Dopamine and the Left Brain

In dopamine primers 1 and 2, I introduced this useful neurotransmitter and key to the thinking style of humanity. Today we'll go over the different neurotransmitters on the different sides of the brain, and why that matters.

Dopamine is the neurotransmitter that is not only responsible for modulating a lot of our physical movement, but also sex, aggression, motivational drive, and, counter-intuitively, long-term planning and restraint or impulse control. In nearly all right-handed and most left-handed humans who are left-brain dominant, dopamine rules the left side of the brain. Lateral dopamine pathways modulate working memory, cognitive shifting, and other executive functions (such as planning).

On the right side of the brain - the artsy part - serotonin and norepinephrine are more dominant. Serotonin and norepinephrine have more to do with emotional activation and arousal systems. The serotonin systems manage our movements and focus on a close personal level. They work in close concert with the opiate reward system and some other hormonal and neuronal systems associated with close in work - feeding babies, eating - stuff we would do with our gaze directed downward, and usually doesn't require as much planning. Norepinephrine and serotonin networks also manage our vestibular systems, helping us balance, postural control, and knowing which way is up or down. Again, one associates balance with looking down or being centered in space. Norepinephrine tracts in the brain are also heavily involved in the "close-in" sense of touch.

The dopamine systems on the left side of the brain become more active with thinking and planning that is more long term. Scanning the horizon, searching and recognition. These systems rarely operate close in our personal space, as it is rare to bring something within arm's reach that we do not already recognize. The medial dopamine systems are used in exploration, navigation, and orientation to landmarks. Far vision, upward gaze, hearing, and smell are more associated with the dopamine tracts. Dopamine's linkage to distant space seems to have associated itself in humans with distant time as well. There is no species quite so future oriented as Homo sapien. And no other species has such high concentrations of dopamine in the brain.

An obvious and perhaps controversial correlate to these different neurotransmitter systems responsible for close/feeling/balance versus far/navigation/planning is the inherent female/male parallel. Aggressive "male" behaviors are mediated by dopamine, whereas receptive female and maternal behaviors (grooming, feeding) are mediated by close-in cues, norepinephrine, and opiate and oxytocin systems.

Psychiatrically speaking, it is probably not a coincidence that dopamine related disorders, such as schizophrenia, addiction, ADHD and even autism are much more common in men, whereas the serotonin/norepinephrine linked anxiety and depressive disorders are more common in women. Of course dopamine is also associated with depression and opiates with addiction, and men get depressed and anxious while women have ADHD and autism. These are obviously not absolutes, just trends.

It also occurs to me that the differences in personality disorder diagnoses between men and women may relate to the neurotransmitter dominance differences as well.  Many more men have the diagnosis of antisocial personality disorder than women - basically, a sociopath.  A person with antisocial personality disorder generally lacks empathy for others, and often struggles with  impulsivity and aggressive drives and substance abuse.  That combination will get you sociopathic behavior - stealing, murder, etc.  Many more women than men are diagnosed with borderline personality disorder.  Someone who has borderline personality generally has trouble with relationships and containing feelings appropriately.  He or she can struggle with rage and impulsive behavior also, but often the violence is directed at him or herself in suicide attempts or self-injurious behavior.  A person with borderline personality disorder has empathy but has trouble applying it - he or she likely has boundary issues and has a hard time sitting with another person's pain without feeling it too much as his or her own.  Thus he or she will feel very deeply for someone, then when it gets to be too much, push him or her away.  People with borderline also tend to have impulsive behavior and have higher risk for substance abuse.  Both borderline and sociopathic individuals are likely to have experienced abuse or neglect as a child, but some have not and still have the disorder.

So if we run with the rather gross simplification that men are dopamine "left brain" dominant and women perhaps more balanced between the right and left hemispheres, you can see how troubles with regulating dopamine combined with an underactive social/empathy serotonin/norepinephrine system would get you sociopathy in a man.   In a woman, the trouble in borderline personality seems to be more in the poor regulation of both - but perhaps more a deficiency of dopamine and a dysregulation of the social/empathy serotonin/norepinephrine side of things.  Now these are all just my rampant speculations, but I'll keep my eye out for some actual proof.

