Argyrophilic thorny astrocyte clusters in association with Alzheimer’s disease pathology in possible primary progressive aphasia

Abstract

Although most cases of primary progressive aphasia (PPA) have one of the varieties of frontotemporal lobar degeneration (FTLD) as their pathological substrate, a subset shows Alzheimer's disease (AD) pathology. We report that all eight cases in our clinic diagnosed as possible PPA, on account of the presence of episodic memory diYculties in addition to severe language impairment at the onset of disease, showed AD pathology. Neither focal accentuation of AD pathology nor vascular lesions in language-related areas was observed. Seven of these eight patients showed large argyrophilic thorny astrocyte clusters (ATAC) in the fronto-temporo-parietal cortex and subcortical white matter. The intensely tau immunoreactive astrocytes in ATAC were morphologically similar to the perivascular, subpial, and subependymal astrocytes in elderly brains, but ATAC diVer from the latter by the cortical and subcortical location, widespread distribution outside the medial temporal lobe, and intense argyrophilia. The location of ATAC was related to neither local variations in the load of AD pathology, nor the myelin density of white matter. ATAC were not seen in a comparison group of six cases of AD without a prominent aphasia syndrome. Because of the similarity of astrocytes in ATAC to those seen independently of AD pathology in several subtypes of FTLD and two reported cases of PPA we hypothesize that they are a marker of a pathological process concurrent with AD, and related to the focality of the clinical presentation.

Mesial Temporal Astrocyte Tau Pathology in the MRC-CFAS Ageing Brain Cohort

“…This was associated with 64-and 68-kD bands of Sarkosyl insoluble tau (similar to the band pattern in progressive supranuclear palsy and corticobasal degeneration) with a predominance of 4R tau revealed by dephosphorylation. However, the morphology of these astrocytes differed from those in the clusters described by Munoz et al [36], in having finer processes similar to tufted astrocytes.…”

“…There is evidence that focal accumulations of TSA in cortex and white matter, which have been designated 'argyrophilic thorny astrocyte clusters' , are distinct from those in a subpial location. Furthermore, in contrast to the age-relationship of subpial TSA, the former have been associated with primary progressive aphasia due to Alzheimer's pathology [36]. Wakabayashi et al [37] also described a case of primary progressive aphasia associated with glial pathology.…”

A critical review of chronic traumatic encephalopathy

“…In an unselected sample of 2,332 autopsies between age 1 and 100, 89% of those under age 30 (93 total) had tau depositions . Astrocytic tau, subpial tau, subependymal tau, tau in superficial cortical neurons, tau in the medial temporal lobe, and tau in the brainstem tegmentum and spinal cord all occur with age and in AD (Braak and Braak, 1991;Dugger et al, 2013;Munoz et al, 2007;Nishimura et al, 1995;Serrano-Pozo et al, 2011;Thom et al, 2011). The presence of NFTs in the absence of Aβ plaques has recently been termed "primary age-related tauopathy," and in these people the NFTs are mostly found in structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (Crary et al, 2014).…”

Astrogliopathy in Tauopathies

“…However, some tau-containing astrocytes are found in different tauopathies-for example, TSAs occur in aging, AGD, AD, PSP and CBD [14,19,[67][68][69][70][71][72], and in traumatic chronic encephalopathy [73]. Granular/fuzzy astrocytes are seen in the elderly and ARTAG [26,70], but also in other tauopathies such as in PSP [37].…”

“…However, some tau-containing astrocytes are found in different tauopathies-for example, TSAs occur in aging, AGD, AD, PSP and CBD [14,19,[67][68][69][70][71][72], and in traumatic chronic Astrocytic plaques in corticobasal degeneration (CBD), stained with 4Rtau, P-tauThr181, AT8 (P-tau Ser202-Thr205) and antibody PHF1 (P-tauSer396-Ser404). Paraffin sections slightly counterstained with hematoxilin, bar = 25 µm.…”