Decreased Cerebrospinal Fluid Flow is Associated with Cognitive Decline
Many neurodegenerative conditions are associated with the accumulation of forms of metabolic waste in the central nervous system, protein aggregates that form solid deposits between or within cells. Tauopathies such as frontotemporal dementia are associated with tau aggregates, synucleinopathies such as Parkinson's disease with α-synuclein, and amyloidoses with varying forms of amyloid, such as the amyloid-β found in elevated amounts in Alzheimer's disease patients. Alzheimer's itself is an amyloidosis that also becomes a tauopathy in its later stages. These protein aggregates and their surrounding halos of harmful biochemistry disrupt normal brain function and, in the worse cases, kill neurons. Eventually they kill the patient.
With the exception of certain inherited conditions, in which cellular biochemistry is broken due to an unfortunate and unlucky mutation, why is it that protein aggregates form in significant amounts only in older individuals? This seems an important question to keep in mind when working towards therapies for neurodegenerative conditions. In Alzheimer's disease, amyloid-β builds up for a decade or more prior to the point at which its consequences become noticeable. But why? In recent years researchers have found ever more supporting evidence for the hypothesis that impaired drainage of cerebrospinal fluid is an important factor. Metabolic wastes in the brain can be carried away for disposal via the various pathways for drainage of cerebrospinal fluid. These pathways falter or become occluded with age, however, and the degree to which that happens in any given individual may well be an important determinant of risk of dementia.
Several groups are working on approaches to the treatment and prevention of neurodegenerative conditions based on the impaired drainage hypothesis. Some of these lines of work have left the laboratories and entered commercial development. To pick two examples, Leucadia Therapeutics is quite far along towards means of restoring cerebrospinal fluid drainage through the cribriform plate, while EnClear Therapies is working on filtration of harmful metabolic waste from cerebrospinal fluid in a process akin to apheresis of blood. We can hope that these first efforts will be joined by others in the years ahead, and also hope that means of rejuvenation that target the underlying molecular damage of aging will prove to at least partially reverse loss of drainage of cerebrospinal fluid.
Decreased Cerebrospinal Fluid Flow Is Associated With Cognitive Deficit in Elderly Patients
The cerebrospinal fluid (CSF) is an important part of the central nervous system, as it allows exchange of water, small molecules, and proteins between the brain parenchyma and arterial and venous blood, by either passive diffusion or active transport. The CSF therefore plays an important role in regulating brain homeostasis, waste clearance, as well as intracranial pressure and blood supply. During aging, CSF turnover can be disrupted which could contribute to the etiology of age-related neurocognitive disorders. Several studies revealed that patients with Alzheimer's disease (AD) have disrupted CSF pressure, turnover, and oscillations. Moreover, biomarkers for AD are found in the CSF, and their abundance was shown to have predictive value for clinical progression.
The increase of intracranial pressure during the cardiac cycle causes a flow from the blood and brain interstitial fluid to the CSF, and a net CSF flow toward its extracerebral compartment and venous blood. Since this CSF flow is important for protein clearance from the brain, it is possible that impaired CSF flow could be associated with cognitive decline. Moreover, CSF flow is linked with brain perfusion, defects of which are known causes of neurocognitive disorders in the elderly. A number of studies suggested that the choroid plexus and the ventricular walls degenerate with the progression of AD, but none could determine whether disrupted CSF flow causes cognitive decline, or whether it is a by-product of AD or normal aging.
To the authors' knowledge, there are no published studies that investigated the relationship between CSF flow alterations and cognitive deficit in the elderly, adjusting for cardiovascular risk factors for the development of neurocognitive disorders. The purpose of this study was therefore to evaluate the association of CSF flow in the brain ventricles and cervical spine with cognitive deficit in a cohort of elderly patients admitted to our geriatric unit for non-acute reasons. The hypothesis was that reduced CSF flow would be associated with cognitive deficit.