And, of course, there are borderline men and antisocial women (think Sharon Stone in "Basic Instinct").  There is some question that some of our social male/female constructs keep us from wanting to diagnose women with antisocial personalities, and perhaps the same social constructs, pressures, and expectations mean that an abused boy child has the risk of growing up into a sociopath, and an abused girl child has the risk of becoming a borderline.  I'm inclined to believe some of that is going on, but that the biology is also at play.  Of course, many abused children grow up without having personality disorders as well.


I'll finish up with a discussion of how our brains end up the way they do in the first place. The same gravimetric serotonin-driven vestibular systems that help us stay balanced are responsible for the migration and localization of the dopamine tracts as they are formed in early development. The theory goes that our bipedalism keeps us oriented differently than other primates or other animals in utero, leading to different gravity signals and a more lateralized brain development (meaning our right and left brains are simply more different than the right and left brains of any other animals.). There are no known genes that act as master directors for this lateralization - it all seems to be related to epigenetic factors and serotonin availability in the right place at the right time.

Natural human movement, then, is what may make our brains human.

(once again I'm drawing from Previc's The Dopaminergic Mind in Human Evolution and History).
Also Previc's paper "The neuropsychology of 3-D space" http://www.ncbi.nlm.nih.gov/pubmed/9747184)

carok and madura culture

Excessive reverence for the dignity and worth of Madura was often the root causes of conflicts and violence. This condition occurred because almost every offense is always ascribed to / or claimed as harassment or humiliation of dignity and their self-esteem. Some young children in overseas ─ Madura usually do not obtain adequate educational opportunities ─ deliberately looked highlight negative

madura unique culture

The most fundamental issue really lies in the cultural meaning of compliance in the context of subordination, hegemony, exploitation, and stand to lose a lifetime. Meaning it needs to be put in place a just and proportionate. If the hierarchical obedience to figures I and II because there is no problem stretching to obtain and change cyclically the hierarchical compliance efforts untak change in

madurese leadership skill election

Description about the Madurese compliance to these four major figures can actually be traced standard reference on the side of cultural religiosity. As the majority of the inhabited islands (+ 97-99%) Muslims, Madura keberislamannya revealing characteristic, especially in the actualization of adherence to the normative teachings of their religion (Wiyata, 2002:42). Adherence to both parents is a

Acne, Depression, Omega 3, Vitamins, and Minerals

In 2008 some folks from a Beverly Hills skin clinic wrote up a short paper in Lipids in Health and Disease called Acne vulgaris, mental health and omega-3 fatty acids: a report of cases (free full text). The experiment itself was an open-label trial of a mineral/omega-3 supplement on five patients, so useful only as a reason to do further research. But a lot of interesting science tidbits on acne, omega-3s, and minerals are noted in the article, so it's worth a peek.

Acne is a disease of civilization which, like depression, has increased the last half century, especially in women. As we discussed in my blog post, Acne and Suicide, patients with acne are more likely to be depressed, angry, and suicidal. In fact, patients with acne struggle more with mental health issues than even patients with epilepsy or diabetes (according to a study comparing questionnaires between sufferers of acne and other general medical conditions).

Acne is accompanied by the overproduction of Sebum, a waxy oil, in addition to inflammation, hormonal shifts, and infection. Inflammation is one of the earliest manifestations of the disease, particularly mediated by a leukotriene called LTB4. This inflammatory chemical helps up-regulate sebum production, and you might be interested to know that the omega 6 fatty acid derivative arachidonic acid is made into LTB4, while the omega 3 fatty acid EPA (from fish) inhibits the conversion of arachidonic acid to LTB4. A study of 1000 teenagers in North Carolina showed lower incidence of pustules, acne cysts, and oily skin in those teenagers consuming the most fish. Another study showed that patients with acne ate low amounts of seafood. In my own clinical experience, young adults with acne have experienced a reduction in severity when they begin to supplement with fish oil (though it is not a complete cure, and doesn't seem to help everyone). However, many have a very noticeable improvement. There is a prescription drug, zileuton, that inhibits LTB4 and improves acne, but it would seem a fish prescription might be more practical.

