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.
Thursday, October 21, 2010
Fish Oil is Not Magick - But it Might Lengthen Your Pregnancy
I promise that one of these days I will get back to Alzheimer's and saturated fat and ApoE. Though y'all already know the punchline, right? Saturated fat is good for you. But more on that later.
Today I wanted to comment on the JAMA article that was splashed all across the news yesterday. "Effect of DHA Supplementation During Pregnancy on Maternal Depression and Neurodevelopment of Young Children: A Randomized Controlled Trial."
JAMA is a good journal, and this was a good study. Called the DOMInO trial, 2399 women were enrolled at less than 21 weeks pregnancy from various Australian perinatal centers. They were randomized to either 800mg DHA (a type of omega 3 fatty acid that is highly necessary for proper brain function) and 100mg EPA or 800 mg vegetable oil (gak). Each woman was instructed to take the capsules daily from study entry until birth. Trial assistants telephoned the women every 6 weeks or so, and at birth the cord blood was measured for DHA levels via gas chromatography. The moms were screened for postpartum depression at 6 weeks and 6 months after birth, and the kids were screened at 18 months with cognitive scales. A whopping 96.7% of the women completed the trial, which may be the best completion rate for a large multi-center relatively long term trial I've ever heard.
And the results? Fewer women in the DHA group complained of postpartum depression, but the result was non-significant (9.67% vs 11.19%). Mean cognitive scores in the toddlers did not differ either, though fewer children in the DHA group had severely delayed cognition - on the other side, girls from the DHA group had a lower language and "mean adaptive behavior" scores than girls in the control group. There were fewer preterm deliveries in the DHA group (1.09% vs. 2.25%), but more postterm deliveries requiring induction or C-section in the DHA group (17.59% vs 13.72%). There was no difference in bleeding or hemorrhage between the two groups. 3.01% of the DHA infants experienced "serious adverse events" (such as admission to the NICU, major congenital abnormality, or death), whereas 4.49% of the control group had serious adverse events - this difference was not significant (p=.06), though the admissions to the NICU piece was significantly worse for the control infants, probably because there were more preterm births. One other major finding - for the 4% of women who had a history of depression enrolled in the study, the number of the DHA group who had postpartum depression was significantly reduced.
Past epidemiological studies (1)(2) showed a stronger positive effect from fish consumption during pregnancy for a reduction in postpartum depression and an increase in the babies' cognition. The JAMA editorial from the same issue, Fish, Fish Oil, And Pregnancy, notes that DHA uptake is maximal during the second half of pregnancy, and is vital for brain and eye development. It is recommended that women get 200 mg DHA daily during pregnancy, yet the average intake in the USA was estimated to be 73 mg daily. Since many fish species are high in mercury, American guidelines recommend avoiding many types of fish during pregnancy. Since fish oil supplements are generally molecularly distilled to remove heavy metals, they are deemed safe from mercury contamination. However, real honest to goodness fish has some other benefits that fish oil does not - iodine, selenium, and Vitamin D.
The editorial also critiques the Bayley scores used to measure the toddler's cognition, saying Bayley scores are not extremely sensitive, and also didn't show higher cortical differences that are better measured at 4 years of age or later (4). In the DINO trial (3), DHA supplementation for infants showed benefit for kids at older ages but not in infancy, and the most benefit was found for preterm infants, who seem to miss out on big-time third trimester transfer of DHA.
The conclusion of the editorial: "Fish oil supplements are safe, well tolerated, and reduce risks for early preterm birth, which is associated with poor neurocognitive outcomes and maternal depression. Whether fish consumption during pregnancy will confer similar or perhaps even greater benefits for mothers and their children requires more investigation, including large randomized trials such as the DOMInO trial. For now, pregnant women should take care to get the recommended intake of 200 mg/d of DHA,2 either by including low-mercury, high-DHA fish in their diets or by taking a daily n-3 PUFA supplement."
What do you think would happen if omega 6 PUFAs were reduced to 4% or less of calories? Or if pregnant mothers enjoyed a real food paleolithic-style diet? I'm sure there's an epidemiologist out there who could use her computer to add up iodine, chromium, selenium, fish oil, magnesium, protein, etc. A Real Food number. That's what we need.
Today I wanted to comment on the JAMA article that was splashed all across the news yesterday. "Effect of DHA Supplementation During Pregnancy on Maternal Depression and Neurodevelopment of Young Children: A Randomized Controlled Trial."
JAMA is a good journal, and this was a good study. Called the DOMInO trial, 2399 women were enrolled at less than 21 weeks pregnancy from various Australian perinatal centers. They were randomized to either 800mg DHA (a type of omega 3 fatty acid that is highly necessary for proper brain function) and 100mg EPA or 800 mg vegetable oil (gak). Each woman was instructed to take the capsules daily from study entry until birth. Trial assistants telephoned the women every 6 weeks or so, and at birth the cord blood was measured for DHA levels via gas chromatography. The moms were screened for postpartum depression at 6 weeks and 6 months after birth, and the kids were screened at 18 months with cognitive scales. A whopping 96.7% of the women completed the trial, which may be the best completion rate for a large multi-center relatively long term trial I've ever heard.
And the results? Fewer women in the DHA group complained of postpartum depression, but the result was non-significant (9.67% vs 11.19%). Mean cognitive scores in the toddlers did not differ either, though fewer children in the DHA group had severely delayed cognition - on the other side, girls from the DHA group had a lower language and "mean adaptive behavior" scores than girls in the control group. There were fewer preterm deliveries in the DHA group (1.09% vs. 2.25%), but more postterm deliveries requiring induction or C-section in the DHA group (17.59% vs 13.72%). There was no difference in bleeding or hemorrhage between the two groups. 3.01% of the DHA infants experienced "serious adverse events" (such as admission to the NICU, major congenital abnormality, or death), whereas 4.49% of the control group had serious adverse events - this difference was not significant (p=.06), though the admissions to the NICU piece was significantly worse for the control infants, probably because there were more preterm births. One other major finding - for the 4% of women who had a history of depression enrolled in the study, the number of the DHA group who had postpartum depression was significantly reduced.
Past epidemiological studies (1)(2) showed a stronger positive effect from fish consumption during pregnancy for a reduction in postpartum depression and an increase in the babies' cognition. The JAMA editorial from the same issue, Fish, Fish Oil, And Pregnancy, notes that DHA uptake is maximal during the second half of pregnancy, and is vital for brain and eye development. It is recommended that women get 200 mg DHA daily during pregnancy, yet the average intake in the USA was estimated to be 73 mg daily. Since many fish species are high in mercury, American guidelines recommend avoiding many types of fish during pregnancy. Since fish oil supplements are generally molecularly distilled to remove heavy metals, they are deemed safe from mercury contamination. However, real honest to goodness fish has some other benefits that fish oil does not - iodine, selenium, and Vitamin D.
The editorial also critiques the Bayley scores used to measure the toddler's cognition, saying Bayley scores are not extremely sensitive, and also didn't show higher cortical differences that are better measured at 4 years of age or later (4). In the DINO trial (3), DHA supplementation for infants showed benefit for kids at older ages but not in infancy, and the most benefit was found for preterm infants, who seem to miss out on big-time third trimester transfer of DHA.
The conclusion of the editorial: "Fish oil supplements are safe, well tolerated, and reduce risks for early preterm birth, which is associated with poor neurocognitive outcomes and maternal depression. Whether fish consumption during pregnancy will confer similar or perhaps even greater benefits for mothers and their children requires more investigation, including large randomized trials such as the DOMInO trial. For now, pregnant women should take care to get the recommended intake of 200 mg/d of DHA,2 either by including low-mercury, high-DHA fish in their diets or by taking a daily n-3 PUFA supplement."
What do you think would happen if omega 6 PUFAs were reduced to 4% or less of calories? Or if pregnant mothers enjoyed a real food paleolithic-style diet? I'm sure there's an epidemiologist out there who could use her computer to add up iodine, chromium, selenium, fish oil, magnesium, protein, etc. A Real Food number. That's what we need.
Monday, October 18, 2010
Did I Mention that Depression Is Inflammatory?
Brand new paper today in Nature Medicine - "A negative regulator of MAP kinase causes depressive behavior." I know that doesn't sound particularly exciting, but it was the top news in my daily American Psychiatric Association email digest, and made a splash in the press as well. The short version is that researchers found a gene that was twice as active in the brain of people with depression than in people without depression. Since depression has an economic burden of 100 billion dollars annually, finding genes and elucidating the so far mysterious mechanisms is a big deal, even in a small study. And just wait until we talk about what the gene does!
First, the research methods. The scientists took brains (post-mortem, obviously) from 21 individuals with depression and 18 "healthy" (but still post-mortem) age and gender matched controls. Then they took out two little sections of the hippocampus (which is the epicenter of depression in the brain) and extracted all the RNA. Just a little genetics primer - our genes are encoded in material called DNA. We have machinery that unwinds the DNA and reads the code, making RNA, which is then read by different machinery and made into proteins to do all the things we do in the body. So the DNA is kind of like your bank account, and the RNA is rather like your bank statement - it tells you how much money you accessed, and when and where. The money is the proteins. Sort of. Okay. So back to the RNA - the researchers put the RNA in their machines and copied it, and then compared the copies with 48,958 known genomic probes. The biggest difference between the depressed hippocampi and the healthy hippocampi? A little gene that codes for MKP-1 (that would be mitogen-activated protein kinase phosphatase-1). Turns out that MKP-1 expression was significantly higher (2.3 and 2.4 fold increase in the hippocampal areas measured) in the depressed individuals. The researchers checked their results with a few other methods, and also checked again in a separate cohort of subjects with major depressive disorder, and found MKP-1 increased again.
