Ischemia and Loss of Vascular Autoregulation in Ocular and Cerebral Diseases: A New Perspective

In 4 rhesus monkeys fed an atherogenic diet for more than 12 years, 14 C-deoxyglucose was taken up by the outer retina substantially more than in younger animals on a normal diet, suggesting that either aging or atherosclerosis enhances retinal glycolytic energy production.

The ability to elevate perfusion in response to altered tissue needs, classically defined as metabolic autoregulation, exists in many tissues and is apparently well preserved in the healthy retina. First, it remains unclear if the human retina responds in like fashion to light and dark; studies using laser Doppler velocimetry suggest that dark adaptation substantially increases human retinal perfusion.

It remains possible though it has never been approached experimentally that some conditions of increased retinal energy demand exceed the vasodilatory capacity of retinal vessels, leading to tissue hypoxia. In this context, individual differences, aging effects, and vascular disease might increase the risk for ischemia perhaps in specific retinal regions 25 during episodes of elevated metabolic demand. More than 40 years ago, it was recognized from fundus photography that breathing pure oxygen caused a vasoconstriction of the larger retinal vessels, and that this vasoconstriction was blunted in patients with diabetes.

For example, it is unknown if persons experiencing arterial hypoxia eg, patients with chronic lung disease or people who venture to high altitudes suffer from a reduced retinal oxygen supply. The decisive factor for cerebrovascular smooth muscle is the arterial carbon dioxide tension; cerebral blood flow rises linearly and steeply over a wide PCO 2 range.

A summary of major questions regarding retinal blood flow autoregulation is given in Table 1. Autoradiographic studies of regional optic nerve head flow in cats find constant blood flow over a range of ocular perfusion pressure. Moreover, despite evidence for marked interindividual variation in the blood supply pattern of the optic nerve head, 7 , 57 , 58 the importance of these anatomic differences for optic nerve head pressure autoregulation is unclear.

In cerebral circulation, chronic hypertension shifts the autoregulatory plateau to a higher pressure range; 59 , 60 structural changes in the vascular endothelium enhance the capacity for vasoconstriction. These structural changes reduce the ability to vasodilate when perfusion pressure falls.

Such changes could help explain the apparent propensity of older persons to glaucomatous damage under conditions of reduced perfusion pressure. The effects of aging and atherosclerosis on optic nerve head pressure autoregulation have recently been studied in old monkeys maintained on an atherogenic diet. When subjected to increased IOP that reduced directly measured ocular perfusion pressure to 30 mm Hg, these monkeys showed increased 14 C-deoxyglucose uptake in the optic nerve head, suggesting increased anaerobic glycolysis.

Animal studies using the laser Doppler flowmeter and flickering light find that optic nerve head perfusion rises 2- to 3-fold over steady light conditions.

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Patients with glaucoma exhibit decreased optic nerve head perfusion 69 and higher levels of 3 isoforms of nitric oxide synthase locally, 70 suggesting that excessive amounts of nitric oxide, perhaps synthesized in response to blood flow deficiency, may in turn be neurodestructive in this illness. As in the retina and whole brain, increasing and decreasing arterial oxygen content fosters reciprocal changes in perfusion within the optic nerve head.

Retinal and optic nerve head blood flow regulation mirrors cerebral circulatory regulation: These general statements, however, are oversimplifications, and critical aspects of retinal and optic nerve head blood flow control remain inadequately explored. These include, 1 aging and atherosclerosis, whose well-defined cerebral circulatory effects, if replicated in the eye, could predictably lead to a pathologic condition; 2 IOP elevation and arterial pressure reduction, which may act synergistically as risk factors for reduced ocular perfusion; and 3 the possibility that individual variation in regulation possibly linked to different vessel architecture 7 , 57 , 58 could increase disease susceptibility.

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Exploration of these and other issues regarding hemodynamic control in the eye will increase understanding of both disease mechanisms and potential routes to therapy. Invest Ophthalmol Vis Sci. Graefes Arch Clin Exp Ophthalmol. Invest Opthalmol Vis Sci. Trans Am Clin Climatol Assoc. Clin Exp Pharmacol Physiol. Aviat Space Environ Med.

