title: Frontal white matter hyperintensities, clasmatodendrosis and gliovascular abnormalities in ageing and post-stroke dementia.
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, clasmatodendrocytes 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 >2-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 (P < 0.023) 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 of the 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.
authors.affiliation: 1 Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, UK.
authors.forename: Aiqing
authors.initials: A
authors.lastname: Chen
authors.affiliation: 1 Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, UK.
authors.forename: Rufus O
authors.initials: RO
authors.lastname: Akinyemi
authors.affiliation: 1 Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, UK.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hase
authors.affiliation: 1 Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Firbank
authors.affiliation: 2 Institute of Primate Research, National Museums of Kenya, Kenya.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Ndung'u
authors.affiliation: 1 Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Foster
authors.affiliation: 1 Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, UK.
authors.forename: Lucy J L
authors.initials: LJ
authors.lastname: Craggs
authors.affiliation: 1 Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, UK.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Washida
authors.affiliation: 1 Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, UK.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: 1 Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, UK.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Thomas
authors.affiliation: 1 Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, UK.
authors.forename: Tuomo M
authors.initials: TM
authors.lastname: Polvikoski
authors.affiliation: 1 Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, UK.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Allan
authors.affiliation: 1 Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, UK.
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Oakley
authors.affiliation: 1 Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, UK.
authors.forename: John T
authors.initials: JT
authors.lastname: O'Brien
authors.affiliation: 3 Centre for Neuroregeneration, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Horsburgh
authors.affiliation: 4 Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
authors.affiliation: 1 Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle Upon Tyne, UK raj.kalaria@ncl.ac.uk.
authors.forename: Raj N
authors.initials: RN
authors.lastname: Kalaria
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology*; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D001812:Blood-Brain Barrier / Q000473:pathology; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000473:pathology; D003704:Dementia / Q000150:complications* / Q000473:pathology*; D005260:Female; D005625:Frontal Lobe / Q000098:blood supply / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D009483:Neuropsychological Tests; D000587:Oxidoreductases Acting on CH-NH Group Donors; D048530:Papio anubis; D020521:Stroke / Q000150:complications* / Q000473:pathology; D066127:White Matter / Q000098:blood supply / Q000473:pathology*; D000099295:Formyltetrahydrofolate Dehydrogenase
chemical_list: D000444:Aldehyde Dehydrogenase; D051401:Aquaporin 4; D005904:Glial Fibrillary Acidic Protein; D000587:Oxidoreductases Acting on CH-NH Group Donors; D000099295:Formyltetrahydrofolate Dehydrogenase
keywords: ageing; blood–brain barrier; clasmatodendrocyte; post-stroke dementia; white matter