Considerable information is currently available from neuroimaging, pathological, and population-based prospective studies showing that vascular risk factors are independently associated with an ...increased risk of Alzheimer's disease (AD). Many of these studies indicate that vascular risk factors can predict the clinical development of cognitive dysfunction and AD onset. This review examines the role of cerebral hemodynamics and vasoactive molecules that contribute to the regulation of cerebral perfusion and how three common vascular risk factors to AD, namely, hypertension, diabetes type 2, and atherosclerosis, can alter cerebral blood flow (CBF) regulation and generate perfusion pressure deficits. It is proposed that these vascular risk factors (and presumably other vascular risk factors) initiate chronic brain hypoperfusion that ultimately impair signaling from neurons, astrocytes, and endothelial cells to vascular smooth muscle controlling vessel diameter. Impaired signaling involving vascular pathways in the elderly can attenuate vessel tone and deregulate CBF. Noxious cerebral hemodynamic responses to vascular risk factors and chronic brain hypoperfusion are partly explained by Poiseuille's Law which states that miniscule changes in vessel diameter can have a dramatic effect on vessel resistance and on the rate of blood flow. Using Poiseuille's model, even minor narrowing of arteriolar diameter can lead to major reductions in CBF and in suboptimal delivery of high energy nutrients to the brain, with lethal consequences to brain cells that participate in cognitive function. Regional brain cell loss sets the stage for age-related cognitive impairment and AD onset. Keeping cerebral hemodynamic homeostasis by careful management of vascular risk factors could be a decisive therapeutic target in the prevention of AD.
Heart disease is the major leading cause of death and disability in the world. Mainly affecting the elderly population, heart disease and its main outcome, cardiovascular disease, have become an ...important risk factor in the development of cognitive decline and Alzheimer’s disease (AD). This paper examines the evidence linking chronic brain hypoperfusion induced by a variety of cardiovascular deficits in the development of cognitive impairment preceding AD. The evidence indicates a strong association between AD and cardiovascular risk factors, including ApoE4, atrial fibrillation, thrombotic events, hypertension, hypotension, heart failure, high serum markers of inflammation, coronary artery disease, low cardiac index, and valvular pathology. In elderly people whose cerebral perfusion is already diminished by their advanced age, additional reduction of cerebral blood flow stemming from abnormalities in the heart-brain vascular loop ostensibly increases the probability of developing AD. Evidence also suggests that a neuronal energy crisis brought on by relentless brain hypoperfusion may be responsible for protein synthesis abnormalities that later result in the classic neurodegenerative lesions involving the formation of amyloid-beta plaques and neurofibrillary tangles. Insight into how cardiovascular risk factors can induce progressive cognitive impairment offers an enhanced understanding of the multifactorial pathophysiology characterizing AD and ways at preventing or managing the cardiovascular precursors of this dementia.
There is growing evidence that chronic brain hypoperfusion plays a central role in the development of Alzheimer's disease (AD) long before dyscognitive symptoms or amyloid-β accumulation in the brain ...appear. This commentary proposes that dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and Creutzfeldt-Jakob disease (CJD) may also develop from chronic brain hypoperfusion following a similar but not identical neurometabolic breakdown as AD. The argument to support this conclusion is that chronic brain hypoperfusion, which is found at the early stages of the three dementias reviewed here, will reduce oxygen delivery and lower oxidative phosphorylation promoting a steady decline in the synthesis of the cell energy fuel adenosine triphosphate (ATP). This process is known to lead to oxidative stress. Virtually all neurodegenerative diseases, including FTD, DLB, and CJD, are characterized by oxidative stress that promotes inclusion bodies which differ in structure, location, and origin, as well as which neurological disorder they typify. Inclusion bodies have one thing in common; they are known to diminish autophagic activity, the protective intracellular degradative process that removes malformed proteins, protein aggregates, and damaged subcellular organelles that can disrupt neuronal homeostasis. Neurons are dependent on autophagy for their normal function and survival. When autophagic activity is diminished or impaired in neurons, high levels of unfolded or misfolded proteins overwhelm and downregulate the neuroprotective activity of unfolded protein response which is unable to get rid of dysfunctional organelles such as damaged mitochondria and malformed proteins at the synapse. The endpoint of this neuropathologic process results in damaged synapses, impaired neurotransmission, cognitive decline, and dementia.