The cohort comprised 71 women and 21 men, aged 73 to 96 years. Patients with lower CSF flow had significantly worse memory, visuo-constructive capacities, and verbal fluency. It is therefore possible that CSF flow alterations are responsible for at least a part of the cognitive deficit observed in our patients. Better diagnosis and treatment of CSF flow alterations in geriatric patients suffering from neurocognitive disorders is therefore recommended.
I have a comment if they are still open.
My comment did not make it the first time. So here goes.
There is a plant medicine used among native tribes in the Amazon that the claim helps them to have better night vision. I have tried it. It is administered via eye drops. It is not a pleasant experience, but the impression it gives me is that it stimulates the flow of CSF. I would love to find if that is the case
The following hypothesis explains how an impaired pumping mechanism for the flow of cerebrospinal fluid occurs and is the primary cause of Alzheimer's disease..
The wide-ranging hypothesis outlined below offers a related pathogenesis for the development of Alzheimer's disease, type 2 diabetes and vascular disorders which leads to the identification of prophylactic preventative measures for reducing the risk of developing those disorders. This information may be of interest to you.
As indicated in the hypothesis, precursor infrastructure damage (i.e. atherosclerosis) which will eventually cause onset of Alzheimer's disease (AD) and type 2 diabetes gradually builds up in the brain and everywhere else in the human body starting from an early age and the damage is irreversible so there is no possible cure for the resulting disorders. Therefore, the only really effective strategy for combating those disorders is preventative prophylactic action started from the earliest possible age which would reduce the risk of developing them by slowing down the build-up of the infrastructure damage and starting to do that as soon as possible to minimize the damage that has already occurred.
The hypothesis describes prophylactic measures for effective preventative action. It also identifies the biomarker described below which would enable people to monitor their risk of developing AD and type 2 diabetes up to many years in the future and thus be able to assess the effectiveness of improvements in their lifestyle, diet and prophylactic therapy at an early enough time in life to effectively minimize the risk of developing those disorders
The hypothesis shows that the level in blood of plasma total homocysteine is a biomarker for the rate that precursor infrastructure damage is building up in the brain and everywhere else in the human body to eventually cause the onset of Alzheimer's disease, type 2 diabetes and/or a range of different vascular disorders. Achieving and maintaining a low monitored level of that biomarker not exceeding 10 micromoles per litre and ideally a level of about 4 micromoles per litre starting from the earliest possible age before much precursor damage has already occurred will minimize the risk of developing Alzheimer's disease and the other disorders in later life.
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The following summary explains how the stress hormones cortisol, epinephrine and norepinephrine promote the cleavage of elastic polypeptide chains and their associated disulfide bridges in the walls of the arteries to cause a gradual build-up of atherosclerosis as a precursor for the development of other vascular disorders, of type 2 diabetes and of Alzheimer's disease.
Cortisol promotes the presence of BACE 1 which cleaves peptide bonds in the polypeptide chains to produce amyloid beta as a misfolded protein remnant of the cleavage process while a COMT reaction with epinephrine or norepinephrine breaks the disulfide bond in connected disulfide homocysteine bridges to produce total homocysteine which consists of homocysteine that is primarily still bonded to other protein remnants from cleavage of the polypeptide chains by BACE 1.
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The following hypothesis outlines the pathology for development of vascular disorders, type 2 diabetes and Alzheimer's disease:
An observed correlation between cortisol and increased risk of vascular disorders, type 2 diabetes & Alzheimer's disease occurs because cortisol promotes production of the enzyme BACE 1 which then cleavages elastic polypeptide chains in the walls of the arteries when the disulfide bond in the connected disulfide homocysteine bridges is broken in a COMT reaction with norepinephrine and epinephrine.
