Multiple system aging‐related tau astrogliopathy with complex proteinopathy in an oligosymptomatic octogenarian

Abstract

The combination of multiple neurodegenerative proteinopathies is increasingly recognized. Together they can potentiate neuronal dysfunction and contribute to complex neurological symptoms. We report an octogenarian female case of multiple extraneural metastases of a rectal carcinoma. She attempted suicide, which ultimately led to cardiorespiratory failure nine days after hospital admission. Apart from the suicide attempt and late‐onset depression, other psychiatric or neurological symptoms were not reported. Unexpectedly, histopathologic examination revealed prominent aging‐related tau astrogliopathy (ARTAG) of all five types (subpial, subependymal, grey and white matter, and perivascular) affecting cortical and subcortical brain regions. This pathology was associated with intermediate Alzheimer's disease neuropathologic change (A2B2C2 score), cerebral amyloid angiopathy, Lewy body‐type α‐synuclein proteinopathy (Braak stage 4), and a multiple system transactivation response DNA‐binding protein of 43 kDa (TDP‐43) proteinopathy also involving the astroglia. In summary, we report a complex and extensive combination of multiple proteinopathies with widespread ARTAG of all five types in a patient who had attempted suicide. Although longitudinal psychometric tests and neuropsychological evaluations were not performed, this report poses the question of thresholds of cognition and pathology load, describes ARTAG affecting unusually widespread brain regions, and supports the notion that complex proteinopathies should be regarded as a frequent condition in the elderly.

Structure-based classification of tauopathies

“…Astroglial tau pathology has been increasingly recognized during aging; these cases have been subsumed under the umbrella term of ARTAG (31), which is characterized by the presence of thorn-shaped and granular/fuzzy astrocytes with 4R tau inclusions (32)(33)(34). Like AGD, ARTAG usually coexists with other tau pathologies.…”

“…Different types of ARTAG can be distinguished in grey and white matter, as well as in subpial, subependymal and perivascular locations (31). We determined the cryo-EM structures of the majority species of tau filaments from the hippocampus of a case of ARTAG (34). Most tau filaments were identical to AGD type 2 and type 3 filaments.…”

“…Abundant 4R tau-immunoreactive argyrophilic grains were in evidence, with some coiled bodies and bush-like astrocytes. ARTAG was identified in an 85-year-old woman with a 1-year history of cancer and depression (34). At autopsy, she had prominent ARTAG (subpial, subependymal, grey matter, white matter and perivascular).…”

Cryo-EM Structures of Amyloid-β 42 Filaments from Human Brain

“…ARTAG was seen in an 85-year-old woman with a 1-year history of cancer and depression (43). Upon neuropathological examination, she had prominent ARTAG (subpial, subependymal, grey matter, white matter and perivascular).…”

Alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy

“…The amounts of aggregated α-synuclein as well as the GCI and neuronal cytoplasmic inclusion (NCI) burden were assessed by α-synuclein immunohistochemistry in the 13 brain regions mentioned above using the 5G4 staining. For semi-quantitative analyses, we used a 4-point scale: 0, absent; 1, mild; 2, moderate; and 3, severe, as previously described [ 22 ].…”