Abstract The vascular hypothesis of Alzheimer disease (AD), first proposed by us in 1993, provides substantial evidence that suggests vascular risk factors (VRF) play a critical role in the ...development of cognitive decline and AD during aging. Cardiovascular and carotid artery disease, two major risk factors to AD, can conspire or independently induce chronic brain hypoperfusion (CBH) decades before any symptoms of cognitive impairment are expressed. The pathologic construct linking CBH to cognitive impairment and AD remains unclear but evidence shows that it may provide an opportunity to intervene in the prevention or delay of dementia onset. A preliminary randomized clinical study in cognitively healthy middle age individuals to undergo screening using carotid Doppler ultrasound, echocardiography and ankle-brachial index is proposed. These office tools are non-invasive, cost-effective, easily applied in one session and relatively accurate procedures with no inherent harmful effects. More importantly, ultrasound can help identify asymptomatic patients most likely to develop progressive cognitive decline due to persistent CBH secondary to progressive cardiovascular or carotid artery pathology. When these VRF are detected within the heart or carotid arteries, optimal medical treatment or management may be indicated to prevent or slow down further disease progression that fosters cognitive deterioration generated from such conditions. Secondary screening tools such as neuroimaging, neurocognitive testing and CSF markers may be used to confirm ultrasound findings. Prevention-by-detection of VRF and target treatment, if found effective, could significantly promote healthier mental and physical aging and lessen the socio-economic calamity anticipated from the growing prevalence of dementia.
This review attempts to examine two key elements in the evolution of cognitive impairment in the elderly who develop heart failure. First, major left side heart parts can structurally and ...functionally deteriorate from aging wear and tear to provoke hemodynamic instability where heart failure worsens or is initiated; second, heart failure is a major inducer of cognitive impairment and Alzheimer's disease in the elderly. In heart failure, when the left ventricular myocardium of an elderly person does not properly contract, it cannot pump out adequate blood to the brain, raising the risk of cognitive impairment due to the intensification of chronic brain hypoperfusion. Chronic brain hypoperfusion originates from chronically reduced cardiac output which progresses as heart failure worsens. Other left ventricular heart parts, including atrium, valves, myocardium, and aorta can contribute to the physiological shortfall of cardiac output. It follows that hemodynamic instability and perfusion changes occurring from the aging heart's blood pumping deficiency will, in time, damage vulnerable brain cells linked to specific cognitive regulatory sites, diminishing neuronal energy metabolism to a level where progressive cognitive impairment is the outcome. Could cognitive impairment progress be reversed with a heart transplant? Evidence is presented detailing the errant hemodynamic pathways leading to cognitive impairment during aging as an offshoot of inefficient structural and functional heart parts and their contribution to heart failure.
Cardiovascular and cerebrovascular diseases are major risk factors in the development of cognitive impairment and Alzheimer's disease (AD). These cardio‐cerebral disorders promote a variety of ...vascular risk factors which in the presence of advancing age are prone to markedly reduce cerebral perfusion and create a neuronal energy crisis. Long‐term hypoperfusion of the brain evolves mainly from cardiac structural pathology and brain vascular insufficiency. Brain hypoperfusion in the elderly is strongly associated with the development of mild cognitive impairment (MCI) and both conditions are presumed to be precursors of Alzheimer dementia. A therapeutic target to prevent or treat MCI and consequently reduce the incidence of AD aims to elevate cerebral perfusion using novel pharmacological agents. As reviewed here, the experimental pharmaca include the use of Rho kinase inhibitors, neurometabolic energy boosters, sirtuins and vascular growth factors. In addition, a compelling new technique in laser medicine called photobiomodulation is reviewed. Photobiomodulation is based on the use of low level laser therapy to stimulate mitochondrial energy production non‐invasively in nerve cells. The use of novel pharmaca and photobiomodulation may become important tools in the treatment or prevention of cognitive decline that can lead to dementia.
The cause of Alzheimer's disease (AD) is unknown. This gap in knowledge has created a stumbling block in the search for a genuinely effective treatment or cure for this dementia. This article ...summarises the arguments for a causal role for either amyloid deposition or cerebrovascular pathology as the primary trigger in the development of non-genetic AD. A bare-bones survey of the published research reveals no compelling evidence that amyloid deposition is neurotoxic in human beings or that it results in neurodegenerative changes involving synaptic, metabolic, or neuronal loss in human or transgenic-mouse brains. By contrast, the data supporting AD as a primary vascular disorder are more convincing. Findings suggesting a vascular cause of AD come from epidemiological, neuroimaging, pathological, pharmacotherapeutic, and clinical studies. The consensus of these studies indicates that chronic brain hypoperfusion is linked to AD risk factors, AD preclinical detection and pharmacotherapeutic action of AD symptoms.
