The role of cerebral blood flow in the pathogenesis of Alzheimer's Disease Dementia
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Abstract
Aging is accompanied by a decrease in cerebral blood flow (CBF), especially in the presence of preclinical cognitive decline. The role of cerebrovascular physiology including regulatory mechanisms of CBF in processes underlying aging and subclinical cognitive decline is, however, not fully understood. We explored changes in cerebrovascular CO2 reactivity and dynamic cerebral autoregulation (dCA) through the eighth decade of life, and their relation with early cognitive decline. After 10.9 years, twenty-eight (age, 80.0 3.5 years; 46% female) out of forty-eight healthy older adults who had participated in a previous study (age at baseline, 70 4 years; 42% female), underwent repeated transcranial Doppler assessments. Linear mixed-model analyses revealed small reductions in cerebrovascular CO2 reactivity with aging (0.37%/mmHg, P ¼ 0.041), whereas dCA was modestly enhanced (gain: 0.009 cm/s/mmHg, P ¼ 0.038; phase: þ8.9 degrees, P ¼ 0.004). These changes were more pronounced in participants who had developed subjective memory complaints at follow-up. Our observations confirm that dCA is not impaired in aging, despite lower cerebral perfusion and cerebrovascular reactivity. Altogether, this unique longitudinal study highlights the involvement of cerebrovascular health in preclinical cognitive decline, which is of clinical relevance in the development of dementia management strategies.I have penchant for infographics.
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Dr. Peat has talked about the benefits of living at high altitudes (up to 14,000 ft). The increased retention of carbon dioxide at high altitudes has several health benefits, including reduced stress reactions, lower cancer and heart disease mortality rates, and protection against aging-related diseases. The "lactate paradox" and the Haldane effect are key mechanisms through which these benefits are realized.
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Two papers from the 1940s.
THE LAWS OF COMBINATION OF H1E: MOGLOBIN WITH CARBON MONOXIDE AND OXYGEN. BYC. G. DOUGLAS, B.M., J. S. HALDANE, M.D., F.R.S.,AND J. B. S. HALDANE,
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@DavidPS said in The role of cerebral blood flow in the pathogenesis of Alzheimer's Disease Dementia:
Dr. Peat has talked about the benefits of living at high altitudes (up to 14,000 ft). The increased retention of carbon dioxide at high altitudes has several health benefits, including reduced stress reactions, lower cancer and heart disease mortality rates, and protection against aging-related diseases. The "lactate paradox" and the Haldane effect are key mechanisms through which these benefits are realized.
Tangled up in this topic of cerebral blood flow, Alzheimer's Disease, and carbon dioxide is vitamin B1 (thiamine). Blood flow is facilitated by nitric oxide acting on the vessels. Thiamine is key for proper nitric oxide function. see here: Thiamine deficiency leads to reduced nitric oxide production and vascular dysfunction in rats "Thiamine deficiency modulates eNOS-dependent NO production, leading to a decreased vasorelaxation and an increased contractile response in the rat aorta."
In efficient oxidative metabolism, ATP is made and carbon dioxide is the end byproduct. Thiamine acts as a co-factor for several enzymes used in this process. If thiamine is deficient, oxidative metabolism is derailed and lactic acid is the end byproduct instead of carbon dioxide. In addition, Thiamine is considered a carbonic anhydrase Inhibitor. So poor thiamine status definitely negatively effects carbon dioxide levels in more than one way.
As people age, the ability to absorb thiamine through the intestinal wall diminishes which leads to a greater likelihood of thiamine deficiency. Thiamine deficiency is now believed to be a major factor in all the dementias, including Alzheimer's.
Vitamin B1 (thiamine) and dementia
"Glucose metabolism in the brain, like in other tissues, requires thiamine at critical regulatory steps and has unique features:
Thiamine-dependent enzymes act at key steps of glucose metabolism: transketolase in the pentose shunt, pyruvate dehydrogenase complex (PDHC) linking glycolysis and the tricarboxylic acid (TCA) cycle, and the α-ketoglutarate dehydrogenase complex (KGDHC) in the TCA cycle. Glucose metabolism in the brain is unique in that it is much higher than in other tissues. The brain represents only 2% of body mass, but it uses 20% of the glucose. The high rate of metabolism may account for the brain's sensitivity to thiamine deficiency. Another unique feature of brain glucose is that it also provides substrates for the synthesis of multiple neurotransmitters, including both glutamate and acetylcholine. The two major types of cognitive drugs approved for the treatment of AD interact with these two neurotransmitters, as epitomized by memantine (Namenda) and cholinesterase inhibitors (e.g., donepezil). Current methods to assess brain metabolism are limited. For example, [18F]FDG PET only measures the first step of metabolism, and it is likely that other changes precede alterations measured by [18F]FDG PET.
