Zombieland 2 - You Are What You Eat, Mommyblogger Style

First the Zombieland movie trailer, just for fun.  Now take a peek at one of my more popular posts, Zombieland, which a brilliant psychiatrist friend of mine described as "food for thought."  The post was about phospholipids, primarily phosphatidylserine and phosphatidylcholine, delectable and important nutrients nature has supplied most richly in the consumption of brains (though eggs are perhaps a more palatable source).  (Linus Pauling Institute article about choline is here.)

(Hey, Nephropal is back!  Sorry about the jump around.  I spent a good part of the morning playing video games and my attention span is shot, though my reaction times are *awesome*!)

Little did I know that choline would become a very fashionable nutrient in the paleoblogosphere.   Chris Masterjohn, Paul Jaminet, and Stephan Guyenet all did a post or three, and everyone who is anyone doubled down on his or her egg consumption thereafter.  Much of the to-do was focused on fatty liver disease (one really must eat choline to protect one's liver from the rigors of modern life).  But, as it turns out, while the liver is on the front lines, the brain is where the battle really rages.

The data in humans is... scarce (there are some small human trials of induced choline deficinecy and fatty liver, reversed by choline repletion).  But let's throw out what we have, be it epidemiology or mice or rats, and do some speculation. 

First off, choline is part of the folate cycle, which I discussed a bit in this post here.  The folate cycle is exceptionally important for liver and brain/nerve health, and includes some key players - iron, vitamin B6, vitamin B12, folate, methionine, choline, oxidized choline (called betaine), SAM, niacin, and riboflavin.  All the players need to be on the field for the full folate cycle to run efficiently.  Most choline absorbed by humans is immediately made into phosphatidylcholine and incorporated into cell membranes.  Choline is also made into betaine in the liver, where it serves as a methyl donor for many important chemical reactions (1). One of the phosphorylated products of these many reactions is phosphocreatine, by the way.  Also important to neurons and the brain is sphingomyelin.

Problems or deficiencies in the folate cycle (including choline deficiency) are implicated in fatty liver disease, neural tube defects (like spina bifida), cardiovascular disease, and cancer.   The cycle begins with methionine (an amino acid), which using various B vitamin cofactors is made into SAM.  SAM is a methyl donor and is vital in nearly sixty important chemical reactions in the liver, from making neurotransmitters to cell membranes to DNA.   After being used as a methyl donor, SAM becomes SAH which becomes homocysteine.  Having high homocysteine is associated with dementia and cardiovascular disease - in my mind it is associated with poor nutrition in general.  Without all the players, homocysteine has a hard time being recycled for use in the folate cycle again.  In order to get the majority of the players, you need to eat a lot of whole grains, or vitamins, or organ meats/eggs.   Whole grains have their issues, so I'll stick to the latter sources, thank you very much.

All right, so choline is necessary, but why?  Fatty liver develops because you need choline to make VLDL particles.  VLDL carries triglycerides from the liver into the bloodstream.  If you don't have enough phospholipids like phosphatidylcholine to form the coat of the VLDL particle, you end up with triglycerides stuck in the liver ==> fatty liver.  Now if you don't have enough phospholipids to even get your triglycerides out of the liver, how could you possibly have enough for use in your other cell membranes (or in the neurons of the brain, which are especially rich in phospholipids)?  And how would they even get there without your cholesterol/fat carrying particles?  Fatty liver is just a harbinger of even more serious problems to follow. 

Neural tube defects are extremely common birth defects that result from faulty closing of the ends of the neural tube.  In very early development, we humans spend some time being sort of flat, like an elongated pancake.  Then we roll up in a couple of ways to become more... wormlike, before we grow limb buds and all sorts of other interesting things to become babies.  Rolling up properly requires the folate cycle to be running at full efficiency.  And, sure enough, epidemiologic studies have linked choline deficiency in human mothers to neural tube defects in their offspring (those in the bottom 25% of choline intake have 4 times the risk of babies with neural tube defects as those in the top 25%), and in mice, choline restriction is shown to cause neural defects.

Pregnancy and lactation are periods in a woman's life when she needs some serious choline to keep the machinery going.  Placental/amniotic fluid levels of choline are nearly 10 times mother's serum levels (2)  Moms seem to benefit from an enhanced choline-making machinery during pregnancy, but mom still ends up with depleted levels after childbirth (which will continue during lactation).  It's best to have time to replete this vital nutrient between kiddos.

