Asymmetry of Hippocampal Tau Pathology in Primary Age-Related Tauopathy and Alzheimer Disease

Abstract

Primary age-related tauopathy (PART) is a neurodegenerative entity defined as neurofibrillary degeneration generally restricted to the medial temporal region (Braak stage I–IV) with complete or near absence of diffuse and neuritic plaques. Symptoms range in severity but are generally milder and later in onset than in Alzheimer disease (AD). Recently, an early predilection for neurofibrillary degeneration in the hippocampal CA2 subregion has been demonstrated in PART, whereas AD neuropathologic change (ADNC) typically displays relative sparing of CA2 until later stages. In this study, we utilized a semiquantitative scoring system to evaluate asymmetry of neurofibrillary degeneration between left and right hippocampi in 67 PART cases and 17 ADNC cases. 49% of PART cases demonstrated asymmetric findings in at least one hippocampal subregion, and 79% of the asymmetric cases displayed some degree of CA2 asymmetry. Additionally, 19% of cases revealed a difference in Braak score between the right and left hippocampi. There was a significant difference in CA2 neurofibrillary degeneration (p = 0.0006) and CA2/CA1 ratio (p < 0.0001) when comparing the contralateral sides, but neither right nor left was more consistently affected. These data show the importance of analyzing bilateral hippocampi in the diagnostic evaluation of PART and potentially of other neurodegenerative diseases.

The relationship between hippocampal amyloid beta burden and spatial distribution of neurofibrillary degeneration

“…To compare the Aperio ImageScope‐generated quantitative measurements against previously established semiquantitative measurements, we established a direct correlation between Thal phase and overall Aβ burden PPP (r = 0.69; P < 0.0001; Figure S3A in supporting information), Braak stage and overall p‐tau burden PPP (r = 0.57; P < 0.0001; Figure S3B), and CA2/CA1 p‐tau ratio (determined by previous semiquantitative scoring systems 7,21 ) and quantitative CA2/CA1 p‐tau ratio (r = 0.64; P < 0.0001; Figure S3C), confirming the validity of both techniques. These data also suggest, however, that there is a great deal of variation in hippocampal Aβ burden in Thal phase 2 and p‐tau burden in Braak stages III and IV, suggesting that the quantitative measures may be better at capturing the full extent of hippocampal pathology than more topographical measurements such as Thal phase and Braak stage (Figure S3A‐B).…”

TDP‐43 Pathology Exacerbates Cognitive Decline in Primary Age‐Related Tauopathy

“…11,26 The severity of cognitive impairment often observed in individuals with PART is surprising given the low level and localized nature of the tangle pathology, even considering greater than expected hippocampal CA2 region involvement 27 or medial temporal left-right asymmetry. 28 We therefore hypothesized that other age-related copathologies such as LATE-NC or vascular pathology may play a significant role in the cognitive decline of these patients. We also hypothesized that, in the presence of low levels of tau pathology, amyloid may contribute to cognitive decline independently of other copathologies.…”

Severe cerebrovascular pathology of the first supercentenarian to be autopsied in the world

“…Neurofibrillary degeneration with a predilection for the hippocampal CA2 subregion, a feature of primary age-related tauopathy (PART), was not clearly observed. 20 In addition, AGs and extracellular ghost tangles, which are a characteristic feature in age-related NFTs, were mild. 11,[21][22][23][24] The mildness of tau pathological changes in neurons, in other words the resistance of neurons to tau pathologies, may be a factor in her exceptional longevity.…”