The same gene's expression is found to be increased in depressed mice, and using viruses to give more MKP-1 gene to poor unsuspecting mouse brains also makes the mice depressed. Chronic antidepressant treatment (fluoxetine) seems to normalize stress-induced MKP-1 increases (in rats), and mice lacking the gene for MKP-1 are especially resilient to stress. All told, that's a persuasive argument, despite the small size of the human samples, that something spooky is going on with the MKP-1. (Of the depressed humans in the studies, 12 had filled prescriptions for antidepressants in the last month before their deaths, but only one had a measurable antidepressant levels in the blood).
So what does MKP-1 do? The important thing is what MKP-1 will undo. There is a major signaling pathway in the neuronal functioning, plasticity, and survival cascade, called the MAPK cascade. We've talked about some end-products of the MAPK cascade before - particularly BDNF, which is brain fertilizer. It helps the brain repair and change and recover. MAPK cascade is good! MKP-1 will rain all over your MAPK cascade, shutting it down. Lots of MKP-1, limited brain recovery and repair.
(If you want to get really into the mechanisms, there are quite a few MKP-1 mouse papers out there. This one in Nature Neuroscience found that MKP-1 can regulate how BDNF remodels the way the neurons grow and link to one another. In the cells, we make tiny microtubule scaffolding, and BDNF helps direct how the scaffolding is made, and whether there are branches and whatnot.)
MKP-1 is part of a stress-induced inflammatory pathway that flogs our brain to keep going - neurons fire fire fire - until the neurons get worn ragged and beaten to death. Sometimes we need to be spurred for survival, but we were never designed for chronic stress with no off switch. It's rather astonishing how the modern diet seems to have piled up all the inflammatory elements it can while the elements that put the breaks on the stress hormone response are deficient or missing. A perfect storm.
Saturday, October 16, 2010
Alzheimer's Disease and Saturated Fat - Is Butter Part of the Recipe for Dementia?
First, some possible bad news for Paleo/Primal diet fans. See, there's a prospective cohort study of people >65 out of New York City. 2148 elderly were followed for about 4 years, and every 1.5 years they were given neurological and neuropsychological tests. In addition, a food frequency questionnaire was done at the beginning of the study to look into dietary patterns (DP). I'll just copy and paste the results:
RESULTS: Two hundred fifty-three subjects developed [Alzheimer's Dementia] during a follow-up of 3.9 years. We identified a DP strongly associated with lower AD risk: compared with subjects in the lowest tertile of adherence to this pattern, the AD hazard ratio (95% confidence interval) for subjects in the highest DP tertile was 0.62 (0.43-0.89) after multivariable adjustment (P for trend = .01). This DP was characterized by higher intakes of salad dressing, nuts, fish, tomatoes, poultry, cruciferous vegetables, fruits, and dark and green leafy vegetables and a lower intake of high-fat dairy products, red meat, organ meat, and butter.
Oof! Say it ain't so! (One will note that the protective diet was similar to a Mediterranean style diet, but not a saturated fat and organ meat friendly evolutionary-based diet.)
In a previous post, I discussed how cohort studies link diets high in omega 3 fatty acids and a reduced risk of Alzheimer's. The same review article I relied on in that post looked at several studies that seemed to show an increased risk with the consumption of saturated fat. The ApoE proteins are apolipoproteins - they are the key to how lipoproteins carry fats around in the brain rather like apolipoproteins such as apoB on LDL help carry fats around in the blood. ApoE4 is famously linked with an increased risk of developing Alzheimer's dementia.
That's worth peering at more closely, I think. It's all fair and good when we can snigger at the USDA for sloppy science. But are the Alzheimer's researchers also hopelessly biased by the lipid hypothesis? Stephan and Peter have done it a million times - picked apart study after study showing that the saturated fat could be an innocent bystander to high sugar or low omega 3 consumption. Is the same true here?
One advantage of Alzheimer's is that it is big news, and big money has gone into it. That means there are a zillion studies, and a number of thoughtful review articles with details spelled out. I'm not the world's expert on fat metabolism by any means, so having some of it spelled out is useful. If I need answers, perhaps some of them can be found here, in "Dietary fats, cerebrovascular integrity, and Alzheimer's disease risk." Let's roll up our sleeves and dive in.
First, an interesting quote: "The mechanisms by which dietary fats such as SFA increase AD risk may seem less of a scientific priority to delineate compared to dietary compounds that confer protection. Yet in some chronic disorders this approach has proven pivotal to developing effective therapeutic strategies for prevention and treatment of disease. For example, elucidating the role of cholesterol in atherosclerosis and cardiovascular disease led to the evolution of relatively safe and effective cholesterol-lowering drugs." Looks like lipid hypothesis fans at work! But they talk in detail about the actual biochemistry, and the actual biochemistry is even interesting, so let's go further.
In some previous posts, we talked a bit about the pathophysiology of Alzheimer's dementia. First you get a long build up of amyloid plaque, then tau protein tangles, inflammation, and brain cell death. But it turns out, the blood vessels of dementia patients are none to happy either. Changes in the blood vessels, including smooth muscle cell and endothelial cell proliferation seem to precede the last stages of plaque build up. In addition, the blood brain barrier (BBB), which functions to protect our brain much as our gut is supposed to protect our body from outside insults, seems to be poorly functioning in patient's with Alzheimer's.
Then there are the animal models. Saturated fat and cholesterol-rich diets seem to make amyloidosis worse in amyloid-prone strains of mice. And there is something interesting about fat metabolism and amyloid - when we eat fat, it is disassembled and then reassembled and escorted by chylomicrons through the blood to the liver for further processing. Turns out that amyloid-beta loves to hang out with chylomicrons too, so the more chylomicrons we have, the more amyloid-beta in the blood. And here is something very, very interesting - compared to low-fat diet fed control rats, saturated fat increased the amount of amyloid beta in the blood, whereas fasting rats seemed to have no amyloid beta in the blood at all. Low-carb diet fans (including me!) like to compare low-carb dieting to fasting. But there is a difference between eating fat and fasting - the fat floating from the gut to the liver via the chylomicrons. Here is a theory that suggests that ingestion of saturated fat causes a "post-prandial-hyperamyloidemia." Couple this theory with the finding that folks with Alzheimer's and mild cognitive impairment have greater amyloid beta in blood plasma measurements that include chylomicrons, and a saturated fat eater might have cause to be worried. However, there isn't much good evidence that a significant amount the gut-derived amyloid beta gets from the blood through the BBB into the brain, even in studies of mice designed to measure this effect. The worst thing reasearchers found was that the blood vessels in the brain don't seem to do so well if there is a lot of amyloid beta hanging around. It seems to cause constriction of the blood vessels and rigidity, rather like accelerated aging.
Accelerated aging? Hmmm. I usually don't associated fat with accelerated aging processes - I usually associate that with hyperglycemia (high blood glucose). And here's something interesting - RAGE, the receptor for advanced glycosylation end-products (pro-oxidant nasties that are especially prevalent in diabetics), is one small way that amyloid beta can get from the blood into the brain.
So what is the real meat of the saturated fat causes Alzheimer's hypothesis? Well, the researchers blame lipotoxicity. Yes, that lipotoxicity. Damage that long-chain saturated fat (particularly palmitic acid) causes to endoplasmic reticulum and cells by triggering cell death (apoptosis). Polyunsaturated and monounsaturated fatty acids are supposed to be protective.
A whole host of organ damage is blamed on this phenomenon - "the process has also been implicated in endothelial dysfunction and atherosclerosis, heart failure, kidney failure, steatohepatitis [fatty liver] and liver failure, autoimmune inflammatory disorders, susceptibility to infections, cancer and ageing." The researchers say the brain is particularly vulnerable, as cortical astroglia metabolize a heck of a lot of fat.
Oh, and remember, this end-organ damage occurs in the context of "fat-induced insulin resistance."
Stepping back to the big picture, please remember that "fat-induced insulin resistance" is physiologic, not pathologic. It is one of the ways a body adapts to a low carb diet. Pathologic insulin resistance occurs in the context of metabolic syndrome and diabetes - conditions exacerbated by the consumption of high carbohydrate and inflammatory Western diets. If you don't have pathologic insulin resistance, can you have lipotoxicity? I seriously doubt it.
The paper continues past the lipotoxicity theory to a discussion of membranes and lipid rafts. They review studies of mice and rabbits fed a "a Western diet rich in saturated fats and cholesterol" versus a similar diet enriched with DHA (an omega 3 fatty acid derived from fish oil). They suggest that the DHA helps membrane fluidity, enabling better transport and degradation of amyloid beta, whereas the straight-up cholesterol and saturated fat rich rats had the extra gut-derived amyloid and a woeful lack of lipid rafts to help the excess amyloid be disposed of. Here we go again - known health effects from a deficiency of omega 3 is being blamed on the saturated fat part of the Western diet.
The next theory that saturated fat causes Alzheimer's in the paper relates membrane toxicity to oxidized lipids. This is something we can all agree on! Oxidized lipids and cholesterol are bad, and cause inflammation, even in the brain. Problem is, sources of dietary oxidized cholesterol include skim milk, especially powdered skim milk, and saturated fats are actually far more difficult to oxidize than polyunsaturated fats such as vegetable oils and omega 3s.
