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.

Keywords: Alzheimer disease; Braak; CA1; CA2; Neurofibrillary tangles; Primary age-related tauopathy; Thal.

FIGURE 1.

Bar graphs demonstrating a significantly higher level of p-tau-positive neurofibrillary degeneration between ADNC and PART in the entorhinal, CA1, CA3, and CA4 regions of the hippocampi (p < 0.0001 in all cases), but no significant difference was found between ADNC and PART in overall CA2 p-tau burden (p = 0.4705) (A). There is a significant difference in total CA2/CA1 ratio between total PART and ADNC cases (p = 0.0003), between the PART and ADNC cases on the side with the more severe p-tau burden (p = 0.002), and between the sides with less and more severe p-tau burden within the PART group (p < 0.0001) (B). There was a significant difference in p-tau pathology only in the CA2 region (p = 0.0006) and CA4 region (p = 0.0034) of PART cases between the sides with more and less severe p-tau pathology (C), however, there is no significant difference in p-tau-positive neurofibrillary degeneration between right and left sides in any region in either disease process (D).

FIGURE 2.

p-Tau (AT8) staining of bilateral hippocampi from 2 representative cases of PART, with hippocampal overview and higher magnification of entorhinal cortex, CA1, and CA2 hippocampal, demonstrating variable asymmetry in CA2 (example case #1) and entorhinal cortex, CA1, and CA2 (example case #2). Scale bars for hippocampal overview panels = 4 mm, all other scale bars = 300 µm.