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Demonstrating a reduced capacity for removal of fluid from cerebral white matter and hypoxia in areas of white matter hyperintensity associated with age and dementia

Demonstrating a reduced capacity for removal of fluid from cerebral white matter and hypoxia in areas of white matter hyperintensity associated with age and dementia
Demonstrating a reduced capacity for removal of fluid from cerebral white matter and hypoxia in areas of white matter hyperintensity associated with age and dementia

White matter hyperintensities (WMH) occur in association with dementia but the aetiology is unclear. Here we test the hypothesis that there is a combination of impaired elimination of interstitial fluid from the white matter together with a degree of hypoxia in WMH. One of the mechanisms for the elimination of amyloid-β (Aβ) from the brain is along the basement membranes in the walls of capillaries and arteries (Intramural Peri-Arterial Drainage - IPAD). We compared the dynamics of IPAD in the grey matter of the hippocampus and in the white matter of the corpus callosum in 10 week old C57/B16 mice by injecting soluble Aβ as a tracer. The dynamics of IPAD in the white matter were significantly slower compared with the grey matter and this was associated with a lower density of capillaries in the white matter. Exposing cultures of smooth muscle cells to hypercapnia as a model of cerebral hypoperfusion resulted in a reduction in fibronectin and an increase in laminin in the extracellular matrix. Similar changes were detected in the white matter in human WMH suggesting that hypercapnia/hypoxia may play a role in WMH. Employing therapies to enhance both IPAD and blood flow in the white matter may reduce WMH in patients with dementia.

Fibronectin, Intramural periarterial drainage, Laminin, White matter hyperintensities
2051-5960
MacGregor Sharp, Matthew
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Saito, Satoshi
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Keable, Abby
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Gatherer, Maureen
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Aldea, Roxana
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Agarwal, Nivedita
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Simpson, Julie E.
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Wharton, Stephen B.
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Weller, Roy O.
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Carare, Roxana O.
0478c197-b0c1-4206-acae-54e88c8f21fa
MacGregor Sharp, Matthew
ec57c53a-a10a-4b8a-94fe-03eca85ab7c3
Saito, Satoshi
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Keable, Abby
334f0dca-e41d-4c17-9435-df52bab191b2
Gatherer, Maureen
b0aae216-21c4-4737-b042-865a65658f06
Aldea, Roxana
f9a0de86-7ff3-4bff-abc9-b1537e14f2b8
Agarwal, Nivedita
ec451638-a8e6-477f-864d-25c653fa70a0
Simpson, Julie E.
4f5435d8-fc27-40f2-be80-2bf40569cd7d
Wharton, Stephen B.
dc1ee8f7-ec50-4cb2-983c-4156a50a2005
Weller, Roy O.
4a501831-e38a-4d39-a125-d7141d6c667b
Carare, Roxana O.
0478c197-b0c1-4206-acae-54e88c8f21fa

MacGregor Sharp, Matthew, Saito, Satoshi, Keable, Abby, Gatherer, Maureen, Aldea, Roxana, Agarwal, Nivedita, Simpson, Julie E., Wharton, Stephen B., Weller, Roy O. and Carare, Roxana O. (2020) Demonstrating a reduced capacity for removal of fluid from cerebral white matter and hypoxia in areas of white matter hyperintensity associated with age and dementia. Acta Neuropathologica Communications, 8 (1), [131]. ().

Record type: Article

Abstract

White matter hyperintensities (WMH) occur in association with dementia but the aetiology is unclear. Here we test the hypothesis that there is a combination of impaired elimination of interstitial fluid from the white matter together with a degree of hypoxia in WMH. One of the mechanisms for the elimination of amyloid-β (Aβ) from the brain is along the basement membranes in the walls of capillaries and arteries (Intramural Peri-Arterial Drainage - IPAD). We compared the dynamics of IPAD in the grey matter of the hippocampus and in the white matter of the corpus callosum in 10 week old C57/B16 mice by injecting soluble Aβ as a tracer. The dynamics of IPAD in the white matter were significantly slower compared with the grey matter and this was associated with a lower density of capillaries in the white matter. Exposing cultures of smooth muscle cells to hypercapnia as a model of cerebral hypoperfusion resulted in a reduction in fibronectin and an increase in laminin in the extracellular matrix. Similar changes were detected in the white matter in human WMH suggesting that hypercapnia/hypoxia may play a role in WMH. Employing therapies to enhance both IPAD and blood flow in the white matter may reduce WMH in patients with dementia.

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Accepted/In Press date: 1 August 2020
Published date: 8 August 2020
Keywords: Fibronectin, Intramural periarterial drainage, Laminin, White matter hyperintensities

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Local EPrints ID: 445015
URI: http://eprints.soton.ac.uk/id/eprint/445015
DOI:
ISSN: 2051-5960
PURE UUID: 6ee8d898-47c0-4c5f-a483-3fa2742b9675
ORCID for Matthew MacGregor Sharp:

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Date deposited: 18 Nov 2020 13:16
Last modified: 18 Nov 2020 13:16

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Contributors

Author: Matthew MacGregor Sharp
Author: Satoshi Saito
Author: Abby Keable
Author: Maureen Gatherer
Author: Roxana Aldea
Author: Nivedita Agarwal
Author: Julie E. Simpson
Author: Stephen B. Wharton
Author: Roy O. Weller
Author:

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