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Frontal white matter hyperintensities, clasmatodendrosis and gliovascular abnormalities in ageing and post-stroke dementia

Lookup NU author(s): Dr Aiqing Chen, Dr Rufus Akinyemi, Dr Yoshiki Hase, Dr Michael FirbankORCiD, Michael Ndung'U, Dr Lucy Craggs, Dr Kazuo Washida, Professor Alan ThomasORCiD, Dr Tuomo Polvikoski, Dr Louise Allan, Arthur Oakley, Professor John O'Brien, Dr Masafumi Ihara, Professor Raj KalariaORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

White matter hyperintensities as seen on brain T2-weighted magnetic resonance imaging are associated with varying degrees of cognitive dysfunction in stroke, cerebral small vessel disease and dementia. The pathophysiological mechanisms within the white matter accounting for cognitive dysfunction remain unclear. With the hypothesis that gliovascular interactions are impaired in subjects with high burdens of white matter hyperintensities, we performed clinicopathological studies in post-stroke survivors, who had exhibited greater frontal white matter hyperintensities volumes that predicted shorter time to dementia onset. Histopathological methods were used to identify substrates in the white matter that would distinguish post-stroke demented from post-stroke non-demented subjects. We focused on the reactive cell marker glial fibrillary acidic protein (GFAP) to study the incidence and location of clasmatodendrosis, a morphological attribute of irreversibly injured astrocytes. In contrast to normal appearing GFAP + astrocytes, plasmatodendrocytes were swollen and had vacuolated cell bodies. Other markers such as aldehyde dehydrogenase 1 family, member L1 (ALDH1L1) showed cytoplasmic disintegration of the astrocytes. Total GFAP + cells in both the frontal and temporal white matter were not greater in post-stroke demented versus post-stroke non-demented subjects. However, the percentage of clasmatodendrocytes was increased by 42-fold in subjects with post-stroke demented compared to post-stroke non-demented subjects (P = 0.026) and by 11-fold in older controls versus young controls (P50.023) in the frontal white matter. High ratios of clasmotodendrocytes to total astrocytes in the frontal white matter were consistent with lower Mini-Mental State Examination and the revised Cambridge Cognition Examination scores in post-stroke demented subjects. Double immunofluorescent staining showed aberrant co-localization of aquaporin 4 (AQP4) in retracted GFAP + astrocytes with disrupted end-feet juxtaposed to microvessels. To explore whether this was associated with the disrupted gliovascular interactions or blood–brain barrier damage, we assessed the co-localization of GFAP and AQP4 immunoreactivities in post-mortem brains from adult baboons with cerebral hypoperfusive injury, induced by occlusion of three major vessels supplying blood to the brain. Analysis ofthe frontal white matter in perfused brains from the animals surviving 1–28 days after occlusion revealed that the highest intensity of fibrinogen immunoreactivity was at 14 days. At this survival time point, we also noted strikingly similar redistribution of AQP4 and GFAP + astrocytes transformed into clasmatodendrocytes. Our findings suggest novel associations between irreversible astrocyte injury and disruption of gliovascular interactions at the blood–brain barrier in the frontal white matter and cognitive impairment in elderly post-stroke survivors. We propose that clasmatodendrosis is another pathological substrate, linked to white matter hyperintensities and frontal white matter changes, which may contribute to post-stroke or small vessel disease dementia.


Publication metadata

Author(s): Chen A, Akinyemi RO, Hase Y, Firbank MJ, Ndung'u MN, Foster V, Craggs LJL, Washida K, Okamoto Y, Thomas AJ, Polvikoski TM, Allan LM, Oakley AE, O'Brien JT, Horsburgh K, Ihara M, Kalaria RN

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2016

Volume: 139

Issue: 1

Pages: 242-258

Print publication date: 01/01/2016

Online publication date: 14/12/2015

Acceptance date: 29/09/2015

Date deposited: 06/01/2016

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/brain/awv328

DOI: 10.1093/brain/awv328


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Funding

Funder referenceFunder name
Alzheimer's Research (ARUK)
Alzheimer's Society
ART as part of the Brains for Dementia Research Project
ESRC
LLHW
MRC
Newcastle University
SENSHIN Medical Research Foundation, Osaka, Japan
BBSRC
EPSRC
Great Britain Sasakawa Foundation, London, UK
International Brain Research Organization (IBRO)
Newcastle Centre for Brain Ageing and Vitality
Newcastle NIHR Biomedical Research Centre in Ageing and Age Related Diseases award
G0400074UK MRC
G0500247Medical Research Council (MRC)
R277/0213Dunhill Medical Trust UK

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