Thiamine-dependent enzymes play key and sometimes rate-limiting roles in metabolism. For example, as mentioned above, transketolase plays a key role in the pentose shunt, PDHC links glycolysis to the TCA cycle, and KGDHC is often the rate-controlling step in the TCA cycle. Thus, a deficiency of thiamine would have a profound effect on glucose metabolism. The deficiency in glucose metabolism in Wernicke syndrome can be reversed by addition of thiamine. This suggests that, if the deficits in AD are related to thiamine deficiency, they could also be reversed by appropriate administration of thiamine."
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@mostlylurking - Thanks, I look at images of Alzheimer's brains and think that the brain is chronically malnourished. The entire brain looks withered. I might be doue to diminished blood flow, inadequate dietary nutrients, or just too many bad lifestyle choices.
The deficiency in glucose metabolism in Wernicke syndrome can be reversed by addition of thiamine. This suggests that, if the deficits in AD are related to thiamine deficiency, they could also be reversed by appropriate administration of thiamine."
It is very encouraging that it can be reversed. Wikipedia shares this belief stating.
Lesions can be reversed in most cases with immediate supplementation of thiamine.
My concern is that once the brain withering has progressed to the point that it is clearly a form of dementia, the brain structure may not be able to be restored.
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The medical/pharmaceutical industry has embraced the amyloid hypothesis despite its repeated failures.. At first it seems to be the best and the only option. However 20 years ago, Jack C. de la Torre provided an alternative hypothesis that Alzheimer's (AD) is the results of decades of hypoperfusion in the brain.
From 2004: Is Alzheimer’s disease a neurodegenerative or a vascular disorder?
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 ortransgenic-mouse brains. By contrast, the data supporting AD as aprimary vascular disorder are more convincing. Findings suggesting avascular 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.
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Choline (formerly classified as vitamin B4) is another player.
Choline: An Essential Nutrient for Public Health that we’re not getting enough of in our diet
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@DavidPS I think it's thiamine deficiency. My father died of Alzheimer's in 2012. About 5 years prior to his diagnosis of Alzheimer's, he got food poisoning while on vacation. The doctors gave him ciprofloxacin which is known for blocking thiamine function (lots of pharmaceutical drugs, especially antibiotics do). I didn't know about this issue at the time so didn't get my Dad on thiamine supplementation. So looking back on witnessing my father's decline definitely affected my perspective. It has made me keenly aware when reading about the causes of Alzheimer's.
https://hormonesmatter.com/cognitive-testing-post-adverse-reaction-lost-opportunity/
I've heard it said that people with Parkinson's Disease and people with Alzheimer's eventually wind up at the same spot. Dr. Costantini successfully treated Parkinson's Disease patients with high dose thiamine hcl. The before and after videos of his patients tell the story.
My own thiamine function was blocked by Bactrim antibiotic in 2020. I developed all the symptoms of Wernicke's Encephalopathy. I've been taking high dose thiamine hcl orally ever since. It has given me my life back.
I don't think that it matters whether Alzheimer’s disease is a neurodegenerative or a vascular disorder because thiamine deficiency causes both issues.
Some results from searching for "cholinergic system and thiamine":
A Review of the Biochemistry, Metabolism and Clinical Benefits of Thiamin(e) and Its Derivatives
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@mostlylurking
I've been doing s lot of thinking, and while I have gone into megadose thiamine therapy, I'm still in search for an alternative explanation for my current state of ataxia.
Serendipity stepped in lately, and I find myself going into my 4th week of being bedridden because my cat bit my ankle hard leaving me with a wound that won't heal. To make a long story short, a doctor I consulted (belatedly) told me wounds near bones (in my case the ankle bone) are more difficult to heal and he taught me the way to heal such wounds.
So anyway, I had spent a lot of time lying down all this time because it is painful to walk. While I won't know for sure, it seems all this lying down has made it easier for blood to flow to my brain, and I don't seem to have ataxia anymore.
It may be too good to be true, but maybe, just maybe, a little help from gravity may be all it takes.
Until my wound heals and I can go back to freely walking, there is no telling for sure.
