Language and spatial dysfunction in Alzheimer disease with white matter thorn-shaped astrocytes

Neurology. 2020 Mar 31;94(13):e1353-e1364. doi: 10.1212/WNL.0000000000008937. Epub 2020 Jan 30.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / complications
  • Alzheimer Disease / pathology*
  • Astrocytes / pathology*
  • Brain / pathology
  • Cross-Sectional Studies
  • Female
  • Humans
  • Language Disorders / etiology*
  • Language Disorders / pathology
  • Male
  • Middle Aged
  • Phenotype
  • Spatial Behavior / physiology*
  • White Matter / pathology*