Beyond the neural tube defect issue is the memory issue.  Neural tube defects usually begin within the first month of pregnancy, so by the time you realize you are expecting, it's pretty much too late to do anything about it.  But studies of rats have shown that choline depleted mothers in the latter half of rat pregnancy results in offspring with lousy memories.  The hippocampus is the part of the brain at the epicenter of memory (and depression).   Pregnant rats who have plenty of choline seem to be able to make all the membranes, DNA, and stem cells you need to make an awesome hippocampus.  Pregnant rats without choline have baby rats who just don't remember as well.  In addition, choline supplementation in the second half of pregnancy seems to protect offspring rats from the detrimental brain effects of alcohol given to their mothers (3).  There are no studies in humans showing this link.  However, elevated human maternal homocysteine levels are linked with preeclampsia, prematurity, and low birth weight, and most studies have shown that the higher a mother's choline levels, the lower her homocysteine tends to be.

Other studies (including the Nurses Health Study and the Framingham Offspring Study) have shown that higher choline levels are associated with lower inflammatory markers of many kinds, including IL-6, TNF-alpha, and C reactive protein.  Keep in mind that in the PROSPECT-EPIC study, even those women in the highest quartile of choline intake fell below the Institutes of Medicine number for Adequate Intake of 425 mg a day for women (to get that amount, you need to eat half a pound of chicken, two eggs, and a quart of 1% milk (not sure why anyone would be drinking that, but okay)! And those are relatively rich sources!) In the Nurses' Health Study, 95% of women fell below an average daily intake of 411 mg.  In addition, nearly 50% of seem to have a genetic polymorphism where we have a hard time making methionine into choline, meaning choline becomes even more of an essential nutrient.  This fact may be why some people have bulletproof livers, and others develop fatty liver just by looking at a bottle of wine. 

The women with adequate intake in these large studies had a higher than average intake of eggs.  I wonder if choline is the reason recent studies have shown that eggs in conjunction with a calorie restricted diet seem to improve diabetes, despite all that fat and cholesterol. (I like these studies and how they seem to annihilate the lipotoxicity hypothesis). 

I find the information about choline to be convincing, and I eat eggs for breakfast about 4X a week (as do my kids).  The perinatal period where baby rats' brain development benefits from increased choline consumption can be extrapolated to about 4 years old in humans.  So eat up your eggs and offal, especially if you are a rugrat or plan to have rugrats any time soon!

*Wheat germ and soy lecithin are the richest vegetarian sources, but they won't be on my menu.

Happy New Year

One of my favorite Copland pieces is the second movement from Rodeo - the Corral Nocturne (right click in new tab to play).  It's on most of my lullaby playlists, and is modern and sweet without being precious.  It is also quite brief at a little over three and a half minutes, so lean back, close your eyes, and sit a spell, if you do that sort of thing.  I find many people can't unwind, can't unfold.  Corral Nocturne might help if you are in that predicament.  Orchestral music may not be terribly old, but it sure does speak to something within us. 

Here's a picture we took on the last evening of 2010, looking forward to 2011.

Closing Out 2010

For many, like my beloved Texas Longhorns, 2010 was a difficult year. I started the year in a plateau, having gained and lost (and gained and lost) quite a few pounds during and after pregnancies for my two little girls. Nutrition was an interest of mine for many years, however. I had read Good Calories, Bad Calories and the works of Micheal Pollan, and for years had been avoiding too much fake processed food and vegetable oil. But it wasn't until I found the idea of a paleolithic-style diet that everything began to have focus, and made perfect sense. I started out with a nutritionist who had a paleolithic bent (but a distaste of fat and a fondness for brown rice and oatmeal nonetheless). I would describe his plan as Loren Cordain meets Body For Life. I followed his plan for 3 months, losing all the excess baby weight and then some, then discovered The Primal Blueprint, where paleo meets Good Calories, Bad Calories, and Food and Western Disease (paleo meets academia). I added back the fat, ditched the post-workout brown rice and oatmeal, and through a perusal of the forums found the wonderful resources of the paleo and traditional foods blogs, and the rest is history.

None of that had much to do with psychiatry. But with my biochemistry knowledge and front lines experience with mental illness, it seemed an obvious route to take with a blog. As a population, we are long-lived and expensive and sick. It didn't seem to me that hunter-gatherers could have been so afflicted and survive very long. And many of my patients (and myself) had the look - the extra pounds, the flushed skin, the thin hair - something was wrong. Very wrong.

