For this post I'm reviewing a paper from Neurology, October 2010, "Homocysteine and holotranscobalamin and the risk of Alzheimer's disease" along with the accompanying editorial, "Beauty and the beast: B12, homocysteine, and the brain: A bemusing saga!" (Neurologists don't have much time for poetry, I'm guessing.)(Dear neurologists and cardiologists, sorry for making fun of you all the time.)(As if a neurologist or cardiologist would bother to read this blog).(There I go again.)
So what's the scoop? We know the brain needs B12. Why? B12 is a cofactor in all sorts of enzymatic reactions to make neurotransmitters. Without neurotransmitters, the brain is left high and dry. Rather like a rock band without groupies or a fan club. Homocysteine is a part of the B vitamin processing shenanigans, and high levels homocysteine tend to indicate low levels of B12 and folate. Past observational studies have more or less shown that people with high homocysteine have more heart attacks, strokes, and dementia, while people with low vitamin B12 seem to have more dementia, cognitive impairment, and an increased rate of brain atrophy. I say more or less, because some studies don't show a connection, but overall, the tendency is for B12 to be associated with a happy brain, and for homocysteine to be associated with an unhappy brain. This tendency makes biological sense, so we can nod our heads a little in consideration.
(Important note - the organ meat eating "dietary pattern" that was associated with Alzheimer's disease in this study was especially high in B12! Weird, huh? As in totally doesn't make any biologic sense? Chris Masterjohn covers the silliness of dietary pattern studies in this wonderful post. I have a number of posts on certain dietary patterns and mental health disorders - I post on them because they are pretty much the only studies of diet and mental health we have, but I hope everyone understands the limitations of these studies. As in, they are extremely limited, incredibly vulnerable to data mining, and observational in nature. We can't make too many conclusions from the studies, though they may offer some ideas for some future hypotheses.)
Here's probably the most interesting thing about this study ("homocysteine and holotranscobalamin and the blah blah") - instead of measuring straight up serum B12, they measure the biologically active fraction, holotranscobalamin - otherwise known as holoB12. They suggest that holoB12 is the best lab test to measure B12 deficiency, which is news to me. And since I test B12 all the time, that's useful information. What is little known to psychiatrists and primary care docs is that B12 levels that are in the low range of normal can be associated with psychiatric symptoms, such as depression. Most lab tests of B12 will suggest 200 to 1200 is normal. 200-400 is probably too low, however, and most people I test are in that range unless they are dedicated liver eaters (rare) or multivitamin takers. The latest practice guidelines for prescribing antidepressants suggests that antidepressants won't work as well until the B12 level is higher than 400. Who knows what holoB12 would show?
Back to the study! 271 dementia-free Finnish participants in the CAIDE study were examined in 1998 and 2005-2006. Serum blood levels of holoB12, homocysteine, and folate were available in 1998 along with MMSE scores, and at the follow-up several years later, individuals were examined for dementia with the MMSE (a short, rather crappy test for dementia), and those who scored badly or whose scores decreased significantly from 1998 were more closely examined with much better neuropsychologic tests, brain imaging, CSF analysis, and blood tests. This is yet another observational study, and a basic one, though at least no waters are muddied with "dietary pattern" adjustments.
Results! 17 of the 271 folks ended up with Alzheimer's. People who developed Alzheimer's were older, had a lower BMI, and higher frequency of the ApoE4 allele. They also had lower holoB12 and higher homocysteine compared to subjects without dementia. Folks with higher homocysteine tended to be older, male, and had lower holoB12. Folate (another B vitamin whose deficiency is associated with nerve problems, depression, and dementia) didn't seem to have much to do with anything. My own clinical experience with folate is that no one seems to be low, and supplementing with special bioavailable folate doesn't seem to help much. The deplin folks should have been powdering grass fed beef liver and putting it into pills, I suppose.
Discussion! High homocysteine and low holoB12 in 1998 showed increasing risk for dementia many years later, independent of other known risk factors, such as age or ApoE4 status. In the Framingham study and some other long term population observational studies also showed high homocysteine to be a risk factor for later Alzheimer's, dementia, and cognitive impairment.
What could be going on then, biologically? High homocysteine levels are associated with low B12, endothelial dysfunction, atherosclerosis, and poor nitric oxide activity. Elevated homocysteine might be a part of beta amyloid generation, cause DNA damage, and impair DNA repair. Oh - here's something interesting - homocysteine can become homocysteic acid, which is highly neurotoxic and an NMDA receptor activator!
Some more interesting biochem - remember SAMe? Well, vitamin B12 is desperately needed to add methyl groups to homocysteine to make methionine, and then SAM. Lack of SAM is linked to nerve damage, depression, cognitive decline, and dementia.
Well! A few years ago, it was noticed that low folate levels was associated with high homocysteine and heart disease. A number of studies and clinical trials were attempted, and were basically a total bust. Turns out, maybe it wasn't folate after all, but B12 instead. Which makes more sense, seeing as how it is relatively easy to be fine in folate levels on a SAD, but rather difficult to be replete in B12. We're still waiting for the clinical (randomized controlled) trials of B12. Maybe the answers of the homocysteine mystery will be found there?
Music link for the week - La Befana, Respighi, Fountains of Rome. Another unbelievable recording. Happy Halloween!
Sunday, October 31, 2010
Friday, October 29, 2010
Depression, Anxiety, and Obesity 2
Quick review. The hypothalamus in our brains secretes CRH, a hormone that tells our pituitary gland to secrete ACTH, which then travels down through the blood to the adrenal glands (which sit on top of the kidneys). When stimulated by ACTH, the adrenal glands spit out adrenaline and cortisol. Pow! You are ready to fight, or run, or do whatever it is you need to do with your jacked-up stress hormones.
