Cerebrovascular disease in ageing and Alzheimer's disease

Abstract

Cerebrovascular disease (CVD) and Alzheimer's disease (AD) have more in common than their association with ageing. They share risk factors and overlap neuropathologically. Most patients with AD have Aβ amyloid angiopathy and degenerative changes affecting capillaries, and many have ischaemic parenchymal abnormalities. Structural vascular disease contributes to the ischaemic abnormalities in some patients with AD. However, the stereotyped progression of hypoperfusion in this disease, affecting first the precuneus and cingulate gyrus, then the frontal and temporal cortex and lastly the occipital cortex, suggests that other factors are more important, particularly in early disease. Whilst demand for oxygen and glucose falls in late disease, functional MRI, near infrared spectroscopy to measure the saturation of haemoglobin by oxygen, and biochemical analysis of myelin proteins with differential susceptibility to reduced oxygenation have all shown that the reduction in blood flow in AD is primarily a problem of inadequate blood supply, not reduced metabolic demand. Increasing evidence points to non-structural vascular dysfunction rather than structural abnormalities of vessel walls as the main cause of cerebral hypoperfusion in AD. Several mediators are probably responsible. One that is emerging as a major contributor is the vasoconstrictor endothelin-1 (EDN1). Whilst there is clearly an additive component to the clinical and pathological effects of hypoperfusion and AD, experimental and clinical observations suggest that the disease processes also interact mechanistically at a cellular level in a manner that exacerbates both. The elucidation of some of the mechanisms responsible for hypoperfusion in AD and for the interactions between CVD and AD has led to the identification of several novel therapeutic approaches that have the potential to ameliorate ischaemic damage and slow the progression of neurodegenerative disease.

Keywords: Ageing; Alzheimer’s disease; Cerebrovascular disease; Endothelin-1; Hypoperfusion; Myelin proteins.

Figures

Fig. 1

Infarction associated with Aβ amyloid angiopathy. a Microinfarct in cerebral cortex. The lesion is rarefied and gliotic, and includes a few macrophages. b Aβ immunohistochemistry on an adjacent section revealed moderately severe Aβ amyloid angiopathy. Note the circumferential deposition of Aβ in a sulcal arteriole overlying the microinfarct. Bar 250 μm

Fig. 2

Perivascular tau associated with Aβ amyloid angiopathy. a Arteriolar and dyshoric deposition of Aβ in a patient with severe amyloid angiopathy. b Immunolabelling of an adjacent section for phospho-tau showed accentuated accumulation of tau around the affected arteriole. Bar 250 μm

Fig. 3

Microhaemorrhage associated with Aβ amyloid angiopathy. a Accumulation of numerous haemosiderin-laden macrophages around a cortical arteriole with a strongly eosinophilic wall. b The arteriole is immunopositive for Aβ, as demonstrated in this adjacent section. Bar 500 μm

Fig. 4

Stereotyped pattern of spread of hypoperfusion in AD. The arrows in this diagram indicate the progression of hypoperfusion, starting from the precuneus, well before the onset of dementia, and spreading to the rest of the parietal cortex and the cingulate gyrus, then the frontal and temporal cortex, largely sparing the occipital cortex until late disease

Fig. 5

Schematic illustration of the distribution of MAG (Pink dots) and PLP1 (Green dots) in the myelin sheath. When the supply of oxygen and glucose is insufficient to meet the metabolic needs of the oligodendrocyte, as occurs in hypoperfusion, the first part of the cell to degenerate is the adaxonal loop of myelin—the part of the oligodendrocyte that is furthest away from the cell body (so-called dying-back oligodendrogliopathy). Because MAG is restricted to the adaxonal loop of myelin whereas PLP1 is widely distributed throughout the myelin sheath, hypoperfusion leads to greater loss of MAG than PLP1. In contrast, degeneration of nerve fibres causes loss of both MAG and PLP1. The severity of ante-mortem hypoperfusion can be assessed by measuring the MAG:PLP1 ratio

Fig. 6

Oxygenation of the precuneus is reduced in early Alzheimer’s disease. aBar chart showing a reduction in the ratio of myelin glycoprotein (MAG) to proteolipid-1 protein (PLP-1) (MAG:PLP1) in the precuneus in AD. The bars indicate the mean and SEM. b Bar chart showing marked variation in MAG:PLP1 (P = 0.027) with disease stage. For this analysis, control and AD cases were combined and grouped according to Braak tangle stage (0–II, III–IV and V–VI). Post hoc analysis revealed that MAG:PLP1 was significantly reduced in early AD (Braak stage III–IV) compared to controls (P = 0.027). c Bar chart showing elevated vascular endothelial growth factor (VEGF), an independent marker of cerebral perfusion, in AD. d Scatterplot showing the highly significant negative correlation between MAG:PLP1 and VEGF concentration in the precuneus (r = −0.40, P = 0.0007). The best-fit linear regression line and 95 % confidence interval are superimposed. **P < 0.001, ***P < 0.0001. Reproduced with permission from [106]

Fig. 7

Reduced oxygenation of the precuneus in AD is associated with elevated endothelin-1 (EDN1). aBar chart showing significantly increased EDN1 in AD within the precuneus. bBar chart showing increased EDN1 levels in relation to disease severity when control and AD cases were subdivided according to Braak tangle stage (0–II, III–IV and V–VI) irrespective of the presence or absence of a history of dementia. Scatterplots showing the inverse correlation between EDN1 concentration and MAG:PLP1 ratio (r = −0.31) (c), and the positive correlation between EDN1 and VEGF (r = 0.29) (d). *P < 0.05, ***P < 0.001, ****P < 0.0001. Reproduced with permission from [106]