Space-occupying brain lesions, trauma-related tau astrogliopathy, and ARTAG: a report of two cases and a literature review

Abstract

Astrocytes with intracellular accumulations of misfolded phosphorylated tau protein have been observed in advanced-stage chronic traumatic encephalopathy (CTE) and in other neurodegenerative conditions. There is a growing awareness that astrocytic tau inclusions are also relatively common in the brains of persons over 70 years of age—affecting approximately one-third of autopsied individuals. The pathologic hallmarks of aging-related tau astrogliopathy (ARTAG) include phosphorylated tau protein within thorn-shaped astrocytes (TSA) in subpial, subependymal, perivascular, and white matter regions, whereas granular-fuzzy astrocytes are often seen in gray matter. CTE and ARTAG share molecular and histopathologic characteristics, suggesting that trauma-related mechanism(s) may predispose to the development of tau astrogliopathy. There are presently few experimental systems to study the pathobiology of astrocytic-tau aggregation, but human studies have made recent progress. For example, leucotomy (also referred to as lobotomy) is associated with a localized ARTAG-like neuropathology decades after the surgical brain injury, suggesting that chronic brain injury of any type may predispose to later life ARTAG. To examine this idea in a different context, we report clinical and pathologic features of two middle-aged men who came to autopsy with large (> 6 cm in greatest dimension) arachnoid cysts that had physically displaced and injured the subjects’ left temporal lobes through chronic mechanical stress. Despite the similarity of the size and location of the arachnoid cysts, these individuals had dissimilar neurologic outcomes and neuropathologic findings. We review the evidence for ARTAG in response to brain injury, and discuss how the location and molecular properties of astroglial tau inclusions might alter the physiology of resident astrocytes. These cases and literature review point toward possible mechanism(s) of tau aggregation in astrocytes in response to chronic brain trauma.

Tauopathies: new perspectives and challenges

“…In Olmsted County, the incidence of PSP and CBS (corticobasal syndrome) increased over time, being 2.6 per 100,000 person-years and 0.4 per 100,000 person-years respectively [22], while another study found similar prevalence between them (around10.84/100,000) [23]. Most of patients are diagnosed at the age of 78 (70)(71)(72)(73)(74) for PSP, 75-79 for CBS [23]) with median survival time around 6 years [22].…”

Enhanced expression of autophagy‐related p62 without increased deposits of neurodegeneration‐associated proteins in glioblastoma and surrounding tissue – An autopsy‐based study

“…Recently, two patients with arachnoid cysts and a history of repetitive concussions were described to have extensive ARTAG and CTE‐pathology. The authors suggest that chronic mechanical stress could represent another trigger of astrocytic tau pathology [ 39 ]. In our study about one third of glioblastoma patients exhibited mild ARTAG, but the frequency and distribution did not differ from both control groups.…”

Aging-Related Tau Astrogliopathy in Aging and Neurodegeneration

“…It has also recently been suggested that TSAs might be related to trauma while GFAs relate to neurodegeneration. Indeed, during a small case study of two individuals with large arachnoid cysts it was found that TSA pathology had resulted from long-term mechanical stress, and it is proposed that these inclusions may be different from neurodegenerative-associated ARTAG in the form of GFAs [ 89 ]. Further investigation in larger cohorts of cases of mechanical stress would be needed to answer this question.…”

“…The results demonstrated that tau propagation in HEK cells required pairing of tau isoforms between the inoculum and the recipient substrate, meaning that propagation only occurs between cells expressing like-for-like tau [ 98 ]. Thus, there are currently two propagation hypotheses for ARTAG development, the first where neurons release tau which is taken up by nearby astrocytes and the second where astrocytes upregulate tau expression and kinases which lead to hyperphosphorylation and spread to other cells- see Figure 3 [ 89 ]. Whilst there is convincing support from cellular and animal models for the former hypothesis, this mode of propagation is not supported in disorders such as PiD where 4R ARTAG exists in association with 3R neuronal and astrocyte inclusions [ 78 ].…”