Characterizing Limbic-Predominant Age-Related TDP-43 Encephalopathy Without Alzheimer's Disease and Lewy Body Dementia in the Oldest Old: A Case Series.

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.

Longitudinal hippocampal atrophy in hippocampal sclerosis of aging.

Hippocampal sclerosis of aging (HS-A) is a common degenerative neuropathology in older individuals and is associated with dementia. HS-A is characterized by disproportionate hippocampal atrophy at autopsy but cannot be diagnosed during life. Therefore, little is known about the onset and progression of hippocampal atrophy in individuals with HS-A. To better understand the onset and progression of hippocampal atrophy in HS-A, we examined longitudinal hippocampal atrophy using serial MRI in participants with HS-A at autopsy (HS-A+, n = 8) compared to participants with limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) without HS-A (n = 13), Alzheimer's disease neuropathologic change (ADNC) without HS-A or LATE-NC (n = 16), and those without these pathologies (n = 7). We found that participants with HS-A had lower hippocampal volumes compared to the other groups, and this atrophy preceded the onset of dementia. There was also some evidence that rates of hippocampal volume loss were slightly slower in those with HS-A. Together, these results suggest that the disproportionate hippocampal atrophy seen in HS-A may begin early prior to dementia.

Association of vascular and degenerative brain pathologies and past medical history from the National Alzheimer's Coordinating Center Database.

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.

Utility of MRI in the identification of hippocampal sclerosis of aging.

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, ηp2  = 0.14; right P = .001, ηp2  = 0.09) and subiculum (left P < .001, ηp2  = 0.139; right P = .001, ηp2  = 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, ηp2  = 0.235; right P = .002, ηp2  = 0.137) and CA1 (left P < .001, ηp2  = 0.137; right P = .006, ηp2  = 0.070). DISCUSSION: Subiculum and CA1 atrophy from clinical MRI may be a promising in vivo biomarker for HS.