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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

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]
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Fig7: 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]

Mentions: More recently, we looked at MAG:PLP1, SVD, Aβ amyloid angiopathy, EDN1 level, ACE level and activity, and AngII level in precuneus from post-mortem human brains showing a spectrum of severity of AD (as indicated by Braak tangle stage). We showed that MAG:PLP1 declined in the precuneus even in early AD (i.e. in Braak stage III–IV disease) (Fig. 6). Indeed, despite progressive elevation in EDN1 concentration with disease progression, the MAG:PLP1 ratio was lower in early than in late AD (Fig. 7), presumably reflecting falling metabolic demand with increasing synaptic and neuronal damage. In the precuneus, unlike in the frontal cortex in advanced AD, we did not find elevation of ACE or AngII.Fig. 6


Cerebrovascular disease in ageing and Alzheimer's disease.

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

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]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig7: 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]
Mentions: More recently, we looked at MAG:PLP1, SVD, Aβ amyloid angiopathy, EDN1 level, ACE level and activity, and AngII level in precuneus from post-mortem human brains showing a spectrum of severity of AD (as indicated by Braak tangle stage). We showed that MAG:PLP1 declined in the precuneus even in early AD (i.e. in Braak stage III–IV disease) (Fig. 6). Indeed, despite progressive elevation in EDN1 concentration with disease progression, the MAG:PLP1 ratio was lower in early than in late AD (Fig. 7), presumably reflecting falling metabolic demand with increasing synaptic and neuronal damage. In the precuneus, unlike in the frontal cortex in advanced AD, we did not find elevation of ACE or AngII.Fig. 6

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