Temporal thinking is the faculty that’s
engaged by an enriched environment, but it’s
wrong to call it “thinking,” because it’s simply
the way organisms exist... - Ray Peat Nov 2017 Newsletter -
@yerrag said in The role of cerebral blood flow in the pathogenesis of Alzheimer's Disease Dementia:
@mostlylurking
I've been doing s lot of thinking, and while I have gone into megadose thiamine therapy, I'm still in search for an alternative explanation for my current state of ataxia.
Serendipity stepped in lately, and I find myself going into my 4th week of being bedridden because my cat bit my ankle hard leaving me with a wound that won't heal. To make a long story short, a doctor I consulted (belatedly) told me wounds near bones (in my case the ankle bone) are more difficult to heal and he taught me the way to heal such wounds.
So anyway, I had spent a lot of time lying down all this time because it is painful to walk. While I won't know for sure, it seems all this lying down has made it easier for blood to flow to my brain, and I don't seem to have ataxia anymore.
I'm so sorry about your cat bite on your ankle! I've had a few cat bites myself, but they seem to always go for my fatty thighs. So no bones endangered.
It sounds like you've been given a clue all right. About the blood flow to your brain. Dr. Lonsdale talked about the part of dysautonomia that caused people to get dizzy and faint if they stood up too quickly which caused the blood to fall from their brains. Something about the autonomic nervous system controlling the tone of the blood vessels which is supposed to keep the blood flowing at a consistent pressure no matter the posture of the body.
It may be too good to be true, but maybe, just maybe, a little help from gravity may be all it takes.
It would be better if you could stand up and walk around....
Until my wound heals and I can go back to freely walking, there is no telling for sure.
Take a look at Dr. Lonsdale's book about dysautonomia here: https://www.sciencedirect.com/book/9780128103876/thiamine-deficiency-disease-dysautonomia-and-high-calorie-malnutrition
You're taking thiamine, right? What kind are you taking? How much?
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@yerrag said in The role of cerebral blood flow in the pathogenesis of Alzheimer's Disease Dementia:
To make a long story short, a doctor I consulted (belatedly) told me wounds near bones (in my case the ankle bone) are more difficult to heal and he taught me the way to heal such wounds.
Blood flow into the region below the calf and above the ankle is very poor. Older people lose their body hair in this region. Some bioenergetic things that increase blood flow are red and green lights, PEMF and carbon dioxide.
THE ROLE OF LIGHT EMITTING DIODE IN WOUND HEALING: A SYSTEMATIC REVIEW OF EXPERIMENTAL STUDIES
An integrative review of pulsed electromagnetic field therapy (PEMF) and wound healing
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@mostlylurking
Yes, I'm taking thiamine HCl at 1500mg/day, but being in a bedridden position for a while seems to be healing me with blood flow improved going to the brain and fixing me of ataxia.
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@yerrag said in The role of cerebral blood flow in the pathogenesis of Alzheimer's Disease Dementia:
So anyway, I had spent a lot of time lying down all this time because it is painful to walk. While I won't know for sure, it seems all this lying down has made it easier for blood to flow to my brain, and I don't seem to have ataxia anymore.
Movement is very important for healing. Consider finding the minimum dose of time lying down to send your ataxia into remission.
Couch potatoes loose muscle mass and bone mass. Too much inactivity will make you frail very quickly and it is difficult to restore their levels. It is difficult to tell what is happening. I have been using a biometric scale for almost 10 years and my bone weight is higher than when I started recording bone weight.
Using a Biometric scale to infer changes in bone health over time. (N=1)
The best way to cure a dietary disease is to improve the diet.
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@mostlylurking - Thanks for the information. I am looking into thiamine and have increased my dosage.
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@yerrag said in The role of cerebral blood flow in the pathogenesis of Alzheimer's Disease Dementia:
@mostlylurking
Yes, I'm taking thiamine HCl at 1500mg/day, but being in a bedridden position for a while seems to be healing me with blood flow improved going to the brain and fixing me of ataxia.
@yerrag Can you tell me how much you weigh? I'm following Dr. Costantini's protocol and according to my weight (150 lbs), I need 2 grams/day, divided into 2 doses, taken with water, mid morning, and then again mid afternoon.
I did not achieve my best response until I increased the dose to Dr. Costantini's recommended amount. When I increased from 1500mgs/day up to 2 grams/day I had a most notable improvement within 2 days; my entire digestive tract normalized.
"Finding the Correct Dose
The correct dose varies on the basis of:
Duration of the disease (the longer is the duration of the disease, the higher will be in general the doses;
Severity of the symptoms and rate of progression of the disease; Weight and physical characteristics of the patient sensitivity/responsiveness to the treatment.
