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

Abstract

Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aβ) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progress extensively to neocortical regions. Given this restricted pathoanatomical pattern and variable symptomatology, there is a need to reexamine and improve upon how PART is neuropathologically assessed and staged. We performed a retrospective autopsy study in a collection (n = 174) of post-mortem PART brains and used logistic regression to determine the extent to which a set of clinical and neuropathological features predict cognitive impairment. We compared Braak staging, which focuses on hierarchical neuroanatomical progression of AD tau and Aβ pathology, with quantitative assessments of neurofibrillary burden using computer-derived positive pixel counts on digitized whole slide images of sections stained immunohistochemically with antibodies targeting abnormal hyperphosphorylated tau (p-tau) in the entorhinal region and hippocampus. We also assessed other factors affecting cognition, including aging-related tau astrogliopathy (ARTAG) and atrophy. We found no association between Braak stage and cognitive impairment when controlling for age (p = 0.76). In contrast, p-tau burden was significantly correlated with cognitive impairment even when adjusting for age (p = 0.03). The strongest correlate of cognitive impairment was cerebrovascular disease, a well-known risk factor (p < 0.0001), but other features including ARTAG (p = 0.03) and hippocampal atrophy (p = 0.04) were also associated. In contrast, sex, APOE, psychiatric illness, education, argyrophilic grains, and incidental Lewy bodies were not. These findings support the hypothesis that comorbid pathologies contribute to cognitive impairment in subjects with PART. Quantitative approaches beyond Braak staging are critical for advancing our understanding of the extent to which age-related tauopathy changes impact cognitive function.

Keywords: ARTAG; Aging; Braak; Dementia; PART.

Fig. 1

Comparison of amyloid and tau pathology in primary age-related tauopathy (PART) versus Alzheimer disease (AD). a Immunohistochemical staining using antisera to hyperphosphorylated tau in an AD brain shows marked hyperphosphorylated tau (p-tau)-containing neurofibrillary tangles (NFT) in the hippocampus which extends past the collateral sulcus into the parahippocampal gyrus and other neocortical regions. b, c Subjects with mild to severe PART have elevated p-tau levels in the hippocampus predominantly restricted to the medial temporal lobe. d, e, f Subjects with AD neuropathologic change have abundant Aβ-containing plaques in neocortical structures, whereas those with PART have sparse or none. These neuropathologic changes in AD and PART are seen in association with varying degree of cognitive impairment ranging from cognitively normal to demented

Fig. 2

Distribution of age, Braak neurofibrillary tangle (NFT) stage and cognitive status. a The number of normal and cognitively impaired subjects across the age spectrum. b The number of cognitively normal and impaired subjects by Braak stage. c The number of subjects across the aging spectrum by Braak stage

Fig. 3

Computer-assisted morphometrics to assess pathological tau burden. a, b Quantitative assessment of hyperphosphorylated tau (p-tau) burden was performed on whole slide images of the hippocampus stained for p-tau (AT8) using immunohistochemistry. Positive pixel counts were determined in two regions (hippocampus proper and entorhinal region). Results were normalized to the total area assessed. A third summary score of the total p-tau burden of the medial temporal lobe was calculated by summing positive pixels in both. c High power image shows high intensity in red, medium intensity in yellow and negative staining in blue. d Parallel plot showing the relationship between Braak stage and the computer morphometric quantification of p-tau using the normalized medial temporal lobe (hippocampus and entorhinal region). Scale bar = 150 μm

Fig. 4

Pathological tau burden in normal and cognitively impaired subjects across the aging spectrum. a–c Generalized linear models of age versus tau burden show significant differences between cognitively normal and cognitively impaired subjects in the hippocampus proper (p = 0.047), and combined entorhinal region and hippocampus regions (p < 0.048), but not in the entorhinal region alone (p = 0.07). d Generalized linear model of age vs Braak NFT staging did not show significant differences between cognitively normal and cognitively impaired subjects (p = 0.73)