Eventually, cortisol itself can tell the hippocampus to tell the hypothalamus cool it - stop producing CRH, and the cycle shuts down. Or that's how it is supposed to work. In depression, anxiety, and obesity, the cycle is broken. Cortisol stays high. The brain and adrenal glands try to compensate by downregulating some of the receptors, but it doesn't seem to work, at least not long term. Once you have an out of whack hormonal system, all the elements of the hormonal system seem to get out of whack at the same time. I've only introduced the main characters so far - the HPA axis itself - the supporting cast is many-fold and regulates sleep, appetite, and mood. Some of the members will be familiar to you - leptin, orexin, and serotonin among others (1).
Let's discuss the supporting cast in more depth, starting with an anecdote about the hormonal system in general:
Cushing's disease results when the adrenal glands produce too much cortisol. Symptoms of Cushing's disease are weight gain, sleep disruption, hypertension, insulin resistance, depression (even psychosis) - and the depressed mood is often the first sign of the illness. Removal of an adrenal tumor producing the cortisol or adding medications that suppress the function of the adrenal gland will improve all the symptoms, including the depressed mood. Simply giving someone tons of cortisol (or glucocorticoids) will cause the same symptoms - removing the excess cortisol will resolve the symptoms.
Elevated CRH has been found in the brains of suicide victims, in the cerebrospinal fluid of living depressed people, and people with major depressive disorder seem to have an increased response (increased ACTH and cortisol production) in response to CRH stimulation in the dexamethasone suppression test compared to people without major depression. Interestingly, family members of people with major depression show similar increased hormonal activation. Depressed "comfort food" overeaters actually have lower cerebrospinal CRH levels - suggesting that the comfort food somehow soothes the savage HPA axis beast but leads to obesity.
Successful antidepressant treatment seems to resolve these hormonal abnormalities in humans (the ones that are easily tested) and the brain abnormalities in rats. In rats, administration of antidepressants seems to down regulate the expression of the CRH gene both in stressed rats AND in rats who are just hanging out and having a good old time (right up until their brains are examined microscopically, that is). This finding would suggest that antidepressants have an ability to directly affect the hormonal axis, decreasing response to stress.
Newer studies of people with different CRH receptor gene types seem to show differential response to antidepressant treatment - for some people it will work well, for others with a different CRH receptor gene, the antidepressant won't work. (In the Future Envisioned by Big Pharma and Big Medicine, once you show up at my office with symptoms of major depressive disorder or anxiety, I'll send you for genetic testing, and once the results come back, I'll be able to pick a medicine regimen fit for your genetic profile. Eventually doctors would hardly be needed - we're expensive, after all - and you'll just take a depression quiz at the insurance company website and then show up to the processing center for the genetic testing and appropriate pill. Maybe I'm being too post-industrial. Or maybe I can just see what goes on in the gleeful and industrious minds of businesspeople in health care. Heaven forbid we all eat well and take enough vacation and exercise in a guerrilla prevention campaign.)
Leptin is perhaps familiar to you. It is a hormone that regulates appetite. In general, the higher the leptin, the more your appetite should be suppressed. Obese people usually have high leptin, however, showing that this primary regulation mechanism is broken in the development of obesity. Leptin tends to have a diurnal variation - an evening rise in leptin is normal, but in obesity, this rise doesn't seem to happen (resulting in night munching?). Also, leptin has the ability to suppress cortisol production at the adrenal gland, but for some reason in obesity this suppression doesn't work well either. There are some rare leptin-deficient individuals who end up obese - they tend to be obese, anxious, and depressed, and the administration of leptin alone seems to solve all those issues.
Orexin is a brain chemical that stimulates appetite. Nom nom. It is also related to sleep disorders (most famously narcolepsy). In depression, orexin neurons seem to be less numerous (perhaps one reason why depressed individuals classically lost weight, whereas in the Land of Vegetable Oil and HCFS, when we get depressed, we generally gain weight). Orexin seems to activate catecholamines (like norepinephrine and dopamine) and our internal cannabis system (yeah, the chemicals we make in our brains that are rather like the major active ingredient in marijuana - munch munch). Serotonin seems to tell orexin to cool it. Drugs that activate system-wide serotonin (such as phentermine and the recently withdrawn meridia) are used as appetite suppressants to treat obesity. (My discussion of serotonin and heart valves and why 5-HTP skeeves me out is in this post - be sure to read the comments too.) Drugs that block serotonin cause weight gain. SSRIs (which ostensibly increase the amount of serotonin hanging out in the synapse) are used to treat emotional eating and often result in weight loss. (And yes, antidepressants often cause weight gain as well - this is likely due to the antihistamine effect of these agents rather than so much a direct serotonin effect, though I will go into this issue more fully in a subsequent post if there is interest).
And, last but not least, IL-6. IL-6 is an inflammatory cytokine that is elevated in obesity and depression. This little bugger is found in abundance in fat cells, suggesting it may have to do with metabolism itself. IL-6 is supposed to be low during the day - in depressed individuals, the levels are especially high during the day, even in depressed individuals who don't have measurable deranged HPA axis issues yet. IL-6 is an immune system activator - Inflammation - and is common to depression, anxiety, and metabolic syndrome.
All right then. Nifty! All these players do similar things in depression, anxiety and obesity, and those conditions are commonly found together. But then there is the skinny depressed person, and the happy overweight person. Rather similar to the obese person without diabetes, and the slender type II diabetic. The review papers that discuss the generalities of these conditions tend to explain these differences with; "It's complicated. More studies are being done. Genetics! Big genetics studies! Answers are at hand!"
So I'll finish today with... it's complicated. Don't get stressed! Protect your HPA axis with good food and friends and relaxation. Depression and anxiety are just as real as obesity, just not quite as visible.
Eventually, cortisol itself can tell the hippocampus to tell the hypothalamus cool it - stop producing CRH, and the cycle shuts down. Or that's how it is supposed to work. In depression, anxiety, and obesity, the cycle is broken. Cortisol stays high. The brain and adrenal glands try to compensate by downregulating some of the receptors, but it doesn't seem to work, at least not long term. Once you have an out of whack hormonal system, all the elements of the hormonal system seem to get out of whack at the same time. I've only introduced the main characters so far - the HPA axis itself - the supporting cast is many-fold and regulates sleep, appetite, and mood. Some of the members will be familiar to you - leptin, orexin, and serotonin among others (1).