Reference values of arterial oxygen tension in the middle-aged and elderly. J Am Soc Nephrol. Laser doppler flowmetry measurement of changes in human optic nerve head blood flow in response to blood gas perturbations. Privacy Policy Terms of Use. Mechanisms of Ophthalmic Disease. Response to Oxygen and Carbon Dioxide. As a consequence, these individuals are given antihypertensives for the rest of their lives which can lower their blood pressure subnormally.

It must be remembered that in the aging individual, diastolic hypotension can not only introduce cerebral hypoperfusion, but also the prospect of AD [ 9 ]. The best way to avoid falsely treating WCH is for physicians to place the new patient on the recumbent position and measure blood pressure several times during a 30 minute visit. The other side of the coin is not treating moderate or high hypertension or preventing hypotension, and this choice can lead to cardiac and cerebrovascular complications and the threat of death.

For these reasons, more studies are rapidly needed that can guide the practitioner in managing a patient with blood pressure anomalies.

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Heart failure is a condition in which the heart can not adequately pump enough blood to meet the body's needs. It is marked by weakness, tissue edema, and shortness of breath. The most common cause of heart failure occurs from stenosis of the coronary arteries which supply oxygen to the heart. Heart failure is often associated with other comorbid vascular risk factors for AD including ischemic heart disease, hypertension, and atrial fibrillation [ 45 ]. Brain hypoperfusion is a common outcome of heart failure [ 9 ]. As blood flow pumped out of the heart slows down, returning venous blood to the heart backs up, causing tissue edema particularly in the lungs.

Heart failure is the most common reason for hospitalization among older adults [ ] and has been reported to worsen cognitive impairment [ ] and increase the risk of AD. A recent report by Alves and her colleagues [ ] indicates that heart failure in elderly persons is associated with lowered cerebral blood flow in the posterior cingulate gyrus and the lateral temporoparietal cortex, regions that are linked to memory and visuospatial orientation. This finding is of interest since memory and visuospatial dysfunction are two of the earliest signs in imminent AD.

Although CBF and cognitive function is reduced in heart failure, this syndrome can improve following implantation of a pacemaker in patients with bradycardia or from the use of selective cardiovascular agents [ ]. Clearly, aggressive treatment of heart failure to reverse brain hypoperfusion could have a significant impact in reducing the incidence of AD in these patients. Coronary artery disease CAD is the single leading cause of mortality in the United States, resulting in over , deaths annually.

CAD is associated with a decreased blood supply to the heart, also known as ischemic heart disease. This happens when the arteries that supply blood to the heart muscle become hardened and narrowed due to a build-up of subintimal fatty deposits called plaques.

Cardiovascular Risk Factors Promote Brain Hypoperfusion Leading to Cognitive Decline and Dementia

These atheromatous plaques are made up of a chemical bouillabaisse that includes cholesterol, fatty compounds, inflammatory cells, calcium, and fibrin. Plaques are the basis of atherosclerosis in coronary, peripheral, or cerebral blood vessels. When a plaque suddenly ruptures, platelets aggregate around it inducing intraluminal thrombosis or increased narrowing of the vessel, a condition that can result in myocardial infarction or stroke.

The use of platelet deaggregators such as aspirin and clopidogrel or cilostazol, a phosphodiesterase type 3 inhibitor that can widen vessel lumen to increase blood flow, has been used to prevent cognitive dysfunction after intraarterial plaque rupture. Stroke and CAD are known to reduce brain blood flow and potentially impair cognitive function, and both are reported to be vascular risk factor for AD [ 78 , ]. The risk to AD could stem primarily from atherosclerotic coronary vessels that damage endothelial cells and lower the heart's pumping ability to optimally perfuse the brain.

This thinking is supported by the presence of high levels of cholesterol, low density lipoprotein and triglycerides found in the blood of probable AD subjects [ ]. A number of studies are now in progress testing whether cholesterol homeostasis and lipoprotein disturbances using cholesterol-lowering statins can alter AD pathology. However, the results of these studies are inconclusive and controversial with regard to the potential neuroprotective effects of statins [ ].



