Deciphering Alzheimer's Disease Pathogenic Pathway: Role of Chronic Brain Hypoperfusion on p-Tau and mTOR.

This review examines new biomolecular findings that lend support to the hemodynamic role played by chronic brain hypoperfusion (CBH) in driving a pathway to Alzheimer's disease (AD). CBH is a common clinical feature of AD and the current topic of intense investigation in AD models. CBH is also the basis for the vascular hypothesis of AD which we originally proposed in 1993.

Hemodynamic Instability in Heart Failure Intensifies Age-Dependent Cognitive Decline.

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.

Can mild cognitive impairment be stabilized by showering brain mitochondria with laser photons?

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.

Treating cognitive impairment with transcranial low level laser therapy.

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.

Are Major Dementias Triggered by Poor Blood Flow to the Brain? Theoretical Considerations.

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).

Cerebral Perfusion Enhancing Interventions: A New Strategy for the Prevention of Alzheimer Dementia.

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.

In-house heart-brain clinics to reduce Alzheimer's disease incidence.

The incidence rate in Alzheimer's disease (AD) is expected to quadruple worldwide by 2050. To limit this impending socio-medical calamity, a fulcrum change from how AD is presently managed is crucial. The present approach has not averted the stress of AD on medical resources nor reduced the already cost-strained government health care programs.

Vascular risk factors: a ticking time bomb to Alzheimer's disease.

Evidence is growing that vascular risk factors (VRFs) for Alzheimer's disease (AD) affect cerebral hemodynamics to launch a cascade of cellular and molecular changes that initiate cognitive deficits and eventual progression of AD. Neuroimaging studies have reported VRFs for AD to be accurate predictors of cognitive decline and dementia. In regions that participate in higher cognitive function, middle temporal, posterior cingulate, inferior parietal and precuneus regions, and neuroimaging studies indicate an association involving VRFs, cerebral hypoperfusion, and cognitive decline in elderly individuals who develop AD.

Cardiovascular risk factors promote brain hypoperfusion leading to cognitive decline and dementia.

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.

Cerebral hemodynamics and vascular risk factors: setting the stage for Alzheimer's disease.

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.

A turning point for Alzheimer's disease?

Despite an archive of over 73,000 research papers published in the last two decades on the subject of Alzheimer's disease (AD), little clinical progress has been made relative to how people get sporadic AD and what can be done to help them avoid it. This review spotlights strategic steps that could be a turning point in the dramatic lowering of Alzheimer prevalence. The main strategy includes application of four pillars of prevention: 1) early identification of AD vascular risk factors; 2) early detection of AD vascular risk factors; 3) early intervention of AD vascular risk factors based on evidence-based medical decisions; 4) patient follow-up to assess and modify interventions as needed.

Three postulates to help identify the cause of Alzheimer's disease.

Two centuries ago, the German bacteriologist Robert Koch proposed three postulates to support a causal relationship between a specific microbe and an infectious disease. Similarly, three postulates are formulated here to help evaluate hypothetical proposals attempting to explain the pathogenesis of Alzheimer's disease (AD). The first postulate requires that the cause of AD precedes the cognitive decline and neurodegenerative pathology that characterize AD.

Vascular risk factor detection and control may prevent Alzheimer's disease.

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.

Alzheimer's disease is incurable but preventable.

The dramatic rising incidence and costs of Alzheimer's disease (AD) require that research efforts and funding be primarily directed on either finding a cure or applying preventive measures to curb this disorder. A cure for AD appears unlikely when significant cognitive loss has occurred because the neuronal networks that controlled the perturbed cognitive abilities are either dead or irreversibly damaged and replacing them, even if it were technically possible, would not reconstruct the intellectual identity of the host. Prevention of risk factors to sporadic AD is a more realistic stratagem and treatment, when indicated, ideally should begin in cognitively intact individuals as part of a mass screening effort.

The vascular hypothesis of Alzheimer's disease: bench to bedside and beyond.

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.

Carotid artery ultrasound and echocardiography testing to lower the prevalence of Alzheimer's disease.

The use of two clinic office techniques, carotid artery ultrasound and echocardiography (CAUSE), to detect deficient brain blood flow delivery in the healthy, cognitively normal, older individual is proposed. Evidence indicates that persistent heart-to-brain blood flow deficit involving low cardiac output or low ejection fraction and carotid artery narrowing can promote cognitive impairment and that such impairment may lead to Alzheimer's disease (AD) or vascular dementia (VaD). A number of independent epidemiologic studies reported cardiovascular and cerebrovascular disease to be risk factors to AD and VaD.

Cerebrovascular and cardiovascular pathology in Alzheimer's disease.

Presently, compelling evidence indicates that Alzheimer's disease (AD) is a vascular disorder with neurodegenerative consequences and should be treated as such. A substantial body of evidence including epidemiological, pharmacotherapeutic, and neuroimaging studies support the concept of AD as a vascular disorder or vasocognopathy that initiates as brain hypoperfusion, creating a neuronal energy crisis. The neuronal energy crisis provokes the cellular and molecular changes that characterize this dementia.

Pharmacology of dimethyl sulfoxide in cardiac and CNS damage.

The pharmacological effects of dimethyl sulfoxide (DMSO) administration include some desirable properties that may be useful in the treatment of medical disorders resulting in tissue injury and compromised organ systems. These properties include the reported effects of DMSO on impaired blood flow, suppression of cytotoxicity from excess glutamate release that may result in lethal NMDA-AMPA activation, restriction of cytotoxic Na(+) and Ca(2+) entry into damaged cells, blocking tissue factor (TF) from contributing to thrombosis, reduction of intracranial pressure, tissue edema, and inflammatory reactions, and inhibition of vascular smooth muscle cell migration and proliferation that can lead to atherosclerosis of the coronary, peripheral, and cerebral circulation. A review of the basic and clinical literature on the biological actions of DMSO in cardiac and central nervous system (CNS) damage or dysfunction indicates that this agent, alone or in combination with other synergistic molecules, has been reported to neutralize or attenuate pathological complications that harmed or can further harm these two organ systems.