Early Selective Vulnerability of the CA2 Hippocampal Subfield in Primary Age-Related Tauopathy

Abstract

Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.

Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s disease

“…CA2/3, followed by CA4, were observed to have the highest AUC and be the best discriminator between AD and CTE. However, a predominance of CA2 tau is observed in other diseases such as PART, CBD, PSP, and argyrophilic grain disease (AGD) [ 21 , 33 , 40 ]. It is unlikely that CBD, PSP, or AGD are driving the CA2/3 findings in the current study as any case with a comorbid disease diagnosis were excluded from the cohort.…”

Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study

“…Formalin-fixed paraffin embedded (FFPE) tissue from the frontal cortex and hippocampus as well as fresh-frozen tissue from frontal cortex were derived from autopsy brains from a subset of individuals from a previously described collection [61]. Specifically, the cohort included cases from the Oregon Health Sciences University (Portland, OR, USA), Banner Sun Health Research Institute (Sun City, AZ, USA), Emory (Atlanta, GA, USA), Northwestern (Evanston, IL, USA), the University of Pennsylvania (Philadelphia, PA, USA), University of Pittsburgh (Pittsburgh, PA, USA), University of Texas Southwestern Medical Center (Dallas, TX, USA), and the Medical University of Vienna (Vienna, Austria).…”

Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study

“…There are numerous approaches to assessing lesion burden of p-tau and other pathologies [8,26,28,29,38,39,42], including cell counting and stereology [3,4,11,19,25,64]. While each of these approaches have intrinsic advantages, they are limited in that they are labor intensive and for this reason and others, these methods have not been widely adopted in neuropathology laboratories [18,62]. One approach that may have potential to better assess p-tau in PART is using computer-assisted quantitative morphometrics on digital whole slide images, which may be well suited for staging PART.…”