Title:
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Hypoperfusion of cerebral grey matter in dementia
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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.
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