Another approach we and others have recommended is to pharmacologically increase endothelial vascular nitric oxide, a powerful vasodilator with antithrombotic, anti-ischemic, and antiatherosclerotic activities [ ]. Carriers of the ApoE 4 allele may be at higher risk of cognitive decline because among other things, the presence of this gene predisposes to an increased risk of cardiovascular pathology [ ]. Aside from sharing many environmental risk factors for AD and for cardiovascular disease, there appears also to be an overlap between genetic risk factors for both conditions. Although the functional activity of ApoE 4 varies considerably, one association found in the Baltimore Longitudinal Study of Aging was that carriers of this genotype but not noncarriers had greater decline in cerebral blood flow in nondemented older adults [ ].

This decline in cerebral blood flow was observed in the frontal, parietal, and temporal cortices, which are the common brain regions initially affected in Alzheimer's disease [ ]. Aortic stiffening is associated with advanced aging and hypertension ribkin. Evidence indicates that cognitive impairment induced by damaged cerebral microcirculation can be induced by aortic stiffness [ ].

The damage to brain microvessels from aortic stiffening would occur as follows. The aorta is known to be a reservoir of pulsatile energy delivered by left ventricular ejection during systole and discharges that energy during diastole. Since the aorta is normally more compliant distensible than the stiffer carotid arteries, it is believed to absorb the ventricular ejection and dampen pulsatile flow into the distal vasculature, a hemodynamic condition called the Windkessel effect [ ].

The Windkessel effect is a protective mechanism that dampens excessive transmission of pulsatile flow that can damage the cerebral microvasculature [ ]. The normal proximal aorta consequently reduces aortic-carotid wave reflection, a physiologic event called impedance mismatch, that avoids excess transmission to the cerebral arterioles and capillaries. However, during aging, hypertension, or atherosclerosis, there is a loss of elastin which provides elasticity to the aorta, markedly reducing aortic compliance with the net effect of increasing pulse pressure and systolic pressure hypertension and reducing wave reflection at the carotid arteries.

This hemodynamic phenomenon is worsened in the presence of vascular risk factors [ ] Figure 2. When this happens, exaggerated pulsatile flow or pulse wave velocity is transmitted to microvessels in the brain where white matter hyperintensities and damage to endothelial cells that participate in controlling cerebral blood flow may result [ ].

This pathologic event assumes a mechanistic link between cerebral hypoperfusion and cognitive impairment whose primary trigger is loss of the Windkessel effect [ ]. Progressive increases of pulse wave velocity are theorized to result in increasing cognitive decline and eventual AD [ ]. Chronic brain hypoperfusion is not a disease but a sign that cerebral perfusion is functioning improperly. Cerebral blood flow is known to decline with aging and under normal circumstances in the absence of vascular disease will not result in significant cognitive loss [ 62 ].

To appreciate the clinical importance of developing suboptimal brain blood flow during advanced aging, it is important to point out that chronic brain hypoperfusion has been reported within the last few years to be a preclinical condition to mild cognitive impairment and a most accurate indicator for predicting whether people will develop AD [ 5 , 62 — 64 , 73 ].

The vascular hypothesis of Alzheimer's disease AD , which we proposed in [ ], has become a mother lode of interdisciplinary research involving mainly the brain, the heart, and the circulation [ — ]. The collective evidence supporting the vascular hypothesis offers the possibility of employing interventions that limit the effects of vascular risk factors on the heart and brain.

This action could prevent, delay, or reverse further progression of the inherent cognitive deterioration that often precedes AD and VaD [ ]. Following our vascular hypothesis proposal in [ ] we observed in [ ] that conditions such as advanced aging, a former head injury, and apoE 4 genotype became risk factors to AD by virtue of their potential to lower blood flow to the brain. Since then, several dozen heterogenous vascular risk factors to AD have been reported in the literature [ 16 , 64 , 73 , — ].

But, if chronic brain hypoperfusion is initially involved in AD, how does cardiovascular disease become a risk factor for AD? We believe that cardiovascular disease and the risk factors that characterize it promote brain hypoperfusion in the aging individual by inducing cerebral hemodynamic deficits and reducing blood flow to the brain through various vasculopathic pathways [ 17 ] Figure 2.

One likely pathway is the further burden that vascular risk factors add to the already reduced cerebral blood flow that is present as a result of aging [ 22 — 26 ]. This double burden on blood flow can readily lead to a neuronal energy crisis characterized by a cerebral hypometabolic state that can usher cognitive decline and dementia [ ]. The neuronal energy crisis is typically followed by progressive neuronoglial dysfunction and eventual neuronal death.

