Cerebral autoregulation in AD and MCI Introduction Dementia is one of the principal neurological disorders in elderly. Recent studies 11, 15, 21 have indicated that vascular risk factors are involved in the pathogene- sis of cognitive disorders and dementia. For adequate function, the brain is critically dependent on continuous blood supply. Therefore, the cerebral vascula- ture is endowed with neurovascular control mechanisms that assure that the blood supply of the brain is commensurate to the energy needs of its cellular constituents. The regulation of cerebral blood flow (CBF) during brain activity involves the coordinated interaction of neurons, glia, and vascular cells. Altera- tions of the vascular regulatory mechanisms may lead to brain dysfunction and disease. A more and more emerging view is that cerebrovascular dysregulation is a feature not only of cerebrovascular pathologies, such as stroke, but also of neurodegenerative conditions, such as Alzheimer’s disease (AD) 11. First epide- miological studies have shown that risk factors for vascular diseases are impor- tant risk factors for AD 5. Small ischemic lesions substantially aggravate the dementia 26. Interaction of cerebral ischemia with AD pathology enhances the clinical manifestations of the disease. Moreover, AD patients have more severe atherosclerosis in large cerebral arteries at the base of the brain (circle of Willis) than age-matched controls without AD 19. AD is the most common form of dementia and is often characterized by deposi- tion of amyloid "-peptide in the blood vessels (amyloid angiopathy). Cerebral micro vessels are reduced in number and cerebrovascular function is also altered in AD. Resting CBF is reduced and the increase in CBF produced by activation (neurovascular coupling) is attenuated 25. The cerebrovascular dysfunction often precedes the onset of cognitive impairment suggesting a role in the mecha- nisms of dementia 11. Iadecolaet al 11 pose a hypothetical time-course of the interplay between vascular dysregulation, neuropathological alterations and decline in brain function in AD. In the latent phase vascular dysregulation is already apparent when patients are asymptomatic. During the prodromal phase neuropathological alterations begin to manifest and cognitive function begins to decline. At this time, cognitive alterations are likely to result from amyloid ß- peptide (Aß) induced neuronal dysfunction and vascular dysregulation. As the disease progresses, the neuropathological changes evolve. Cerebrovascular disease deteriorates in parallel with cognitive function, reflecting in addition to Aß induced vascular effects, the deleterious cerebrovascular effects of synaptic loss and vascular amyloid. In the late phase of the disease, brain function and vascular regulation are maximally compromised. 61
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