Limits...
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

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4835514&req=5

Fig5: 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

Mentions: We recently developed a post-mortem biochemical method to study hypoperfusion in brain tissue [11, 12, 96]. The method is based on the differential susceptibility of different myelin proteins to ischaemia. The myelin proteins are synthesised in the oligodendrocyte cell body and require energy-dependent transport to reach their sites of insertion into the myelin sheath. Myelin-associated glycoprotein (MAG) is one of the myelin proteins inserted furthest away from the cell body, in the adaxonal loop of myelin, the first part of the sheath to degenerate when blood supply is insufficient to meet the energy demands of the oligodendrocyte. Measurement of the ratio of MAG to another myelin protein such as proteolipid protein-1 (PLP1), present throughout the myelin sheath, indicates the extent to which the blood supply meets the energy requirements of the oligodendrocyte (Fig. 5).Fig. 5


Cerebrovascular disease in ageing and Alzheimer's disease.

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

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig5: 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
Mentions: We recently developed a post-mortem biochemical method to study hypoperfusion in brain tissue [11, 12, 96]. The method is based on the differential susceptibility of different myelin proteins to ischaemia. The myelin proteins are synthesised in the oligodendrocyte cell body and require energy-dependent transport to reach their sites of insertion into the myelin sheath. Myelin-associated glycoprotein (MAG) is one of the myelin proteins inserted furthest away from the cell body, in the adaxonal loop of myelin, the first part of the sheath to degenerate when blood supply is insufficient to meet the energy demands of the oligodendrocyte. Measurement of the ratio of MAG to another myelin protein such as proteolipid protein-1 (PLP1), present throughout the myelin sheath, indicates the extent to which the blood supply meets the energy requirements of the oligodendrocyte (Fig. 5).Fig. 5

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