Chronic cerebral hypoperfusion-related neuropathologic changes and compromised cognitive status: window of treatment

Neurodegenerative disorders, and dementia in particular, have been shown to have a cerebrovascular pathogenic component often in the form of reduced cerebral blood flow. The debate whether such a reduced brain perfusion is a primary trigger or a secondary symptom in the neuropathological progression of dementia has not been conclusively decided yet. However, compelling experimental evidence has been collected to demonstrate an initiating role of reduced cerebral blood flow in neurodegenerative processes. Along these lines, experimental cerebral hypoperfusion in rodents was shown to impair spatial learning and to generate neuronal damage and associated gliosis in sensitive brain regions like the hippocampus and frontoparietal cortex. Since suboptimal cerebral blood supply was thus identified as a potential trigger of cognitive decline, the improvement of cerebral blood flow in cognitive disorders has emerged as an alternative treatment to moderate the symptoms and to delay the onset of advanced dementia. Various drugs, such as cholinergic compounds, hemorheologic agents and vascular smooth muscle relaxants, have already been tested in some instances for their efficacy to increase brain perfusion. In this respect, both clinical and preclinical trials delivered positive data. Furthermore, not only the treatment but also the prevention of the development of cognitive deficiency can target the cerebrovascular system. For this purpose, long-chain polyunsaturated fatty acids derived from fish oil (also known as n-3 PUFAs) have been considered as dietary supplements. These fatty acids appeared particularly effective in the prevention of hypertension-associated vascular pathology. The present review provides an overview of the actions of these compounds focusing on cerebral blood flow, neurodegeneration and cognitive decline.