Let's discuss the supporting cast in more depth, starting with an anecdote about the hormonal system in general:
Cushing's disease results when the adrenal glands produce too much cortisol. Symptoms of Cushing's disease are weight gain, sleep disruption, hypertension, insulin resistance, depression (even psychosis) - and the depressed mood is often the first sign of the illness. Removal of an adrenal tumor producing the cortisol or adding medications that suppress the function of the adrenal gland will improve all the symptoms, including the depressed mood. Simply giving someone tons of cortisol (or glucocorticoids) will cause the same symptoms - removing the excess cortisol will resolve the symptoms.
Elevated CRH has been found in the brains of suicide victims, in the cerebrospinal fluid of living depressed people, and people with major depressive disorder seem to have an increased response (increased ACTH and cortisol production) in response to CRH stimulation in the dexamethasone suppression test compared to people without major depression. Interestingly, family members of people with major depression show similar increased hormonal activation. Depressed "comfort food" overeaters actually have lower cerebrospinal CRH levels - suggesting that the comfort food somehow soothes the savage HPA axis beast but leads to obesity.
Successful antidepressant treatment seems to resolve these hormonal abnormalities in humans (the ones that are easily tested) and the brain abnormalities in rats. In rats, administration of antidepressants seems to down regulate the expression of the CRH gene both in stressed rats AND in rats who are just hanging out and having a good old time (right up until their brains are examined microscopically, that is). This finding would suggest that antidepressants have an ability to directly affect the hormonal axis, decreasing response to stress.
Newer studies of people with different CRH receptor gene types seem to show differential response to antidepressant treatment - for some people it will work well, for others with a different CRH receptor gene, the antidepressant won't work. (In the Future Envisioned by Big Pharma and Big Medicine, once you show up at my office with symptoms of major depressive disorder or anxiety, I'll send you for genetic testing, and once the results come back, I'll be able to pick a medicine regimen fit for your genetic profile. Eventually doctors would hardly be needed - we're expensive, after all - and you'll just take a depression quiz at the insurance company website and then show up to the processing center for the genetic testing and appropriate pill. Maybe I'm being too post-industrial. Or maybe I can just see what goes on in the gleeful and industrious minds of businesspeople in health care. Heaven forbid we all eat well and take enough vacation and exercise in a guerrilla prevention campaign.)
Leptin is perhaps familiar to you. It is a hormone that regulates appetite. In general, the higher the leptin, the more your appetite should be suppressed. Obese people usually have high leptin, however, showing that this primary regulation mechanism is broken in the development of obesity. Leptin tends to have a diurnal variation - an evening rise in leptin is normal, but in obesity, this rise doesn't seem to happen (resulting in night munching?). Also, leptin has the ability to suppress cortisol production at the adrenal gland, but for some reason in obesity this suppression doesn't work well either. There are some rare leptin-deficient individuals who end up obese - they tend to be obese, anxious, and depressed, and the administration of leptin alone seems to solve all those issues.
Orexin is a brain chemical that stimulates appetite. Nom nom. It is also related to sleep disorders (most famously narcolepsy). In depression, orexin neurons seem to be less numerous (perhaps one reason why depressed individuals classically lost weight, whereas in the Land of Vegetable Oil and HCFS, when we get depressed, we generally gain weight). Orexin seems to activate catecholamines (like norepinephrine and dopamine) and our internal cannabis system (yeah, the chemicals we make in our brains that are rather like the major active ingredient in marijuana - munch munch). Serotonin seems to tell orexin to cool it. Drugs that activate system-wide serotonin (such as phentermine and the recently withdrawn meridia) are used as appetite suppressants to treat obesity. (My discussion of serotonin and heart valves and why 5-HTP skeeves me out is in this post - be sure to read the comments too.) Drugs that block serotonin cause weight gain. SSRIs (which ostensibly increase the amount of serotonin hanging out in the synapse) are used to treat emotional eating and often result in weight loss. (And yes, antidepressants often cause weight gain as well - this is likely due to the antihistamine effect of these agents rather than so much a direct serotonin effect, though I will go into this issue more fully in a subsequent post if there is interest).
And, last but not least, IL-6. IL-6 is an inflammatory cytokine that is elevated in obesity and depression. This little bugger is found in abundance in fat cells, suggesting it may have to do with metabolism itself. IL-6 is supposed to be low during the day - in depressed individuals, the levels are especially high during the day, even in depressed individuals who don't have measurable deranged HPA axis issues yet. IL-6 is an immune system activator - Inflammation - and is common to depression, anxiety, and metabolic syndrome.
All right then. Nifty! All these players do similar things in depression, anxiety and obesity, and those conditions are commonly found together. But then there is the skinny depressed person, and the happy overweight person. Rather similar to the obese person without diabetes, and the slender type II diabetic. The review papers that discuss the generalities of these conditions tend to explain these differences with; "It's complicated. More studies are being done. Genetics! Big genetics studies! Answers are at hand!"
So I'll finish today with... it's complicated. Don't get stressed! Protect your HPA axis with good food and friends and relaxation. Depression and anxiety are just as real as obesity, just not quite as visible.
Thursday, October 28, 2010
Depression, Anxiety, and Obesity 1
It seems like a straightforward topic. How does obesity affect the brain? The associations are complicated, chicken and egg sorts of problems. Does being depressed make you unable to care for yourself and exercise, so you pack on the pounds? Does being anxious send you straight for the Doritos? Or does being obese and the social stigma lead to increased stress, depression, and anxiety? Does a third underlying inflammatory mechanism cause all three conditions? Is it all of the above?
The prevalence of all three disorders is extraordinarily high these days. Lifetime prevalence of depression is up to 21% of the general population, anxiety 31% (1), and obesity 32.2% in the United States, and between 7 and 27% in Europe (2).