Patients with acne, being in a state of systemic inflammation, also seem to have lower serum amounts of several vitamins and minerals, specifically zinc, vitamins A and C, and selenium. Studies of all these supplements, some administered topically, some orally, or both seemed to show some benefit. In addition, EGCG from green tea has been "suggested to be helpful in acne due to its well documented anti-inflammatory and antioxidant activity."

Acne is also worse in people with poor control of blood glucose, and the supplement chromium is known to have some minor benefit in that area. There was one open label trial of 400 mcg of chromium daily that seemed to help.

So in this experiment, five patients (three males and two females aged 18-23) were given a supplement with 1000 mg of EPA, EGCG 200mg, zinc gluconate 15 mg, selenium 200 mcg, and chromium 200 mcg to take daily. They didn't use any new topical treatments or change their diets in any way. The number of pimples and amount of inflammation was noted with a standardized acne scale at the beginning, and measured again at the end of two months. In addition, each patient took a before and after test measuring mental, emotional, and social well-being.

The results? Four of the five had improvement in number of lesions, and all seemed to have a reduction of general skin inflammation. Sense of well-being improved 24% (with a range in the five patients of 20-27%). The authors thought this improvement might be due to the EPA, but since EPA seems less important in the brain than its sister fish oil, DHA, I'm prone to be skeptical. I wonder if the improvement might be due to the generalized reduction in inflammation.

All told, this tiny little open-label trial can't allow us to draw too many conclusions. Without a control and some more data points, we can only tuck the information away as something to look at further. Now a healthy Paleolithic diet with organ meats and fish would provide the vitamins, minerals, and EPA (not sure about the EGCG). Especially in an active hunter-gatherer who would consume and burn more calories, and therefore more nutrients along the way. I feel saturated fat itself helps the skin (thinking of the adolescent Masai warriors, or the beautiful people of Thailand, and my own experience starting with a more Cordain-inspired lower fat paleo diet, and a few months later switching to a higher fat primal diet.) My skin is much less sensitive and I'm not prone to breakouts at all with the absence of gluten and the increase in saturated fat of my primal-style diet. In fact, one of the ways I know I've been slipping a little too much (a birthday party here, a wedding to go to there) is if a little spot pops up.

Everyone benefits from an improvement in looks. One of the fastest ways to improve mental health in my clinical experience is to help someone successfully get into fat-burning mode and clear the skin. Clinical experience and common scientific sense is one thing. Real controlled trials are something else. Bring them on.

madurese paternal religious system2

Therefore, obedience to the Madurese typical figure of the teacher be a marker of their culture (probably) no need to doubt its validity.

Generative cycle of compliance Madurese (as students) to the figure of the teacher was not in itself can be realized as the obedience of children to the figures I and II, father and mother. This condition occurred because not all of Madurese have the

Happy Thanksgiving! Chow Down on Dopamine Primer 2

Hope you are having a great time on your Turkey Day (assuming you celebrate it as the majority of my blog readership does). I baked a paleo pumpkin pie last night, and today I'll make (and eat) the crab stuffed mushrooms (finally, a use for the oregano plant we mostly killed in the fall) from the same Everyday Paleo page. We're having our turkey (I'm told it is organic free range, and if it isn't, I don't want to know) with some relatives on Saturday, so by then no doubt I will have baked another pie to bring with me to the gathering, only this time I'll likely add vanilla and coconut flakes to the butter pecan hazelnut crust. Yum! Gotta love a Thanksgiving where you don't even mentally count the fat grams. Just avoid the gluten...but the rolls and stuffing were never my favorites anyway. Give me meat and pie and I'll be happy.

