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Symposium Reports |
1 Institute of Science & Technology in Medicine, School of Medicine, Keele University, Staffordshire ST5 5BG, UK Email: d.corfield{at}keele.ac.uk
This issue contains two papers based on a symposium entitled Cerebrovascular function: changes in health and disease, which took place at Life Sciences 2007 in Glasgow, UK on 10th July 2007.
The brain produces energy by the metabolism of oxidizable substrates; however, as the brain contains no endogenous stores of energy, it is dependent upon cerebral perfusion for the constant replenishment of oxygen and glucose and for the removal of waste. Therefore, perfusion is tightly and dynamically regulated to meet the brain's metabolic demands. In addition, brain blood flow must respond to alterations in the blood gas status and must safeguard the brain from fluctuations in systemic arterial pressure. When cerebral perfusion falls below that required for metabolism, cerebral function is impaired; if sustained, tissue damage may result. The presentations at the symposium highlighted how cerebrovascular function could be altered both by disease and by normal changes in physiological state; such changes in cerbrovascular function can affect brain function both acutely and chronically.
The first paper, by Professor E. Hamel, considered the role of oxidative stress on cerebral vascular dysfunction in Alzheimer's disease (AD; Hamel et al. 2008). Several factors have been implicated in the pathology of AD but none has been shown to be causative. Alzheimer's disease is commonly characterized by vascular pathologies that include the accumulation of amyloid β (Aβ) peptide in the cerebral vessel walls and vascular fibrosis. These changes result in chronic cerebral hypoperfusion which, it is proposed, may lead to cognitive deficits. Studies from Professor Hamel's laboratory have shown that transgenic mice overproducing Aβ suffer from oxidative stress and cerebrovascular dysfunction. Anti-oxidant treatment in the same mice restores vascular function, suggesting a potential therapy for AD-related cerebrovascular pathology.
Dementia resulting directly from disease of the cerebral circulation (vascular dementia) is the second most common form of dementia after AD. It has a pathology distinct from that of AD and results from disease affecting the small perforating end arteries within the brain. In addition to vascular dementia, such small vessel disease (SVD) is an important cause of stroke. In the second paper, Professor Markus presented evidence that endothelial dysfunction was a risk factor for SVD (Markus, 2008); in particular, the increased expression of markers of endothelial dysfunction, such as intracellular adhesion molecule 1 (ICAM-1) and thrombomodulin, have been associated with SVD. A genetic predisposition for such cerbrovascular dysfunction is likely, and a number of genes involved in endothelial regulation have been implicated as risk factors. However, Professor Markus concluded that the importance of these genetic influences is likely to be answered only by much larger studies than those undertaken to date.
In the third presentation, I discussed the normal physiological changes in cerebrovascular regulation that occur during sleep. Sleep is a state of reversible but reduced consciousness; associated with these changes in consciousness are changes in brain metabolism. In slow wave sleep, both metabolism and cerebral blood flow are reduced. Studies from my laboratory have shown that slow wave sleep is associated with marked changes in cerebrovascular regulation (Corfield & Meadows, 2006). In particular, cerebral vascular responses to hypercapnia and isocapnic hypoxia are drastically reduced or even abolished in healthy subjects during this sleep state compared with wakefulness. Nocturnal hypoxia and hypercapnia are characteristics of cardiorespiratory diseases such as obstructive sleep apnoea and congestive heart failure. I speculated that the failure of the cerebral circulation to respond to such insults, in these disease states, would result in hypoperfusion and in an increased risk of cerebral ischaemia and infarction.
For the final presentation, Professor Secher considered a further state in which central nervous system function may be compromised by normal physiological limitations in cerebral perfusion. When voluntary muscle contractions are performed repeatedly, an inability to sustain the required force develops; this phenomenon of fatigue may be due to limitations in the muscle itself (peripheral fatigue) but it can also reflect limitations in the central nervous system (central fatigue). Professor Secher reviewed the evidence that supports the existence of central fatigue; he argued that such fatigue results from a failure in cerebral metabolism. Furthermore, this failure in metabolism may be secondary to limitations in cerebral perfusion.
In conclusion, the symposium considered changes in cerebrovascular function that were brought about either by disease or by changes in physiological state. In common were the implications for brain function; each change in cerebrovascular function, by very different routes, potentially threatened or compromised normal brain function. It is interesting to speculate on the importance of the interactions between these physiological and pathophysiological states. For example, how might brain function be further affected by the changes in cerebrovascular regulation that would occur in dementia during sleep?
References
Corfield DR & Meadows GE (2006). Control of cerebral blood flow during sleep and the effects of hypoxia. Adv Exp Med 588, 65–73.[CrossRef]
Hamel E, Nicolakakis N, Alboulkassim T, Ongali B & Tong X-K (2008). Oxidative stress and cerebrovascular dysfunction in mouse models of Alzheimer's disease. Exp Physiol 93, 000–000.
Markus HS (2008). Genes, endothelial function and cerebral small vessel disease in man. Exp Physiol 93, 000–000.
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