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Cerebrovascular disease in ageing and Alzheimer's disease.

Love S, Miners JS - Acta Neuropathol. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Neurosciences, School of Clinical Sciences, Learning and Research Level 2, Southmead Hospital, University of Bristol, Bristol, BS10 5NB, UK. seth.love@bris.ac.uk.

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.

No MeSH data available.


Related in: MedlinePlus

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
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Fig2: 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

Mentions: In a series of studies of human brain tissue and animal models, Weller, Carare, Hawkes and colleagues showed that interstitial fluid drains from the brain along perivascular spaces and basement membranes [164, 174], and that Aβ within the interstitial fluid tends to precipitate within the perivascular basement membranes [165, 166]. Further evidence that Aβ amyloid angiopathy reflected the precipitation of Aβ from the interstitial fluid came from the finding of Jucker and colleagues that neuron-specific overexpression of Aβ precursor protein caused the development of Aβ amyloid angiopathy in APP23 mice [22, 63]. Vascular deposition of Aβ is increased by possession of APOE ϵ4 [27]; this is probably partly related to elevation of the ratio Aβ40:42 [48, 63] and partly to alterations in the composition of the perivascular basement membranes [60]. Vascular deposition of Aβ is also increased if drainage is impeded by Aβ amyloid angiopathy or by age-related changes to the perivascular basement membranes [58, 59, 76, 166]. The full range of downstream effects of impeded drainage of solutes in Aβ amyloid angiopathy remains to be determined. One probable consequence is an increase in the phosphorylation of tau, as evidenced by the more abundant neurofibrillary pathology around Aβ-laden than non-Aβ-laden parenchymal arterioles in AD (Fig. 2) [169]. A similar increase in neurofibrillary pathology was demonstrated adjacent to parenchymal arterioles in the amyloid angiopathy of familial British dementia, in which there is vascular deposition of ABri [66], which, like vascular Aβ, probably impedes the drainage of interstitial fluid.Fig. 2


Cerebrovascular disease in ageing and Alzheimer's disease.

Love S, Miners JS - Acta Neuropathol. (2015)

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4835514&req=5

Fig2: 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
Mentions: In a series of studies of human brain tissue and animal models, Weller, Carare, Hawkes and colleagues showed that interstitial fluid drains from the brain along perivascular spaces and basement membranes [164, 174], and that Aβ within the interstitial fluid tends to precipitate within the perivascular basement membranes [165, 166]. Further evidence that Aβ amyloid angiopathy reflected the precipitation of Aβ from the interstitial fluid came from the finding of Jucker and colleagues that neuron-specific overexpression of Aβ precursor protein caused the development of Aβ amyloid angiopathy in APP23 mice [22, 63]. Vascular deposition of Aβ is increased by possession of APOE ϵ4 [27]; this is probably partly related to elevation of the ratio Aβ40:42 [48, 63] and partly to alterations in the composition of the perivascular basement membranes [60]. Vascular deposition of Aβ is also increased if drainage is impeded by Aβ amyloid angiopathy or by age-related changes to the perivascular basement membranes [58, 59, 76, 166]. The full range of downstream effects of impeded drainage of solutes in Aβ amyloid angiopathy remains to be determined. One probable consequence is an increase in the phosphorylation of tau, as evidenced by the more abundant neurofibrillary pathology around Aβ-laden than non-Aβ-laden parenchymal arterioles in AD (Fig. 2) [169]. A similar increase in neurofibrillary pathology was demonstrated adjacent to parenchymal arterioles in the amyloid angiopathy of familial British dementia, in which there is vascular deposition of ABri [66], which, like vascular Aβ, probably impedes the drainage of interstitial fluid.Fig. 2

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Neurosciences, School of Clinical Sciences, Learning and Research Level 2, Southmead Hospital, University of Bristol, Bristol, BS10 5NB, UK. seth.love@bris.ac.uk.

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.

No MeSH data available.


Related in: MedlinePlus