Back to dopamine. My favorite neurotransmitter, and also (I'm assuming) the favorite neurotransmitter of Dr. Fred H. Previc who wrote The Dopaminergic Mind in Human Evolution and History which will be, once again, the major source for much of the information here, though there will be some from the psychiatry clinical trenches too (let's assume I did learn something in residency). Dopamine is special because it divides the humans from the beasts, as it were, and yet some of our more bestial qualities stem from chasing that dopamine feeling - via ultimate fighting, cocaine, speed, and also the reward pathways in binge eating, drinking, gambling, shopping, etc. etc. etc. Anything that involves competitiveness, drive, sex, planning, working memory, concentration, aggression... dopamine plays a role.

Dopamine is distributed quite differently on the different sides of the human brain, and is is speculated that this lateralization is responsible for how very human we are. The left brain (in almost all right-handed and most left-handed people) is responsible for language, linear reasoning, mathematics, that sort of thing, whereas the right side is usually responsible for intuition, holistic reasoning, some elements of music and speech intonation, etc. It's funny, really, how different the sides of the brain are. They look much the same. My right and left lungs look a little different, but they have the same function. My right and left feet do pretty much the same thing. But remove my left brain, and I'll be a different person. Amazingly, if one is young enough, half the brain can be scooped out and removed (if necessary, usually to control intractable seizures), leaving the child with pretty normal intellectual functioning (though motor functioning on one side is usually irrevocably lost). This finding (among others) led one prominent neuroscientist to pen a famous chapter called "Is Your Brain Really Necessary?"



The human brain has 100 billion neurons. Only 20,000 or so carry dopamine, and they do so along four major tracts. Keep in mind that the brain is a gorgeous and mysterious place with many wonderful names, like Rivendell or Brigadoon. The areas are named either anatomically (the dorsolateral prefrontal cortex) or because it reminded the anatomist of yore of some other important anatomical structure (the mammilary bodies). Or for some other obscure reason (the tegmentum? Oh, that's Latin for "covering." Okay!)

Dopamine is made in two little areas in the deep animal recesses of the brain - the substantia nigra and the ventral tegmental area. From these starting gates, the dopamine tracts reach out to various segments.

1) The nigrostriatal tract is important to neurologists. It brings dopamine from the substantia nigra to the striatum or "basal ganglia." These neurons are responsible for a lot of the motor control of the body. Death of dopaminergic neurons in the substantia nigra leads to the symptoms of Parkinson's disease - tremor, stiffness, loss of voluntary movement (though someone with advanced Parkinson's may not be able to toss a ball to you, if you toss a ball to him, he might be able to use different reflex motor brain tracts and catch it). This pathway is also affected in various choreas, such as the possibly wheat-related Huntington's Chorea.

2) The mesolimbic pathway goes from the ventral tegmental area to the limbic system. The limbic system of the brain controls reward and emotion, and includes the hippocampus and the medial frontal cortex. This is the pathway that is thought to be responsible for addiction and psychosis.

3) The mesocortical pathway goes from the ventral tegmental area to the dorsolateral frontal cortex. This is the pathway responsible for planning, responsibility, prioritizing, motivation, and some elements of emotional response. This is one of the damaged areas in ADHD and depression.

4) The tuberoinfundibular pathway has my favorite name (though not as fun a name as the as the anterior inferior thoracoacromial artery). It's a dopamine pathway between the hypothalamus and the pituitary gland, and the most important part is that dopamine inhibits prolactin release. So inhibiting dopamine means prolactin increases, enabling breastfeeding and whatnot.

Having fun yet? In psychiatric terms, the mesolimbic and mesocortical pathways are by far the most important. They have a lot to do with how we behave, and who we are. Now go eat some turkey and be happy.

madurese paternal religious system

There is no precise vocabulary to refer to other terms except submission, obedience, and submission to the fourth figure.