The crisis-dysfunction-death spectre begins in ischemic-sensitive zones such as the hippocampus and specific cortical areas [ ] and will be clinically expressed initially by mild memory impairment [ ] Figure 2. A relentless and progressive brain hypoperfusion can then spread to other parts of the brain where more ischemic-resistant neurons are slowly destroyed. This action is seen to spin out of control when additional cognitive impairment becomes full-blown AD.

An eloquent example of how dependent neurons and glia are metabolically coupled to regional brain blood flow is shown in a PET study using [ 18 F]fluorodeoxyglucose that mapped cerebral blood flow in normal human brain. That study found that within a vascular territory, measures of cerebral blood flow and glucose metabolic rate are practically linear [ ]. Moreover, this study revealed that the cerebellum, despite its significantly lower metabolic activity relative to the hippocampus, is as richly perfused as the hippocampus [ ].

This finding is strikingly compelling in explaining the subcellular changes and markers of damage that occur in the hippocampal neurons but not in the less-active cerebellar neurons prior to AD. What may occur here is that a neurono-glial crisis begins to build up following chronic brain hypoperfusion which in time is expressed by abundant deposition of amyloid-beta containing plaques Abeta and neurofibrillary tangles NFTs in the hippocampus an area critical for learning and memory but basically spares the cerebellum, even at an advanced stage of AD. This difference between abundant AD lesions in the hippocampus but not in the cerebellum is dependent on the separate metabolic activity discharged by each neuronal population and the fact that energy supply and demand is greater in the hippocampus than in the cerebellum.

These diverging metabolic activities expressing neuronal death markers in the hippocampus but not in the cerebellum may be due to two pathologic events occurring prior to AD neurodegeneration. The first pathologic event explains how cardiovascular disease is capable of inducing brain hypoperfusion and become an AD risk factor during aging.

Although energy consumption is much greater in the hippocampal neurons than those in the cerebellum, the glucose energy supply is similar to both neuronal populations. However, while the cerebellum is allowed to keep its neurons well-fed energetically, even when glucose delivery is reduced due to cardiovascular insufficiency, the hippocampal neurons struggle to survive with the same glucose deficiency that is parsimoniously available to all neurons from the hypoperfused state. This selective brain cell energy crisis is the direct result of blood flow supply not meeting energy demand in highly metabolically active neurons whose vascular reserve capability has reached its limits from persistent cerebral hypoperfusion [ ].

At this stage, hippocampal and cortical neurons undergo oxidative and endoplasmic reticulum stress that provide less ATP, the main energy fuel for cells [ ], necessary to maintain normal function required for cell survival. This activity negatively affects posttranslation processing steps resulting in impaired protein transport, synthesis, assembly, and folding.

Defects occurring during their synthesis, assembly, or folding can compromise the normal intracellular and extracellular secretory transport pathway, threatening brain cell survival that results in progressive cognitive decline [ 46 ]. A fundamental principle in cell biology is seen by the use of chemical energy in the form of ATP to assemble, disassemble, and alter protein structure. Since proteins do most of the work to keep neurons healthy, their proper production and folding are crucial for normal behavior, particularly involving learning and memory.

Protein misfolding is a process in which proteins are unable to attain or maintain their biologically active shape [ ]. Most proteins require assistance from molecular chaperones for proper folding [ ]. These chaperones are specialized proteins which protect other unfolded proteins from misfolding and clumping aggregating together extracellularly Figure 2.

Although protein folding is thought to be a spontaneous process not requiring energy input from nucleotide triphosphates [ ], the steps leading to it, involving transcription, translation, and protein synthesis, are energy dependent [ , ]. Given the complexity of the folding process, it is not surprising that things can go wrong particularly in the presence of reduced cerebral perfusion and lowered energy substrate delivery during advanced aging. Defects occurring during protein synthesis, assembly, or folding can compromise the normal intracellular and extracellular secretory transport pathway, threatening brain cell survival that results in progressive cognitive decline [ 46 ].

Protein cleavage abnormalities and reduced degradation of oxidized proteins by the ubiquitin-proteasome pathway may facilitate BACE-1 expression, the proteolytic enzyme responsible for generating Abeta peptide [ ]. This time-bound subcellular corruption climaxes with synaptic loss and neuronal death [ ].

