Showing posts with label inflammation. Show all posts
Showing posts with label inflammation. Show all posts

Monday, 29 August 2016

Mediterranean Diet and Cognition

The evidence for a beneficial effect of a Mediterranean style diet (MedDiet) on brain health grows on a regular basis.

For those interested in a good summary of the effects of the MedDiet on cognition, I recommend reading the free full text review recently published in Frontiers in Neuroscience.

In this review, Roy Hardman and colleagues searched for research studies on cognition and the Mediterranean diet published between 2000 and 2015.

A figure in the review proposed several mechanisms where components in a MedDiet may contribute to brain function:

  • Cardiovascular: effect on blood pressure/blood lipids and arterial stiffness
  • Inflammation: lowering of blood inflammatory markers including C-reactive protein and cytokines
  • Neurotrophic effects: Increased levels of BDNF, insulin growth factor stimulating neurogenesis
  • Cell signalling
  • Cellular energy metabilism
  • Lowering of oxidative stress

Using a rigorous selection process, Hardman and colleagues identified 18 high-quality recent studies of the MedDiet and adult human cognition. These studies generally demonstrated an positive effect for subjects with higher compliance with MedDiet elements. These positive effects included research supporting:

  • A slower rate of cognitive decline with aging
  • A reduced risk of developing mild cognitive impairment
  • Improved recognition memory and delayed recognition memory
  • Improved cognitive reserve on the Mini-mental status examination test (MMSE)
  • Improved attention

The authors conclude that evidence to date supports prospective randomized clinical trials of MedDiet nutritional intervention. These studies should included standardized batteries of cognitive function that can be administered via a computer or tablet.

For readers with more interest in the review, you can access the free full-text manuscript by clicking on the PMID link in the citation below.

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Photo in this post of foods found in the Mediterranean diet is from my personal files.

Hardman RJ, Kennedy G, Macpherson H, Scholey AB, & Pipingas A (2016). Adherence to a Mediterranean-Style Diet and Effects on Cognition in Adults: A Qualitative Evaluation and Systematic Review of Longitudinal and Prospective Trials. Frontiers in nutrition, 3 PMID: 27500135

Wednesday, 24 June 2015

Bipolar Disorder Link to Rheumatoid Arthritis

Finding links between disorders felt to be distinct is a helpful tool in understanding genetics and pathophysiology. 

An example would be the discovery that individuals with genetically determined elevated cholesterol levels had higher rates of cardiovascular disease. This led to drug development of cholesterol lowering agents leading to reduced rates of cardiovascular disease and mortality.

A recent population-based study from a research team in Taiwan identified an increased risk of bipolar disorder in patients with rheumatoid arthritis.

In their study, 2,570 patients with a diagnosis of rheumatoid arthritis were identified from a national insurance database.

A comparison group of 2,570 patients without rheumatoid arthritis were identified as a control group.

The key finding from the study was an approximate doubling of the risk for a diagnosis of bipolar disorder in those with rheumatoid arthritis (odds ratio 2.13, 95% confidence interval 1.12-4.24). Rheumatoid arthritis patients had additional elevated bipolar riks if they also had asthma, cirrhosis of the liver or an alcohol use disorder. 

The research team noted a possible explanation for increased risk of bipolar disorder following rheumatoid arthritis is inflammatory immune dysfunction.

Peripheral markers of inflammation in rheumatoid arthritis have been linked to upregulation of central nervous system inflammation. The authors note peripheral markers of inflammation known as cytokines may reach the brain through blood brain barrier leaks, active transport, activation of endothelial cells or cytokine receptor binding.

The clinical implications of this finding are important. Early active treatment of rheumatoid arthritis may reduce risk for central nervous system complications including bipolar disorder. Clinicians treating patients with rheumatoid arthritis should actively monitor for emergence of mood disorders including bipolar disorder. 

One potential confounding issue in this study is the potential for rheumatoid arthritis medications to induce mood symptoms. Corticosteroid drugs such as prednisone are commonly used in rheumatoid arthritis. This class of drug is known to induce insomnia and hypomanic or manic states in some individuals.

Reader with more interest in this topic can access the free full-text manuscript by clicking on the PMID link below.

Photo of water lilies is from the author's files. 

Follow the author on Twitter @WRY999

Hsu CC, Chen SC, Liu CJ, Lu T, Shen CC, Hu YW, Yeh CM, Chen PM, Chen TJ, & Hu LY (2014). Rheumatoid arthritis and the risk of bipolar disorder: a nationwide population-based study. PloS one, 9 (9) PMID: 25229610

Tuesday, 23 June 2015

Bipolar Disorder Linked to Increased Dementia Risk

A variety of risk factors have been identified in Alzheimer's disease and other types of dementia.

The risk for dementia following major psychiatric syndromes in mid-life is an important research area.

Renate Zilkens and colleagues in Australia recently published an informative study of psychiatric disorders and later dementia risk. This study used a population-based case control methodology.

The key elements in the design of this study included the following:

  • Subjects: General population in Western Australia
  • Data sources: inpatient, outpatient and emergency medical records along with death records
  • Cases: Incident cases of dementia between ages of 65 and 84 years of age
  • Controls: Age and sex-matched individuals without incident dementia diagnosis
  • Psychiatric diagnoses: medical record diagnoses that were required to be present at least ten years prior to dementia onset
  • Statistical analysis: odds ratio using conditional logistic regression


The research group in this study used a variety of models to assess risk based on specific medical and psychiatric disorders.

For simplicity, I have used data from the study to put together the summary graph in this post.

This graph estimates later dementia odds ratios for specific disorders when that disorder is present during the 65-69 year age period.

There is evidence of a strong increase in risk for dementia following bipolar disorder diagnosis (odds ratio 4.71, 95% confidence interval 2.29 to 9.65). Bipolar disorder is the psychiatric disorder with the second highest odds ratio being topped only by schizophrenia with an estimated odds ratio of 12.1. The odds ratio with depression was only slight lower than that associated with a diabetes diagnosis (odds ratio 2.77 vs 3.47). Anxiety disorder had a small but statistically significant increased odds ration for later dementia (odds ratio 1.37, 95% confidence interval 1.14-1.65)

Alcoholism diagnosis by age 65 years of age is also associated with a marked increase in dementia risk (odds ratio 4.14, 95% confidence interval 2.25 to 7.61).