Depression is certainly found more often in people with obesity, as is anxiety. Depression and anxiety also share common risk factors with obesity, including increased rates of cardiovascular disease and type II diabetes. An inactive lifestyle is found more often among depressed, anxious, and obese individuals (3). An educated understanding of obesity makes one realize that the underlying metabolic derangements leading to obesity precede sloth, not the other way around. It is easier to see the basics of how being depressed would keep you from exercising, and then lack of exercising would exacerbate the depression. Depression and anxiety can lead to social isolation - does social isolation leave you nothing to do but stay at home watching TV and eating?
And then, of course, there is the dysregulation of the hypothalamic-pituitary-adrenal axis. Yes, hormones, cortisol, and stress. It's pretty clear to everyone that the HPA axis is screwed up in depression and especially in depression with anxiety (4). There are also correlates between excess cortisol and abdominal obesity, abdominal obesity and insulin resistance, insulin resistance and depression...
But what (besides stress) can cause the dysregulation of the HPA axis? I still have some more papers to read, but it's funny how the speculation in most research articles stops right there. We get to the HPA axis and stress and, voila, the answer to Life, Depression, Obesity, and Everything. You all know what I think about modern stress, right? Sure, life is stressful - but it can't just be stress. We were stressed in the 1900s, the 1920s, the 1940s... and we sure have a heck of a lot more obesity, depression, and anxiety now than we had then.
What else is different? We have a lot more electronics (maybe). And reality television. Oh, and, certainly, we eat a lot differently than we used to. I've found two major possible links between diet and changes in the HPA axis over the past few months. We are undoubtedly low on magnesium as a population, and magnesium plays a role in cooling off the cortisol/stress side of the HPA axis. Also, we don't consume nearly as many phospholipids as we used to, especially since we were all told to go low fat and low cholesterol, and some studies show a link between phospholipid consumption and the reactivity of the HPA axis.
There's more to understanding depression and obesity, and I hope to use the next post to delve into the neurotransmitters and biochemistry a bit more. The truth is, of course, that HPA axis issues are just one step in the chain to our portly, sad population. Serotonin, dopamine, and norepinephrine are involved too. And anyone who can explain how obesity is related to depression and anxiety also have to explain how depression and anxiety can also lead to weight loss.
There's a lot of explaining to do.
The prevalence of all three disorders is extraordinarily high these days. Lifetime prevalence of depression is up to 21% of the general population, anxiety 31% (1), and obesity 32.2% in the United States, and between 7 and 27% in Europe (2).
Depression is certainly found more often in people with obesity, as is anxiety. Depression and anxiety also share common risk factors with obesity, including increased rates of cardiovascular disease and type II diabetes. An inactive lifestyle is found more often among depressed, anxious, and obese individuals (3). An educated understanding of obesity makes one realize that the underlying metabolic derangements leading to obesity precede sloth, not the other way around. It is easier to see the basics of how being depressed would keep you from exercising, and then lack of exercising would exacerbate the depression. Depression and anxiety can lead to social isolation - does social isolation leave you nothing to do but stay at home watching TV and eating?
And then, of course, there is the dysregulation of the hypothalamic-pituitary-adrenal axis. Yes, hormones, cortisol, and stress. It's pretty clear to everyone that the HPA axis is screwed up in depression and especially in depression with anxiety (4). There are also correlates between excess cortisol and abdominal obesity, abdominal obesity and insulin resistance, insulin resistance and depression...
But what (besides stress) can cause the dysregulation of the HPA axis? I still have some more papers to read, but it's funny how the speculation in most research articles stops right there. We get to the HPA axis and stress and, voila, the answer to Life, Depression, Obesity, and Everything. You all know what I think about modern stress, right? Sure, life is stressful - but it can't just be stress. We were stressed in the 1900s, the 1920s, the 1940s... and we sure have a heck of a lot more obesity, depression, and anxiety now than we had then.
What else is different? We have a lot more electronics (maybe). And reality television. Oh, and, certainly, we eat a lot differently than we used to. I've found two major possible links between diet and changes in the HPA axis over the past few months. We are undoubtedly low on magnesium as a population, and magnesium plays a role in cooling off the cortisol/stress side of the HPA axis. Also, we don't consume nearly as many phospholipids as we used to, especially since we were all told to go low fat and low cholesterol, and some studies show a link between phospholipid consumption and the reactivity of the HPA axis.
There's more to understanding depression and obesity, and I hope to use the next post to delve into the neurotransmitters and biochemistry a bit more. The truth is, of course, that HPA axis issues are just one step in the chain to our portly, sad population. Serotonin, dopamine, and norepinephrine are involved too. And anyone who can explain how obesity is related to depression and anxiety also have to explain how depression and anxiety can also lead to weight loss.
There's a lot of explaining to do.
Monday, October 25, 2010
End of Season CSA Soup and Blog Talk Radio
My interview with Leslie Irish Evans is at 3pm EST today (Monday Oct. 25th) on Blog Talk Radio. I have the honor of being her last guest on Blog Talk before she moves onward and upward to the I'm Thankful Radio Network with a potential audience of millions of people. Go Leslie!
Here's a soup I threw together Sunday afternoon, a bit regretfully, as this week and next week will be our last CSA shares until late spring 2011. The coconut was not from the CSA share, but rather purchased at Whole Foods. I'm not particularly concerned about being ultra low-carb as long as the carbohydrates are non-toxic. For dinner I had a small bowl full and a few smoked muscles* on the side.
End of the Season Butternut Squash Coconut Curry Soup
1 butternut squash, peeled and seeded and chopped
Water from one coconut (drill a hole in the eye and drain)
Meat from 1/2 coconut (Mister Doctor Deans used his machete, or maybe the band saw).
2 shallots (or small red onions)
3 purple dragon carrots (from the CSA share - regular carrots are just as good, but not as pretentious)
1 purple top turnip
1 clove garlic
2 tbs coconut oil
2 tbs green curry paste
cinnamon
salt
pepper
dulse flakes
several glops of olive oil
1 container of chicken broth (we got the free range low sodium stuff. More awesome folks would have chicken stock frozen and available, but not I)
Simmer the whole lot for 35-40 minutes or so.
Blend with stand blender off the heat to desired chunkiness.
Season to taste.
Eat.