Adherence or obedience to the Father and Mother (buppa 'tires Babbu') as the natural parents or nasabiyah already clear, firm, and recognized keniscayaannya. Culturally obedience and submission to a person to his parents is absolute. If not, speech or designation

Madurese is religious people

In the context of religiosity, the Madurese are known to hold strong (memedomani) Islamic teachings in any pattern of his life despite leaving a 'dilemma', to mention a deviation / contradiction between Islamic teaching (formal and substantive) and socio-cultural behavior patterns in their religious praxis. The recognition that the formal teachings of Islam as believed and followed in the ethnic

Depression and Diabetes, Together Again

Waaay back in June I wrote up Depression 1, which referenced a few of the studies linking depressive disorders to metabolic syndrome and diabetes.  Today a new study came out from some of our favorite epidemiologists, Frank Hu and crew.  Dr. Hu actually wrote an editorial questioning the wisdom of population-wide nutritional advice that resulted in replacing saturated fat with refined carbohydrates.  However, he also signed off on that monumentally silly paper about "low carb" meat eaters versus low carb veggie-lovers that everyone made fun of a few months back.

Today's paper is "Bidirectional Association Between Depression and Type 2 Diabetes Mellitus in Women" from the Archives of Internal Medicine.  The researchers followed 65,381 women in the Nurses' Health Study from 1996 to 2006.  Clinical depression was defined by having diagnosed depression or using antidepressants, and depressed mood was defined as having a high score on the 5 item Mental Health Index questionnaire.  The nurses self-reported having type 2 diabetes which was validated by medical record review. 

During the 10 years of follow up, there were 2844 new cases of type 2 diabetes.  Those with poor mood had a higher chance of developing diabetes.  7415 women developed clinical depression, and women who were on insulin to control type 2 diabetes had a risk ratio of 1.53 for developing clinical depression.  Overall, the data showed that diabetes increased the risk of depression, and depression increased the risk of diabetes, and that more severe depression and more severe diabetes increased the risk of the other illness even more.  Countless covariates did not explain the bidirectional connection.

On a population level, 23.5 million American adults have diabetes (about 10%, though about 23% of those >=60).  6.7% (14.8 million) of the US adult population has depression in any given year, with a  lifetime incidence in women of around 20%.  A previous meta-analysis (1) found that the odds of depression in the diabetic group was twice that of the nondiabetic comparison group.  In a couple of papers, diabetes risk was increased by 60% in patients who had diagnosed depression.  Frank Hu's group paper from this week made some effort to figure out what comes first - depression or diabetes?  Depression (atypical depression that is) can make you crave carbs and leave you unmotivated to perform exercise.  Having diabetes is usually pretty stressful too, putting you at greater risk for depression, and "depression may result from the biochemical changes directly caused by diabetes."

That last quote is perilously close to my theory, that metabolic syndrome and leptin/insulin derangements probably underlie both disorders.  That's more "big picture" evolutionary medicine style thinking than I'm used to in reading the discussions of these papers, but don't get too hopeful, it was only touched on in that one sentence.  I discussed the underlying mechanisms of depression and metabolic syndrome and how they are connected in Stress is Metabolic Syndrome and Chronic Stress is Chronic Illness.  These aren't really radical ideas.  Oh well.

Madurese culture behavior

Madurese are known to have a distinctive culture, unique, stereo-typical, and stigmatik. Cultural identity is considered as a generalized description of individual and communal identity in the ethnic Madurese behave and berkehidupan. Their lives in places of origin and in overseas often brings ─ and always understood by other ethnic community on the basis of collective identity ─ it. As a result,

Dopamine Primer

Hi! Tonight a quick basic post for some necessary background. I will try to make it as painless as possible. But we need to examine dopamine more closely. Why? Well, dopamine may well be the secret to what makes us human. Meaning awfully bright, able to plan ahead, and resist impulses when necessary.

What is dopamine? It's a neurotransmitter. It controls communication in the brain - it's a chemical that can tell a neuron to fire off a signal or not, and modulates the signals. Dopamine is ancient - found in lizard brains and every other animal along the evolutionary tree up to homo sapiens. But humans have a great deal of dopamine, and over many generations we have evolved to have more and more.