The authors note their findings support the role of psychiatric disorders in contributing to brain vascular abnormalities that can contribute to later cognitive decline. Additionally, they note there is increasing evidence that psychiatric disorders are associated with brain inflammation and immune system dysfunction, areas know to contribute to cognitive decline.

This study is important is suggests at lease five psychiatric disorders need to be considered as potential risk factors for dementia (bipolar disorder plus schizophrenia, depression, anxiety and alcoholism). Adding these risk factors may allow for improvement in detection and prevention efforts.

Additionally, the finding suggest dementia populations may have higher rates of psychiatric disorders. These psychiatric disorders can complicate dementia management and increase the need for psychiatric assessment and consultation in geriatric care settings.

Readers with more interest in this topic can access the free full-text manuscript by clicking on DOI link below.

Follow the author on Twitter @WRY999

Zilkens, R., Bruce, D., Duke, J., Spilsbury, K., & Semmens, J. (2014). Severe Psychiatric Disorders in Mid-Life and Risk of Dementia in Late- Life (Age 65-84 Years): A Population Based Case-Control Study Current Alzheimer Research, 11 (7), 681-693 DOI: 10.2174/1567205011666140812115004

Monday, 1 June 2015

Top Research in Bipolar Disorder: Reading Links

In June I will be looking for some of the top recent research advances in bipolar disorder.

Although less common than unipolar depression, bipolar disorder is a serious disorder with high rates of disability and hospitalization.

I will try to cover the spectrum of important areas in bipolar disorder during the month including: epidemiology, risk factors, biomarkers, genetics, brain imaging, neuropsychology, psychopharmacology and psychological interventions.

Here is a starting group of important studies. Some will be covered in more detail in a future post. Click on the study title to be taken to the full abstract and the free full-text manuscript.

Suicidal behavior in bipolar disorder with antidepressant use

This study examined participants in the Collaborative Depression Study, a naturalistic longitudinal study of bipolar I, bipolar II and unipolar depression. The study found a 54% reduction in suicidal behavior in bipolar I subjects receiving antidepressant therapy and a 35% reduction in bipolar II subjects receiving antidepressants. Of note, use of antidepressants in unipolar depression was not linked to change in suicidal behavior frequency. 

Anti-inflammatory markers in bipolar disorder: Effects of celecoxib (Celebrex)

Mood disorders are commonly linked to elevated markers of inflammation including serum cytokines. In this study, subjects with bipolar disorder receiving electroconvulsive therapy were randomly assigned to the anti-inflammatory drug celecoxib versus placebo. Celecoxib treatment was linked to reduced levels of tumor necrosis factor-alpha but not to reduced levels of two interleukin levels and c reactive protein levels.

Biomarkers in bipolar disorder

This manuscript is a review of the literature in biomarker research for bipolar disorder. The authors found support for several brain structural markers including reduced gray matter volumes in the prefrontal cortex. Serum measures of neutrophic factors, oxidative stress and inflammation also hold promise as biomarkers in bipolar disorder.

Brain connectivity in bipolar disorder vs schizophrenia vs controls

A study of resting state connectivity using functional magnetic resonance imaging targeted a group of subjects with bipolar disorder, schizophrenia and healthy controls. The study found significant differences in connectivity between bipolar subjects and controls although these differences were less pronounced than the differences between a group of schizophrenics and controls.

Genome-wide association studies of schizophrenia, bipolar disorder and unipolar disorder

This study examined results from 60,000 subjects in the Psychiatric Genomics Consortium. The study found evidence for common pathways across the schizophrenia, bipolar and unipolar groups that involve neuronal, immune function and histone methylation.

Follow me on Twitter for updates in neuroscience research. @WRY999

Photo of orangutan is from the author's files.





Monday, 9 February 2015

Exercise and the Brain: Research Links

I am posting links to some of the most recent research related to exercise effects on the brain.

These come from a process of selecting posts to examine in more detail this month.

Clicking on the links will take you to the PubMed abstract. Most of the abstracts also have free full text links.

Enhancing brain activity through multidisciplinary interventions in the elderly

This Chinese study examined the effects of cognitive training, Tai Chi exercise and counseling on a group of 17 elderly individuals compared to controls. The study examined brain low frequency fluctuations and found improved intrinsic activity in the intervention group for the middle frontal gyrus, superior frontal gyrus and anterior cerebellum. The study noted the value of a group intervention for increasing social support ratings.

Single episode of exercise changes resting state brain networks

This study examined the effects of a 20 minutes of moderate intensity aerobic exercise on resting state connectivity of the brain using functional MRI. Exercise produced significant changes from baseline in several brain regions and connections suggesting a valid model for testing the brain effects of acute exercise.

Dietary and lifestyle guidelines for prevention of Alzheimer's disease

This manuscript summarizes results of an expert consensus guideline on prevention of Alzheimer's disease. The experts recommended the equivalent of 40 minutes of brisk walking three times per week.

Physical activity, inflammation, and volume of the aging brain

This longitudinal study in older adults measured self-reported physical activity and a marker of inflammation known as tumor necrosis factor alpha (TNF-alpha). Greater levels of physical activity and lower levels of TNF-alpha (lower inflammation) were correlated with less brain atrophy. 

The effects of chronic exercise on attentional networks

This study examined the correlation between physical activity levels and performance on a task of attention in healthy young adults. The authors found support for exercise as a potential therapeutic modality to improve attention in health young adults.

Photo of sunset at South Padre Island, TX from the author's files.

Follow the author on Twitter WRY999






Monday, 26 January 2015

Obesity, Inflammation and Cognitive Decline

The rate of cognitive decline with aging is quite variable

Identifying important components of this process is needed for developing interventions to reduce the burden of Alzheimer's and other dementias.

Excess inflammation has been linked to obesity as well as aging-related cognitive decline.