The second pathologic event explains why there is a scarcity of amyloid plaques and NFTs in the cerebellum while substantial aggregation is seen in the hippocampus of AD brains. During chronic brain hypoperfusion, the cerebellum enjoys all the glucose it needs to supply its less energy-consuming neurons, while the energy-starved and highly active hippocampal neurons undergo progressive subcellular changes due to their greater demand for energy supply.

The neuronal bias that generates an unequal energy crisis in brain regions of high metabolic demand such as the hippocampus and lower metabolic activity such as the cerebellum is a testament to the argument that amyloid plaque aggregation is a product not a cause of selective neuronal energy failure [ , ]. Supporting this conclusion are studies by us [ , , ] showing that after chronic brain hypoperfusion in aging rats, memory loss, and a selective reduction of cytochrome oxidase, reflecting lower ATP activity, was found uniquely in the CA1 region of the hippocampus and in the posterior parietal cortex, two regions associated with memory function and the initial targets of AD neurodegeneration [ , ].

A more detailed description of this neuronal energy crisis inequity can be found in our previous publications [ 19 , , , , ]. Finally, much confusion has been generated surrounding the terms cerebral hypoperfusion and cerebral ischemia , when they have been used interchangeably in the literature. To avoid this confusion, the term cerebral hypoperfusion should be used to describe the relatively slow pathologic process involving months or years when brain perfusion is not commensurate with neurometabolic demand.

Can anything be done to slow down the total number of new AD cases expected in the next few decades? In our judgment [ — ] and those of others [ — , — ] and in the absence of finding a rapid cure for this dementia, preventive measures to lower the prevalence rate of AD and by default, VaD through the management of potential or actual risk factors is a reasonable clinical strategy.

A structured clinical approach can be employed for this purpose. It should be noted that ischemic heart disease or ischemic stroke are not the sole vasopathogenic triggers of AD. Many other vascular-related risk factors that increase the burden of age-related cerebral hypoperfusion also appear to accelerate the development of Alzheimer dementia, and these have been reviewed in other publications [ 6 — 8 ]. This is a theme that has not received wide-attention in the medical literature despite its obvious importance.

Based on cross-sectional and longitudinal epidemiologic studies involving mostly elderly subjects, a variety of cardiovascular-related risk factors to AD have been reported. Comorbid presence of two or more such risk factors tends to increase the probability of acquiring AD [ ]. When any or several of these risk factors, are discovered during clinical examination, the physician should be suspicious of actual or impending structural heart damage. Structural heart damage may involve aortic or mitral valve thickening, chronic valvular regurgitation, left ventricular wall motion abnormalities, ventricular filling defects, and left ventricular hypertrophy.

Structural heart damage can reduce cardiac output and ejection fraction or cardiac index thus directly affecting cerebral perfusion [ , ]. In addition, cardiac damage resulting in hemodynamic pump dysfunction can be the source of ischemic stroke or cerebral hypoperfusion [ 47 , ] which in the elder population frequently evolves into cognitive impairment [ ] and possible conversion to AD or VaD. Many of these cardiac risk factors, however, can be corrected or treated successfully if identified in time [ ].

For example, high blood pressure is a major risk factor for stroke and for heart failure and as we have noted, is also closely correlated with cognitive decline and dementia. Its treatment with anti-hypertensive drugs in the elderly has been shown to reduce cognitive decline and dementia [ ] and to partially counteract the risk of heart failure on dementia [ ].

The heart-brain connection to memory function can be appreciated from experimental data on rodents. We reported that during exposure to chronic brain hypoperfusion in aged rats, vulnerable brain cells initially undergo a hypometabolic state that reduces memory function while neurons remain structurally intact [ ]. Even after memory impairment is induced in these aged rats, the metabolically-compromised neurons can return to a normal state if and when cerebral perfusion is restored after 5 weeks following brain hypoperfusion [ ].

These findings indicate two important points: If this rat model is indicative of that which may occur in elderly humans who develop chronic brain hypoperfusion prior to AD, a therapeutic target focusing on brain blood flow insufficiency could be a major breakthrough. The notion of neuronal rescue from the hypoperfused state is supported by clinical findings in human brain [ , ]. It is also pertinent to note that brain hypoperfusion induced by cardiac pathology can promote not only VaD but also AD since these pathologic states pose important risk factors to both dementias [ ].