I'm a bit biased. But so far I'm not impressed. It seems easy to poke holes in all the saturated fat causes Alzheimer's theories. Frankly, the most damning evidence is that Manhattan dietary study, which does not constitute proof. But we'll see. In the next post (most likely), I'll take a closer look at ApoE4 and fat metabolism.
RESULTS: Two hundred fifty-three subjects developed [Alzheimer's Dementia] during a follow-up of 3.9 years. We identified a DP strongly associated with lower AD risk: compared with subjects in the lowest tertile of adherence to this pattern, the AD hazard ratio (95% confidence interval) for subjects in the highest DP tertile was 0.62 (0.43-0.89) after multivariable adjustment (P for trend = .01). This DP was characterized by higher intakes of salad dressing, nuts, fish, tomatoes, poultry, cruciferous vegetables, fruits, and dark and green leafy vegetables and a lower intake of high-fat dairy products, red meat, organ meat, and butter.
Oof! Say it ain't so! (One will note that the protective diet was similar to a Mediterranean style diet, but not a saturated fat and organ meat friendly evolutionary-based diet.)
In a previous post, I discussed how cohort studies link diets high in omega 3 fatty acids and a reduced risk of Alzheimer's. The same review article I relied on in that post looked at several studies that seemed to show an increased risk with the consumption of saturated fat. The ApoE proteins are apolipoproteins - they are the key to how lipoproteins carry fats around in the brain rather like apolipoproteins such as apoB on LDL help carry fats around in the blood. ApoE4 is famously linked with an increased risk of developing Alzheimer's dementia.
That's worth peering at more closely, I think. It's all fair and good when we can snigger at the USDA for sloppy science. But are the Alzheimer's researchers also hopelessly biased by the lipid hypothesis? Stephan and Peter have done it a million times - picked apart study after study showing that the saturated fat could be an innocent bystander to high sugar or low omega 3 consumption. Is the same true here?
One advantage of Alzheimer's is that it is big news, and big money has gone into it. That means there are a zillion studies, and a number of thoughtful review articles with details spelled out. I'm not the world's expert on fat metabolism by any means, so having some of it spelled out is useful. If I need answers, perhaps some of them can be found here, in "Dietary fats, cerebrovascular integrity, and Alzheimer's disease risk." Let's roll up our sleeves and dive in.
First, an interesting quote: "The mechanisms by which dietary fats such as SFA increase AD risk may seem less of a scientific priority to delineate compared to dietary compounds that confer protection. Yet in some chronic disorders this approach has proven pivotal to developing effective therapeutic strategies for prevention and treatment of disease. For example, elucidating the role of cholesterol in atherosclerosis and cardiovascular disease led to the evolution of relatively safe and effective cholesterol-lowering drugs." Looks like lipid hypothesis fans at work! But they talk in detail about the actual biochemistry, and the actual biochemistry is even interesting, so let's go further.
In some previous posts, we talked a bit about the pathophysiology of Alzheimer's dementia. First you get a long build up of amyloid plaque, then tau protein tangles, inflammation, and brain cell death. But it turns out, the blood vessels of dementia patients are none to happy either. Changes in the blood vessels, including smooth muscle cell and endothelial cell proliferation seem to precede the last stages of plaque build up. In addition, the blood brain barrier (BBB), which functions to protect our brain much as our gut is supposed to protect our body from outside insults, seems to be poorly functioning in patient's with Alzheimer's.
Then there are the animal models. Saturated fat and cholesterol-rich diets seem to make amyloidosis worse in amyloid-prone strains of mice. And there is something interesting about fat metabolism and amyloid - when we eat fat, it is disassembled and then reassembled and escorted by chylomicrons through the blood to the liver for further processing. Turns out that amyloid-beta loves to hang out with chylomicrons too, so the more chylomicrons we have, the more amyloid-beta in the blood. And here is something very, very interesting - compared to low-fat diet fed control rats, saturated fat increased the amount of amyloid beta in the blood, whereas fasting rats seemed to have no amyloid beta in the blood at all. Low-carb diet fans (including me!) like to compare low-carb dieting to fasting. But there is a difference between eating fat and fasting - the fat floating from the gut to the liver via the chylomicrons. Here is a theory that suggests that ingestion of saturated fat causes a "post-prandial-hyperamyloidemia." Couple this theory with the finding that folks with Alzheimer's and mild cognitive impairment have greater amyloid beta in blood plasma measurements that include chylomicrons, and a saturated fat eater might have cause to be worried. However, there isn't much good evidence that a significant amount the gut-derived amyloid beta gets from the blood through the BBB into the brain, even in studies of mice designed to measure this effect. The worst thing reasearchers found was that the blood vessels in the brain don't seem to do so well if there is a lot of amyloid beta hanging around. It seems to cause constriction of the blood vessels and rigidity, rather like accelerated aging.
Accelerated aging? Hmmm. I usually don't associated fat with accelerated aging processes - I usually associate that with hyperglycemia (high blood glucose). And here's something interesting - RAGE, the receptor for advanced glycosylation end-products (pro-oxidant nasties that are especially prevalent in diabetics), is one small way that amyloid beta can get from the blood into the brain.
So what is the real meat of the saturated fat causes Alzheimer's hypothesis? Well, the researchers blame lipotoxicity. Yes, that lipotoxicity. Damage that long-chain saturated fat (particularly palmitic acid) causes to endoplasmic reticulum and cells by triggering cell death (apoptosis). Polyunsaturated and monounsaturated fatty acids are supposed to be protective.
A whole host of organ damage is blamed on this phenomenon - "the process has also been implicated in endothelial dysfunction and atherosclerosis, heart failure, kidney failure, steatohepatitis [fatty liver] and liver failure, autoimmune inflammatory disorders, susceptibility to infections, cancer and ageing." The researchers say the brain is particularly vulnerable, as cortical astroglia metabolize a heck of a lot of fat.
Oh, and remember, this end-organ damage occurs in the context of "fat-induced insulin resistance."
Stepping back to the big picture, please remember that "fat-induced insulin resistance" is physiologic, not pathologic. It is one of the ways a body adapts to a low carb diet. Pathologic insulin resistance occurs in the context of metabolic syndrome and diabetes - conditions exacerbated by the consumption of high carbohydrate and inflammatory Western diets. If you don't have pathologic insulin resistance, can you have lipotoxicity? I seriously doubt it.
The paper continues past the lipotoxicity theory to a discussion of membranes and lipid rafts. They review studies of mice and rabbits fed a "a Western diet rich in saturated fats and cholesterol" versus a similar diet enriched with DHA (an omega 3 fatty acid derived from fish oil). They suggest that the DHA helps membrane fluidity, enabling better transport and degradation of amyloid beta, whereas the straight-up cholesterol and saturated fat rich rats had the extra gut-derived amyloid and a woeful lack of lipid rafts to help the excess amyloid be disposed of. Here we go again - known health effects from a deficiency of omega 3 is being blamed on the saturated fat part of the Western diet.
The next theory that saturated fat causes Alzheimer's in the paper relates membrane toxicity to oxidized lipids. This is something we can all agree on! Oxidized lipids and cholesterol are bad, and cause inflammation, even in the brain. Problem is, sources of dietary oxidized cholesterol include skim milk, especially powdered skim milk, and saturated fats are actually far more difficult to oxidize than polyunsaturated fats such as vegetable oils and omega 3s.
I'm a bit biased. But so far I'm not impressed. It seems easy to poke holes in all the saturated fat causes Alzheimer's theories. Frankly, the most damning evidence is that Manhattan dietary study, which does not constitute proof. But we'll see. In the next post (most likely), I'll take a closer look at ApoE4 and fat metabolism.
Thursday, October 14, 2010
Lessons from Biosphere 2
As I mentioned in my last post, the first Biosphere 2 closure experiment in 1991-1993 was rough going. Considering the circumstances (starvation, suffocation, split factions) and the poor management, I find it incredible the eight humans sealed inside finished out the two years at all. Biospherian Jane Poynter reports the overarching issue that divided the crew into four against four was respect for science versus respect for the project and the two year closure goal. To be honest, she put it far more politely than I ever could. As in the last post, much of my information here is from her book, The Human Experiment: Two Years and Twenty Minutes Inside Biosphere 2
When problems began in the Biosphere 2, most notably the lack of food and the disappearing oxygen, the management tended to want to keep such issues a secret from the public. In addition, management's position was for the Biospherians to "make it work" no matter what. It lead to extreme decisions such as when the team's doctor, who was also the oldest crew member by several decades, began to have periods of incoherence and collapse with the low oxygen levels and informed the management that he felt he would not be able to attend another crew member in need, they were originally told that oxygen would only be piped in if it was suspected the crew could survive no more than two days, or there was an immediate medical emergency.
(Interesting side note - the Biospherians did not experience typical low oxygen adaptation despite an extremely gradual drop in levels over many months. Normally, if we go to higher altitude, within a few days to weeks our bodies adapt by making more red blood cells, so we are capable of carrying more oxygen in the blood. The Biospherians did not make more red blood cells, probably because they were so malnourished. Instead their hemoglobin changed shape slightly so that it could carry oxygen at lower oxygen pressures.)
