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Abstract
Objectives Alzheimer disease (AD) shows a broad array of clinical presentations, but the mechanisms underlying these phenotypic variants remain elusive. Aging-related astrogliopathy (ARTAG) is a relatively recent term encompassing a broad array of tau deposition in astroglia outside the range of traditional tauopathies. White matter thorn-shaped astrocyte (WM-TSA) clusters, a specific ARTAG subtype, has been associated with atypical language presentation of AD in a small study lacking replication. To interrogate the impact of WM-TSA in modifying clinical phenotype in AD, we investigated a clinicopathologic sample of 83 persons with pure cortical AD pathology and heterogeneous clinical presentations.
Methods We mapped WM-TSA presence and density throughout cortical areas and interrogated whether WM-TSA correlated with atypical AD presentation or worse performance in neuropsychological testing.
Results WM-TSA was present in nearly half of the cases and equally distributed in typical and atypical AD presentations. Worsening language and visuospatial functions were correlated with higher WM-TSA density in language-related and visuospatial-related regions, respectively. These findings were unrelated to regional neurofibrillary tangle burden. Next, unsupervised clustering divided the participants into 2 groups: a high–WM-TSA (n = 9) and low–WM-TSA (n = 74) pathology signature. The high–WM-TSA group scored significantly worse in language but not in other cognitive domains.
Conclusions The negative impact of WM-TSA pathology to language and possibly visuospatial networks suggests that WM-TSA is not as benign as other ARTAG types and may be explored as a framework to understand the mechanisms and impact of astrocytic tau deposition in AD in humans.
Glossary
- AD=
- Alzheimer disease;
- ARTAG=
- aging-related tau astrogliopathy;
- ATAC=
- argyrophilic thorn-shaped astrocyte clusters;
- CDR=
- Clinical Dementia Rating;
- FTLD=
- frontotemporal lobar degeneration;
- lvPPA=
- logopenic variant primary progressive aphasia;
- MAC=
- Memory and Aging Center;
- MCI=
- mild cognitive impairment;
- NFT=
- neurofibrillary tangles;
- PPA=
- primary progressive aphasia;
- SE=
- standard error;
- TDP-43=
- TAR DNA binding protein-43;
- TSA=
- thorn-shaped astrocytes;
- UCSF=
- University of California, San Francisco;
- WM-TSA=
- white matter thorn-shaped astrocytes
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally to this work.
- Received April 18, 2019.
- Accepted in final form October 8, 2019.
- © 2020 American Academy of Neurology
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