Archana Singh-Manoux and colleagues recently published a study of the association between blood markers of inflammation and cognitive decline.

This study used data from the U.K. Whitehall II cohort, a group of men and women between the ages of 35-55 at intake.

This cohort has now been studied over a 20 year follow up with interval assessments about every five years.

Two blood markers of inflammation were studied in this cohort: interleukin-6 (IL-6) and C-reactive protein (CRP).


The study found strong associations between both blood markers of inflammation and rates of obesity (BMI >30) in the chart shown here.

Cognitive decline was measured by decrease scores on the Minimental Status Exam and other neuropsychological tests during the follow up period.

The primary finding from the study was that elevated IL-6 levels but not CRP levels at baseline were associated with accelerated cognitive decline.

Subjects in the highest IL-6 blood level group showed an 85% increased rate in losing 3 or more points on the Minimental Status Exam.

The authors note there study does not prove causality between IL-6 levels and cognitive decline but that:
"Inflammation is likely to play a role because of its impact on cerebral small-vessel disease, which could lead to changes that affect cognitive ageing."
It is also possible, that some of the link between obesity and cognitive decline may be attributable to increased obesity-related inflammation.

The practical clinical potential would be to attempt to identify and reduce inflammation in those most at risk. Anti-inflammatory drugs such as naproxen (Aleve in U.S.) have not been generally effect in trials to reduce rates of Alzheimer's disease.

However, these trials have typically not targeted groups with the highest blood markers of inflammation.

Readers with more interest in this topic can access the free full-text manuscript by clicking on the link in the citation below.

Photo of great blue heron from South Padre Island, TX is from the author's files.

Chart is an original figure from data abstracted from the manuscript.

Follow me on Twitter WRY999

Singh-Manoux A, Dugravot A, Brunner E, Kumari M, Shipley M, Elbaz A, & Kivimaki M (2014). Interleukin-6 and C-reactive protein as predictors of cognitive decline in late midlife. Neurology, 83 (6), 486-93 PMID: 24991031

Monday, 19 January 2015

Mediterranean Diet and Aging

There is a growing research body of evidence to support beneficial effects of a Mediterranean diet on brain health.

In previous posts I have reviewed research on the Mediterranean diet and:

Cognitive Decline

Alzheimer's Disease Prevention

A recent study adds an important element in potential mechanisms for the beneficial effects of the Mediterranean diet.

Marta Crous-Bou and colleauges from Harvard University and the University of Washington published a study of the Mediterranean diet and chromosome telomere length.

This analysis used the large Nurses' Health Study cohort, blood samples and dietary questionnaires. Blood samples were analyzed for chromosome telomere length.

Chromosome telomere length has emerged as a biomarker of aging. DNA chromosome telomere lengths decline with age and shortened telomere lengths are associated with shortened life expectancy. 

The natural process of telomere shortening appears accelerated by inflammation and may be modified by lifestyle behaviors including dietary composition.

In the current study, subjects regularly completed dietary questionnaires. These questionnaires were rated on compliance with the Mediterranean diet on nine variables:

  1. Vegetables
  2. Fruits
  3. Nuts
  4. Whole grains
  5. Legumes
  6. Fish
  7. Monounsaturated fat to saturated fat ratio
  8. Red meat consumption
  9. Alcohol intake

Median values for variables 1-8 were identified and subjects received a score of 1 if they were above the median (below median for red meat consumption). One point was awarded for consuming between 5 and 15 grams of alcohol per day.

Telomere length shortening was associated with older age and heavier cigarette consumption history.

Subjects were grouped into quintiles (20%) groups from lowest to highest Mediterranean diet score.

After adjusting for confounding variables, telomere length was statistically linked to Mediterranean diet score. Those with higher ratings on Mediterranean diet had longer telomeres indicating better aging.

The highest quintile group reported the following mean daily servings for each category: Vegetables (4.3 servings per day), fruits (3.2), whole grains (2.1), fish (0.5), red meat (0.5), legumes (0.6) and nuts (0.5).

The authors note they were unable to identify any single variable that had a strong independent effect. The effect appeared to be a combined global effect of the Mediterranean diet score.

This is an important study because it adds evidence for a biological mechanism for some of the previously reported clinical advantages associated with a Mediterranean diet. 

However, this study is limited by being primarily cross-sectional in design. It does not inform on whether changing diet to a Mediterranean type reduces rate of telomere shortening. 

Readers with more interest in this research can access the free full-text manuscript by clicking on the citation link below.

Photo of foods highlighted in the Mediterranean diet is an original photo from my files.

Follow me on Twitter WRY999

Crous-Bou M, Fung TT, Prescott J, Julin B, Du M, Sun Q, Rexrode KM, Hu FB, & De Vivo I (2014). Mediterranean diet and telomere length in Nurses' Health Study: population based cohort study. BMJ (Clinical research ed.), 349 PMID: 25467028

Monday, 19 September 2011

Inflammation, Depression and Heart Disease

Sunset in Santa Fe, New Mexico
Major depression appears linked to risk for coronary artery disease and an adverse outcome following myocardial infarction.  The mechanism for this association is unclear.

One proposed mechanism relates to systemic markers of inflammation.  Elevated serum blood levels of inflammatory markers such as interleukin-6 and C-reactive protein are risk factors for heart disease.  Some research point to higher inflammatory markers levels in samples of individuals with depression.

Duivis and colleagues from the Netherlands and the United States recently published an informative study on this issue in the American Journal of Psychiatry.  Their study prospectively examined a series of patients with heart disease with measurements of depression and markers of inflammation.  The key elements of the design of their study included:

Subjects: 667 individuals with documented coronary artery disease interviewed yearly for 5 years
Depression Assessment: 9-item Patient Health Questionnaire corresponding to the 9 items making up the criteria for major depression in DSM-IV.  Subjects were grouped into three categories: never scoring 10 or more on the PHQ, scoring 10 or more at one time, scoring 10 or more at 2 or more interviews
Inflammatory Markers: Fasting blood samples measured for high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and fibrinogen.