It is not that hard to find inflammation. A new commenter on an older post noted that it seems to be in fashion to blame everything on inflammation. And to some extent I agree - when I was pregnant, all the little discomforts (loose joints, weight gain, bleeding gums) were blamed on "hormones." Inflammation is a big word, covering a vast landscape of biochemical processes. But it is a place to start, beyond psychology, beyond stress. Inflammation is where vegetable oil meets the modern stressful life. And that is where psychopathology lies as well.

There are a number of ways to attack psychopathology. Therapy, exercise, proper sleep and avoidance of addictive poisons. And here I focus on food, and parse the details. This is science so the definitive is less than we would like. But this is science, so we can question dogma.

Fortunately, I have all my friends to parse with me. And that is the greatest blessing from 2010. Not the skinny jeans, the clear skin, or the vibrant hair (though those are quite nice). The greatest blessing is the community. My old friend Dan from medical school, gorgeous Jamie and Julianne all the way in New Zealand. Stephan in the northwest US, Dr. BG and Aaron Blaisdell in southern California. Steve Parker in Arizona. Paul Jaminet a few miles away in Cambridge. Melissa in NYC.  Thanks to   Leslie Irish Evans and Robert Su for the podcast opportunities! Andrew on his boat. Enigmatic paleo rock star Kurt Harris in the midwest. Dr. Eades and Richard Nikoley. The commenters and facebook friends and twitter community who are all ready to look at a new angle and take apart a new or old idea.  Tear it apart.  That's what leads us forward.

Evolutionary medicine in the 21st century is a breathtaking enterprise. I can be a doctor and use my powers for good. My plans for the blog include (yes, at long last) the thyroid, delving more into phospholipids and the now-famous choline, and looking more into sleep. I'll endeavor along the way to keep up with the latest news and papers (though I still have a day job, a husband, and two adorable little girls). I'm looking forward to a gluten-free January, and more pairs of skinny jeans. Mostly I follow the winds, and my nose, and my gut, which I suppose is more or less what my ancestors did.

It is nice to be able to use one's powers for good. Happy New Year.

Your Brain On Creatine

Thank you, good paleo fairy, Melissa McEwan. By my count, next time I'm in NYC I owe you a half dozen NorCal Margaritas. And thank you also former primal muse who has now moved over to That Paleo Guy (I should just send you a margarita machine.) I now have in my little hands several creatine fed to vegetarians papers (1)(2)(3). Seems that cognition researchers (and athletic performance researchers) simply love giving vegetarians creatine - a practice that might seem curious until you look at these facts:

1) Creatine is an amino acid found only in animal flesh but most abundantly in skeletal muscle flesh (like steak). It is not an essential amino acid, as we can synthesize is from other amino acids found also in plant foods, but as with changing the plant-based omega 3 fatty acid ALA to the marine animal based omega 3 acid DHA, the synthesis is inefficient. It is known that vegetarians have lower tissue (measured directly via muscle biopsy) amounts of creatine than omnivores (4).

2) Why should we care if we have creatine? Well, if you recall, our cells run on energy supplied by ATP. Whether we fuel up with glucose or ketones, eventually those raw materials get transformed into ATP, which as it is broken down powers all sorts of energy-requiring processes. We will obviously burn through ATP faster in our muscles when we are running or jumping or performing various feats of strength, but we also burn through ATP faster when we are using our noggins for something a bit complicated. Our little brain (the size of your two fists held together) burns through 20% of the energy we use each day, primarily to keep those ion gradients fueled that allow our neurons to charge up and then be discharged to communicate information.

3) Creatine can bind to phosphate (P) to make phosphocreatine, and this acts as a "buffer" to make ATP lickety-split. Turns out we can make ATP 12 times faster using phosphate reserves from phosphocreatine than by using oxidative phosphorylation and a whopping 70 times faster than making ATP de novo. When we think hard, brain levels of phosphocreatine can drop pretty acutely while ATP levels stay constant, showing that we can bust into that reserve to keep our thinking sharp. In short, creatine improves brain efficiency.