Control of dopamine and where it ends up in the brain isn't just determined by straight up mendalian genetics. As I discussed in this post, our mothers' neurochemical environment had a lot to do with how our dopamine machinery migrates and works in our brains.

Another special thing about humans is our bipedalism. Being upright while mom is pregnant exposes our fetal brains to different vestibular environments than other primates, so the theory is this elevated the dopamine levels in the left hemisphere of most people's brains. I know. Go with it for a minute. It's just a theory.

Humans also eat a lot of meat and fish compared to other primates - meat and fish give us more dopamine precursors. More dopamine is also associated with both greater competitiveness, aggression, and impulse control - one could see how that particular combination of traits would be selected for over human evolution.

Serotonin, another neurotransmitter, is our oldest neurotransmitter and the original antioxidant - dopamine is what made humans so successful.

Now the biochemistry. Dopamine is a type of neurotransmitter called a catecholamine. Catecholamines have, not surprisingly, a catechol chemical group attached to an amine.

How do we get dopamine? We eat it. The precursor amino acid from the protein we eat is called tyrosine. Tyrosine becomes dopa via the enzyme tyrosine hydroxylase, and dopa becomes dopamine via the actions of dopa decarboxylase. (One more chemical reaction can turn dopamine into its best buddy neurotransmitter, norepinephrine, but more on that later). As is the case with serotonin and its precursor tryptophan, tyrosine can cross the blood brain barrier, but dopamine itself cannot. That means that the dopamine our brain needs must be manufactured from dopamine machinery and precursors in the brain.

Still with me? What happens without dopamine, or with screwy dopamine machinery or inefficient dopamine? Well, in development this lack can cause mental retardation, which is the case in a rare genetic disease called PKU and cretinism (a type of mental retardation caused by iodine deficiency). Dopamine problems are implicated in ADHD, Alzheimer's, Parkinson's, depression, bipolar disorders, and schizophrenia. Having too much dopamine in the wrong place can make you psychotic. Illicit drugs that dump loads of dopamine (or strongly inhibit its reuptake, which is similar to dumping loads of dopamine) include cocaine and methamphetamines. Therefore high amounts of dopamine can cause euphoria, aggression and intense sexual feelings.

We need dopamine in the right place at the right time in the right amounts. When it all comes together, we are the awesomest ape around. When it doesn't, problems ensue (not surprisingly). Dopamine is linked to everything interesting about metabolism, evolution, and the brain. There's a feast of scientific info out there. Hopefully we can make some sense of it.

Information from this post is taken mostly from The Dopaminergic Mind in Human Evolution and History by Fred Previc.

Maduranese culture not always crime

A writer from Madura, Mahwi Freshwater, said, Madurese culture is not always synonymous with celurit and violence.

This is revealed in Madura cultural dialogue and book "Eyes Blater" which contains a collection of short stories short story writer's Freshwater Mahwi together a number of Madurese culture expert at the University of Jember Research Institute auditorium on Friday.

"Madura not only

Cleaning Up

In lieu of a new and interesting post, something possessed me to organize the place this morning. So up on the right there I now have some more advanced disclaimers and a brand new site map. It's not finished yet (right now I only have the first three months up, I'm updated now - might be some fun reading for those of you newer to the site) and not pretty (a graphic designer I am not, and blogger can be fairly unwieldy with the font sizes and formatting).

My youngest child is amusing herself by trying to eat her hand. Good thing she doesn't have that many teeth. On the positive side, she learned how to say "vitamin" today! I better stop now as I need a certain aura of mystery to maintain my shamanistic role as a psychiatrist. Though it is likely the last vestiges of my dignity were lost when I joined Twitter.

A couple of music links (right click in new tab and you can enjoy them while you peruse the new map!)

The Limousines - "Internet Killed the Video Star" - The kids are disco dancing, they're tired of Rock and Roll. I try to tell them hey that drum machine ain't got no soul.

If you are of a more classical bent - Aaron Copeland* classic, "Fanfare for the Common Man." Copland has a unique sound due to what he left out - the major 3rd.

* Thanks music Doc - It's Copland. Not sure why but spelling was never my strong suit.