Subjects with two or more periods with significant depressive symptoms showed statistically higher levels of hsCRP and IL-6 than the other two subject groups (fibrinogen levels showed a trend for higher levels, p=.06)

Subjects with two or more periods with significant depressive symptoms tended to be younger, have a diagnosis of myocardial infarction, use aspirin daily and have lower levels of good (HDL) cholesterol.
They also were more likely to be physically inactive, be a current smoker and have higher levels of obesity (BMI).  This association appeared to occur in only one direction--depression predicted later higher inflammatory markers, high inflammatory markers did not predict subsequent development of depression.

When potential key inflammatory confounding variables were controlled (BMI, smoking and inactivity), the association of depression and higher inflammatory biomarkers washed out.    The authors note that this finding suggests the inflammation linked to depression in heart disease may be amenable to increased efforts to "improve health behaviors".

It is unclear from this study how many subjects received pharmacotherapy or psychotherapy for a diagnosis of depression.  Primary treatment of depression may be necessary to engage and motivate those with depression and heart disease to improve their lifestyle choices and behaviors.

Photo of sunset in Santa Fe, New Mexico from the author's collection.

Duivis, H., de Jonge, P., Penninx, B., Na, B., Cohen, B., & Whooley, M. (2011). Depressive Symptoms, Health Behaviors, and Subsequent Inflammation in Patients With Coronary Heart Disease: Prospective Findings From the Heart and Soul Study American Journal of Psychiatry, 168 (9), 913-920 DOI: 10.1176/appi.ajp.2011.10081163

Monday, 1 August 2011

Novel Use of a Diabetes Drug in Depression

The search for better treatment options in major depression is important because current antidepressant drugs fail to produce remission in a majority of patients.  Current research efforts are exploring novel antidepressant mechanisms. Some of the compounds being studied include pharmacologic agents with the following mechanisms:
  • Neurotrophic and neuroplasticity agents
  • Glutamine neurotransmitter agents
  • Extracellular receptor coupled kinase agents
  • Inhibitors of glycogen synthetase kinase-3
  • Modulators of insulin signaling pathways
Insulin targeted drugs hold promise for several reasons.  Obesity and cardiometabolic disorders occur commonly in those treated in clinical populations with depression.  Elevated abdominal fat levels are associated with greater likelihood of developing depression.  Additionally, insulin resistance and metabolic syndrome appear to increase depression risk.  


Kemp and colleagues at Case Western Reserve University in Cleveland, Ohio have recently published a study of the diabetes drug pioglitazone in major depression.  Subject inclusion criteria for this study included:
  • Outpatients aged 18 to 70
  • Current diagnosis of major depression
  • Abdominal obesity (waist circumference 36 inches or more in women or 40 inches or more in men) OR
  • Metabolic syndrome (three of the following--elevated blood pressure, insulin resistance, elevated triglyceride levels with low HDL cholesterol, abdominal obesity)
  • No current use of a glucose-lowering agent
  • No recent drug alcohol alcohol dependence
Subjects could be taking standard antidepressant drugs but were required to have a significant level of depression at the time of study drug initiation.

The study drug was pioglitazone (U.S. trade name Actos) started at 15 mg per day and increased to 45 mg during the study as tolerated.  The study was an open-label study with all subjects receiving study drug with both subject and investigator unblinded to the study drug.

Twenty study subjects completed the trial and the reduction in depression symptom scores were pretty impressive.  The Inventory of Depressive Symptoms (IDS) declined from a mean of 40.3 at baseline to 19.2 at 12 weeks.  Sixty five percent of the group met criteria for response (50% reduction in IDS score) and 22% of the subjects met criteria for remission.  Response and remission rates were similar to rates found in outpatients with depression treated with standard antidepressant drugs. 

So how might a drug targeting insulin produce improvement in depression.  Insulin is known to regulate dopamine neurotransmitter release in animals.  Additionally the authors note pioglitazone has been shown to reduce CNS markers of inflammation including inflammatory cytokines.  Inflammatory cytokines have been noted to be correlated with symptoms of depression.  

This study will need to be replicated in a randomized double-blind controlled trial.  Nevertheless, the authors suggest that treatment of metabolic defects in those with depression holds promise for improving both the symptoms of depression as well as improving metabolic status (i.e. insulin sensitivity, blood glucose and blood lipid parameters).

Photo of sunrise at Juno Beach, Florida from author's collection.


Kemp DE, Ismail-Beigi F, Ganocy SJ, Conroy C, Gao K, Obral S, Fein E, Findling RL, & Calabrese JR (2011). Use of insulin sensitizers for the treatment of major depressive disorder: A pilot study of pioglitazone for major depression accompanied by abdominal obesity. Journal of affective disorders PMID: 21782251

Monday, 20 December 2010

Inflammation Nation

In the last post we talked about the stress response, and how it seems like the modern human body’s reaction to various stressors is overactive. This overactivation, many believe, is linked to the increasing presence of Arachidonic Acid in our bodies. Arachidonic acid is the precursor to what are known as Series 2 Prostaglandins, a class of predominantly pro-inflammatory (although not all) eicosanoids with undeniably close ties to dozens of inflammatory diseases that have risen with breathtaking rapidity over the course of the last century.

But I think few understand just how much of an inflammatory tidal wave we’ve been hit with, and how it’s increasing at exponential speed. Incidence of asthma for example, has increased like 70-something percent in the last 15 years. Anyone who has kids these days knows that food allergies are the norm, not the exception. Kids aren’t even allowed to bring food to share (like cupcakes) to school anymore due to the liability of it containing allergens that another child might react to. Hypersensitive is really the best word to describe the newest generation.

Although the war cannot be solely won on the Arachidonic acid front, I don’t think there’s any question whatsoever that it is, at very least, highly involved in the inflammation phenomenon. The higher the production of Arachidonic-Acid derived inflammatory molecules, generally the greater the incidence and severity of inflammation-related diseases.  (I also believe that when the body temperature is sub-normal, which is extremely common as you can read about in THIS FREE EBOOK, the enzymes and molecules involved in immunity do not work properly, and may, in part, give rise to a state of overcompensation and hypervigilance on behalf of the immune system - leading to allergy and autoimmunity).