So let's look at these papers, shall we? In both the cognition study papers, healthy college students were recruited (colleges being both a good source of research volunteers and vegetarians) and divided into creatine or placebo supplementation groups. The British study compared vegetarians and vegan young women to omnivores, the Australian study used only vegetarians and vegans, but had a crossover design (all subjects got both placebo and creatine along the way). Both studies did various measures of cognitive and memory testing (number of words you can remember from a list read to you, how many F or P words you can say in 2 minutes, how many numbers you can repeat backwards from a string of numbers read to you, recognizing strings of three even or odd numbers in a series of numbers read at 100 per second). The British study added a measure of reaction time (subjects had to press a button corresponding to a light as fast as they could once it was lit). The Australian study was 6 weeks, the British study was 5 days, and both used 5g creatine monohydrate as the supplement and dextrose (glucose) as the control.

Because glucose administration has been shown to (immediately) increase cognitive performance (5), all the cognitive testing was done fasted and on a day with no supplementation.

The results? First off, everyone, vegetarian or omnivore, on placebo or creatine in the British study did worse the second time around on the memory tests (maybe they got bored?). But compared to the placebo group, the omnivores in the British study were about the same as the creatine supplement group (omnivores have been shown to benefit from a maximum of 20 grams a day at first then maintenance 2-5 grams per day supplementing for athletic performance), suggesting that us animal flesh eaters have a physiologically appropriate amount of phophocreatine reserve in the brain for interesting tasks such as pushing buttons in response to light stimuli and complicated mental tasks that involve the prefrontal cortex and the hippocampus.

The vegetarians in the creatine group did much better than the vegetarians in the placebo group on the second battery of tests involving word recall and measures of variability of reaction times. More simple mental tasks didn't improve in the vegetarians or the omnivores, suggesting, interestingly enough, that complicated thinking burns more energy than uncomplicated thinking (so do smart people burn more calories?? I'm not aware of any research to that effect, in fact I thought there wasn't much of a difference, but we'll look into it...). In some of the measures, vegetarians were higher than omnivores at baseline, by the way, and in general the memory tests between the two groups did not vary at baseline - the vegetarians just seemed to benefit much more from creatine supplementation.

In the Australian study (using only vegans and vegetarians), creatine supplementation had a significant positive effect on working memory (using backwards digit span) and intelligence measures requiring processing speed. Various cognitive tasks that were worse in the placebo vegetarians compared to creatine vegetarians are similar to those that are affected in ADHD, schizophrenia, dementia, and traumatic brain injury. In addition, people with the Apoe4 allele and therefore more vulnerable to developing Alzheimer's seem to have lower brain levels of creatine.

There. Simple - when we are not being simple, we do better with creatine.

Except there are a few wee wrinkles. It turns out that creatine supplementation seems to have an effect on glucose regulation (3)(6). Weirdly, the first study shows a higher glucose level to a oral glucose tolerance load (in vegetarians), and the second study (in young athletically active males) shows a lower amount of area under the oral glucose tolerance test curve (that's good - shows increased glycemic control) with creatine supplementation. But if we consider the fact that a ready supply of glucose in the short term can improve cognitive performance, the British investigators were wondering if creatine supplementation increased glucose in vegetarians, thus increasing cognitive performance. They didn't bother to measure the glucose in the subjects, though, so who knows. In the Australian study, glucose was measured in the fasting subjects but specific levels were not reported in the paper, but it didn't seem that anyone had a high level.

In addition, creatine in the tissue doesn't necessarily equal creatine in the brain - however, animal studies have shown that problems with the creatine transporter into the brain shows up as cognitive problems similar to the unsupplemented human vegetarians (compared to their supplemented vegetarian brethren). However, it is likely that the synthesis and transport mechanisms are upregulated in vegetarians (as they have low levels of creatine), so creatine might pack more punch early on for the veggies, until levels become saturated.

Well, I'm not all that interested in supplementing with creatine. But I am interested in continuing to eat steak, and in having the most efficient energy reserves available for my brain.

And another question - if low levels of creatine can contribute to Parkinson's, are vegetarians more vulnerable to Parkinson's? I'm not sure of the provenance of this very interesting document I found on the internet - but it seems to be written by vegetarian physician and advocate Joel Furhman (though his suggested food pyramid does allow for animal products at the small tippy top) about two case studies of vegans developing Parkinson's, blaming low levels of DHA, and Dr. Furhman then peddling his vegan DHA product. But maybe creatine deficiency could be implicated? Who knows? I'll be eating plenty of meat just to be safe.