The resulting artery damage and loss of elasticity causes stiffening of the artery walls that impairs the mechanism for pumping and circulation of pancreatic fluid and of CSF which eventually results in the onset of type 2 diabetes and Alzheimer's disease. The following reference describes the relationship between cortisol and BACE 1:
"Membrane-Associated Effects of Glucocorticoid on BACE1 Upregulation and Aβgeneration: Involvement of Lipid Raft-Mediated CREB Activation" jJ Neuroscience, Aug 30, 2017
(In light of the foregoing information it is possible that a daily prophylactic dosage of Actinogen Medical's drug, Xanamem, which inhibits production of cortisol, might potentially reduce the risk of developing type 2 diabetes and Alzheimer's disease if the daily dosage was started at an early enough age.)
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The Vascular Hypothesis: (The pathology of atherosclerosis as a precursor for other vascular disorders, for Alzheimer's disease and for type 2 diabetes.)
Elastic polypeptide chains in the inside walls of arteries everywhere in the body are cleaved by the enzyme beta-secretase (BACE 1) when the disulfide bond in connected disulfide homocysteine bridges is broken in a COMT reaction with norepinephrine and epinephrine released from the adrenal glands into the blood stream. BACE 1 together with norepinephrine and epinephrine released directly into the pancreas from the adrenal glands to regulate the insulin/glycogen ratio and promote release of insulin does the same type of damage to the outside walls of arteries in the pancreas. Also, BACE 1 together with epinephrine (and/or dopamine) released from neurons in some areas of the brain does the same type of damage to the outside walls of arteries in those areas of the brain. Therefore, in the pancreas and in some areas of the brain both the inside and the outside walls of the arteries incur a gradual concurrent build-up of ongoing damage. Beta amyloid is the misfolded protein remnant of cleaved elastic polypeptide chains from the walls of the arteries and plasma total homocysteine in the blood is produced as a cleaved product which includes homocysteine from the broken disulfide homocysteine "bridges". Also, in the transferase reaction norepinephrine and epinephrine are transformed into normetanephrine and metanephrine which can be recovered from the blood or from the urine.
Atherosclerosis gradually builds up in the arteries as a result of the damage done by BACE 1, norepinephrine and epinephrine and causes the development of hypertension. Under increased blood pressure from hypertension the weakened walls of the damaged arteries may break down thus creating an increased risk for aneurysms and hemorrhages.
Beta amyloid and cholesterol would be unlikely to adhere to the continually flexing smooth walls of pulsating healthy elastic arteries and would probably be washed away in the flow of blood rather than building up as deposits that tend to clog the arteries, Therefore a significant build-up of atherosclerosis from artery damage by BACE 1, norepinephrine and epinephrine probably has to harden and roughen the artery walls, reduce their flexing and also reduce the cleansing flow of blood as a precursor for a significant build-up of beta amyloid and cholesterol in the arteries to create an increased risk for cardiovascular disease, strokes and vascular dementia.
Mental, physical and chemical types of stress, an unhealthy lifestyle and diet and a metabolic magnesium deficiency are all factors that tend to promote the release of cortisol, norepinephrine and epinephrine thus accelerating the build-up of atherosclerosis for an increased risk of developing the resulting disorders during a person's lifetime. Some examples of chemical stress are tobacco smoking, vaping, consumption of alcohol, coffee & salt and exposure to herbicides and pesticides.
The role of BACE 1, norepinephrine and epinephrine in the pathology for Alzheimer's disease is explained in the following hypotheses. (Type 2 diabetes also develops in a similar manner from vascular damage in the pancreas by cortisol, norepinephrine and epinephrine released from the adrenal glands directly into the pancreas.)
