Citations

Background: Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with hippocampal atrophy in Alzheimer’s disease (AD), but whether the association is modified by other factors is unknown. Objective: To evaluate whether the associations between TDP-43 and hippocampal volume and atrophy rate are affected by age, gender, apolipoprotein E ( APOE) ɛ4, Lewy bodies (LBs), amyloid-β (Aβ), or Braak neurofibrillary tangle (NFT) stage. Methods: In this longitudinal neuroimaging-clinicopathological study of 468 cases with AD neuropathological changes (Aβ-positive) that had completed antemortem head MRI, we investigated how age, gender, APOE ɛ4, presence of LBs, Aβ, TDP-43, and Braak NFT stages are associated with hippocampal volumes and rates of atrophy over time. We included field strength in the models since our cohort included 1.5T and 3T scans. We then determined whether the associations between hippocampal atrophy and TDP-43 are modified by these factors using mixed effects models. Results: Older age, female gender, APOE ɛ4, higher field strength, higher TDP-43, and Braak NFT stages were associated with smaller hippocampi. Rate of atrophy was greater with higher TDP-43 and Braak NFT stage, but lower in older patients. The association of TDP-43 with greater rate of atrophy was enhanced in APOE ɛ4 carriers ( p = 0.04). Conclusion: Neurodegenerative effects of TDP-43 seem to be independent of most factors except perhaps APOE in cases with AD neuropathological changes. TDP-43 and tau appear to behave independently of one another.

AbstractIntroductionComparison of tau (flortaucipir) positron emission tomography (FTP‐PET) to autopsy is important to demonstrate the relationship of FTP‐PET to neuropathologic findings.MethodsAutopsies were performed on 26 participants who had antemortem FTP‐PET. FTP‐PET standardized uptake value ratios (SUVRs) were compared to autopsy diagnoses and Braak tangle stage. Quantitative tau burden was compared to regional FTP‐PET signal.ResultsParticipants with Braak stages of IV or greater had elevated FTP‐PET signal. FTP‐PET was elevated in participants with Alzheimer's disease. An FTP‐PET SUVR cut point of 1.29 was determined to be optimal. Quantitative measurements of hippocampal and temporal lobe tau burden were highly correlated to FTP‐PET signal (rho's from 0.61 to 0.70, P ≤ .02).DiscussionElevated FTP‐PET reflects Braak IV or greater neuropathology. Participants with primary age‐related tauopathy and hippocampal sclerosis did not show elevated FTP‐PET signal. Secondary neuropathologic diagnoses of Alzheimer's disease neuropathologic change can lead to borderline elevated FTP‐PET signal.

Abstract BRCA1 plays an important roles in several biological events during the DNA damage response (DDR). Recently, some reports have indicated that BRCA1 dysfunction is involved in the pathogenesis of Alzheimer disease (AD). Furthermore, it has also been reported that BRCA1 accumulates within neurofibrillary tangles (NFTs) in the AD brain. In this study, we examined the immunohistochemical distribution of BRCA1 and another DDR protein, p53-Binding Protein 1 (53BP1), in AD, Pick disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration, and frontotemporal dementia with parkinsonism linked to chromosome 17. In control subjects, neither BRCA1 nor phosphorylated BRCA1 (pBRCA1; Ser1524) immunoreactivity was observed in neurons or glial cells; and that for pBRCA1 (Ser1423) and 53BP1 were slightly detected in neuronal nuclei. The immunoreactivity for both BRCA1 and pBRCA1 (Ser1423) was localized within phosphorylated tau inclusions in all tauopathies, whereas that for pBRCA1 (Ser1524) was mainly associated with Pick bodies in PiD and to a lesser extent with NFTs in AD. On the other hand, 53BP1-immunoreactive deposits tended to be increased in the nucleus of neurons in AD and PSP compared with those in control cases. Our results suggest that DDR dysfunction due to cytoplasmic sequestration of BRCA1 could be involved in the pathogenesis of tauopathies.