Perhaps because I'm a doctor, or maybe because I've watched too many episodes of Star Trek, when I read about the refusal of management to pump in oxygen at the request of the team doctor, I was amazed. I might have said something unladylike, such as, "What the #%=$?". The rigid dedication of management to "nothing in or out" threatened not only the safety of the crew, but the entire experiment. And, frankly, as long as you keep what goes in or out to a necessary minimum and keep track of all the tons of gas or calories of food, does it really matter scientifically if the shakedown cruise of Biosphere 2 needed a little help from the outside?
Eventually, reason prevailed, and oxygen was pumped in. But the split in the crew was already a firm barrier. What I consider the sensible side wanted to share the news with the public and get the finest scientific minds working on the problems. The closure or bust side seemed to exist in an unscientific and philosophical logjam where a rigidly defined successful mission was the only possibility, or everyone be damned.
How it all happened involves a little history of science and some psychology. See, in science there is a bit of a hierarchy. The hard sciences such as chemistry and physics are seen as more tangible and real than soft sciences such as ecology or even evolutionary biology. Biosphere 2 was a big crazy ecology experiment with no control run by non-scientists. The management were leaders of the Synergist movement - literally traveling adventurers who had weekly meditation, philosophy meetings, and theatre troupes. The charismatic head of the Synergists and leader of the Biosphere 2 project was John Allen. I can't make any diagnosis of the man, having never met him, but I can say that charismatic leaders of international groups who demand weekly meetings where the leader himself gives lectures, or increasingly angry and pointless rants, as Jane describes, will tend to be on the narcissistic side.
One prominent feature of narcissism is splitting. That is, picking some people to be your best friend, and other people to be the scapegoats to be shamed and kicked out so the group is all better again. You all went through it in middle school, on one side or the other. Again, from Jane's book, John Allen's reaction the the reality that the Biosphere 2 Agriculture would support only 80% of the crew's needs was to fire the crew chief and two others (including Jane Poynter) a few weeks prior to the beginning of the first closure experiment. Jane and another crew member were reinstated after John's rage passed. I'm just giving one example - there are many more. Suffice it to say that when one is managing an isolated group of people, where splitting into factions is the norm (according to Mir and Antarctic mission histories), having management that actively promotes fear and splitting, and denies the Biospherians free counseling that had been funded through an arranged experiment, is just a super bad idea. Things became so dire towards the end that the Chairman of Psychiatry from the University of Arizona was called in to interview everyone to make sure no one had lost touch with reality. No one had. The Biospherians were resilient folk.
So don't let yourself be sealed into an unproven ecological chamber at the whim of a charismatic group leader! But that's not why I'm writing this blog.
I'm writing this blog because evolutionary medicine is Biosphere 2. Our bodies are a hugely complex ecosystem with no control. The evolutionary paradigm has too many variables to be properly studied in a hard science sort of way. Another key vulnerability of narcissism is a predisposition to insecurity.
Cardiologists are near the top of the medical hierarchy. They have EKGs and interventional medicine and pacemakers and Lipitor. They get paid a lot and use electricity and hard science.
Psychiatrists are near the bottom of the medical hierarchy. Our only procedures are shock therapy (not a popular one) and transcranial magnetic stimulation. We may use some electricity but our science is psychology and exceedingly soft. Not too many people can describe what it is we actually do.
For contrast : "Dr. Kelly my cardiologist looked at my EKG and my blood tests, and he told me to take Lipitor, and he told me to eat margarine with plant sterols in it."
"Dr. Deans my psychiatrist asked me a lot of really nosy questions. She told me to eat pasture butter and became nearly incoherent with rage when the subject of plant sterol margarine came up."
But that is no reason to be insecure. What makes me hopeful for the future of evolutionary medicine is the apparent absence of a guru. We seem to be okay with making theoretical mistakes and being wrong from time to time. We don't let insecurity and unknowns force us in to positions of no return. We rely on science, but it must be science based on some nominal biological plausibility.
Arrogance and rigidity will destroy soft science, as it eventually destroyed the sealed experiments of Biosphere 2. The second closure experiment ended prematurely after federal marshals were called in to evict the management at the behest of the investors.
Columbia University took over management of Biosphere 2, followed by the University of Arizona. One of the first things they did was allow flow through of air and to divide up the key ecosystems for more careful, controlled study.
Such smaller experiments are useful, but it is important not to forget the big picture. Think for yourself. Study, and question. The more authority you have, the more important the lessons of Biosphere 2.
When problems began in the Biosphere 2, most notably the lack of food and the disappearing oxygen, the management tended to want to keep such issues a secret from the public. In addition, management's position was for the Biospherians to "make it work" no matter what. It lead to extreme decisions such as when the team's doctor, who was also the oldest crew member by several decades, began to have periods of incoherence and collapse with the low oxygen levels and informed the management that he felt he would not be able to attend another crew member in need, they were originally told that oxygen would only be piped in if it was suspected the crew could survive no more than two days, or there was an immediate medical emergency.
(Interesting side note - the Biospherians did not experience typical low oxygen adaptation despite an extremely gradual drop in levels over many months. Normally, if we go to higher altitude, within a few days to weeks our bodies adapt by making more red blood cells, so we are capable of carrying more oxygen in the blood. The Biospherians did not make more red blood cells, probably because they were so malnourished. Instead their hemoglobin changed shape slightly so that it could carry oxygen at lower oxygen pressures.)
Perhaps because I'm a doctor, or maybe because I've watched too many episodes of Star Trek, when I read about the refusal of management to pump in oxygen at the request of the team doctor, I was amazed. I might have said something unladylike, such as, "What the #%=$?". The rigid dedication of management to "nothing in or out" threatened not only the safety of the crew, but the entire experiment. And, frankly, as long as you keep what goes in or out to a necessary minimum and keep track of all the tons of gas or calories of food, does it really matter scientifically if the shakedown cruise of Biosphere 2 needed a little help from the outside?
Eventually, reason prevailed, and oxygen was pumped in. But the split in the crew was already a firm barrier. What I consider the sensible side wanted to share the news with the public and get the finest scientific minds working on the problems. The closure or bust side seemed to exist in an unscientific and philosophical logjam where a rigidly defined successful mission was the only possibility, or everyone be damned.
How it all happened involves a little history of science and some psychology. See, in science there is a bit of a hierarchy. The hard sciences such as chemistry and physics are seen as more tangible and real than soft sciences such as ecology or even evolutionary biology. Biosphere 2 was a big crazy ecology experiment with no control run by non-scientists. The management were leaders of the Synergist movement - literally traveling adventurers who had weekly meditation, philosophy meetings, and theatre troupes. The charismatic head of the Synergists and leader of the Biosphere 2 project was John Allen. I can't make any diagnosis of the man, having never met him, but I can say that charismatic leaders of international groups who demand weekly meetings where the leader himself gives lectures, or increasingly angry and pointless rants, as Jane describes, will tend to be on the narcissistic side.
One prominent feature of narcissism is splitting. That is, picking some people to be your best friend, and other people to be the scapegoats to be shamed and kicked out so the group is all better again. You all went through it in middle school, on one side or the other. Again, from Jane's book, John Allen's reaction the the reality that the Biosphere 2 Agriculture would support only 80% of the crew's needs was to fire the crew chief and two others (including Jane Poynter) a few weeks prior to the beginning of the first closure experiment. Jane and another crew member were reinstated after John's rage passed. I'm just giving one example - there are many more. Suffice it to say that when one is managing an isolated group of people, where splitting into factions is the norm (according to Mir and Antarctic mission histories), having management that actively promotes fear and splitting, and denies the Biospherians free counseling that had been funded through an arranged experiment, is just a super bad idea. Things became so dire towards the end that the Chairman of Psychiatry from the University of Arizona was called in to interview everyone to make sure no one had lost touch with reality. No one had. The Biospherians were resilient folk.
So don't let yourself be sealed into an unproven ecological chamber at the whim of a charismatic group leader! But that's not why I'm writing this blog.
I'm writing this blog because evolutionary medicine is Biosphere 2. Our bodies are a hugely complex ecosystem with no control. The evolutionary paradigm has too many variables to be properly studied in a hard science sort of way. Another key vulnerability of narcissism is a predisposition to insecurity.
Cardiologists are near the top of the medical hierarchy. They have EKGs and interventional medicine and pacemakers and Lipitor. They get paid a lot and use electricity and hard science.
Psychiatrists are near the bottom of the medical hierarchy. Our only procedures are shock therapy (not a popular one) and transcranial magnetic stimulation. We may use some electricity but our science is psychology and exceedingly soft. Not too many people can describe what it is we actually do.
For contrast : "Dr. Kelly my cardiologist looked at my EKG and my blood tests, and he told me to take Lipitor, and he told me to eat margarine with plant sterols in it."
"Dr. Deans my psychiatrist asked me a lot of really nosy questions. She told me to eat pasture butter and became nearly incoherent with rage when the subject of plant sterol margarine came up."
But that is no reason to be insecure. What makes me hopeful for the future of evolutionary medicine is the apparent absence of a guru. We seem to be okay with making theoretical mistakes and being wrong from time to time. We don't let insecurity and unknowns force us in to positions of no return. We rely on science, but it must be science based on some nominal biological plausibility.
Arrogance and rigidity will destroy soft science, as it eventually destroyed the sealed experiments of Biosphere 2. The second closure experiment ended prematurely after federal marshals were called in to evict the management at the behest of the investors.
Columbia University took over management of Biosphere 2, followed by the University of Arizona. One of the first things they did was allow flow through of air and to divide up the key ecosystems for more careful, controlled study.