In order to determine the right dose, we usually stick to the following protocol:
In case of recent onset of the disease in patients whose weight is between 50 to 65 kg (110 – 145 lbs), we begin the therapy with two grams of thiamine per day, before and after lunch.
In case the patient weighs more, the dose can be three grams per day, always divided into two administrations.
Oral thiamine should not be taken with juices or any sour beverage, water only.
The equivalent Intramuscular administration of thiamine would be:
For 2 grams/day orally = 1 x 100mg injectable solution per week;
For 3 grams/day orally = 2 x 75mg injectable solution per week;
For 4 grams/day orally = 2 x 100 mg injectable solution per week.NOTE: When it is administrated through intramuscular injections treatment could lead to allergic reactions (we observed 4 cases in 2,500+ patients). Mainly there are dermatological rushes and allergic phenomena. "
from here: https://highdosethiamine.org/hdt-therapy/
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@DavidPS said in The role of cerebral blood flow in the pathogenesis of Alzheimer's Disease Dementia:
@mostlylurking - Thanks for the information. I am looking into thiamine and have increased my dosage.
you're welcome.
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I'm still doing some moving and thanks for reminding me. I once was confined to total bedrest after a car accident for a month. My legs had atrophied and I had lost temporarily my walking ability when I was discharged. I WS in my twenties then.My legs became skinny but I was amazed it didn't take long for my very developed calves to gain back its tone and mass. Talk about memory!
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@mostlylurking
I weigh about 150 lbs.
The reason I am willing to consider lying down as therapeutic was because I had been hypoxic due to my lung issue. Being deprived of oxygen, many red blood cells died as s result and my blood vessels are clogged with sludge from dead red blood cells that is still being cleared by the body. A lymph gland is still swollen as well. My lungs still give out clear or white phlegm and I suspect the lungs is helping clear red dead blood cells, although a lot of gallbladder activity is going on during sleep clearing dead red blood cells.
I am not a doctor definitely but I can observe and don't take lightly these observations. Though you may not take this observation as seriously (who would?), it is a habit I have developed that has served me well over the years.
But if my neurological condition is from blood flow simply not being adequate to the brain, it is possible because I have a lot of of sludge that impedes the flow.
I track my ESR, and my ESR has been much high higher ever since my lung issue began, and I believe it is the sludge causing my ESR to be that high. My ESR was perfect at zero 5 years ago when I began tracking it over the years. So as s thinking man who doesn't restrict oneself to studies made by others I have to entertain this possibility, which In consider more of a probability.
I thought you should also be open even though you have invested a lot on the invincibility of the mega dosing thiamine idea. Time will tell, and when my wound heals, and if I still retain my ataxic condition, then I will retreat on my hunch.
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@yerrag said in The role of cerebral blood flow in the pathogenesis of Alzheimer's Disease Dementia:
@mostlylurking
I weigh about 150 lbs.
OK; so your Dr. Costantini recommended dose would be 2 grams/day, same as me. He explained that 2 grams of thiamine hcl, taken orally per day for 7 days, equals the same dose as a single 100mg injection of thiamine hcl. This is because of the poor absorption rate when taking the hcl type orally. I think that this assumes that the person has reasonably OK intestinal function. Some people would need more, but I couldn't tolerate more. I tried a higher dose one time (2.5 grams) in a day; it gave me shooting electrical zapping pains in my thighs that night.
The reason I am willing to consider lying down as therapeutic was because I had been hypoxic due to my lung issue. Being deprived of oxygen, many red blood cells died as s result and my blood vessels are clogged with sludge from dead red blood cells that is still being cleared by the body. A lymph gland is still swollen as well. My lungs still give out clear or white phlegm and I suspect the lungs is helping clear red dead blood cells, although a lot of gallbladder activity is going on during sleep clearing dead red blood cells.
How much time has passed since your hypoxia/lung injury? I'm left with the idea that this has been a longer term situation? Are you seeing slow improvement over all? Or have you plateaued?
I am not a doctor definitely but I can observe and don't take lightly these observations. Though you may not take this observation as seriously (who would?), it is a habit I have developed that has served me well over the years.
You know your body better than anyone. It is wise to take seriously information perceived from your body. I do the same thing.
But if my neurological condition is from blood flow simply not being adequate to the brain, it is possible because I have a lot of of sludge that impedes the flow.
Can you say how long a time this sludge issue has been going on?
Do you believe that your lungs are permanently injured or do you believe that healing/improvement in lung function is possible/happening?