One more for Thanksgiving week coming up - Vampire Weekend, "Holiday."

The Wild and Compelling Theory that Alzheimer's Dementia is Caused by Infectious Disease

As you recall, Alzheimer's Disease is a slowly progressive illness of neuronal degeneration.  The cardinal symptoms are cognitive impairment and memory loss, but the condition eventually leads to death.  I've dedicated many posts to Alzheimer's, which is a reflection of the amount of research out there.  And for today's post, I'm going to begin with a nice review article from 2008, and over another post (or several) try to finish out with some more specific looks at the various papers. 

Even if you don't find Alzheimer's that compelling, if infectious agents contribute to its pathology, then you have to open your mind to the idea that many neurodegenerative processes could be due to (or accelerated by) infection.  Neurodegenerative diseases include many neurological illnesses, but also depression, bipolar disorder, schizophrenia, autism...

What is the argument against infection as an ongoing contributing factor?  Well, where's the bug? Do a spinal tap - does the fluid grow any bacteria in culture?  Are there white blood cells (sign of active infection).  Is there an elevated level of protein (a sign of viral infection)?  Over the last hundred years we've become pretty good at finding bugs.  It's hard to imagine them hiding from us, even in the protected environment of the human skull.  So if you bring up the idea of infections causing Alzheimer's disease to a physician friend and he or she scoffs at you - that's why.  Where's the bug?

With that in mind, let's plunge forward into the review by Urosevic and Martins from the Journal of Alzheimer's Disease, "Infection and Alzheimer's Disease: The Apoe epsilon4 Connection and Lipid Metabolism."

The whole theory breaks down like so - there's a continuous, chronic infection supplying persistent live microorganisms, and their toxic products stimulate the host's (that's you) inflammation.  The pathogen itself damages the neurons, and the brain's inflammatory response also damages the neurons.  Remember that ApoE4 is the  Alzheimer's vulnerable variant of apolipoprotein, the molecular key on the lipoprotein that invites cholesterol and triglycerides into the brain. As an added bonus, any infectious disease theory of Alzheimer's also has to explain why having ApoE4 makes you more likely to get Alzheimer's.

What infectious agents are we talking?  Some viruses immediately come to mind, specifically herpes viruses.  These little guys are exceedingly common and come in lots of different flavors, and are well known to hide out in nerve cells for the duration of the host's life (an easy example of "There's the bug.")  HSVI, associated with cold sores, infects people early in life and hangs out in the trigeminal ganglia (the nerve root of the trigeminal nerve that innervates a good part of the face).  Some people get cold sores, some people don't, but those who do are more likely to be ApoE4 carriers.  People infected with HSVI are also more likely to develop Alzheimer's.  ApoE4 mice were more likely to carry invasive HSVI and have brain colonization of the virus.

Other viruses implicated include human herpes virus 6 (cause of roseola, a common childhood illness of high fever followed by a characteristic rash), HIV, hepatitis C, and cytomegalovirus (a cause of mononucleosis-like illness and fatigue symptoms).  It is well known that HIV causes a form of AIDS dementia (which happens to be more common in carriers of ApoE4), so it would make sense that other common viruses that infiltrate the neurons might lead to other types of dementia.

All the common inflammation players (TNFalpha, IL-6, nitric oxide synthase) are involved in fighting off viral infections.  We know these players have a role in Alzheimer's pathology and in depression and bipolar disorder.  Interestingly, as we get older, our immune response becomes less aggressive, and it is perhaps then that the infectious agents hold sway, leading to Alzheimer's pathology.  Other inflammation-mediated brain disease occurs at different developmental stages - late adolescence and early adulthood for schizophrenia, and infancy for autism.

There are also suspected bacterial causes.  The "spirochetes" are a type of sneaky bacteria that are known to infect nerves (as in syphillis and Lyme disease).  Some spirochetes that cause gum disease are found in the mouths of Alzheimer's patients and healthy folks, but in the Alzheimer's patients, they are found in the brain more often than in healthy folks.  Certain spirochetes have been found in the amyloid plaques in the brains of patients with Alzheimer's (once again - there's the bug).