Such smaller experiments are useful, but it is important not to forget the big picture. Think for yourself. Study, and question. The more authority you have, the more important the lessons of Biosphere 2.
Tuesday, October 12, 2010
Semi-Starvation Experiment in Arizona - Biosphere 2
Do you guys know Martin Levac? I don't either. He's someone who has been active and entertaining in the comments section of Denise Minger's big China Study post, and towards the end of those comments he started to mention some human experiments in semi-starvation. Semi-starvation means cutting lots of calories to lose weight, and is eerily close to what the government recommends for us to try when we are trying to lose some extra pounds. In the human experiments where people actually lost some meaningful weight (only successfully done under lockdown), it has been a disaster.
Martin not only mentioned the famous Ancel Keys study from WWII (I have a brief post on it from July, but the bigger link is to a more thorough post Dr. Eades did in 2007 - and if you are really interested, he linked a video a few months later), but also the experience of the eight people more or less hermetically sealed into a big greenhouse in Arizona for two years in 1991-1993. The big greenhouse is "Biosphere 2" and the tale of this $200 million experiment is both amazing and flabbergasting. Worth a post or two.
Much of my information in this series of posts will be from one of the biospherian's books, The Human Experiment: Two Years and Twenty Minutes Inside Biosphere 2. There are also a number of published scientific papers available, some accessible from the Biosphere 2 website, and a decent wikipedia article.
First, a little background. Biosphere 2 was meant to be a study of a large (3.15 acre) sealed ecosystem, with desert, ocean, rainforest, agriculture etc. along with human habitat and support. In some respects it would offer the first experimental large-scale look at how ecosystems interact, insights into the carbon and nitrogen cycles, and also a possible first blueprint for recreating Earth (biosphere 1) for space colonization. The project was originally conceived and executed by a group of adventurers, artists, and philosophers known as the Synergists, who had the backing of Texas gazillionaire Ed Bass. They had a number of other enterprises, including an art gallery in London, a cattle ranch and pastoral restoration project in Australia, a ranch and retreat in New Mexico, and an oceanic research vessel called the Heraclitus. Biosphere 2 was a heroic effort, and beautifully constructed.
Martin not only mentioned the famous Ancel Keys study from WWII (I have a brief post on it from July, but the bigger link is to a more thorough post Dr. Eades did in 2007 - and if you are really interested, he linked a video a few months later), but also the experience of the eight people more or less hermetically sealed into a big greenhouse in Arizona for two years in 1991-1993. The big greenhouse is "Biosphere 2" and the tale of this $200 million experiment is both amazing and flabbergasting. Worth a post or two.
Much of my information in this series of posts will be from one of the biospherian's books, The Human Experiment: Two Years and Twenty Minutes Inside Biosphere 2
. There are also a number of published scientific papers available, some accessible from the Biosphere 2 website, and a decent wikipedia article.First, a little background. Biosphere 2 was meant to be a study of a large (3.15 acre) sealed ecosystem, with desert, ocean, rainforest, agriculture etc. along with human habitat and support. In some respects it would offer the first experimental large-scale look at how ecosystems interact, insights into the carbon and nitrogen cycles, and also a possible first blueprint for recreating Earth (biosphere 1) for space colonization. The project was originally conceived and executed by a group of adventurers, artists, and philosophers known as the Synergists, who had the backing of Texas gazillionaire Ed Bass. They had a number of other enterprises, including an art gallery in London, a cattle ranch and pastoral restoration project in Australia, a ranch and retreat in New Mexico, and an oceanic research vessel called the Heraclitus. Biosphere 2 was a heroic effort, and beautifully constructed.
As a private venture, the designers and leaders had a lot of leeway as to how the whole experiment would be conducted, and what sort of people would be chosen as the 8 member crew who were to live in the sealed ecosystem for two years. Thus the crew had some scientific experience, and there was a doctor, but many were adventurers who had lived a Synergist life, sailing the world doing research and working in the Outback. Since the two years would be isolating and require hard physical labor, ingenuity, and technical skills, these weren't the worst people to close up inside. But the human element remained problematic throughout the history of Biosphere 2.
The overall "success or fail" goal of the first Biosphere experiment was to keep the darn thing sealed for the whole two years. Nothing other than thermodynamic energy (such as sunlight) and electronic communications would go in or out. Everything would be recycled. In case of medical emergency, an airlock was created so it would be possible for supplies and humans to go in and out without messing up all the measurements. But considering that for the first time, humans were creating a complex ecosystem and populating it with everything from scorpions to microbes to coral reefs to crops and pests, to have success or failure balance on the "closure" of the experiment for such a long time seems, well, ridiculous. But that is how the media, the biospherians, and the leadership of the venture viewed it then. That goal led to some fairly... interesting decisions along the way, especially with respect to the health of the crew. But turns out we did get another semi-starvation experiment out of it!
Prior to closure, the biospherians were already working inside the Biosphere, growing crops, making sure everything worked, etc. From this work, the crew member responsible for Agriculture, Jane Poynter, had predicted that they would be able to grow 80% of the food they needed within the biosphere. This was actually quite an achievement as the farm was 1/2 acre or so, and had to be entirely organic and self-sufficient - so no chemical fertilizers, no pesticides (as any poisons they sprayed on the plants would be sealed up inside the Biosphere with them). According to Jane, however, this number was not acceptable to management, and that 80% was somehow turned into 100% by putting the crew on a "calorie restricted, low-fat, nutrient-dense diet." Insult was added to injury by the fact that the diet was nearly vegan (they consumed a little goat milk, and meat and eggs perhaps once a week). To give you an idea, over the course of the first year, the diet was about 50% sweet potato, and 31% of the fat they consumed was from the bananas.
The doctor on the crew, Roy Walford, had spent much of his career researching low-calorie diets as they relate to longevity, so this was the perfect experiment for him! Unfortunately he would die of ALS at the age of 71 in 2004. But he did publish several papers on the Biopsherian diet, one of which we'll review now, which is optimistically titled: "The calorically restricted low-fat nutrient-dense diet in Biosphere 2 significantly lowers blood glucose, total leukocyte count, cholesterol, and blood pressure in humans." Free full text, so go take a look. Actually, go ahead if you haven't already and scan my little post on semi-starvation in WWII and then go take a look.
It is perhaps predictable that Biosphere 2 had some crop problems, and the crew in the first six months was restricted to an average of 1780 calories daily. Now that's more, actually, than Weight Watchers (tm) would likely have me eat on a weight loss diet (20 points, I think, would be my allotment!), but the Biopsherians were engaged in hard physical labor much of the day. The carbon dioxide levels were rising, so they continuously had to harvest and sequester biomass all over the facility, and shovel and scrape carbonate off their home-made natural CO2 scrubber. Not to mention the farming itself, harvesting rice paddies, threshing wheat, milking goats, the whole shebang.
Some of the glass panels admitted UV light to help the reptiles survive, but the humans were allowed supplementation with 400 IU vitamin D, vitamin B12, folic acid, 400 IU vitamin E, 500 mg of vitamin C, and calcium. They ate three meals a day, equal portions between men and women.
Not surprisingly, the Biospherians lost weight. Lots of weight. Men lost 16% of their BMI in 6 months, women 11%. Average systolic blood pressure decreased from 109 to 89, and diastolic BP decreased from 74 to 58. Mean total cholesterol decreased from 191 to 123. HDL fell from 62 to a dismal 38. The "risk ratio" of total cholesterol to HDL remained about the same. Triglycerides decreased in men (from 139 to 96) and increased in women (from 78 to 114). Fasting glucose fell from 92 to 74.
So how much fun did the crew have on this diet? Well, Walford is practically mute on the subject in his paper. There's one sentence. "At six months, both sexes were at a body fat composition at the lower bounds of normal but reported no ill effects." Enter The Human Experiment: Two Years and Twenty Minutes Inside Biosphere 2, where Jane Poynton describes hunger, fatigue, mental fog, licking each plate rather obsessively and elaborate food rituals, and depression. Her descriptions very much remind me of the rituals in this book: Wasted: A Memoir of Anorexia and Bulimia (P.S.)
. The blood pressures described above also remind me of the ones of teenage girls in the child psych unit where I worked as a resident - girls who were there due to eating disorders.
, where Jane Poynton describes hunger, fatigue, mental fog, licking each plate rather obsessively and elaborate food rituals, and depression. Her descriptions very much remind me of the rituals in this book: Wasted: A Memoir of Anorexia and Bulimia (P.S.). The blood pressures described above also remind me of the ones of teenage girls in the child psych unit where I worked as a resident - girls who were there due to eating disorders.Some quotes from Jane's book:
"We were, however, becoming ever more obsessed with food." "When watching a film, I would focus on the eating scenes, forgetting the plot." "Sometimes we lined up in the second story windows of the Habitat and took turns peering through binoculars at fat people (for everyone seemed overweight to us then, even the slender people) who were spurting ketchup on sausages and shoveling them into their mouths. We were culinary voyeurs." "I dragged myself from chore to chore, taking twice as long to weed a sweet-potato field as it should have taken, skipping other chores. I am used to being strong and vital and I felt far from that most of the time." Jane notes that the only locked door in the Biosphere 2 was the door to the banana room, as the succulent fruit was far too tempting.