This report examines the potential of low level laser therapy (LLLT) to alter brain cell function and neurometabolic pathways using red or near infrared (NIR) wavelengths transcranially for the ...prevention and treatment of cognitive impairment. Although laser therapy on human tissue has been used for a number of medical conditions since the late 1960s, it is only recently that several clinical studies have shown its value in raising neurometabolic energy levels that can improve cerebral hemodynamics and cognitive abilities in humans. The rationale for this approach, as indicated in this report, is supported by growing evidence that neurodegenerative damage and cognitive impairment during advanced aging is accelerated or triggered by a neuronal energy crisis generated by brain hypoperfusion. We have previously proposed that chronic brain hypoperfusion in the elderly can worsen in the presence of one or more vascular risk factors, including hypertension, cardiac disease, atherosclerosis and diabetes type 2.
Although many unanswered questions remain, boosting neurometabolic activity through non-invasive transcranial laser biostimulation of neuronal mitochondria may be a valuable tool in preventing or delaying age-related cognitive decline that can lead to dementia, including its two major subtypes, Alzheimer's and vascular dementia. The technology to achieve significant improvement of cognitive dysfunction using LLLT or variations of this technique is moving fast and may signal a new chapter in the treatment and prevention of neurocognitive disorders.
•A neuronal energy crisis leading to cognitive decline is proposed.•ATP bioenergetic failure is generated by chronic brain hypoperfusion.•Low level laser therapy applied transcranially can restore ATP to delay cognitive decline.
The vascular hypothesis of Alzheimer's disease (AD) which we first proposed in 1993, has become a useful concept in identifying vascular risk factors for AD or vascular dementia that can be modified ...through appropriate treatment to prevent, reduce or delay the onset of cognitive impairment and dementia onset. Among the more than two dozen vascular risk factors already identified for AD, are cardiovascular disease and carotid artery atherosclerosis, which may exert their pathology by chronically lowering cerebral hypoperfusion during aging. We propose and plan to initiate a clinical study to screen middle-aged, cognitively intact individuals, with carotid artery ultrasound and echocardiography to identify potentially progressive pathology in the heart and carotid artery that is considered modifiable with optimal medical treatment. This clinical strategy, if found effective in preventing pathologic conditions suspected of contributing to severe cognitive impairment, could significantly reduce AD prevalence if applied on a wide scale and help promote healthier mental and physical aging while providing a compelling economic benefit to society.
There is now substantial evidence that cerebral blood flow (CBF) declines with age. From age 20 to 60, CBF is estimated to dip about 16% and continues to drop at a rate of 0.4%/year. This CBF dip ...will slowly reduce oxygen/glucose delivery to brain thus lowering ATP energy production needed by brain cells to perform normal activities. Reduced ATP production from mitochondrial loss or damage in the wear-and-tear of aging worsens when vascular risk factors (VRF) to Alzheimer's disease develop that can accelerate both age-decline CBF and mitochondrial deficiency to a level where mild cognitive impairment (MCI) develops. To date, no pharmacological or any other treatment has been successful in reversing, stabilizing or delaying MCI. For the first time in medical interventions, a non-pharmacological, non-invasive, well-tolerated, easy to perform, free of significant side effects and cost-effective treatment may achieve what virtually all AD treatments in the past have been unable to accomplish. This intervention uses transcranial infrared brain stimulation (TIBS), a form of photobiomodulation (PBM). PBM is a bioenergetic non-ionizing, therapeutic approach using low level light emission from laser or light emitting diodes. PBM has been used in a number of neurological conditions including Parkinson's disease, depression, traumatic brain injury, and stroke with diverse reported benefits. This brief review examines the impact of reduced energy supply stemming from chronic brain hypoperfusion in the aging brain. In this context, the use of TIBS is planned in a randomized, placebo-controlled study of MCI patients to be done at our University Clinic.
This article is part of the special issue entitled ‘The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders’.
•There is now mounting evidence that cerebral blood flow declines with age.•Reduced ATP production from mitochondrial loss or damage worsens with vascular risk factors to Alzheimer's disease.•Phosphobiomodulation has been used successfully in Parkinson's disease, traumatic brain injury, depression and stroke.•Amnestic MCI is basically an impairment in learning and retaining new information.•Axonal transport of vesicular cargo normally declines with age.
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