When the body confronts some kind of stressor, like an allergen, an infection, injury, the systemic pounding of running a moron-a-thon let’s say, and potentially various forms of psychological stresses as well, the immune system becomes activated and the manufacture and release of Arachidonic Acid-derived molecules gets switched on. The formula appears to be pretty simple. For example, describing Arachidonic Acid-derived leukotrienes, Floyd “Ski” Chilton, author of Inflammation Nation writes:

“The amount of leukotrienes present at the scene of the white blood cells’ attack influences the scale of that attack.”

Chilton goes on to describe how the composition of the diet goes on to directly determine this…

“…research has proven that a high AA diet has the potential actually to change normal immune responses to abnormal, exaggerated ones. A study carried out in 1997 by Dr. Darshan S. Kelley and colleagues at the Western Human Nutrition Research Center in California showed that people on high-AA diets generated four times as many inflammatory cells after a flu vaccination as people on low-AA diets.”

Joe Blair, who I generally speak of highly, has also crafted a theory that Arachidonic Acid excess is really the key in the development of most diseases. We can all be subjected to stressors, but only those with excesses of Arachidonic Acid in their tissues will trigger a reaction strong enough to manifest as one of dozens of inflammatory diseases. Having low levels of arachidonic acid, which Joe Blair has worked hard to achieve in the conquering of his own health problems, evidently can lead to an excess production of quotation marks…

“The key point in all of this is that arachidonic acid is very unstable and toxic, and is released from cells upon the most minor of stressors. Then it can stress the "germs," which cause "disease" by the "clinging" action, provoking the "inflammatory" process, which is too potent and sustained in people with arachidonic acid in their cells, and then the damage that is called one "disease" or another eventually appears.”

Quite simply… Minor stressors cause big, destructive, disease-causing explosions. Is this not exactly what we were getting at in the last post as we examined stress vs. the RESPONSE to stress?

The big question is, what caused the excesses of Arachidonic Acid in our tissues and what can be done to reverse it?

In the last post I mentioned my growing doubt over the belief that by keeping polyunsaturated fat intake exceedingly low, this overzealous stress response could be lowered to a healthy level. Heck, I’ve eaten a very low omega 6 diet for an entire year now, with, if anything, an increasing inflammatory response.

So the timing was good when I came across Ski Chilton and his 2007 book, Inflammation Nation: The First Clinically Proven Eating Plan to End Our Nation’s Secret Epidemic on the shelf of my local library. Of course, when I see the phrase “clinically proven” I automatically assume someone is peddling something that will yield a seemingly-miraculous health improvement followed by the growth of a 3rd nipple, bloody diarrhea, and an unexpected stroke. But I was willing to give Doc Chilton the benefit of the doubt, as I always strive to do.

Chilton had some insights that would rock the sphincters of the likes of Barry Sears, Ray Peat, and Joe Blair – who seem to be convinced that the consumption of seed oils is the primary culprit in our increasingly-inflammatory reaction. Chilton has a new twist on this. I’m not saying this is the be-all, end-all, or that there aren’t other important reasons to avoid vegetable oils (free radical damage), but it does re-awaken the omega 6 conversation. Note, linoleic acid, or LA as referred to in the quote, is what I typically am referring to when I say “omega 6” or “666” if you will…

“Does this mean that if you want to stop making so much AA, you should stop eating LA? Actually, it doesn’t. A number of recent studies indicate that we convert very little LA into AA. Our bodies aren’t good at the first conversion of LA to GLA. Consequently, eating even a lot of LA (as almost all of us do every day) won’t really have a major influence on AA, or on the number of inflammatory messengers you produce.


We didn’t always know this – for a very simple reason. Not all species so limit this conversion. Rodents, including mice, are actually very good at it, which means that they convert a great deal of the LA they eat into AA. So what? Many of the studies examining how the body processes different fatty acids were carried out in mice, which means that some of the conclusions scientists drew about the connection between dietary LA and elevated levels of AA in humans were incorrect.”

According to Chilton, the problem with AA-overload has a heck of a lot more to do with modern farm animals being fed lots of Linoleic acid in their feed (excluding ruminant animals) than it does humans actually consuming Linoleic acid directly (although that is certainly a contributor, and he has no love for corn and soy oil I assure you).

Also, like Barry Sears, he focuses on insulin being a trigger for the Delta 5 Desaturase enzyme, which triggers greater production of AA out of the LA in our diet and tissues. Of course, this water becomes increasingly murky (insulin resistance is most likely the cause of chronic excessive insulin production, and postprandial spikes are meaningless), as he goes on to recommend a rather high-protein diet just like Sears under the belief that carbohydrates raise insulin more than protein, which is typically not true unless you are talking about refined carbohydrates. Still, he’s all about complete avoidance of refined carbohydrates while eating a diet centered more around unrefined starches, fruit, and vegetables along with fatty fish and shellfish, beef, and dairy products (which are closer to being inflammation neutral).  This is not too far off from MY GENERAL RECOMMENDATIONS. 

To this he has a fatty acid supplement protocol that is designed to decrease AA production based on some studies that he co-authored and found to be effective, such as the poetically-named…

Addition of Eicosapentaenoic Acid to y-linolenic Acid-Supplemented Diets Prevents Serum Arachidonic Acid Accumulation in Humans

In short, he recommends a high daily level of GLA (borage or evening primrose oil) split into 2 doses of roughly 250mg each, with the use of 1 normal 180mg fish oil capsule (which you can avoid if you eat fatty fish several times per week according to Chilton) taken twice daily along with the borage/primrose. This is very similar to Barry Sears’s pioneering work except that Chilton has focused entirely on the suppression of AA production, which ended up requiring much more GLA than Sears ever recommended along with far LESS fish oil – a recommendation I’m more at ease with.

The AA and inflammation debate is far from over, but is just heating up.  I thought it necessary to share another point of view with you. Brian Peskin, another researcher who seems to have entered his own new paradigm on fatty acids due to his own independent research, feels like the war against AA is a huge misunderstanding – as AA produces some amazing anti-inflammatory, anti-cancer molecules like prostacyclin. I’ll be giving more thought to Chilton’s program (and reading his latest book), as well as reviewing Peskin’s work in the year ahead. The lengths I go to in order to keep myself out of trouble!