We can't separate the diet of the Biospherians from the low light, increasingly low oxygen (turns out oxygen was reacting with the concrete structure, leading to gradually and continuously lower levels, until the Biospherians had sleep apnea and couldn't complete sentences, so eventually oxygen had to be piped in during the second year), and the difficulty of isolation. For the last 14 months of the first mission, the eight crew members were split into two factions and would not make eye contact or speak to each other unless absolutely necessary. Apparently, one of the crew set up funding for psychological monitoring and counseling ahead of time, but this experiment was rejected by management. Frankly baffling, considering how useful the information might be for, say, NASA or anyone else planning Antarctic missions or long-term space missions. Not to mention you have 8 starving, oxygen deprived, suffering Biospherians running the $200 million experiment. Never would have passed an institutional review board at an academic medical center!
There's more to this tale of the Biospherians, and some lessons for medical science. But for now, just remember, semi-starvation is a tough row to hoe. Each and every time it is tried.
Sunday, October 10, 2010
Blue Velvet
A little nubbin of a post tonight, mostly to get my brain churning about a topic that I need to do a bit more reading on. The Journal of Affective Disorders has a number of intriguing papers this month and next, one of them being "Association between inducible and neuronal nitric oxide synthase polymorphisms and recurrent depressive disorder."
What? Doesn't sound intriguing to you? I keep an eye out for nitric oxide in the literature. See, my pet (and as far as I know completely unproven) theory is that the strong link between insulin resistance and depression is not just in the inflammation of hyperglycemia, but also due to insulin resistance making the endothelium (inner cell layer) of blood vessels less responsive to nitric oxide. This can make one hypertensive and prevent men from getting erections (if that doesn't make men want to go low-carb, I'm not sure what would). But endothelial nitric oxide synthase (an enzyme that is part of the pathway that makes nitric oxide in the blood) is thought to be part of a larger neuroprotective and regenerative pathway that (in part) could explain the anti-depressant effects of exercise and meditation. This would imply that high blood sugar would be rather like anti-exercise (sloth) and anti-meditation (stress) neurochemically. Again, speculative but not entirely off the wall.
But of course it is never that simple. Anyone reading up on nitric oxide will figure out that in certain areas of the brain, too much nitric oxide is Bad News. It's pro-oxidant and pro-inflammatory. The authors of today's paper state, "we may conclude that NO may have beneficial and detrimental effects depending on its concentrations, location, source, and duration of exposure."
But don't despair. There are three different types (or isoforms) of the enzyme that churns out nitric oxide. They are inducible nitric oxide synthase, neuronal nitric oxide synthase, and endothelial nitric oxide synthase. We'll call them iNOS, nNOS, and eNOS. For the purposes of understanding a healthy brain, iNOS and nNOS are bad, while eNOS is good.
Just to add more excruciating detail to a familiar Evolutionary Psychiatry theme, glutamate binds the NMDA receptor, leading to a flux of calcium into the cell, activating nNOS (via calmodulin, biochem geeks!). In addition, inflammatory cytokines cause brain cells called astrocytes and microglia to make NO via iNOS. This increases glutamate release. So both iNOS and nNOS are part of the glutamate/NMDA/calcium excitotoxic neuron-killing inflammatory cycle of brain badness. This pathway is linked to depression, anxiety, parkinson's dementia, schizophrenia, and even non-psychiatric illnesses such as migraines and rheumatoid arthritis.
So the interesting thing from this paper is that the researchers checked the genetic make-up of 181 (caucasian european) people with recurrent depression (around 4 episodes on average over 8 years) and 149 non-depressed controls. They found that carriers of certain types of nitric oxide synthase genes were more likely to have resistant depression, and other types of nitric oxide synthase genes were protective against having depression. A similar but smaller study was done in Asians and didn't show a linkage.
I have more reading to do to see how this information falls into the overall evo-med scheme, especially the exercise and mindfulness side of things. And I'll link the paper and some of my pertinent previous posts sometime tomorrow - if you are reading Sunday night I'm on the iPad.
And I know it was nitrous oxide (N2O) not nitric oxide (NO) in Blue Velvet, but hey, I've got to get the random googlers somehow. And N2O might act by mimicking NO in the central nervous system. So chew on that for a bit. Time for bed!
What? Doesn't sound intriguing to you? I keep an eye out for nitric oxide in the literature. See, my pet (and as far as I know completely unproven) theory is that the strong link between insulin resistance and depression is not just in the inflammation of hyperglycemia, but also due to insulin resistance making the endothelium (inner cell layer) of blood vessels less responsive to nitric oxide. This can make one hypertensive and prevent men from getting erections (if that doesn't make men want to go low-carb, I'm not sure what would). But endothelial nitric oxide synthase (an enzyme that is part of the pathway that makes nitric oxide in the blood) is thought to be part of a larger neuroprotective and regenerative pathway that (in part) could explain the anti-depressant effects of exercise and meditation. This would imply that high blood sugar would be rather like anti-exercise (sloth) and anti-meditation (stress) neurochemically. Again, speculative but not entirely off the wall.
But of course it is never that simple. Anyone reading up on nitric oxide will figure out that in certain areas of the brain, too much nitric oxide is Bad News. It's pro-oxidant and pro-inflammatory. The authors of today's paper state, "we may conclude that NO may have beneficial and detrimental effects depending on its concentrations, location, source, and duration of exposure."
But don't despair. There are three different types (or isoforms) of the enzyme that churns out nitric oxide. They are inducible nitric oxide synthase, neuronal nitric oxide synthase, and endothelial nitric oxide synthase. We'll call them iNOS, nNOS, and eNOS. For the purposes of understanding a healthy brain, iNOS and nNOS are bad, while eNOS is good.
Just to add more excruciating detail to a familiar Evolutionary Psychiatry theme, glutamate binds the NMDA receptor, leading to a flux of calcium into the cell, activating nNOS (via calmodulin, biochem geeks!). In addition, inflammatory cytokines cause brain cells called astrocytes and microglia to make NO via iNOS. This increases glutamate release. So both iNOS and nNOS are part of the glutamate/NMDA/calcium excitotoxic neuron-killing inflammatory cycle of brain badness. This pathway is linked to depression, anxiety, parkinson's dementia, schizophrenia, and even non-psychiatric illnesses such as migraines and rheumatoid arthritis.
So the interesting thing from this paper is that the researchers checked the genetic make-up of 181 (caucasian european) people with recurrent depression (around 4 episodes on average over 8 years) and 149 non-depressed controls. They found that carriers of certain types of nitric oxide synthase genes were more likely to have resistant depression, and other types of nitric oxide synthase genes were protective against having depression. A similar but smaller study was done in Asians and didn't show a linkage.
I have more reading to do to see how this information falls into the overall evo-med scheme, especially the exercise and mindfulness side of things. And I'll link the paper and some of my pertinent previous posts sometime tomorrow - if you are reading Sunday night I'm on the iPad.
And I know it was nitrous oxide (N2O) not nitric oxide (NO) in Blue Velvet, but hey, I've got to get the random googlers somehow. And N2O might act by mimicking NO in the central nervous system. So chew on that for a bit. Time for bed!
Saturday, October 9, 2010
Zinc Revolution
Back in July, I wrote a number of posts about zinc. There was Zinc! (which remains one of my most popular posts - perhaps it was the exclamation point?), Zinc, Depression, and Everything, and the optimistically titled Zinc Clarity. By all means go back and dig in, but the summary here: rather like magnesium, zinc is wasted and sequestered during periods of inflammation, but zinc is also necessary for our brains to work properly. Low serum levels of zinc have been measured in ADHD, depression, and anorexia, and zinc repletion has been shown to help the symptoms of those illnesses, at least in small studies (though for anorexia with need for weight gain, zinc supplementation should really be standard of care, as the data is good). Hunter gatherers averaged 43 mg daily (above the RDA safety zone "upper tolerable limit" of 40mg daily, but below the lowest level where there begins to be issues with copper absorption, which is around 60mg daily, but is likely not a serious problem until 150mg daily). A Standard American averages much, much less than all those numbers, somewhat below the RDA of 11-15mg daily, and as zinc is available mostly in egg yolks and other animal foods, a vegetarian has a serious risk of being deficient, as does anyone on a thiazide diuretic medication.
Cool. Well, as always, it is not quite that simple. As I mentioned in Zinc, Depression, and Everything, zinc deficiency doesn't necessarily cause depression (though it might play a role). In fact, depression (inflammation) will cause low serum zinc. Low serum levels of zinc are a biomarker for depression, rather like high C reactive protein is a biomarker for inflammation. (Please, please, please do not take Crestor for the sole purpose of lowering your C reactive protein. Don't do it!)
On Wednesday when I was tooling through the Journal of Affective Disorders, I found this new study from the same zinc-obsessed Polish group who have produced a slew of papers over the last several years, "Serum zinc level in depressed patients during zinc supplementation of imipramine treatment."
The researchers took 60 patients diagnosed with Major Depressive Disorder from inpatient units and outpatient clinics, and also recruited 25 healthy age- and sex-matched controls with no mental illness (and, interestingly, no family history of depression or mania). The healthy controls had their serum zinc measured once, the depressed subjects four times (before, and 2, 6, and 12 weeks after starting antidepressant medication treatment).
