Journal ArticleDOI
Cerebral hypoperfusion and glucose hypometabolism: Key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer's disease.
TLDR
The importance of treating comorbid disease conditions to attenuate inflammation and ONS and ameliorate decreased cerebral blood flow and hypometabolism is underscored.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. © 2016 Wiley Periodicals, Inc.read more
Citations
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Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease
TL;DR: The cellular and molecular mechanisms within the neurovascular unit that contribute to CBF control, and neurov vascular dysfunction in neurodegenerative disorders such as Alzheimer disease are examined.
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Alzheimer's disease hypothesis and related therapies.
TL;DR: This review will discuss the existing and emerging hypothesis and related therapies about AD, including abnormal deposit of amyloid β protein in the extracellular spaces of neurons, formation of twisted fibers of tau proteins inside neurons, cholinergic neuron damage, inflammation, oxidative stress, etc.
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Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging
TL;DR: Increasing evidence from epidemiological, clinical and experimental studies indicate that age-related cerebromicrovascular dysfunction and microcirculatory damage play critical roles in the pathoge as discussed by the authors.
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Glucose transporters in brain in health and disease
TL;DR: A comprehensive overview about verified and proposed roles of cerebral glucose transporters during health and diseases is presented, and their roles in learning and memory formation are discussed.
Journal ArticleDOI
Obstructive Sleep Apnea is Associated With Early but Possibly Modifiable Alzheimer’s Disease Biomarkers Changes
Claudio Liguori,Nicola Biagio Mercuri,Francesca Izzi,Andrea Romigi,Alberto Cordella,Giuseppe Sancesario,Fabio Placidi +6 more
TL;DR: It is hypothesized that OSA reducing sleep quality and producing intermittent hypoxia lowers CSF Aβ42 levels, increases CSF lactate levels, and alters cognitive performances in SCI patients, thus inducing early AD clinical and neuropathological biomarkers changes.
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