Food for thought…

This new persepective could potentially reconcile some of the following things…

1) Nuts, seeds, avocado, sesame oil, olive oil, etc. – high in linoleic acid, are referred to as “healthy fats” by mainstream nutrition authorities, as these foods continue to perform well in reducing the rates of many health problems when subjected to study.

2) Seed oils, in large-scale studies don’t typically produce greater incidence of heart disease, obesity, asthma, etc.

3) Pork fat, perhaps the worst AA offender, is what is used in clinical trials and labeled “saturated fat.” This drives smart people like Chris Masterjohn up the friggin’ wall (UTFW), as pork fat is mostly UNsaturated fat. However, pork fat typically yields a lot poorer results than either unsaturated fats including even vegetable oils, or more saturated fats like beef, coconut, or dairy fats. Perhaps most of the negative findings on saturated fat over the years have been due to Arachidonic acid in pork fat, and has nothing to do with the saturation or lack thereof of the fats involved in the studies. Or it could just be part of the pro-seed oil propaganda of the agriculture and food industry lobbying machine.

4) The unhealthiest part of the United States is, and has been for decades, the American South – with typically higher rates of asthma, obesity, type 2 diabetes, obesity, and heart disease. A lot more pork is eaten in the American South than anywhere else in the country. African Americans in the area, who have tremendously poor health compared to national and global averages, also have “soul foods” such as pork chitterlings which happened to be the top ranking food item on Chilton’s Inflammatory Index. Variety meats, ribs, barbecue pork, and fried chicken are also known staples to the point of being used as a common stereotype of Southern African American cuisine. These foods, along with just a few others, are the ones assigned the highest inflammatory index ranking of 100 or above on Chilton’s list.

5) Perhaps this is why many report health improvements on vegan diets – particularly low-fat vegan diets, and during fasts, which limit all forms of dietary arachidonic acid (it’s the nutritionally-incomplete diet itself that most likely causes health problems when continued long-term).  Sadly, these initial and sometimes dramatic health improvements are very seductive, and because of the moralist fervor and health propaganda that surrounds vegetarianism, many stay on this diet long after its therapeutic benefits have fizzled and morphed into a major health liability.

Wednesday, 15 December 2010

Stress vs. Stress Response

The hot topic at 180 these days is stress. But before we continue with the conversation, I think some important groundwork needs to be laid down. Many of us here have had some various form of stress undermine our health, be it an extreme diet, a traumatic event, poor nutrition, endurance exercise, calorie restriction, sleep loss, a job that we hate, or what have you. Many more of us have had stress in the form of food allergy and sensitivity, other allergies and sensitivities, chronic illness, and so on (Read more about some of these issues in THIS FREE EBOOK).

There’s no doubt that the number of things we can encounter in today’s world that trigger a decline in health are endless. But a huge question remains. Is it “X” trigger of our symptoms that is the problem, or is there something going on at a deeper level that makes us respond to various stressors in an exaggerated way? In other words, is the root problem STRESS itself, or our RESPONSE to stress? Here are some brain teasers that may help us to better answer that question.

Pottenger’s Cats

In my early writing I discussed Pottenger’s Cats quite frequently. It’s been a while since I’ve brought these kitties up, but like Austin Powers, International Man of Mystery (who, other than the bad teeth is really who I try to emulate most in life), “I never forget a pussy… Cat.”

Pottenger’s Cats, when fed a nutritious whole foods diet of suitable, uncooked foods including mostly meat and milk, had excellent health and were able to produce litters of strong and equally-healthy kittens. However, a side-by-side comparison of those fed only cooked foods, which has been hypothesized by some to have damaged the amino acid Taurine and caused a deficiency (it could have been the heated lactose, it could have been the denatured proteins in milk, it could have been inability to assimilate the nutrients in cooked milk, or any number of things), revealed that the subsequent generation was all kinds of messed up. While it’s incredibly fascinating that they developed skeletal and facial deformation, which made their teeth crowded just like a modern human’s post-refined foods era, it is of greater interest to our conversation that they developed ALLERGIES.

To me, allergies epitomize what I mean by the stress RESPONSE, and not the STRESS being the root of the problem. In the comment thread on the last post we heard from people with an allergic reaction to everything from cat fur (guilty) to, get this… WATER! There are people with an allergic reaction to sunlight as well. It doesn’t get much more benign than water and sunshine. Fortunately, this allergic reaction to water has been overcome with super anal nutrition (this just means strict avoidance of refined and processed foods – not to be confused with the South Park episode where a new fad emerges in which everyone starts ingesting all their food rectally).

This also speaks volumes about why I generally try to discredit those who blame gluten or lectins or salicylates or nightshade vegetables or dairy or starch or cooked meat or fiber or various carcinogens or whatever for bringing about the demise of mankind. Individual food sensitivities usually spark the quest to unearth all the dirt and grime of the offender, and it’s easy to find supporting evidence for or against any known food these days (for example, one could easily formulate a one-sided counter argument championing Wheat as the ultimate food for digestive health, type 2 diabetes prevention, and more).

I’ve fallen into that trap before, as drinking water once gave me indigestion and I started telling people to stop drinking it while quoting other authors who seemed to have the same problem I did (Aajonus Vonderplanitz and Konstantin Monastyrsky). As character Nick Rivers (Val Kilmer) sang in the movie Top Secret, “How silly can ya get?”

And so, from Pottenger’s experiments, it appears to be that the stress response, and not a particular stressor per se, plays a more primary role in health. This perversion of the stress response looks like it can be most attributed to a general degeneration process, however, keep in mind that there was something about the diet – either presence of some toxic or indigestible substance and/or nutrient deficiency that was a stressor causing the degenerative process itself. Again, we are stuck with a little bit of a chicken or egg question.