The Vulnerable Substantia Nigra

Blogging while out of town has proved more difficult that I thought. For one thing, we have free babysitting, so we've obviously been going out at night rather than staying in. Also, I am mostly limited to the iPad, which isn't as easy to blog from as a normal computer (yes, cry me a river, but true nonetheless). And I was planning on blogging about the creatine and vegetarians paper from the British Journal of Nutrition. However, It turns out my institution doesn't have access to the full text, and I really don't want to shell out $45 for a single paper that tells me to eat meat. I already eat meat, and if you want your brain to be tip top, probably best you do too, or supplement, supplement, supplement with that growing list (B12, zinc, taurine, creatine, carnosine, etc. etc.)

But anyway. A few weeks ago, Dr. Aaron Blaisdell, who I'm told will have access to all the best parties at the Ancestral Health Symposium, was kind enough to send me this paper - "Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1.". The paper is a bit technical. But hearkens back to a previous blog entry, Brain Efficiency. In that entry I talked about how Parkinson's Disease comes about when the dopamine-making neurons of the substantia nigra (thanks, Ned) poop out for some reason. No dopamine in the substantia nigra, and you get stiffness, dementia, tremor - Parkinson's Disease. Parkinson's is another one of those diseases that seems to be increasing faster than we might expect for the aging population. It is postulated that oxidative stress causes the problems (oxidative stress means burn-out, basically. Too much gas for too long, too much build-up of the toxic byproducts of making energy). The burn-out happens in the mitochondria, the energy factories of the cells (which makes sense). But no one knows why the mitochondria in the substantia nigra would be more vulnerable than the mitochondria in other cells.

Increasing the efficiency of the mitochondria by using certain supplements (such as coenzyme Q and creatine) which are also available from meat and organs from animal foods is currently being investigated as treatment for Parkinson's Disease. This new paper has some evidence for a mechanism why the mitochondria in the substantia nigra are so vulnerable as to be the canaries in the coal mine.

In the paper, researchers investigated some mouse substantia nigra(s?) and found that those particular neurons have some interesting properties. They seem to pulse in energy output, rather like a pacemaker of some sort. The pacemaking requires a lot of energy, as the cells have to let go of their energy and then build it up again at regular intervals. Since they burn through more energy doing this pacemaking than other dopamine-making neurons in neighboring brain areas, they seem to be more vulnerable to excess oxidative stress. So more vulnerable to burn-out resulting in Parkinson's Disease.

The solution (or, perhaps better stated as the possible prevention) is, of course, always pretty much the same. Eat a diet of nutrient-rich foods and avoid poisons that will stress your brain. Say no to excess fructose, wheat, and omega 6 fatty-acids and fake, processed foods. I have to say that going out into the real world on this vacation (not my kitchen or pantry) shows me once more just how ubiquitous the poisons are. We checked out some "pizza topping" cheese-like substance in a bag right next to the real cheese which looked like mozzarella, but was actually soybean oil, corn starch, and potato starch. Ick! And guess what - that mayonnaise "with olive oil" is still mostly soybean oil. Avoid!

CoEnzyme Q rides around the body in your cholesterol carriers, so sufficient cholesterol is important. We can make creatine, but when we eat it we get it mostly from muscle flesh. Vegetarians are low in creatine.

We have a certain design spec. It is remarkably flexible, yet in the post-industrial age we have managed to scribble far, far outside the lines of what our bodies consider food. Once again, straying too far for too many meals is really not a good idea.

Secrets of the Synapse

Merry Christmas Eve, y'all! I'm in Texas and therefore blogging in a Texas accent currently. Also, I ate some Tex-Mex, which aside from the vegetable oils and corn and cheese and beans is totally paleo. It is too much to hope that the restaurant we went to used the traditional lard.

But life goes on, the year comes to a close, and earlier this month a lovely "Brief Communication" was published in Nature Neuroscience. Now Nature Neuroscience is some hard core brain journaling. I like to think I know more about the brain than the average soul, but when I read the titles of the articles in Nature Neuroscience, I understand the gist of about half of them.

This paper, "Characterization of the proteome, diseases, and evolution of the human synaptic density" is well worth a squint or two. Here's a full text link. What it comes down to is that the researchers were able to find the actual proteins and their associated genes linked to all sorts of neurological disease via human brain sampling and a rather amazing use of free online databases. It's the wikipedia of neuroscience, without the amateur editing, described in a stunning three pages.

