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.
Highlights
It is widely recognized that abnormal hyperphosphorylated tau (p-tau) deposition is a ubiquitous feature of the aging human brain, observed in both cognitively normal subjects and in those with a range of clinical features, including cognitive, motor and psychiatric symptomsIida et al acta neuropathol commun (2021) 9:134[35]
The term aging-related tau astrogliopathy (ARTAG), which was described in recent consensus criteria on various patterns of astrocytic p-tau observed in aging, has been especially helpful for differentiating age-related changes from chronic traumatic encephalopathy (CTE), both of which have perivascular p-tau deposits, but with differences in cell types involved [36, 40]
We found that computer-assisted morphometrics used to capture p-tau burden in the hippocampus proper and combined region were significantly associated with cognitive impairment in primary age-related tauopathy (PART) (p < 0.05 for both cases)
Summary
It is widely recognized that abnormal hyperphosphorylated tau (p-tau) deposition is a ubiquitous feature of the aging human brain, observed in both cognitively normal subjects and in those with a range of clinical features, including cognitive, motor and psychiatric symptomsIida et al acta neuropathol commun (2021) 9:134[35]. Tauopathies can be differentiated by the neuroanatomical regionality of p-tau aggregates, cell type involvement (i.e., neurons versus glia), preferential isoform accumulation, and filament ultrastructure. Based upon these differentiating features, validated neuropathological diagnostic consensus criteria have been devised and, in some cases, undergone revision. The introduction of criteria for primary age-related tauopathy (PART) to describe individuals who develop AD-type neurofibrillary pathology with or without dementia in the absence of significant amyloid deposition helped to better define this entity and differentiated it from AD [15]. Understanding age-related tauopathy is of critical importance in the context of diagnosis and staging of all the tauopathies given its extremely high prevalence and importance as a comorbidity in essentially all studies evaluating tauopathy
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