Macronutrient ratios: No clue
Yummity deliciousness: 5 stars
(*That's late night posting for "mussels")
Here's a soup I threw together Sunday afternoon, a bit regretfully, as this week and next week will be our last CSA shares until late spring 2011. The coconut was not from the CSA share, but rather purchased at Whole Foods. I'm not particularly concerned about being ultra low-carb as long as the carbohydrates are non-toxic. For dinner I had a small bowl full and a few smoked muscles* on the side.
End of the Season Butternut Squash Coconut Curry Soup
1 butternut squash, peeled and seeded and chopped
Water from one coconut (drill a hole in the eye and drain)
Meat from 1/2 coconut (Mister Doctor Deans used his machete, or maybe the band saw).
2 shallots (or small red onions)
3 purple dragon carrots (from the CSA share - regular carrots are just as good, but not as pretentious)
1 purple top turnip
1 clove garlic
2 tbs coconut oil
2 tbs green curry paste
cinnamon
salt
pepper
dulse flakes
several glops of olive oil
1 container of chicken broth (we got the free range low sodium stuff. More awesome folks would have chicken stock frozen and available, but not I)
Simmer the whole lot for 35-40 minutes or so.
Blend with stand blender off the heat to desired chunkiness.
Season to taste.
Eat.
Macronutrient ratios: No clue
Yummity deliciousness: 5 stars
(*That's late night posting for "mussels")
Sunday, October 24, 2010
Alzheimer's and the Cholesterol Condundrum
I made some pretty bold claims the other day in my post on Alzheimer's and ApoE. I want to look more closely at some of the studies cited yesterday, and to ask some critical questions to see if we can make sense of it all. The exciting thing about a blog is that I'm not the only one looking at all of this information - if you have a bright idea, please chime in with a comment or two.
We have three hypotheses I'm trying to sort out with as much elegance and common sense as possible:
A: High Cholesterol and Bad dietary Fats (or inflammation from a bad fatty diet) cause (or are a part of causing) Alzheimer's disease. In other words, The Lipid Hypothesis of Alzheimer's Disease
B: Cholesterol is absolutely vital to the brain, and a low-fat diet in addition to inflammation and genetic vulnerability causes Alzheimer's disease.
C: Cholesterol and diet have absolutely nothing to do with Alzheimer's disease.
First, "Cholesterol as a risk factor for dementia and cognitive decline: a systemic review of prospective studies with meta-analysis." The long and short of this study (which reviewed data from 18 other prospective studies and 14,331 people with 3 to 29 years of follow up) - High total cholesterol in midlife (prior to age 60) is associated with a higher risk of Alzheimer's Dementia and Vascular Dementia (a type of dementia caused by multiple little strokes). However, low serum cholesterol in late life seemed to be part of the prodrome for Alzheimer's Dementia, especially in those with the genetic vulnerability (ApoE4 allele).
Secondly, a study I cited yesterday: "High cholesterol in late life associated with a reduced risk of dementia." Nearly 400 people were examined from age 70 up through age 88. The subjects in the top quarter of total cholesterol levels at age 70 and 79 had reduced risk of dementia at age 79-88. Total triglycerides had no correlation.
Third! In a previous study I cited way back, serum cholesterol seemed to match up with the amount of cholesterol that is found in the brain: "Fatty acid composition in postmortem brains of people who completed suicide."
And finally, In Alzheimer's patients, fatty acids in the cerebral spinal fluid are low. Super low. "Reduced levels of cholesterol, phospholipids, and fatty acids in cerebrospinal fluid of Alzheimer disease patients are not related to apolipoprotein E4." Phospholipids, total cholesterol, and free fatty acids were reduced compared to controls in the post-mortem CSF of 30 neuropathologically confirmed cases of Alzheimers (compared to 31 controls).
Another important bit of info - while ApoE4 confers higher risk of Alzheimer's, most people who develop Alzheimer's (especially late in life) do not have ApoE4.
And one last bit of important info - myelin is the insulation on the wires of the central nervous system. It helps messages be transmitted over long distances. The main cells that make and repair myelin in the central nervous system are called oligodendrocytes. Part of what these cells do is to make sulfatides. Sulfatides are known to be depleted in early Alzheimer's disease (1), and ApoE and sulfatides work together to clear out amyloid plaque in Alzheimer's disease (2). Cholesterol is absolutely vital to maintaining and repairing the myelin sheath. Therefore, in Alzheimer's we have a shoddy myelin sheath combined with low CSF cholesterol levels.
Back to our three hypotheses:
A: Fat is Bad and will KILL you. I reviewed the pro-Lipid Hypothesis data here and found it wanting. It was mostly hand-waving and fear of lipotoxicity - which is the idea that saturated fat (in combination with hyperglycemia!! My goodness, how does one get hypergycemia? Though eating lots of fat? Or lots of sugar? You tell me.) can cause the endoplasmic reticulum of your cells to self-destruct. Or something. Lipotoxicity never made much sense to me, and I've read a rather large number of papers on it. But the Alzheimer's evidence is that high total cholesterol in mid-life is associated with increased risk of dementia in later life. I break it down thusly: High cholesterol in midlife is associated with inflammation, trans fats, and other yucks. If your system is out of whack enough to produce the high cholesterol to try to repair the inflammatory damage, something seriously bad is going on, and will be going on for the remaining decades of your life, lest you try to fix it. Hey, how would we fix it? Well, we could follow our ancestors and do a paleolithic style diet, go traditional and try a Mediterranean sytle diet, or we could stay on the SAD and take cholesterol-lowering drugs, or we could go on a super low fat Ornish-style diet. What do you think the majority of the people diagnosed with high cholesterol in mid-life do?
