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J Neurosci Res. 2017 Apr;95(4):943-972. doi: 10.1002/jnr.23777. Epub 2016 Jun 27.

Cerebral hypoperfusion and glucose hypometabolism: Key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer's disease.

Author information

1
Sleep Disorders Group, EEE Dept/MSE, The University of Melbourne, Parkville, Victoria, Australia.

Abstract

Aging, hypertension, diabetes, hypoxia/obstructive sleep apnea (OSA), obesity, vitamin B12/folate deficiency, depression, and traumatic brain injury synergistically promote diverse pathological mechanisms including cerebral hypoperfusion and glucose hypometabolism. These risk factors trigger neuroinflammation and oxidative-nitrosative stress that in turn decrease nitric oxide and enhance endothelin, Amyloid-β deposition, cerebral amyloid angiopathy, and blood-brain barrier disruption. Proinflammatory cytokines, endothelin-1, and oxidative-nitrosative stress trigger several pathological feedforward and feedback loops. These upstream factors persist in the brain for decades, upregulating amyloid and tau, before the cognitive decline. These cascades lead to neuronal Ca2+ increase, neurodegeneration, cognitive/memory decline, and Alzheimer's disease (AD). However, strategies are available to attenuate cerebral hypoperfusion and glucose hypometabolism and ameliorate cognitive decline. AD is the leading cause of dementia among the elderly. There is significant evidence that pathways involving inflammation and oxidative-nitrosative stress (ONS) play a key pathophysiological role in promoting cognitive dysfunction. Aging and several comorbid conditions mentioned above promote diverse pathologies. These include inflammation, ONS, hypoperfusion, and hypometabolism in the brain. In AD, chronic cerebral hypoperfusion and glucose hypometabolism precede decades before the cognitive decline. These comorbid disease conditions may share and synergistically activate these pathophysiological pathways. Inflammation upregulates cerebrovascular pathology through proinflammatory cytokines, endothelin-1, and nitric oxide (NO). Inflammation-triggered ONS promotes long-term damage involving fatty acids, proteins, DNA, and mitochondria; these amplify and perpetuate several feedforward and feedback pathological loops. The latter includes dysfunctional energy metabolism (compromised mitochondrial ATP production), amyloid-β generation, endothelial dysfunction, and blood-brain-barrier disruption. These lead to decreased cerebral blood flow and chronic cerebral hypoperfusion- that would modulate metabolic dysfunction and neurodegeneration. In essence, hypoperfusion deprives the brain from its two paramount trophic substances, viz., oxygen and nutrients. Consequently, the brain suffers from synaptic dysfunction and neuronal degeneration/loss, leading to both gray and white matter atrophy, cognitive dysfunction, and AD. This Review underscores the importance of treating the above-mentioned comorbid disease conditions to attenuate inflammation and ONS and ameliorate decreased cerebral blood flow and hypometabolism. Additionally, several strategies are described here to control chronic hypoperfusion of the brain and enhance cognition.

KEYWORDS:

Alzheimer's disease; blood-brain barrier dysfunction; brain atrophy; cerebral amyloid angiopathy; cerebral hypoperfusion; glucose hypometabolism

PMID:
27350397
DOI:
10.1002/jnr.23777
[Indexed for MEDLINE]

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