Primary age-related tauopathy (PART): a common pathology associated with human aging

Abstract

We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.

Fig. 1

Primary age-related tauopathy (PART): gross pathology and low-power photomicrographs. (a) A formalin-fixed left hemisphere from a 103-year-old woman reveals enlargement of the inferior horn of lateral ventricle and severe medial temporal atrophy. Only mild neocortical atrophy is present. (b) A Luxol fast blue-counterstained hematoxylin-eosin section (LHE) shows atrophy of the medial temporal lobe. (c) Phospho-tau (p-tau; AT8)-immunolabeled sections highlight marked tauopathic changes predominantly in the hippocampus and entorhinal cortex. (d) For comparison, a case with advanced AD demonstrates a more severe tauopathy extending into the temporal neocortex.

Fig. 2

Primary age-related tauopathy (PART): histopathology. The neuropathology corresponds to Braak stages I-IV, with involvement of the hippocampal formation (a-c are nearly serial sections from the hippocampus of the same patient) as shown with Luxol Fast Blue-counterstained hematoxylin-eosin (LHE) (a), and p-tau (AT8) immunohistochemistry (b). However, unlike cases with AD, Aβ immunohistochemistry (c) shows minimal or no staining. Gallyas silver impregnation reveals many “ghost tangles” in the hippocampal formation (d), here without amyloid plaques. A key difference between AD and PART pathology is that, by definition, advanced AD (e) shows extensive hyperphosphorylated tau (p-tau) in neocortical areas such as the prefrontal cortex (Brodmann area 9), whereas PART pathology spares the neocortex (f). Scale bar in a = 1 mm for (a-c), scale bar in d = 100 μm, and scale bar in e = 5 mm for (e, f). CA1-4 denote the hippocampal subfields; DG, dentate gyrus.

Fig. 3

The NFTs of PART resemble those of AD by immunohistochemistry, biochemistry, and ultrastructure. (a, b) NFTs in PART reveal immunoreactivity with both 3R and 4R anti-tau monoclonal antisera (RD3 and RD4 respectively). Scale bar = 200 μm for a, b. (c) Immunoblot using polyclonal antisera targeting total tau (tau C) shows a banding pattern similar to that in AD (from ref [122] with permission). (d) The tau fibrils (paired helical filaments) in PART show similar ultrastructural features and periodicity as in AD. Scale bar = 100 nm.