hippocampal sclerosis.

Abstract Objective: To identify the relationship between hippocampal sclerosis (HS) and other common degenerative brain pathologies and to identify neuropsychological impairments associated with HS Background: Hippocampal sclerosis of ageing is a common neuropathological finding in the oldest-old who die with dementia. HS has a strong association with dementia (5 times stronger than Alzheimer’s disease (AD)) and during life, is commonly misdiagnosed as AD. Previous studies have consistently shown a relationship between TDP-43 and HS and conflicting associations between HS and other degenerative pathologies. Design/Methods: We studied 143 participants from the 90+ study, a population based study of people aged 90 and older (the oldest-old). Neuropathology data was available for HS, Alzheimer’s disease, TDP-43, Lewy body disease (LBD), arteriolosclerosis, atherosclerosis, and infarcts. We used Neuropsychological data closest to onset of cognitive impairment or death (for cognitively normal participants). We used regression analyses to study the associations between HS and other neuropathologies and to study the effect of neuropathologies on global and domain specific cognitive measures. Results: 96% (21/22) of participants with HS had dementia at death. In the whole sample, there was no difference in demographics between those with and without HS. Logistic regressions revealed TDP-43 (OR: 20.1, p<0.001) and LBD (OR: 8.7, p=0.007) were associated with HS and arteriolosclerosis (OR: 2.65, p=0.08) trended toward significance. However, there was no association between HS and AD (OR: 1.1, p=0.6). Multiple linear regression revealed that HS, TDP-43 and AD, were independently associated with lower scores on a global cognitive measure (3MS). Linear regressions also revealed associations between HS and TDP-43 with impaired verbal memory and semantic knowledge, and between AD and construction apraxia. Conclusions: In the oldest-old, HS is associated with TDP-43 and LBD but not AD. Differential involvement of cognitive domains in HS and TDP-43 vs. AD might help diagnosing HS during life.

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.

Objective: To determine prevalence of dementia-related neuropathologic changes and examine their association with dementia risk and severity in centenarians, and compare findings with nonagenarians from the same cohort. Background: Centenarians worldwide are projected to increase 50-fold by 2100 with dementia incidence estimated ~40%. Brain autopsy studies in this population are highly limited. Design/Methods: Participants were individuals who agreed to autopsy from The 90+ Study, a longitudinal study of aging. Cognitive diagnoses were assigned during a multidisciplinary conference blinded to autopsy results. Using standardized protocols, dementia-related neuropathologic changes (NCs) were assessed blinded to clinical information and dichotomized for analyses: +Alzheimer’s disease (AD) neuropathologic change (ADNC;intermediate/high), +cerebral amyloid angiopathy (moderate/severe), +arteriosclerosis (moderate/severe), +Lewy body disease (limbic/neocortical), +TDP-43 (hippocampal/cortical), +age-related tau astrogliopathy (ARTAG;present), +microinfarcts (≥2), and +hippocampal sclerosis (present). Mini-Mental State Exam (MMSE) scores nearest to death were used to examine dementia severity. Prevalence and associated odds of dementia were determined for each NC and for the presence of multiple NCs. Results: 388 participants (100 centenarians and 288 nonagenarians) with completed brain autopsies were included. In centenarians, ADNC was most prevalent (75%; vs. 71% in nonagenarians), followed by arteriosclerosis (69%; vs. 55% in nonagenarians) and ARTAG (66%; vs. 60% in nonagenarians). In centenarians, arteriosclerosis (69%) and TDP-43 (39%) were significantly more prevalent compared to nonagenarians (55% and 28% respectively; P=0.01 and P=0.05 respectively). 83% centenarians had 2+NCs and number of NCs was strongly associated with dementia risk. Odds ratio increased from 2.9 (95% Confidence interval (CI):0.49–16.9) for 2NCs, to 12.7 (95%CI:2.34–68.31) for 3, and 63.8 (95%CI:8.78–463.67) for 4NCs. Number of NCs was also associated with dementia severity. Conclusions: Prevalence of dementia-related NCs is exceptionally high in centenarians and greater for arteriosclerosis and TDP-43 compared to nonagenarians. Multiple NCs are typical in centenarians and strongly associated with cognitive impairment, with risk and severity increasing with higher numbers of NCs. Disclosure: Mr. Neuville has nothing to disclose. Ms. Ho has nothing to disclose. The institution of Dr. Sajjadi has received research support from NIH. Dr. Biswas has received research support from European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Actions' fellowship (Grant agreement number 722046). The institution of Dr. Corrada has received research support from NIH. The institution of Dr. Kawas has received research support from NIH.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a recently described neuropathological construct associated with dementia. This study aimed to investigate in an autopsy study, LATE-NC and its associations with potential estrogen-related risk factors collected about 30 years before death. Participants were part of The 90+ Study and had, as part of the Leisure World Cohort Study, provided information on menstrual and reproductive variables and details of use of estrogen replacement therapy (ERT). No menstrual and reproductive variable showed an association with LATE-NC. Use of ERT, especially long-term use (15+ years) and more recent use (within 1 year of completing the questionnaire), was associated with reduced risk. The odds were significantly lower for long-term (0.39, 95% confidence interval [CI]: 0.16-0.95) and recent use (0.39, 95% CI: 0.16-0.91) compared with no use. In conclusion, we found that women who reported long-term ERT in their 50s and 60s had a significantly reduced odds of harboring LATE-NC when they died in the 10th and 11th decades of their lives. Our study adds to the existing literature reporting seemingly protective effect of peri- and postmenopausal ERT against neurodegenerative dementia.

Introduction

Hippocampal sclerosis of aging (HS) is a common pathology often misdiagnosed as Alzheimer's disease. We tested the hypothesis that participants with HS would have a magnetic resonance imaging (MRI)-detectable hippocampal pattern of atrophy distinct from participants without HS, both with and without Alzheimer's disease neuropathology (ADNP).

Methods

Query of the National Alzheimer's Coordinating Center database identified 198 participants with MRI and autopsy. Hippocampal subfields were segmented with FreeSurfer v6. Analysis of covariance for subfield volumes compared HS+ participants to those without HS, both with ADNP (HS-/ADNP+) and without (HS-/ADNP-).

Results

HS+ participants (N = 27, 14%) showed atrophied cornu ammonis 1 (CA1; left P < .001, η_p²  = 0.14; right P = .001, η_p²  = 0.09) and subiculum (left P < .001, η_p²  = 0.139; right P = .001, η_p²  = 0.085) compared to HS-/ADNP+ (N = 100, 51%). Compared to HS-/ADNP- (N = 71, 36%), HS+ also had atrophy in subiculum (left P < .001, η_p²  = 0.235; right P = .002, η_p²  = 0.137) and CA1 (left P < .001, η_p²  = 0.137; right P = .006, η_p²  = 0.070).

Discussion

Subiculum and CA1 atrophy from clinical MRI may be a promising in vivo biomarker for HS.