B: Fat is Good. Your brain is 60% fat. Low fat diets and cholesterol-lowering drugs are disastrous for the brain. Huge shout-out here to Stephanie Seneff and her web essay, "ApoE-4, The Clue to Why Low Fat Diet and Statins may Cause Alzheimer's." She leads the way to this study: "Midlife Serum Cholesterol and Increased Risk of Alzheimer's and Vascular Dementia Three Decades Later." Free full text! Hooray - nearly 10,000 people as part of the Kaiser database in California were followed for a long period of time, from the 70s to the 90s. We had all sorts of info about blood pressure, cholesterol levels, everything. And, just like the first study I cited, high cholesterol in middle age was associated with higher risk of dementia 30 years later. But wait a minute - these folks were part of a managed care plan with managed care doctors who no doubt followed the party line and prescribed lipid-lowering drugs. How did that turn out? "Information on lipid-lowering treatments, which have been suggested to decrease dementia risk [3], was not available for this study."
Not available? Really? Kaiser Pemanente doesn't have the cholesterol-lowering drug usage of its members available for this study? Well, a newer study has come out. "Can statins prevent or help treat Alzheimer's disease?" And the answer is, so far, no! Also, they "were not detrimental to cognition in... systemic review."
Ack. We are left with an exponentially increasing incidence of Alzheimer's disease compared to other diseases (femur fractures) which increase linearly with age (4), which to me suggests environmental factors. Does Alzheimer's have nothing to do with diet or cholesterol (hypothesis C)? I don't think so. It is known that if you are >85 years old, high cholesterol imparts a survival advantage.
So you tell me. What makes more biologic sense? Is Alzheimer's caused by high cholesterol or diminished by high cholesterol?
We have three hypotheses I'm trying to sort out with as much elegance and common sense as possible:
A: High Cholesterol and Bad dietary Fats (or inflammation from a bad fatty diet) cause (or are a part of causing) Alzheimer's disease. In other words, The Lipid Hypothesis of Alzheimer's Disease
B: Cholesterol is absolutely vital to the brain, and a low-fat diet in addition to inflammation and genetic vulnerability causes Alzheimer's disease.
C: Cholesterol and diet have absolutely nothing to do with Alzheimer's disease.
First, "Cholesterol as a risk factor for dementia and cognitive decline: a systemic review of prospective studies with meta-analysis." The long and short of this study (which reviewed data from 18 other prospective studies and 14,331 people with 3 to 29 years of follow up) - High total cholesterol in midlife (prior to age 60) is associated with a higher risk of Alzheimer's Dementia and Vascular Dementia (a type of dementia caused by multiple little strokes). However, low serum cholesterol in late life seemed to be part of the prodrome for Alzheimer's Dementia, especially in those with the genetic vulnerability (ApoE4 allele).
Secondly, a study I cited yesterday: "High cholesterol in late life associated with a reduced risk of dementia." Nearly 400 people were examined from age 70 up through age 88. The subjects in the top quarter of total cholesterol levels at age 70 and 79 had reduced risk of dementia at age 79-88. Total triglycerides had no correlation.
Third! In a previous study I cited way back, serum cholesterol seemed to match up with the amount of cholesterol that is found in the brain: "Fatty acid composition in postmortem brains of people who completed suicide."
And finally, In Alzheimer's patients, fatty acids in the cerebral spinal fluid are low. Super low. "Reduced levels of cholesterol, phospholipids, and fatty acids in cerebrospinal fluid of Alzheimer disease patients are not related to apolipoprotein E4." Phospholipids, total cholesterol, and free fatty acids were reduced compared to controls in the post-mortem CSF of 30 neuropathologically confirmed cases of Alzheimers (compared to 31 controls).
Another important bit of info - while ApoE4 confers higher risk of Alzheimer's, most people who develop Alzheimer's (especially late in life) do not have ApoE4.
And one last bit of important info - myelin is the insulation on the wires of the central nervous system. It helps messages be transmitted over long distances. The main cells that make and repair myelin in the central nervous system are called oligodendrocytes. Part of what these cells do is to make sulfatides. Sulfatides are known to be depleted in early Alzheimer's disease (1), and ApoE and sulfatides work together to clear out amyloid plaque in Alzheimer's disease (2). Cholesterol is absolutely vital to maintaining and repairing the myelin sheath. Therefore, in Alzheimer's we have a shoddy myelin sheath combined with low CSF cholesterol levels.
Back to our three hypotheses:
A: Fat is Bad and will KILL you. I reviewed the pro-Lipid Hypothesis data here and found it wanting. It was mostly hand-waving and fear of lipotoxicity - which is the idea that saturated fat (in combination with hyperglycemia!! My goodness, how does one get hypergycemia? Though eating lots of fat? Or lots of sugar? You tell me.) can cause the endoplasmic reticulum of your cells to self-destruct. Or something. Lipotoxicity never made much sense to me, and I've read a rather large number of papers on it. But the Alzheimer's evidence is that high total cholesterol in mid-life is associated with increased risk of dementia in later life. I break it down thusly: High cholesterol in midlife is associated with inflammation, trans fats, and other yucks. If your system is out of whack enough to produce the high cholesterol to try to repair the inflammatory damage, something seriously bad is going on, and will be going on for the remaining decades of your life, lest you try to fix it. Hey, how would we fix it? Well, we could follow our ancestors and do a paleolithic style diet, go traditional and try a Mediterranean sytle diet, or we could stay on the SAD and take cholesterol-lowering drugs, or we could go on a super low fat Ornish-style diet. What do you think the majority of the people diagnosed with high cholesterol in mid-life do?
B: Fat is Good. Your brain is 60% fat. Low fat diets and cholesterol-lowering drugs are disastrous for the brain. Huge shout-out here to Stephanie Seneff and her web essay, "ApoE-4, The Clue to Why Low Fat Diet and Statins may Cause Alzheimer's." She leads the way to this study: "Midlife Serum Cholesterol and Increased Risk of Alzheimer's and Vascular Dementia Three Decades Later." Free full text! Hooray - nearly 10,000 people as part of the Kaiser database in California were followed for a long period of time, from the 70s to the 90s. We had all sorts of info about blood pressure, cholesterol levels, everything. And, just like the first study I cited, high cholesterol in middle age was associated with higher risk of dementia 30 years later. But wait a minute - these folks were part of a managed care plan with managed care doctors who no doubt followed the party line and prescribed lipid-lowering drugs. How did that turn out? "Information on lipid-lowering treatments, which have been suggested to decrease dementia risk [3], was not available for this study."