Arachidonic Acid

Switching gears for a moment here, we have another leading contender for the perversion of the stress response – arachidonic acid (AA). As a reminder, arachidonic acid is a polyunsaturated fat that is either ingested directly through food (like eggs and liver, a minor source of total AA in the modern world) or is converted from linoleic acid (omega 6) found in greatest abundance in nuts, seeds, and vegetable oil (the primary source of modern AA).

AA is a wildly unstable and inflammatory molecule, and its presence in excessive amounts causes a greater production of the most harmful and vicious inflammatory chemicals produced by the body – such as Interleukin-6 and TNF-Alpha (both of which have very strong ties to all inflammatory conditions from asthma and arthritis to heart disease and obesity).

In fact, the entire series of Zone books by Barry Sears is a long-winded argument and strategy for reducing cellular levels of AA, which he labeled in one of his more recent ramblings, “toxic fat.” Dr. William Lands has dedicated his entire career to lipid research and decided that AA, and therefore omega 6 polyunsaturated fat consumption, is basically the root cause of most modern disease epidemics. Ray Peat and Joe Blair, some of my favorite researchers, have come to similar conclusions and put greater emphasis on reducing AA in the body than on any other nutritional issue. Russ Farris, another of my favorite researchers feels that nearly all health problems can be traced to the production of these first line inflammatory molecules like IL-6, but has somehow failed to make the connection between omega 6 ingestion, AA, and these molecules.

This is the strongest theory I’ve come across in support of the belief that it’s not necessarily the stress your body is exposed to – be it infections, carcinogens and other environmental toxins, potential allergens, psychological stress, injury and other physical stressors, etc., but your body’s reaction to that stress that counts. And the severity of that reaction is believed to be entirely related to the fatty acids present in the cells themselves. Click HERE to read some of Joe Blair’s interesting thoughts about it.

If overloaded with AA, the response to stress is overzealous. If overloaded with omega 3 instead, the response is much less dramatic – however there may be some serious health concerns with having your cells overloaded with omega 3 as well, and in those with these fatty acids in balance, like in the Japanese, there is certainly no shortage of stroke, cancer, autoimmune disease, and other inflammation-related illnesses. But there’s no doubt that omega 3 can displace and blunt the AA overload problem, which is why there is so much hype surrounding fish oil these days.

Ray Peat and Joe Blair feel like the best route to take is to not be overloaded in either omega 6 or omega 3, but consume the minimum of ALL polyunsaturated fats – triggering the production of a different and less explosive fatty acid to take the place of these seemingly-toxic ones. This internally-generated fat is called Mead Acid.

This all sounds amazing in theory. Only problem is, I have personally reduced my polyunsaturated fat intake to a minimum for an entire year now without a reduction in inflammation, pain, sensitivity to allergens, etc. My suspicion is that this theory is missing something. Then again, the process of overcoming AA overload is very slow. It took a century for the cells of Americans to get to this point of imbalance, and it takes several years of a very diligent approach to undo it – and one can’t expect to ever really feel a dramatic change at any point during the process.

Still, when I’m loaded up with pain killers like Advil that shut down the production of AA-derived eicosanoids, any aches and pains I have ever dealt with instantly vanish and activities that normally worsen or even cause the pain (like running) do not seem to do any damage. I used to load up on Advil every day before football practice from age 14 to 18. Without it I could barely walk due to the shin-splint like pains below my calf muscles, but with it I felt no pain during or following practice even after the Advil wore off. So I do KNOW that these molecules are involved with many problems, and maintain faith that avoiding polyunsaturated fat for many years will help.

But when we think back to Pottenger’s Cats, all of whom had the same fatty acid composition in their diets, it’s hard to look at the overall issue of stress overreaction as one that solely resides on the shoulders of cellular fatty acid composition. I also can’t deny overcoming my lifelong seasonal allergies and drastically improving chronic back pain that I had dealt with since I was a teenager while eating a considerable amount of nuts – especially cashews, almonds, and pumpkin seeds (all very high in omega 6), in my first whole foods nutritional bombardment trial back in early 2004.

Layla

The biggest glitch in the theory that STRESS is the cause of disease, as opposed to the body’s REACTION to stress, is my personal dealings with Layla as discussed in THIS OLD POST, and in recent comments.

Layla overthrows many of our modern stress theories because her life was the most stressful of anyone I’ve ever met, yet her health is also the best of anyone I’ve ever met.

She actually provides incredible insight into the argument of stress vs. nutrition in a battle of importance, as her parents’ nutrition, as well as hers during the formative years of her life, was the best of anyone I’ve ever met personally. Her facial development, with 32 teeth in perfect alignment (no dentists, orthodontists, toothbrushes, or toothpaste required) and broad nostrils just as Weston A. Price described, is a testament to that nutritional excellence. When a person with the best health you know had the best nutrition, and the most stressful life, that is one hell of a check mark in the Nutrition box.

Layla was raped and beaten over 100 times before the age of 10. When she was still a young kid war broke out in Somalia and she spent six months on the run with her family. The sound of bombs and gunshots trailed slowly behind them, leaving them in a constant state of fear. They were sleep-deprived, food-deprived, over-stressed, and over-exercised. Her mother was nursing a child the whole time (successfully) while subsisting off of mostly powdered milk. Traumas unimaginable to us were the daily norm, including seeing lions scavenging on human remains daily, and the constant fear that if she were to succumb to exhaustion, a starving person would cut her throat and drink her blood for nourishment (which was rumored to be common). This isn’t even the half of it. She also spent over a year in isolation, separated from her family, traveling thousands of miles by foot and subsisting primarily off of nuts and berries. This tale of trauma goes on and on and on I assure you.

Yet, Layla today runs 100 miles per week. She has less than 10% body fat. She drinks blue Powerade and eats boxed breakfast cereals and glutinous goodies and cooks her food in vegetable oil. Yet, she has never had a menstrual irregularity or negative menstrual symptom, can sleep for 2 hours and not be tired the next day, has no major or even minor health complaints… you get the picture. While the rest of us become allergic to frickin’ water or have all our teeth rot out and wheeze n’ sneeze every day of our lives with 248 food sensitivities from eating a mediocre diet and having to study hard for exams, or that one moron-a-thon we were dumb enough to run, or having an adult fondle us inappropriately a few times when we were a kid, or developing a life-threatening autoimmune disease from petting a cat with a retrovirus, she thrives.

