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Title: Hypoperfusion of cerebral grey matter in dementia
Author: Thomas, Taya Louise
ISNI:       0000 0004 6057 9528
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2016
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Reduced cerebral blood flow (CBF) has been reported in patients with Alzheimer's disease (AD), with increasing evidence to suggest that the hypoperfusion contributes to decline in cognitive function and possibly to progression of the neurodegeneration. Key proteins that are upregulated under conditions of cerebral hypoxia are the hypoxia inducible factor-ia (HIFia) and neuroglobin (NGB) which both induce the transcription of mUltiple genes, including some involved in the production of amyloid-β (Aβ) and the angiogenic growth factor, vascular endothelia growth factor (VEGF). This thesis describes a series of studies to investigate the molecular evidence of hypoxia in post-mortem brain tissue from patients with AD, vascular dementia (VaD), dementia with Lewy bodies (DLB; all cases with little or no cerebrovascular disease) and non-demented controls. qRT-PCR and ELISA were used to investigate the mRNA and protein expression of HIFla, NGB and VEGF. Hypoxia was also indirectly assessed by the measurement of myelinassociated glycoprotein (MAG), which is more sensitive to ischaemia than other myelin proteins, and comparing it to the relatively stable proteolipid protein-1 (PLP). The relationship to the severity of the two main structural abnormalities of the microvasculature, arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), both of which can cause cerebral ischaemia and cognitive impairment; the levels of total Aβ, Aβ1-40 and Aβ1.42 and severity of AD pathology as determined by Braak tangle stage; and the level and activity of angiotensin-converting enzyme (ACE), which catalyses the production of a powerful vasoconstrictor angiotensin II, and the level ofthe vasoconstrictor, endothelin-1 (ET-1) were also assessed. NGB protein level did not differ significantly in AD or VaD compared to controls but MAG protein level was reduced in both disease groups, consistent with what was previously demonstrated in the white matter, and was found to decrease with increasing severity of SVD. In contrast, VEGF protein was elevated in both disease groups but particularly AD; it correlated with the level of insoluble Aβ, Aβ1-42 and the Aβ1-42:Aβ1-40 ratio and to a lesser extent with the Braak tangle stage and ACE activity. There was no relationship between the level of ET-1 and VEGF. There was also only a weak relationship between VEGF or NGB and the severity of SVD or CAA. It seems likely that the increase in VEGF protein in AD is largely related to the accumulation of A~ rather than to SVD or to vasoconstriction mediated by ET-1 or angiotensin II. In DLB, NGB protein level was significantly increased in the cingulate cortex and MAG protein level reduced, although not significantly. There was no significant change in VEGF level. The mechanism of hypoperfusion seems likely to differ from that in AD. Together these findings suggest that the molecular assessment of hypoxia may provide a useful means to investigate different mechanisms of reduced CBF in various forms of dementia.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available