Not available? Really? Kaiser Pemanente doesn't have the cholesterol-lowering drug usage of its members available for this study? Well, a newer study has come out. "Can statins prevent or help treat Alzheimer's disease?" And the answer is, so far, no! Also, they "were not detrimental to cognition in... systemic review."
Ack. We are left with an exponentially increasing incidence of Alzheimer's disease compared to other diseases (femur fractures) which increase linearly with age (4), which to me suggests environmental factors. Does Alzheimer's have nothing to do with diet or cholesterol (hypothesis C)? I don't think so. It is known that if you are >85 years old, high cholesterol imparts a survival advantage.
So you tell me. What makes more biologic sense? Is Alzheimer's caused by high cholesterol or diminished by high cholesterol?
Friday, October 22, 2010
What the Heck Is an ApoE and Other Stories of How Cholesterol Is Good for You
I believe the hierarchy of medicine explains everything. Cardiologists had the EKG as soon as some poor soul was convinced to dunk his feet in (dilute) battery acid. Psychiatrists not only have no procedures (except shock therapy), we eschew modern medicine, not wearing the normal white coat uniform, not even touching our patients. We just observe, and, horrors, talk. And, as we well know, insurance companies pay you to do things to your patients, not talk to them.
Maybe cholesterol hates the heart (I doubt it), but it loves the brain. 25% of our body's cholesterol is found in the brain, and synapses need cholesterol do do their whole "thinking" thing. Without cholesterol, or with low cholesterol, our brains are toast. In addition to forming the synapse and being involved in key signaling processes, cholesterol is vital for the formation of myelin. Myelin is the insulation that keeps our wires from getting crossed in the nervous system. People with Alzheimer's have decreased ability to make and repair damaged myelin. And so we come around to ApoE, an apolipoprotein, and the key to cholesterol in the brain.
My previous post, Alzheimer's Disease and Saturated Fat, was a bit of a red herring. I was trying to be fair and throw around some of the common theories so they could see some air time. But, to be perfectly honest, the high cholesterol theories of Alzheimer's Disease are nonsensical and ridiculous. They make no biologic sense. Let me explain.
Apolipoproteins hang out on lipoproteins. Lipoproteins have an important job - they carry fat and cholesterol through the blood and central nervous system. They are carefully constructed so that the delicate fats survive the dangerous trip through the bloodstream - the fats and cholesterol are carefully esterified to a triacylglycerol molecule and protected by a shell of phospholipid, apolipoprotein marker, and unesterified cholesterol.
The picture is a chylomicron from wikipedia. The transport for dietary fat from the intestines to the liver. Chylomicrons are big and nonspecific. They have all the apolipoproteins hanging out on the surface so they can, presumably, become any kind of lipoprotein that is needed. Apolipoproteins are the keys to different areas of the body and to the different kinds of lipoprotein that carry cholesterol and fat around in the bloodstream. ApoE is the key to the brain. I mean that quite literally - ApoE is recognized by receptors so that ApoE-marked lipoproteins and their cholesterol and fat cargo are allowed into the brain.
The kind of apolipoprotein E we have is determined by genetics. ApoE3 is the most common and is pretty neutral with respect to Alzheimers risk. ApoE4 is linked with a higher incidence of Alzheimers. ApoE2 is linked with a lower incidence of Alzheimers. It is thought that ApoE4 is an inefficient key - that ApoE4 is piss-poor at letting cholesterol and fats get into the brain.
(An important aside - there's a reason dietary fats are carried in big globules like LDL or HDL or chylomicrons - the blood is an oxygen and microbe rich place. The LDL and HDL or whatever particles protect the valuable fats from oxidation and infection while they are transported. Keep that in mind.)
Let me rephrase - Alzheimer's disease is due to lack of the appropriate fat and cholesterol in the brain.
I don't make this stuff up. There are studies, in good journals (1)(2). Maybe it is a dirty secret, but cholesterol and lipids are actually way lower in the CSF of Alzheimer's patients than in healthy controls (as low as 1/6th as much important lipid as in controls). It is quite interesting that people with ApoE4 tend to have high levels of circulating cholesterol. Is this because they need higher blood cholesterol to transport dearly needed cholesterol into the brain? (3)(4).
And what is beta amyloid, anyway? Turns out this pesky accumulating plaque protein actually seems to help the brain use pyruvate as fuel in lieu of glucose. Why the heck would that happen? ApoE can signal the brain to change from glucose as a primary fuel to fats (ketone bodies) and pyruvate. It is postulated this switch is caused when the brain is under microbial attack. In this theory, amyloid beta is not a cause of Alzheimer's, but rather a defense against it. (5) . More evidence for this theory comes from a case study that MCT oil seemed to be protective or reverse symptoms of Alzheimers (6). There is also a theory that Alzheimer's patients suffer from a poor ability to use glucose as fuel in the brain, so that a change to a ketogenic metabolism is exceptionally helpful (7).
While these theories are speculative, at least they make biological sense. As opposed to the lipid hypothesis. More than once, I've helped patients with mild cognitive impairment improve symptoms of foggy thinking by getting rid of the statin. (None of those patients had a previous heart attack, history of stroke, or even exceptionally high cholesterol, so it was an easy sell to the primary care doctor.) Our brains need cholesterol. Desperately. Don't let a cardiologist convince you otherwise.
Maybe cholesterol hates the heart (I doubt it), but it loves the brain. 25% of our body's cholesterol is found in the brain, and synapses need cholesterol do do their whole "thinking" thing. Without cholesterol, or with low cholesterol, our brains are toast. In addition to forming the synapse and being involved in key signaling processes, cholesterol is vital for the formation of myelin. Myelin is the insulation that keeps our wires from getting crossed in the nervous system. People with Alzheimer's have decreased ability to make and repair damaged myelin. And so we come around to ApoE, an apolipoprotein, and the key to cholesterol in the brain.