Chlamydia pneumoniae is an intracellular bacterial pathogen also implicated in Alzheimer's dementia.  Not surprisingly, it is better known as a common cause of pneumonia and other acute respiratory infections, but infected immune cells could presumably carry chlamydia pneumoniae from the upper respiratory tract to the brain if the blood brain carrier is compromised in some fashion.  Chlamydia pneumoniae has been injected into mouse brains and causes amyloid deposits, which anyone will agree is suspicious behavior.  Once again, ApoE4 comes up, as ApoE4 seems to allow for greater bacterial load and numbers of infected cells.

ApoE4 is not only a bad guy when it comes to Alzheimer's.  Carriers are at greater risk of athersclerosis, stroke, and poor recovery from head injury.  And ApoE's role as a molecular marker and director of where lipoproteins go is key.  Lipoproteins are how fat and antioxidants are carried throughout the body.  It is probably not a coincidence that major conditions leading to weight loss without any particular effort are infectious disease and Alzheimer's (along with cancer and melancholic depression).   ApoE4 in particular is associated with poor clearance and recycling of lipoprotein particles.  It's just not an efficient key.  If everything is going along just fine, maybe we don't need an efficient key.  Add stress or infection, though, and you have a greater need for meabolic efficiency.  If you fall behind, garbage builds up.

The ability of a host (you, or me) to handle an infection depends on genetic, dietary, and other environmental factors such as age, stress, and immune status.  Viruses and bacteria are sneaky - I daresay sneakier even than Homo sapiens,  and the closeted nerve cells are a perfect place for an unnoticed infection to simmer for decades.  Microogranisms can continuously release toxins, leading to chronic inflammation and damage.  Treating a chronic infection, if it is found, could possibly be a useful way to fight a number of neurogenerative diseases, even Alzheimer's.

Thursday Already?

It has been a nutty week. And right now I'm cooking steak, and the 18 month old won't let me put her down. But a few things have caught my attention:

Epilepsy's Big, Fat Miracle

A New York Times article about a parent with a kid on a ketogenic diet for epilepsy. Makes ketogenic diets sound completely bonkers, yet effective. I suppose that is the story of my blog.

The 32-year relationship between cholesterol and dementia from midlife to late life

Okay, get this. In animal and cell culture studies, high cholesterol is associated with amyloid beta deposition. YET when one reviews the human studies, the ratio between cholesterol levels and amyloid deposition becomes far more murky (declining cholesterol levels as we age is a risk factor). Also, high dietary cholesterol in RABBITS and genetically modified mice leads to greater amyloid pathology relative to controls!!! Should I eat the top round steak being simmered in grassfed ghee right now? Should I?

Well, high cholesterol in women who had high cholesterol in 1968-69 was not associated with risk of dementia up to 32 years later. Also, a decrease in cholesterol levels over the follow up period (of 32 years) was associated with an increased risk of dementia.

Here's a money quote from the study: "Thus, the unintended decreases in cholesterol levels (e.g. not via medications or cholesterol-lowering diet) greater than expected due to aging may be more indicative of dementia risk than midlife cholesterol levels and may reflect underlying dementia processes. This pattern is observed for other dementia risk factors, such as BMI and blood pressure...consequences of the dementia prodrome such as apathy or reduced olfactory function may lead to decreased energy intake, which may also affect blood cholesterol levels."

Or, just maybe, cholesterol levels are a biomarker of some other process, so following just cholesterol levels leads to confusing and contradictory information regarding dementia risk, and absolutely low cholesterol is usually bad news when it comes to the (human) brain.

It's exhausting, really, slaying the remnants of the lipid hypothesis in 2010.

Dear Conventional Wisdom Nutritional Information Purveyors: I know that allowing fat into the diet makes a big juicy steak that much less naughty. But you don't have to be naughty to have fun!! You can just enjoy a big juicy steak.

Seriously.

Four Healthy Five Perfect