Effect Modifiers of TDP-43-Associated Hippocampal Atrophy Rates in Patients with Alzheimer’s Disease Neuropathological Changes

Abstract

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) 4, Lewy bodies (LBs), amyloid-␤ (A␤), or Braak neurofibrillary tangle (NFT) stage. Methods: In this longitudinal neuroimaging-clinicopathological study of 468 cases with AD neuropathological changes (A␤-positive) that had completed antemortem head MRI, we investigated how age, gender, APOE 4, presence of LBs, A␤, 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 4, 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 4 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.

Concomitant LATE‐NC in Alzheimer's disease is not associated with increased tau or amyloid‐β pathological burden

“…Given that pathologically only LATE-NC status differed between the two cohorts, this may suggest that additional LATE-NC may have an additive detrimental effect on cognitive impairment that is independent of tau pathology. This finding is in agreement with previous longitudinal clinicopathological studies that determined that TDP-43 pathology is associated with cognitive impairment independent of AD pathology and hippocampal sclerosis [53], and the clinical impact of TDP-43 and tau pathology is statistically independent [28] with their clinical effects exhibited at different time points in the disease progression [19]. On the other hand, cognitive decline was not significantly different between the AD/LATE-NC and AD groups indicating the rate of cognitive decline was not accelerated due to the presence of LATE-NC in contrast to a previous clinicopathological study [10].…”

“…Since all of our cases in this study were neuropathologically confirmed AD cases with a Braak stage V/VI, we did not employ this criterion as virtually all of our cases would be classified as type-b. However, TDP type-b was not found to be associated with the robust neuropathological and genetic correlates of AD, such as CERAD neuritic plaques or APOE e4 genotype, which one may expect if TDP-43 and tau are pathologically linked [28]. Therefore, indicating the higher prevalence of type-b inclusions in AD is perhaps reflective of the simultaneous presence of more severe NFT burden.…”

“…For the assessment of LATE-NC, 6 lm paraffin-embedded sections were cut that included the amygdala, subiculum and entorhinal cortex (BA 36,28), dentate gyrus of the posterior hippocampus, occipitotemporal cortex (OTC) (BA 36), inferior temporal cortex (ITC; BA 20) and basal ganglia, that is, putamen, globus pallidus and caudate with associated insular cortex, substantia nigra, midbrain tectum and mid-frontal cortex (BA 8, 9). Sections were mounted onto 4% 3-aminopropyltriethoxysilane (APES)-coated glass slides, and antigen retrieval by microwaving slides in 0.01 ml EDTA for 10 min was performed prior to immunohistochemistry with phosphorylated TDP-43 (antibody phospho-TDP-43; pS0409/410-2; dilution 1:10,000; Cosmo Bio Ltd, Bicester, UK).…”

“…Age at disease onset was significantly associated with AT8-IR measures from the amygdala (q = À0.231, [29] IV, n = 1 IV, n = 1 -V, n = 1 V , n = 3 VI, n = 39 VI, n = 16 Thal Phase [28] 0, n = 0 0 , n = 0 -1, n = 0 1 , n = 0 2, n = 0 2 , n = 0 3, n = 1 3 , n = 1 4, n = 2 4 , n = 3 5, n = 38 5, n = 16 McKeith LB stage [31] Absent, n = 30 Absent, n = 14 -Brain stem, n = 1 Brain stem, n = 1 Amygdala, n = 10 Amygdala, n = 5 VCING [32] Low, n = 37 Low, n = 19 Fisher's, P = 0.466 Moderate, n = 4…”

“…Recently, two distinct subtypes of non-FTLD TDP-43 pathology were reported, namely TDP type-a inclusions, which are not associated with NFTs, and TDP type-b inclusions that are associated with NFTs within the same neurone, of which the latter was associated with AD pathology, specifically hyperphosphorylated tau pathology [25]. NFT/NT burden has been shown to correlate with the cognitive deficits and clinical progression of AD [26], as well as hippocampal atrophy [19,27,28]. Therefore, one may speculate that the interaction of TDP-43 with hyperphosphorylated tau within the neurones may result in synergistic interactions that accelerate the production and aggregation of hyperphosphorylated tau pathology, accounting for the accelerated cognitive decline observed in AD with LATE-NC.…”