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Severe white matter astrocytopathy in CADASIL

Lookup NU author(s): Dr Yoshiki HaseORCiD, Dr Aiqing Chen, Dr Lucinda Craggs, Yumi Yamamoto, Lizzie Gemmell, Arthur Oakley, Dr Viktor Korolchuk, Professor Raj KalariaORCiD


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© 2018 International Society of Neuropathology. Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by strategic white matter (WM) hyperintensities on MRI. Pathological features include WM degeneration, arteriolosclerosis, lacunar infarcts, and the deposition of granular osmiophilic material. Based on the hypothesis that the gliovascular unit is compromised, we assessed the nature of astrocyte damage in the deep WM of CADASIL subjects. Methods: We evaluated post-mortem brains from CADASIL, cerebral small vessel disease, similar age cognitively normal and older control subjects. Standard immunohistochemical, immunofluorescent, and unbiased stereological methods were used to evaluate the distribution of astrocytes, microvessels, and autophagy markers in five different brain regions. Results: Compared to the controls, the deep WM of CADASIL subjects overall showed increased numbers of glial fibrillary acidic protein (GFAP)-positive clasmatodendritic astrocytes (P=0.037) and a decrease in the percentage of normal appearing astrocytes (P=0.025). In accord with confluent WM hyperintensities, the anterior temporal pole contained abundant clasmatodendritic astrocytes with displaced aquaporin 4 immunoreactivity. Remarkably, we also found strong evidence for the immunolocalization of autophagy markers including microtubule-associated protein 1, light chain 3 (LC3), and sequestosome 1/p62 and Caspase-3 in GFAP-positive clasmatodendritic cells, particularly within perivascular regions of the deep WM. LC3 was co-localized in more than 90% of the GFAP-positive clasmatodendrocytes. Conclusions: Our novel findings show astrocytes undergo autophagy-like cell death in CADASIL, with the anterior temporal pole being highly vulnerable. We propose astrocytes transform from normal appearing type A to hypertrophic type B and eventually to clasmatodendritic type C cells. These observations also suggest the gliovascular unit of the deep WM is severely impaired in CADASIL.

Publication metadata

Author(s): Hase Y, Chen A, Bates LL, Craggs LJL, Yamamoto Y, Gemmell E, Oakley AE, Korolchuk VI, Kalaria RN

Publication type: Article

Publication status: Published

Journal: Brain Pathology

Year: 2018

Volume: 28

Issue: 6

Pages: 832-843

Print publication date: 01/11/2018

Online publication date: 09/12/2018

Acceptance date: 14/05/2018

ISSN (print): 1015-6305

ISSN (electronic): 1750-3639

Publisher: Wiley-Blackwell Publishing, Inc.


DOI: 10.1111/bpa.12621

PubMed id: 29757481


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