All the depressed patients were treated with an antidepressant (imipramine), but the 60 patients were divided into receiving placebo + imipramine or zinc + imipramine. During the data analysis after the experiment, "resistant" and "non-resistant" groups were established by how the patients responded to the treatment (it also happened to line up with now long they had been depressed). Got it? So in the end, you have four groups of depressed patients:
Treatment resistant receiving imipramine + zinc
Treatment resistant receiving imipramine + placebo
"Non-resistant" receiving imipramine + zinc
"Non-resistant" receiving imipramine + placebo
Some results (all of these are statistically significant unless I note otherwise). Serum zinc levels were 22% lower on average at baseline in the depressed individuals than in the healthy controls. The serum zinc levels of the long-term "resistant" depressed patients were lowest of all. Serum zinc over the twelve weeks increased in all the depressed patients except the treatment-resistant imipramine + placebo group. Yes, that means that anyone who felt better by depression rating scales at the end of the 12 weeks had a higher zinc level, whether they were given placebo or zinc supplementation. The treatment resistant group who received zinc also had a higher zinc level at the end of the treatment than at the beginning, but it was still much lower than both non-resistant groups. Everyone remained lower than the normal controls, but the treatment responsive groups were fairly close.
Based on review of other zinc studies and the results of this study, the researchers concluded the following: It is unlikely that low blood zinc level in depression is due to lack of appetite or from HPA axis hyper-stimulation that occur with depression. They felt it was specifically due to inflammation (as zinc levels are negatively correlated with inflammatory markers, like IL-6 and neopterin), and even more specifically due to either a decrease in the protein that carries zinc around in the blood, or the increase in IL-6 leading to metallothionein sequestering zinc in the liver. Therefore, "it can be inferred that normalization of the serum zinc level in treatment non-resistant patients was the result of the abatement of inflammatory processes during remission of the depressive episode." (The entire paper reads like that. It is thankfully quite short.) In other words, inflammation causes depression and low zinc levels. Successfully treat the inflammation and your depression gets better and your zinc levels rise.
Why did I call this post "Zinc Revolution?" Well, here we have something heretofore unknown in psychiatry -- a simple blood test that could, if all this pans out in more studies, monitor treatment resistance and treatment response. In the old days they would do tedious dexamethasone suppression tests and even, sometimes, in research, spinal taps to measure serotonin levels and the like. Certain features of depression would correlate with some of the measures, but there was nothing found that would give you a real physiologic clue for most patients with depression.
Not to mention here we have real proof that depression isn't all in your head. It's in your blood, too, right there in the inflammation, measured by the biomarker zinc.
We can measure treatment resistance and response already, via diagnostic interviews and symptom scales. All these are subjective, but similar to how a neurologist would measure treatment response to migraine medication. An objective blood test could be a nice addition to the psychiatric armament, but it is the principle that matters, and I'll repeat it here:
Depression is not all in your head.
Cool. Well, as always, it is not quite that simple. As I mentioned in Zinc, Depression, and Everything, zinc deficiency doesn't necessarily cause depression (though it might play a role). In fact, depression (inflammation) will cause low serum zinc. Low serum levels of zinc are a biomarker for depression, rather like high C reactive protein is a biomarker for inflammation. (Please, please, please do not take Crestor for the sole purpose of lowering your C reactive protein. Don't do it!)
On Wednesday when I was tooling through the Journal of Affective Disorders, I found this new study from the same zinc-obsessed Polish group who have produced a slew of papers over the last several years, "Serum zinc level in depressed patients during zinc supplementation of imipramine treatment."
The researchers took 60 patients diagnosed with Major Depressive Disorder from inpatient units and outpatient clinics, and also recruited 25 healthy age- and sex-matched controls with no mental illness (and, interestingly, no family history of depression or mania). The healthy controls had their serum zinc measured once, the depressed subjects four times (before, and 2, 6, and 12 weeks after starting antidepressant medication treatment).
All the depressed patients were treated with an antidepressant (imipramine), but the 60 patients were divided into receiving placebo + imipramine or zinc + imipramine. During the data analysis after the experiment, "resistant" and "non-resistant" groups were established by how the patients responded to the treatment (it also happened to line up with now long they had been depressed). Got it? So in the end, you have four groups of depressed patients:
Treatment resistant receiving imipramine + zinc
Treatment resistant receiving imipramine + placebo
"Non-resistant" receiving imipramine + zinc
"Non-resistant" receiving imipramine + placebo
Some results (all of these are statistically significant unless I note otherwise). Serum zinc levels were 22% lower on average at baseline in the depressed individuals than in the healthy controls. The serum zinc levels of the long-term "resistant" depressed patients were lowest of all. Serum zinc over the twelve weeks increased in all the depressed patients except the treatment-resistant imipramine + placebo group. Yes, that means that anyone who felt better by depression rating scales at the end of the 12 weeks had a higher zinc level, whether they were given placebo or zinc supplementation. The treatment resistant group who received zinc also had a higher zinc level at the end of the treatment than at the beginning, but it was still much lower than both non-resistant groups. Everyone remained lower than the normal controls, but the treatment responsive groups were fairly close.
Based on review of other zinc studies and the results of this study, the researchers concluded the following: It is unlikely that low blood zinc level in depression is due to lack of appetite or from HPA axis hyper-stimulation that occur with depression. They felt it was specifically due to inflammation (as zinc levels are negatively correlated with inflammatory markers, like IL-6 and neopterin), and even more specifically due to either a decrease in the protein that carries zinc around in the blood, or the increase in IL-6 leading to metallothionein sequestering zinc in the liver. Therefore, "it can be inferred that normalization of the serum zinc level in treatment non-resistant patients was the result of the abatement of inflammatory processes during remission of the depressive episode." (The entire paper reads like that. It is thankfully quite short.) In other words, inflammation causes depression and low zinc levels. Successfully treat the inflammation and your depression gets better and your zinc levels rise.
Why did I call this post "Zinc Revolution?" Well, here we have something heretofore unknown in psychiatry -- a simple blood test that could, if all this pans out in more studies, monitor treatment resistance and treatment response. In the old days they would do tedious dexamethasone suppression tests and even, sometimes, in research, spinal taps to measure serotonin levels and the like. Certain features of depression would correlate with some of the measures, but there was nothing found that would give you a real physiologic clue for most patients with depression.
Not to mention here we have real proof that depression isn't all in your head. It's in your blood, too, right there in the inflammation, measured by the biomarker zinc.
We can measure treatment resistance and response already, via diagnostic interviews and symptom scales. All these are subjective, but similar to how a neurologist would measure treatment response to migraine medication. An objective blood test could be a nice addition to the psychiatric armament, but it is the principle that matters, and I'll repeat it here:
Depression is not all in your head.
Thursday, October 7, 2010
Diet and Mood Disorders
Found two more studies measuring diet pattern and mood disorders!
The first one is Dietary pattern and depressive symptoms in middle age from the British Journal of Psychiatry in 2009 (free full text, go take a look!). This paper is part of the large Whitehall II epidemiological study, where some 10,000 people were screened at baseline (phase 1) for all sorts of demographic characteristics, stress levels, health, lifestyle factors, blood pressure, and some labwork. Every 2&1/2 years or so, the study subjects received a postal questionnaire to fill out (phases 2,4,6,8), and every 5 years a questionnaire and a clinical examination were done (phases 3,5,7). In this paper, the data was taken from 3486 White European participants with data on dietary patterns and all covariates at phase 5 and depression at phase 7. The 175 Black and 331 Asian participants were excluded due to "differences in eating patterns." (!!!)
Dietary "pattern" was determined by a Food Frequency Questionnaire based on the one used in the Nurses Health Study (but changed up to include British sorts of foods - like bangers and mash, or crisps, or yorkshire pudding). Here's a good write-up addressing the (actually rather rigorous, but still hopeless) validity of the FFQ used in the Nurses Health Study. 127 food items were rated according to how often they were consumed - "never or less than once per month" up to "six or more times per day" - the 127 items were divided into 37 groups, and dietary patterns were identified using "principal component analysis" of the 37 groups, and statisticians gleefully addressed the data with graphs and scree plots and tweaks and nudges until a score pops out about each person's diet, falling into "whole foods" or the "processed foods" patterns.
"Whole foods" were diets consisting of vegetables, fruits and fish.
"Processed foods" were diets consisting of "high consumption of sweetened desserts, chocolates, fried food, processed meat, pies, refined grains, high fat dairy products, and condiments."
Depression measures were determined by a 20 question "Center for Epidemiologic Studies Depression Scale." People with a score higher than 15 were considered depressed.
Then the statisticians got a whack at the data again, adjusting for covariates such as age, gender, marital status, employment grade, education, smoking, physical activity, health status (based on clinical findings such as a high hemoglobin A1C (a measure of average blood glucose), blood pressure, being on antidepressants, etc.), a second "GHQ" depression subscale, and a cognitive score based on 65 question test.
Ready for the results yet? What do you think will turn out?
Patients with the highest intake of whole foods were less likely to be depressed (and this association wasn't affected much, actually, by adjusting for all the covariates, which is interesting - suggesting that the association with diet could be as important or more important than all those other covariates.). Patients with a high intake of processed food were much more likely to be depressed.
There is another interesting thing about this study. See, from just the above data, you don't know whether depressed people are too blue to do anything but sit around gorging on meat pies, sugar, and refined grains, or if the diet actually leads to the depression. The depression measures were repeated at phase 5 and phase 7, and when the 427 participants who were depressed at stage 5 were excluded, the data showed that the same people who had crappy diets but were not depressed (yet) at phase 5 were more likely to be depressed at phase 7. In addition, the researchers went back to the phase 3 data, and found no evidence that the dietary patterns in phase 5 were worse for the participants who were depressed at phase 3. These are clues that crappy diet precedes depressive symptoms, not the other way around.