My previous post, Alzheimer's Disease and Saturated Fat, was a bit of a red herring. I was trying to be fair and throw around some of the common theories so they could see some air time. But, to be perfectly honest, the high cholesterol theories of Alzheimer's Disease are nonsensical and ridiculous. They make no biologic sense. Let me explain.
Apolipoproteins hang out on lipoproteins. Lipoproteins have an important job - they carry fat and cholesterol through the blood and central nervous system. They are carefully constructed so that the delicate fats survive the dangerous trip through the bloodstream - the fats and cholesterol are carefully esterified to a triacylglycerol molecule and protected by a shell of phospholipid, apolipoprotein marker, and unesterified cholesterol.
The picture is a chylomicron from wikipedia. The transport for dietary fat from the intestines to the liver. Chylomicrons are big and nonspecific. They have all the apolipoproteins hanging out on the surface so they can, presumably, become any kind of lipoprotein that is needed. Apolipoproteins are the keys to different areas of the body and to the different kinds of lipoprotein that carry cholesterol and fat around in the bloodstream. ApoE is the key to the brain. I mean that quite literally - ApoE is recognized by receptors so that ApoE-marked lipoproteins and their cholesterol and fat cargo are allowed into the brain.
The kind of apolipoprotein E we have is determined by genetics. ApoE3 is the most common and is pretty neutral with respect to Alzheimers risk. ApoE4 is linked with a higher incidence of Alzheimers. ApoE2 is linked with a lower incidence of Alzheimers. It is thought that ApoE4 is an inefficient key - that ApoE4 is piss-poor at letting cholesterol and fats get into the brain.
(An important aside - there's a reason dietary fats are carried in big globules like LDL or HDL or chylomicrons - the blood is an oxygen and microbe rich place. The LDL and HDL or whatever particles protect the valuable fats from oxidation and infection while they are transported. Keep that in mind.)
Let me rephrase - Alzheimer's disease is due to lack of the appropriate fat and cholesterol in the brain.
I don't make this stuff up. There are studies, in good journals (1)(2). Maybe it is a dirty secret, but cholesterol and lipids are actually way lower in the CSF of Alzheimer's patients than in healthy controls (as low as 1/6th as much important lipid as in controls). It is quite interesting that people with ApoE4 tend to have high levels of circulating cholesterol. Is this because they need higher blood cholesterol to transport dearly needed cholesterol into the brain? (3)(4).
And what is beta amyloid, anyway? Turns out this pesky accumulating plaque protein actually seems to help the brain use pyruvate as fuel in lieu of glucose. Why the heck would that happen? ApoE can signal the brain to change from glucose as a primary fuel to fats (ketone bodies) and pyruvate. It is postulated this switch is caused when the brain is under microbial attack. In this theory, amyloid beta is not a cause of Alzheimer's, but rather a defense against it. (5) . More evidence for this theory comes from a case study that MCT oil seemed to be protective or reverse symptoms of Alzheimers (6). There is also a theory that Alzheimer's patients suffer from a poor ability to use glucose as fuel in the brain, so that a change to a ketogenic metabolism is exceptionally helpful (7).
While these theories are speculative, at least they make biological sense. As opposed to the lipid hypothesis. More than once, I've helped patients with mild cognitive impairment improve symptoms of foggy thinking by getting rid of the statin. (None of those patients had a previous heart attack, history of stroke, or even exceptionally high cholesterol, so it was an easy sell to the primary care doctor.) Our brains need cholesterol. Desperately. Don't let a cardiologist convince you otherwise.
Blog Talk Radio Interview on Monday, October 25th
My friend Leslie Irish Evans of Peeling Mom Off the Ceiling is having me on her radio show next Monday, October 25th. You can hear it live at noon pacific time (which is, I hope, 3pm eastern, as that is when the interview is scheduled on my calendar), or play the recording any time thereafter. Leslie has a great website dedicated to helping moms stop being martyrs. As a mom and as a psychiatrist who treats a lot of moms, this issue is close to my heart! I hope you stop by her place, and listen to the interview.
A couple of links to some disturbing (but not surprising) public health stories in the news:
At WebMD: Obesity in Children Increasing Around the World
"The proportion of young children who are overweight or obese has increased about 60% in the past 20 years, the World Health Organization (WHO) says in a new report."
At USA today: "Diabetes may affect as many as 1 in 3 Americans by 2050"
"The future of diabetes in America looks bleak, according to a new Centers for Disease Control and Prevention report out today, with cases projected to double, even triple, by 2050." Currently, 1 in 10 Americans are diabetic.
I detest these kinds of stories because, in general, they engender fear and offer no solutions other than the typical "exercise and eat less" kind of advice. And we all know how well that works. Fortunately, having seen how it is relatively simple to maintain my weight with a paleo/primal style diet and easy exercise regimen, I don't have to be quite so alarmed for myself or my kids. I just wish that anyone who wants to get trim (or stay trim) via lifestyle interventions has the wherewithal to critically examine the different methods out there. Maybe we can prevent this future holocaust of hyperglycemia before it is too late.
A couple of links to some disturbing (but not surprising) public health stories in the news:
At WebMD: Obesity in Children Increasing Around the World
"The proportion of young children who are overweight or obese has increased about 60% in the past 20 years, the World Health Organization (WHO) says in a new report."
At USA today: "Diabetes may affect as many as 1 in 3 Americans by 2050"
"The future of diabetes in America looks bleak, according to a new Centers for Disease Control and Prevention report out today, with cases projected to double, even triple, by 2050." Currently, 1 in 10 Americans are diabetic.
I detest these kinds of stories because, in general, they engender fear and offer no solutions other than the typical "exercise and eat less" kind of advice. And we all know how well that works. Fortunately, having seen how it is relatively simple to maintain my weight with a paleo/primal style diet and easy exercise regimen, I don't have to be quite so alarmed for myself or my kids. I just wish that anyone who wants to get trim (or stay trim) via lifestyle interventions has the wherewithal to critically examine the different methods out there. Maybe we can prevent this future holocaust of hyperglycemia before it is too late.
Subscribe to:
Posts (Atom)