I track my ESR, and my ESR has been much high higher ever since my lung issue began, and I believe it is the sludge causing my ESR to be that high. My ESR was perfect at zero 5 years ago when I began tracking it over the years. So as s thinking man who doesn't restrict oneself to studies made by others I have to entertain this possibility, which In consider more of a probability.
I found this article about clearing dead cells; perhaps you might find it of interest?
Mechanisms and physiology of the clearance of dead cells by efferocytosisI thought you should also be open even though you have invested a lot on the invincibility of the mega dosing thiamine idea. Time will tell, and when my wound heals, and if I still retain my ataxic condition, then I will retreat on my hunch.
I hope your wound heals quickly and that your improvement continues.
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@mostlylurking said in The role of cerebral blood flow in the pathogenesis of Alzheimer's Disease Dementia:
@yerrag said in The role of cerebral blood flow in the pathogenesis of Alzheimer's Disease Dementia:
@mostlylurking
I weigh about 150 lbs.
OK; so your Dr. Costantini recommended dose would be 2 grams/day, same as me. He explained that 2 grams of thiamine hcl, taken orally per day for 7 days, equals the same dose as a single 100mg injection of thiamine hcl. This is because of the poor absorption rate when taking the hcl type orally. I think that this assumes that the person has reasonably OK intestinal function. Some people would need more, but I couldn't tolerate more. I tried a higher dose one time (2.5 grams) in a day; it gave me shooting electrical zapping pains in my thighs that night.
I'm taking 2000mg daily thiamine HCl and I could take it. I have not tried increasing the dosage. I am now taking it together with 200mg niacin (no more itches after s period of adjustment), 100mg b6, and 15mg b2 (lowered as I felt weight gain at a higher dosage).
The reason I am willing to consider lying down as therapeutic was because I had been hypoxic due to my lung issue. Being deprived of oxygen, many red blood cells died as a result and my blood vessels are clogged with sludge from dead red blood cells that is still being cleared by the body. A lymph gland is still swollen as well. My lungs still give out clear or white phlegm and I suspect the lungs is helping clear red dead blood cells, although a lot of gallbladder activity is going on during sleep clearing dead red blood cells.
How much time has passed since your hypoxia/lung injury? I'm left with the idea that this has been a longer term situation? Are you seeing slow improvement over all? Or have you plateaued?
My lung injury started Feb last year. It has been resolved since March this year. I am breathing normally now. I used suppositories of essential oils and it healed my lungs, which I don't believe my pulmologist is trained to do.
I am not a doctor definitely but I can observe and don't take lightly these observations. Though you may not take this observation as seriously (who would?), it is a habit I have developed that has served me well over the years.You know your body better than anyone. It is wise to take seriously information perceived from your body. I do the same thing.
Thanks. It helps as far too often we are told by doctors that they know better.But if my neurological condition is from blood flow simply not being adequate to the brain, it is possible because I have a lot of of sludge that impedes the flow.
Can you say how long a time this sludge issue has been going on?
I would say since my lungs started breathing poorly and my spO2 levels began to drop to lower levels to not be able to adequately provided oxygen to my tissues. I think the body would prefer to sacrifice my red blood cells than cause my organ tissues to be destroyed, as rbc's can be replenished once the crisis is over. And the crisis is over, and the body is in the process of bouncing back to health.
Do you believe that your lungs are permanently injured or do you believe that healing/improvement in lung function is possible/happening?
Lungs have already healed. I think being better nourished for such an event made my lungs heal much more quickly. I had been eating 4 lbs of beef tendon monthly for a while for its cleaner gelatin content, and this has provides MW with ample glutathione needed as antioxidant protection as well as to make sure I have sufficient sulfhydryl bonds needed to effect clearing of phlegm with the thin mucus enabled by sulfhydryl bonds.I track my ESR, and my ESR has been much high higher ever since my lung issue began, and I believe it is the sludge causing my ESR to be that high. My ESR was perfect at zero 5 years ago when I began tracking it over the years. So as s thinking man who doesn't restrict oneself to studies made by others I have to entertain this possibility, which In consider more of a probability.
I found this article about clearing dead cells; perhaps you might find it of interest?
Mechanisms and physiology of the clearance of dead cells by efferocytosisThank you. I have been looking for such info.
I thought you should also be open even though you have invested a lot on the invincibility of the mega dosing thiamine idea. Time will tell, and when my wound heals, and if I still retain my ataxic condition, then I will retreat on my hunch.
I hope your wound heals quickly and that your improvement continues.
I appreciate very much your concern and support.