All in all, a rather cool study, considering the limitations of epidemiology.
The second study is hot off the presses - Diet quality in bipolar disorder in a population-based sample of women from the Journal of Affective Disorders (I think this is the November issue - these are the corrected proofs available online before print). The subjects used were women from the Australian Geelong Osteoporosis Study (I blogged about them back in June). 1046 women randomly recruited from compulsory voting roles volunteered for this particular piece of the study. Each of the women were given the gold standard interview for diagnosis of psychiatric disorders - the SCID (non-patient edition). Patients with depression or anxiety were excluded, allowing for patients with bipolar disorder to be compared to those with no current (or lifetime) psychopathology.
Once again, a food frequency questionnaire was used, and the diets were broken up into "traditional" (vegetables, fruit, beef, lamb, fish, whole grains), "western" (meat pies, processed meats, pizza, chips, hamburgers, white bread, sugar, flavored milk drinks, and beer), and "modern" (fruits, salads, fish, yogurt, nuts, beans, tofu, and red wine). Blah blah blah logistic regression analyses and exposure variables were studiously applied and accounted for (can you tell I'm not an epidemiologist?).
Here's an interesting tidbit that I don't remember from the previous paper I blogged about in June - the researchers note that it was the absolute amount of western style foods that seemed to be related to the risk of depression rather than the amount as a proportion of overall energy consumption. Therefore, the researchers examined the data in this grouping as both absolute amounts, percentage of energy, and covariate confounding. Whew.
Bipolar disorder is less common than depressive or anxiety disorders, so only 23 women in the whole study qualified for the diagnosis (there were 332 with depression or anxiety and therefore excluded from this analysis, and 691 without depressive or anxiety disorders). Participants with bipolar disorder were younger and had higher average daily energy intake, though there was no difference in education, BMI, alcohol intake, education, socioeconomic status, smoking, and physical activity compared to those with no psychopathology. (Interesting - bipolar disorder and substance abuse are highly correlated so it is something to keep in mind that these 23 bipolar ladies didn't seem to smoke or drink more than the 691 "normals.")
Now the diet results! Individuals with a "modern" pattern were more likely to have a diagnosis of bipolar disorder, as were individuals with a "western" pattern, before and after adjustments for energy intake. A "traditional" dietary pattern was protective. These data held even when accounting for age.
As in the previous study (which I addressed in the comments in my previous blog post), the diets were also given a total "DQS" or dietary quality score, associated with how close the diets came to the national recommendations for good diets (similar to the USDA recommendations). DQS score of diets had no correlation with bipolar disorder, protective or not protective.
Overall, the authors noted (as I do now!) that the association with depressive, anxiety, and bipolar disorders are similar - a "traditional" diet being protective, and modern and western diets being similarly dismal. My theory is that an individual's response to diet would be based on genetic risk, so the inflammation level related to similar dietary choices would come out as different psychopathology depending on your genes.
The authors of the second study make note of the results of the first study I mentioned above - they think diet is causative, not a choice as a result of specific psychiatric illness. They note systemic inflammation, oxidative stress, and neurotrophin levels as potential explanations of the demonstrated associations between dietary quality and bipolar disorder. I agree. Wholeheartedly.
Eat real food, folks. It won't hurt. And maybe it will help.
The first one is Dietary pattern and depressive symptoms in middle age from the British Journal of Psychiatry in 2009 (free full text, go take a look!). This paper is part of the large Whitehall II epidemiological study, where some 10,000 people were screened at baseline (phase 1) for all sorts of demographic characteristics, stress levels, health, lifestyle factors, blood pressure, and some labwork. Every 2&1/2 years or so, the study subjects received a postal questionnaire to fill out (phases 2,4,6,8), and every 5 years a questionnaire and a clinical examination were done (phases 3,5,7). In this paper, the data was taken from 3486 White European participants with data on dietary patterns and all covariates at phase 5 and depression at phase 7. The 175 Black and 331 Asian participants were excluded due to "differences in eating patterns." (!!!)
Dietary "pattern" was determined by a Food Frequency Questionnaire based on the one used in the Nurses Health Study (but changed up to include British sorts of foods - like bangers and mash, or crisps, or yorkshire pudding). Here's a good write-up addressing the (actually rather rigorous, but still hopeless) validity of the FFQ used in the Nurses Health Study. 127 food items were rated according to how often they were consumed - "never or less than once per month" up to "six or more times per day" - the 127 items were divided into 37 groups, and dietary patterns were identified using "principal component analysis" of the 37 groups, and statisticians gleefully addressed the data with graphs and scree plots and tweaks and nudges until a score pops out about each person's diet, falling into "whole foods" or the "processed foods" patterns.
"Whole foods" were diets consisting of vegetables, fruits and fish.
"Processed foods" were diets consisting of "high consumption of sweetened desserts, chocolates, fried food, processed meat, pies, refined grains, high fat dairy products, and condiments."
Depression measures were determined by a 20 question "Center for Epidemiologic Studies Depression Scale." People with a score higher than 15 were considered depressed.
Then the statisticians got a whack at the data again, adjusting for covariates such as age, gender, marital status, employment grade, education, smoking, physical activity, health status (based on clinical findings such as a high hemoglobin A1C (a measure of average blood glucose), blood pressure, being on antidepressants, etc.), a second "GHQ" depression subscale, and a cognitive score based on 65 question test.
Ready for the results yet? What do you think will turn out?
Patients with the highest intake of whole foods were less likely to be depressed (and this association wasn't affected much, actually, by adjusting for all the covariates, which is interesting - suggesting that the association with diet could be as important or more important than all those other covariates.). Patients with a high intake of processed food were much more likely to be depressed.
There is another interesting thing about this study. See, from just the above data, you don't know whether depressed people are too blue to do anything but sit around gorging on meat pies, sugar, and refined grains, or if the diet actually leads to the depression. The depression measures were repeated at phase 5 and phase 7, and when the 427 participants who were depressed at stage 5 were excluded, the data showed that the same people who had crappy diets but were not depressed (yet) at phase 5 were more likely to be depressed at phase 7. In addition, the researchers went back to the phase 3 data, and found no evidence that the dietary patterns in phase 5 were worse for the participants who were depressed at phase 3. These are clues that crappy diet precedes depressive symptoms, not the other way around.
All in all, a rather cool study, considering the limitations of epidemiology.
The second study is hot off the presses - Diet quality in bipolar disorder in a population-based sample of women from the Journal of Affective Disorders (I think this is the November issue - these are the corrected proofs available online before print). The subjects used were women from the Australian Geelong Osteoporosis Study (I blogged about them back in June). 1046 women randomly recruited from compulsory voting roles volunteered for this particular piece of the study. Each of the women were given the gold standard interview for diagnosis of psychiatric disorders - the SCID (non-patient edition). Patients with depression or anxiety were excluded, allowing for patients with bipolar disorder to be compared to those with no current (or lifetime) psychopathology.
Once again, a food frequency questionnaire was used, and the diets were broken up into "traditional" (vegetables, fruit, beef, lamb, fish, whole grains), "western" (meat pies, processed meats, pizza, chips, hamburgers, white bread, sugar, flavored milk drinks, and beer), and "modern" (fruits, salads, fish, yogurt, nuts, beans, tofu, and red wine). Blah blah blah logistic regression analyses and exposure variables were studiously applied and accounted for (can you tell I'm not an epidemiologist?).
Here's an interesting tidbit that I don't remember from the previous paper I blogged about in June - the researchers note that it was the absolute amount of western style foods that seemed to be related to the risk of depression rather than the amount as a proportion of overall energy consumption. Therefore, the researchers examined the data in this grouping as both absolute amounts, percentage of energy, and covariate confounding. Whew.
Bipolar disorder is less common than depressive or anxiety disorders, so only 23 women in the whole study qualified for the diagnosis (there were 332 with depression or anxiety and therefore excluded from this analysis, and 691 without depressive or anxiety disorders). Participants with bipolar disorder were younger and had higher average daily energy intake, though there was no difference in education, BMI, alcohol intake, education, socioeconomic status, smoking, and physical activity compared to those with no psychopathology. (Interesting - bipolar disorder and substance abuse are highly correlated so it is something to keep in mind that these 23 bipolar ladies didn't seem to smoke or drink more than the 691 "normals.")
Now the diet results! Individuals with a "modern" pattern were more likely to have a diagnosis of bipolar disorder, as were individuals with a "western" pattern, before and after adjustments for energy intake. A "traditional" dietary pattern was protective. These data held even when accounting for age.
As in the previous study (which I addressed in the comments in my previous blog post), the diets were also given a total "DQS" or dietary quality score, associated with how close the diets came to the national recommendations for good diets (similar to the USDA recommendations). DQS score of diets had no correlation with bipolar disorder, protective or not protective.
Overall, the authors noted (as I do now!) that the association with depressive, anxiety, and bipolar disorders are similar - a "traditional" diet being protective, and modern and western diets being similarly dismal. My theory is that an individual's response to diet would be based on genetic risk, so the inflammation level related to similar dietary choices would come out as different psychopathology depending on your genes.
The authors of the second study make note of the results of the first study I mentioned above - they think diet is causative, not a choice as a result of specific psychiatric illness. They note systemic inflammation, oxidative stress, and neurotrophin levels as potential explanations of the demonstrated associations between dietary quality and bipolar disorder. I agree. Wholeheartedly.
Eat real food, folks. It won't hurt. And maybe it will help.