Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

Abstract

The earliest decline in cerebral perfusion in Alzheimer's disease (AD) is in the medial parietal cortex (precuneus). We have analyzed precuneus in post‐mortem tissue from 70 AD and 37 control brains to explore the pathophysiology of the hypoperfusion: the contribution of arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), and of the vasoconstrictors endothelin‐1 (EDN1) and angiotensin II (Ang II), and the association with Aβ. The myelin‐associated glycoprotein:proteolipid protein‐1 ratio (MAG:PLP1) was used as an indicator of oxygenation of the precuneus prior to death. MAG:PLP1 was reduced ∼50% in early AD (Braak stage III–IV). Although MAG:PLP1 remained low in advanced AD (stage V–VI), the reduction was less pronounced, possibly reflecting falling oxygen demand. Reduction in cortical MAG:PLP1 correlated with elevation in vascular endothelial growth factor (VEGF), another marker of hypoperfusion. Cortical MAG:PLP1 declined nonsignificantly with increasing SVD and CAA, but significantly with the concentration of EDN1, which was elevated approximately 75% in AD. In contrast, with reduction in cortical MAG:PLP1, Ang II level and angiotensin‐converting enzyme (ACE) activity declined, showing a normal physiological response to hypoperfusion. MAG:PLP1 was reduced in the parietal white matter (WM) in AD but here the decline correlated positively (ie, physiologically) with WM EDN1. However, the decline of MAG:PLP1 in the WM was associated with increasing cortical EDN1 and perhaps reflected vasoconstriction of perforating arterioles, which traverse the cortex to perfuse the WM. EDN1 in the cortex correlated highly significantly with both soluble and insoluble Aβ42, shown previously to upregulate neuronal endothelin‐converting enzyme‐2 (ECE2), but not with Aβ40. Our findings demonstrate reduced oxygenation of the precuneus in early AD and suggest that elevated EDN1, resulting from Aβ42‐mediated upregulation of ECE2, is a contributor.

Cerebral Hypoperfusion and the Energy Deficit in Alzheimer's Disease

“…Our own studies found the MAG:PLP1 ratio to be reduced in the cerebral cortex in late, as well as early AD (75,134). However, within the precuneus, the ratio was not as markedly decreased in brain tissue from patients with Braak stage V-VI disease as in those with earlier (Braak stage III-IV) disease and not significantly so in comparison with Braak stage 0-II disease (Figure 2).…”

“…We showed that the MAG:PLP1 ratio, was reduced in the precuneus by ~50% in Braak stage III-IV disease (75), indicating that even in early AD there is a disparity between oligodendrocyte energy demand and supply in the first region of brain to show hypoperfusion.…”

“…EDN1 is a potent vasoconstrictor and its concentration is increased significantly in cerebral cortex from patients with AD (75,97,134). The increase is demonstrable from an early stage of disease, including within the precuneus (75), the first region in which blood flow declines (see above).…”

VEGFR1 and VEGFR2 in Alzheimer’s Disease

“…Blood flow and oxygenation are reduced in the cerebral cortex and underlying white matter in Alzheimer's disease (AD) [1][2][3][4][5][6][7]. Cerebral blood flow (CBF) declines before cognitive decline or brain atrophy [1,8] and is associated with biochemical and MRI evidence of tissue damage [4,9].…”

“…Cerebral blood flow (CBF) declines before cognitive decline or brain atrophy [1,8] and is associated with biochemical and MRI evidence of tissue damage [4,9]. Vessel wall abnormalities such as cerebral amyloid angiopathy (CAA) and arteriolosclerosis, may play a part in the hypoperfusion but its timing and distribution suggest that other factors are more important contributors.…”