We have attempted to show in the present paper the association between chronic brain hypoperfusion and cardiovascular risk factors of AD in a crystallized fashion pointing out the major problems associated with cardiovascular pathology, cerebral hypoperfusion, and development of AD. Cerebral hypoperfusion following cardiovascular pathology during aging is a much neglected research topic in AD that deserves greater attention. It is crucial to note that cardiovascular risk is generally present prior to AD and that AD neurodegenerative lesions such as Abeta and NFTs are not essentially considered precursors or triggers of heart disease but may be more a manifestation of the neuronal energy crisis provoked by vascular risk factors to dementia.

The findings lend support to the design of therapeutic targets aimed at preventing chronic brain hypoperfusion and its consequential neural hypometabolism prior to the onset of cognitive symptoms or neuropathology during normal aging. The therapeutic blueprint will largely depend on early detection of low cerebral blood flow in asymptomatic individuals who present cardiovascular risks factors associated with progressive cognitve decline. National Center for Biotechnology Information , U. Journal List Cardiovasc Psychiatry Neurol v. Published online Dec 3.

Author information Article notes Copyright and License information Disclaimer. Received Aug 1; Accepted Oct This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This article has been cited by other articles in PMC. Abstract Heart disease is the major leading cause of death and disability in the world. Introduction It has been known since the Ebers papyrus [ 1 ] in BC, and probably even before then, that the brain and heart are intimately connected.

Cardiovascular Disease, Cognition, and Cerebral Autoregulation The original association between cardiac pathology and cognitive dysfunction described above as cardiogenic dementia was based on the high incidence of cardiac dysrhythmias seen in patients with dementia solely due to vascular causes [ 6 ].

Open in a separate window. Cardiovascular Disease as a Vascular Risk Factor to Alzheimer's Disease Epidemiological findings indicate that a broad spectrum of cardiovascular risk factors, including heart failure, thrombotic events, hypertension, hypotension, homocysteine, hypercholesterolemia, C-reactive protein, coronary artery disease, valvular disease, heart failure, apoE 4 , and atrial fibrillation are more common in the elderly. Low Ejection Fraction or Low Cardiac Output Ejection fraction a measure of stroke volume based on the dimensions of the left ventricle which is the main pumping chamber and refers to the percentage of blood that is pumped out of a filled left ventricle with each heartbeat contraction.

Atrial Fibrillation Atrial fibrillation is a heart rhythm disorder arrhythmia usually involving a rapid heart rate. Aortic and Mitral Valve Prolapse Few studies have examined the effects of myocardial valve damage and its possible effect on cognitive function. Hypotension Hypotension is a common clinical condition that commonly affects elderly persons over age Heart Failure Heart failure is a condition in which the heart can not adequately pump enough blood to meet the body's needs.

ApoE 4 Allele Carriers of the ApoE 4 allele may be at higher risk of cognitive decline because among other things, the presence of this gene predisposes to an increased risk of cardiovascular pathology [ ]. Aortic Stiffening Aortic stiffening is associated with advanced aging and hypertension ribkin. Cardiovascular Pathology Begets Chronic Brain Hypoperfusion Which Begets Progressive Cognitive Decline Chronic brain hypoperfusion is not a disease but a sign that cerebral perfusion is functioning improperly.

How Neuronoglial Energy Crisis Leads to AD Pathology An eloquent example of how dependent neurons and glia are metabolically coupled to regional brain blood flow is shown in a PET study using [ 18 F]fluorodeoxyglucose that mapped cerebral blood flow in normal human brain.

Slowing AD Prevalence Can anything be done to slow down the total number of new AD cases expected in the next few decades? Conclusions We have attempted to show in the present paper the association between chronic brain hypoperfusion and cardiovascular risk factors of AD in a crystallized fashion pointing out the major problems associated with cardiovascular pathology, cerebral hypoperfusion, and development of AD.

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Brain Physiology - Autoregulation of Blood Flow

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GLAUCOMA AND DEGENERATIVE CHANGES WITHIN THE CENTRAL VISUAL PATHWAY

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