Conclusion

The bottom line is that we are all a pretty sorry lot of degenerates, and poor NUTRITION, not exposure to STRESS – including infections, emotional traumas, overexertion, lack of food, and so on, is the ROOT CAUSE of the health circumstances many of us have found ourselves in.

But a strange twist is that exposure to STRESSORS is now a much more powerful cause of disease than poor nutrition, as it is much more of an immediate threat to our health. For example, a person I know who just completed a moron-a-thon 10 days ago, has had a fever consistently for 10 days and has the first cold sore breakout in a year, which the doctor described as “the worst case I’ve ever seen.” 12 cold sores in total covering the mouth, and even breaking out on the nose and in the ear. More marathons for this person and autoimmune disease, allergy, infertility, bone loss, weight gain, and god knows what else will follow.

I think this strange phenomenon is exactly why so many of us have decimated our health much more on highly restricted diets like vegan or low-carb, doing too much endurance exercise, restricting calories, staying out partying too late, studying too hard, dealing with the loss of a loved one or traumatic event, and so forth than we ever could have just eating white flour and white sugar till the cows came home while otherwise taking great care of ourselves.

Like Paula said in a comment on the last post, all the nutritious food in the world couldn’t counter the stress of repeatedly ingesting gluten, as she is a diagnosed Celiac.

The grand summary is basically that poor nutrition got us into this mess, and while it’s the only thing that will take us back to health collectively, there are far greater pressing and more imminent concerns on an individual basis than diet.

A good analogy would be that of lighting a house on fire by playing with matches. The fire department shows up and gives you a lengthy lecture about how you shouldn’t play with matches, and that’s how fires get started. The appropriate response to that would be…

“Thanks for the tip jagoff, but if you haven’t noticed my frickin’ house is on fire. Can you please help me put out the flames before we have a discussion about how it got started?”
And so the stress conversation will continue. I certainly continue to stand by RRARF, an anti-stress, nutritionally-outstanding strategy that makes a great starting point for those with health problems of all kinds – particularly for those who developed health problems on a superficial quest to find their abs or achieve eternal youth based on the advice of one of the thousands of health authors and bloggers out there.

(BTW, I'm unable to access my e-mail account or post comments to the blog right now, which is frickin' killing me!!!  This may continue until the 19th unfortunately). 

Tuesday, 2 November 2010

Is Bipolar Disorder an Autoimmune Disorder?

Hemmo Drexhage, M.D. from Erasmus Medical College presented the November lecture in the Warren Frontiers of Neuroscience Series in Tulsa, Oklahoma.  His presentation was titled "Immunology Meets Psychiatry" and the lecture covered a series of research efforts examining immunological abnormalities in psychiatric conditions.  Here is a summary of my notes from the presentation:
  • Although we know genetic factors account for 60-80% of the variance for the schizophrenia and bipolar disease risk, the search for specific genes has been disappointing
  • Many genes linked to these two disorders relate to immune function or neurodevelopment
  • It might be better to look at patterns of gene expression involving immune function in these disorders compared to controls
  • Smith in 1991 proposed the macrophage-T cell theory of psychiatric disorders
  • This theory proposed immune cells (monocytes and T cells) are activated in bipolar disorder and schizophrenia
  • This upregulation releases abnormal levels of cytokines (inflammatory chemicals) that affect the brain
  • This effect directly or indirectly produces symptoms of bipolar disorder and/or schizophrenia
  • Drexhage and colleagues research supports the macrophage-T cell theory of psychiatric disorders
  • Pro-inflammatory monocyte gene upregulation has been demonstrated in bipolar disorder and depression
  • Both disorders upregulate two clusters of gene products but the disorders differ in a third cluster
  • The 2C cluster upregulation is found in schizophrenia but not bipolar disorder
  • Transcription factors appear important in driving this inflammatory state
  • Environmental factors appear key in this inflammation based on a twin study
  • So what is this environmental trigger?
  • Candidates include viruses, bacteria, diet, toxin, stress
  • In animal models, inflammation and increased cytokines during pregnancy cause brain microglial abnormalities and behavioral abnormalities in the offspring
  • Antidepressant responders in depression show reduction in inflammatory gene expression to control levels or below
  • Gene expression pro-inflammatory effects are also in the periphery (benzodiazepine receptors) and in the brain hippocampus
  • High risk children for bipolar disorder (children of bipolar parents) show increased levels of inflammatory markers before the onset of illness
  • Inflammatory gene expression studies are hampered by confounders that also increase inflammatory signals--obesity, hyperlipidemia, smoking
  • Potential implications are clear
    • Anti-inflammatory drugs (i.e. Celebrex or similar) deserve study in these disorders
    • Search for viral or bacteria triggers is necessary (i.e. abnormal gut bacterial flora, viral antibody titers)
    • Specific patterns of immunological response may be useful diagnostic markers
Photo of a monocyte in a group of red blood cells from Wikipedia courtesy licensed under the Creative Commons Attribution-Share Alike 3.0 Unported2.5 Generic2.0 Generic and 1.0 Generic license.  Author Bobjgalindo

Drexhage RC, van der Heul-Nieuwenhuijsen L, Padmos RC, van Beveren N, Cohen D, Versnel MA, Nolen WA, & Drexhage HA (2010). Inflammatory gene expression in monocytes of patients with schizophrenia: overlap and difference with bipolar disorder. A study in naturalistically treated patients. The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 13 (10), 1369-81 PMID: 20633309


Drexhage RC, Knijff EM, Padmos RC, Heul-Nieuwenhuijzen L, Beumer W, Versnel MA, & Drexhage HA (2010). The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder. Expert review of neurotherapeutics, 10 (1), 59-76 PMID: 20021321


Padmos RC, Hillegers MH, Knijff EM, Vonk R, Bouvy A, Staal FJ, de Ridder D, Kupka RW, Nolen WA, & Drexhage HA (2008). A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes. Archives of general psychiatry, 65 (4), 395-407 PMID: 18391128