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Alzheimer's Hypothesis
The enzyme beta-secretase BACE 1 together with norepinephrine released in the cortex of the brain breaks down elastic polypeptide chains and associated disulfide homocysteine "bridges" in the outside walls of arteries in the cortex of the brain while BACE1 together with both norepinephrine and epinephrine in the blood stream do the same type of damage to the inside walls resulting in a gradual build-up of atherosclerosis in those arteries. The extent of atherosclerosis that has built up over many years significantly restricts the flow of blood through the arteries causing Alzheimer's brains to shrink from a lack of nourishment and the beta amyloid deposits that form in Alzheimer's brains are the misfolded protein remnants of cleaved polypeptide chains from the outside walls of the damaged arteries. Mental, physical and chemical types of stress, an unhealthy lifestyle and diet and a metabolic magnesium deficiency are all factors that tend to promote the release of cortisol, norepinephrine and epinephrine thus accelerating the build-up of atherosclerosis for an increased risk of developing early onset Alzheimer's disease. Some examples of chemical stress are tobacco smoking, vaping, consumption of alcohol, coffee & salt and exposure to herbicides and pesticides.
Cerebrospinal fluid (CSF) is pumped through aquaporins wound in a covering spiral over the arteries in the brain and under blood pressure, an expansion bulge travels through the elastic arteries as each pulse of blood passes through them and the bulge pushes ahead of it the CSF contained in the aquaporins. In this way, the pulsating elastic expansion and contraction of healthy arteries pressing against the covering of aquaporins provides a pumping mechanism for the flow of CSF through the aquaporins and its circulation throughout the individual areas of the brain served by each artery.
As atherosclerosis builds up in the arteries their walls stiffen and cause the pumping action for circulation of CSF to become reduced due to a loss of pulsating arterial expansion and contraction. The build-up of beta amyloid deposits in the brain also tends to obstruct the circulation of CSF; therefore, the circulation of CSF becomes impaired both by the build-up of beta amyloid deposits and by a steadily decreasing pumped volume of CSF through the aquaporins. (A reduced circulation of CSF due to developing atherosclerosis may be a precursor to the build up of beta amyloid deposits in the brain because a healthy circulation of CSF would tend to wash away beta amyloid material as it is being produced.)
At the start of each activity cycle, neurons in the brain emit a K+ ion and thus acquire an internal negative electrical charge. During recovery from activation a neuron which still retains its negative internal charge before achieving electrical equilibrium will undergo an excitotoxic seizure and be destroyed if it happens to capture a nearby K+ ion which has not been washed far enough away by the circulation of CSF. The circulation of CSF in healthy brains establishes a virtually negligible probability for the capture of K+ ions but the statistical probability for capture of K+ ions during recovery from activation increases exponentially in areas of the brain where the circulation of CSF becomes impaired.
An impaired inadequate circulation of cerebrospinal fluid and the resulting destruction of neurons is the direct cause of Alzheimer's disease. A reference which confirms the destruction of neurons by an impaired circulation of CSF is:
Delayed K+ clearance associated with aquaporin-4 mislocation: Phenotypic defects in brains of α-syntrophin-null mice." Proceedings of the National Academy of Sciences Vol.100 No. 23 13615-13620 Amiry-Moghaddam et al
The tau tangles that form in Alzheimer's brains are the remnants of destroyed neurons.
Brain plasticity is so effective in programming repairs which bypass destroyed neurons that the first symptoms of cognitive impairment only become apparent after too much extensive vascular damage and resulting neuron destruction has already taken place making it impossible to effect a cure for the disease. However, in addition to living with a healthy lifestyle and diet starting from the earliest possible age the incidence of Alzheimer's disease could be significantly reduced in future by the development of a daily prophylactic therapy which would restrict the release of cortisol, norepinephrine and epinephrine and thus slow down the build-up of atherosclerosis in the intracranial arteries. Ideally, such a healthy living program and prophylactic therapy should be commenced at an early age, typically before age 30. A daily supplement of magnesium-L-threonate and vitamins D, B6, B12 and folic acid, possibly accompanied by a dosage of the drug Xanamem might serve as the starting point for development and clinical trials of such a prophylactic therapy. (The same healthy living program and prophylactic therapy could also reduce the incidence of type 2 diabetes and vascular disease.)