Basically, the researchers took brain neocortex samples from 9 adults and used some advanced chemical sorting techniques to to identify all the proteins in the sample, which was calibrated to be a sample of the nerve synapse (specifically the post-synaptic area). Just as when we call all DNA the "genome," when we identify all the proteins, we have what is called a "proteome."

The 748 proteins found in all three replications of the experiment were recorded into a freely available online database. Then the data were compared to the Online Mendelian Inheritance in Man database, which has information about genetic diseases from linkage studies. Linkage studies are usually done comparing siblings and parents with genetic diseases. If there is enough available data, linkage studies will give you sections of chromosomes, and in some cases, even specific genes associated with the diseases (here's a nice mini-primer on the difference between linkage and association genetic studies - my previous post on migraines reviewed an association genetic study).

In short, our researchers compared the data and found 269 diseases resulting from mutations in 199 genes. 133 of these diseases specifically affect the nervous system (80% central, 20% peripheral). Alzheimer's, Parkinson's, Huntington's diseases and disorders resulting in mental retardation, movement disorders and ataxia, epilepsy, and many rare diseases were all scooped up in this analysis.

Breaking down the data further, the scientists found 21 neural phenotypes (a phenotype is a gene expression - we each have genes for blue eyes or brown eyes or both or neither, but our phenotype is our eye color). A phenotype for mental retardation represented 40 genes, while 20 genes represented spasticity. The large number of genes In these sets are thought to mean that the post-synaptic area of the human brain is exceptionally important in these disorders.

The researchers didn't stop there (we're still on the first page of the paper!) The next step was to compare the human data to the much more specific set of mouse data (more specific because we do all sorts of enlightening but gruesome experiments on mice that we are not able to do on humans) From that they were able to find specific sets of genes related to actual cellular morphology linked to certain, especially important "enriched" phenotypes. The enriched phenotypes, associated with lots of neuronal functioning and disease, include components of known very important signaling mechanisms (the NMDA receptor and associated proteins, for example).

Next the human neural coding sequences were compared with various primates and mice using the dN/dS ratio. This data analysis compares the differences in specific samples (the post-synaptic neuron genes from human and chimpanzees, for example) to the expected (average) rate of genetic change over time. Humans and mice diverged 90 million years ago, yet the post-synaptic neuronal genetic dN/dS ratio was "very significantly" less than the variation between the entire human and mouse genome (we're talking a p value of 10 to the -148). Human neuronal genes were, not surprisingly, also very significantly similar to the primate genes studied compared to the whole human and various primate genomes (with similarly minuscule and thus highly significant p values). Mice and rats diverged 20 million years ago from each other, and their post-synaptic genes are also much more similar than you would expect to each other. All this means that the forces of evolution have conserved these important genes over millions of years, meaning they had better work just so, or your offspring won't survive.

The scientists also compared the conservation of these post-synaptic genes to the genes of other areas of the brain (which are also highly conserved), and found the post-synaptic genes were more conserved than the other brain sets, and also more conserved than other genes for basic cellular components (such as the endoplasmic reticulum, the mitochondria, and the nucleus). Highly interconnected "hub" proteins were also more conserved than other post-synaptic genes, showing that the structure of the synapse seems to mediate the evolutionary conservation of the gene sequences involved.

The human [post-synaptic density sampled for this experiment] has a high degree of molecular complexity, with over 1000 proteins,..combinations of proteins regulate the phenotypes of over 130 brain diseases. It is possible, indeed likely, that the proteins identified represent an overall synaptic parts list, with subsets of synapses containing subsets of these proteins... Our data provide a valuable resource and template for investigating human synapse function and suggest new diagnostic and therapeutic approaches.

I'll say. It might also show us that animal studies involving the synapse might give us fairly accurate information related to humans, especially compared to information obtained from dietary studies or the like. The information from this study is a holiday present to neuroscientists everywhere. And shows us the vast potential of comparing existing databases to new data to create working protein maps of what is actually going on in the synapse or other biologic systems.

Amazing. Nearly miraculous. One way or another, the secrets of our complex brains will eventually be revealed.