The level in blood of plasma total homocysteine and/or of plasma amyloid beta is a biomarker for the rate at which atherosclerosis is building up in the arteries to increase the risk of developing early onset Alzheimer's disease. The development of a reasonably priced capability for monitoring such a biomarker would allow people to assess the effectiveness of the prophylactic therapy and to adjust their diet, lifestyle and medication etc to minimize the risk of developing early onset Alzheimer's disease in future. Also, in clinical trials of new therapeutic measures under evaluation that is the biomarker evidence which could provide the verification of effectiveness.
Some interesting conclusions that can be drawn from the hypothesis are noted as follows:
The hypothesis indicates that everyone who survives to an old enough age will eventually succumb to Alzheimer's disease which is the limiting factor that determines the maximum possible human lifespan. This is exemplified by the Mormon population in the state of Utah who have the highest incidence of late onset Alzheimer's disease in the USA because their healthy lifestyle and diet contributes to longevity. The reason why Alzheimer's disease tends to pass down from one generation to another in some families is not necessarily an inherited genetic trait but may occur because children tend to adopt a lifestyle and diet that matches the example set by adult family members, however a metabolic magnesium deficiency might be an inherited trait that predisposes to increased Alzheimer's risk.
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Type 2 Diabetes
The pathogenesis for type 2 diabetes is virtually identical to the pathogenesis for Alzheimer's disease (AD) which is caused by an increasingly impaired circulation of cerebrospinal fluid that results in an increasing statistical probability for neurons to undergo a seizure during their recovery from activity and become destroyed. In type 2 diabetes an impaired circulation of pancreatic fluid results in a similar probability for the destruction of cells in the pancreas during their recovery from activity. The observed formation of beta amyloid and tau both in Alzheimer's brains and in the pancreas of type 2 diabetics is evidence supporting the concept that both disorders develop in parallel from the concurrent build-up of identical precursor vascular damage. However, because of the brain's plasticity which repairs damage and an additional excessive sugar intake factor that increases damage in the pancreas, the onset of type 2 diabetes typically occurs earlier than onset of AD, often leading to the mistaken concept that type 2 diabetes somehow promotes development of AD.
The hypothesis also shows that a high sugar diet would be well tolerated in young people and destructive in old people because the build-up of precursor damage as a person ages creates an increasing statistical probability for destruction of cells in the pancreas (and of neurons in the brain) during the time that the cells and the neurons are recovering from activity. Therefore, the most active cells and neurons are at greatest risk of destruction. In a young pancreas the statistical probability of cell destruction during recovery from activity is negligibly small so a high sugar diet that increases cell activity causes negligible destruction of cells in the pancreas. However, in an old-age pancreas with a significant probability of cell destruction during recovery from activity a high sugar diet makes a significant contribution to cell destruction in the pancreas. Therefore, to reduce the risk of type 2 diabetes, the increasing probability for cell destruction as a person ages has to be slowed down as suggested in th.e hypothesis for Alzheimer's disease and also people need to gradually reduce their sugar intake after about age 30 to 40.
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As noted in the hypothesis and also reported in published manuscripts, a metabolic magnesium deficiency increases the risk of developing vascular disease, type 2 diabetes and Alzheimer's disease .. Other published manuscripts also show that the APOEe4 gene increases the risk of developing those same disorders. Therefore, it is suggested that the APOEe4 gene may promote a metabolic magnesium deficiency as its mechanism for increasing the risk of developing vascular disease, type 2 diabetes and Alzheimer's disease. However, apparently no studies have been undertaken to determine if the APOEe4 gene correlates with a metabolic magnesium deficiency that might be a subject for worthwhile future study
Interesting in that patient's with SIH (spontaneous intracranial hypotension) are noted to have cognitive and memory deficits. This can occur in all age groups, Average age of onset is around 40-45 but can occur at any age. .