- Posted using BlogPress from my iPhone

Alzheimer's and HDL

There are a number of December papers I've been wanting to blog about, but other things came up along the way.  But here I have a moment before the children come home, and the house is quiet except for the cats... I ought to be wrapping presents... but here is a new Alzheimer's paper to add more confusion to the cholesterol and Alzheimer's information.  Overall, the data have suggested that high cholesterol in midlife and low cholesterol in late life both increase risk for the development of Alzheimer's in late life. 

As usual the lipid hypothesis holds sway, and when one reads the analysis in the literature, one gets the idea that the high cholesterol in midlife is likely a causative factor, whereas low cholesterol in late life is "part of the disease process."  (For example, Grandfather must be eating less because he is getting demented, so his cholesterol drops.  For years prior to severe symptoms that might legitimately lead to eating less.)  Of course I'm of the opinion that cholesterol is good for the brain.  But not too many people listen to me.  Or else the  The Primal Blueprint Cookbook: Primal, Low Carb, Paleo, Grain-Free, Dairy-Free and Gluten-Free would be in the top 5 bestselling cookbooks rather than number 5 on the Physician's For Responsible Medicine's Worst Cookbooks of the Year. (Hah they even have the huevos to remark upon the silly "low carb animal" vs. "low carb vegetable" study that came out earlier this year as evidence for avoiding Mark's book!!)  I think I might pick up a few more books on that list of the worst five, frankly.  They look as if they contain many delicious recipes.   

Okay, back to the paper.  Did you know that more than 50% of the adult US population has high cholesterol?  And 1% of people ages 60-69 will develop Alzheimer's, increasing to more than 60% of those over 95.  "There is evidence that cholesterol alters the degredation of the amyloid precursor protein" (supposedly bad) but "cholesterol depletion induces [Alzheimer's Disease]-type injuries in cultured hippocampal slices" (now that sounds quite bad.)  Overall, the observational studies linking dyslipidemias to Alzheimer's have been inconsistent (with the typical take from the literature what I discussed in the 2nd paragraph above).  

Well, high LDL and low HDL have been linked in the past to vascular dementia.  Vascular dementia is kind of the brain version of heart disease.  Arteries get clogged up with plaque (different plaque, actually, than amyloid plaque, things get blocked, mini-strokes occur, and someone gets gradually demented as the amount of damage builds up. Anyhoo, Alzheimer's is a bit different - neuronal amyloid plaque builds up, then you get inflammation and tau tangles, and neuron damage and death.

The authors of this study wanted to examine a cohort of people after the start of widespread use of lipid-lowering agents (primarily statins) in the 1990s.  So these folks in "Northern Manhattan" were recruited from the Medicare roles in 1999-2001, baseline measures of general health and cognitive function were gathered, and they were followed up every 18 months or so.  Out of 1130 individuals who completed the study, 101 were diagnosed with AD, 89 diagnosed as having probable AD, and 12 as possible AD (while Alzheimer's Dementia can only be definitively diagnosed via autopsy, there is a characteristic style of progression of memory loss that makes the performance on certain cognitive tests a decent way of diagnosing the disease).

The mean age of onset of the disease was about 83.  Higher HDL (especially over 56 mg/dl) was protective after adjusting for all sorts of things, including age, ApoE4 status, sex, education, ethnic group, and even vascular risk factors and lipid-lowering treatment.  Interestingly, higher total cholesterol levels and higher LDL cholesterol levels were also protective through all the adjustments except the last two, though became nonsignificant when lipid-lowering treatment and vascular risk factors were adjusted for. (In this cohort, high insulin levels were a strong risk factor also).

The authors put forth the "HDL as garbage trucks" hypothesis of HDL cleaning the cholesterol out, and they postulate the following: "High-density lipoprotein cholesterol might also be linked with small-vessel disease by ...interaction with with APOE and heparan sulfate proteoglycans in the subendothelian space of cerebral microvessels.  Thus, a low HDL-C level could precipitate AD through a cerebralvascular pathway."  (Or how about this theory, which is my own little edit - high HDL-c is associated with low amounts of inflammation and that is the secret to a healthy brain). And more discussion in the paper is about how the study of lipids and Alzheimer's has been confusing all along, and certainly low HDL is associated with stroke, so maybe also some linked pathology is responsible in AD... and previous cohorts with higher total cholesterol in midlife blah blah...  this paper twists and turns about so many times I get confused.

Don't be confused.  Let go of the lipid hypothesis.  Think inflammation.  It's the immune system, not the liver, that is trying to kill us.  Then everything becomes clear, and things start making sense again.  Peace.