Thursday, January 11, 2018

The Role of Dietary Greens in Brain Health

One of the hallmarks of the Bredesen Protocol for Alzheimer’s disease is that most of the treatment is lifestyle based.  There is a tendency to not think that lifestyle factors as simple as what one eats could have such a profound effect on such a complex disease.  A recent study of 1,068 older adults, the Rush Memory and Aging Project, showed just how important a single dietary factor can have pronounced effects.

The subjects' diets were analyzed specifically looking at how many servings of greens including spinach, kale, collards, greens and lettuce/salad were consumed daily.  All subjects had annual cognitive testing over 5 years.  Those consuming 1.5 or more servings daily had cognitive performance scores a striking 11 years younger than those with the lowest consumption (<1 serving/week).  The results remained valid after accounting for other factors that could affect brain health, such as seafood and alcohol consumption, smoking, high blood pressure, obesity, education level and amount of physical and cognitive activities.

The suspected mechanism driving this relationship is likely that greens are a major source of “methylation factors” in the diet.  Methylation is a primary mechanism through which our genes are regulated.  This includes both keeping genes that may increase our disease risk turned off and activating those involved in reactions that tend to be disease preventative.  Methylation factors include vitamin B12, B6, folate, the amino acid methionine and choline.  Methylation reactions occur thousands of times daily in all of our cells literally determining healthy function. 

The methylation cycle involves several enzyme reactions that use the above nutrients to activate.  The end product of these reactions is a methyl group which performs the gene regulation.  The cycle also produces “waste products” such as homocysteine which can increase brain cell degeneration if it is not efficiently removed.  This requires adequate amounts of vitamin B6.

Many studies have found that the brain is very sensitive to loss of proper gene methylation with age causing an increased rate of memory decline.  Acceleration of this decline in gene methylation with age by inadequate dietary provision of the needed nutrients appears to greatly accelerate this process.  Although the concept that just eating multiple servings of greens daily seems too simple to be involved in such a complex disease such as Alzheimer’s, appreciating the scientific concept behind the relationship establishes the importance.

It is likely that some persons are more susceptible to the level of nutrients involved in the methylation cycle.  Genetic variations called polymorphisms can cause any single enzyme in the cycle to be weak under-producing its reaction.  For example, the enzyme that converts dietary folate to the form used in the cycle, 5-methylated folate is variant in perhaps as many as 1 in 5 Westerners.  As higher amounts of dietary folate have been shown to help compensate for this gene variant, these individuals are very sensitive to dietary amounts.

Eating greens by itself is not a total solution to disease prevention and treatment.  The Bredesen Protocol™ derives its success from testing and treating many different factors most of which are lifestyle related.  However, one part of this comprehensive protocol does involve eating multiple servings of greens daily.

The study is to be published in the journal Neurology later this year.

Thursday, December 14, 2017

One of The Strongest Alzheimer’s Preventions

A broad group of lifestyle and behavioral factors have been associated with the risk of developing Alzheimer’s disease including diet, stress, exercise and others.  A new study has increased the importance of one that has been previously known, educational attainment.

The study, CoSTREAM, looked at genetic patterns that have been previously shown to highly correlate with the likelihood of educational attainment. This gene pattern was also highly associated with a reduced likelihood of developing Alzheimer’s.  For every year of educational completion the risk of Alzheimer’s was reduced 11%.  If education included the completion of college, risk was further reduced 26%.

The researchers commented that this association is consistent with the reducing rate of Alzheimer’s disease in the United Kingdom which contrasts to the sharply increasing rate in the United States.  Along with greater emphasis on diet, exercise, and smoking reduction the UK has increased educational emphasis.

The effect is thought to relate to the development of "cognitive reserve". Just as physical exercise causes muscle to build up decreasing the risk of injury and age-related muscle loss, education builds up brain structure and offsets age related brain loss.

While recent losses in financial support for higher education in the US have occurred
 based on “costs”, this may be short-sighted given the staggering cost projections associated with Alzheimer’s disease over the next 30 years.  Saving a dollar now but costing hundreds more in the near future is never a winning strategy.

The best plan is for each individual to do everything to facilitate their own higher education and to continue “brain exercise” with life-long learning.

Larsson et al.  Modifiable pathways in Alzheimer’s disease: Mendelian randomisation analysis.  BMJ 2017; 359.

Thursday, December 7, 2017

Alzheimer’s Genetic Risk Factor Requires Careful Management of Omega-3 Fatty Acid Levels

Some of the risk of developing Alzheimer’s disease is mediated by genetic variation.  The most common and involved variation is a variant of the gene that makes the apoprotein apoE.  This apoprotein is involved in many processes in brain cells including the removal of the toxic protein β amyloid which causes tissue damage if it builds up in excess.

Risk of the disease is greatly increased in those with the variant form of the gene called apoE4.  Nine percent of adults have the apoE4 variant and their disease risk is increased between 3 and 10-fold depending on the presence of 1 or 2 copies of the gene variant.

While the presence of apoE4 increases the disease risk, the final triggering of the disease requires the presence of different environment triggers such as chronic inflammation or insulin resistance.  Both of these processes are worsened by low cell levels of omega-3 fatty acids which must come from diet.  New study has found that this relationship is compounded by the fact that it requires higher amounts of omega-3 FA intake to maintain cell levels in those with the apoE4 gene variant.

The study looked at blood and brain cell omega-3 FA levels in rats that share the traits of development of Alzheimer’s with humans.  The levels were significantly lower in those animals with the apoE4 variant.  The lower levels of omega-3 FAs correlated with cognitive and behavioral deficits typical to human Alzheimer’s.  The lower levels of omega-3 FAs appears to come from increased “catabolism” or breakdown of these fatty acids.  The solution is that those with the apoE4 variant require higher levels of dietary and supplemental omega-3 FAs to maintain cell levels and prevent cognitive decline.

The difficulty in managing omega-3 FA levels is that there is wide variation of intake levels from person to person required to maintain adequate cell levels.  This can be managed by actually measuring cell levels and adjusting supplementation until these levels are adequate.  This is done with a red blood cell test.  Blood cell levels have been correlated with levels in brain cells validating this testing.  The test above shows a low omega-3 FA cell level at 3.72%.  Levels need to be 10% or greater for optimal brain protection.  

The test at the left shows an ideally managed omega-3 FA level at 11%.  The dietary levels required to maintain these levels varies from person to person so supplementation levels should be managed by cell level testing rather than by using an arbitrary consumption level. 

There are several risk factors that have to be managed more carefully in persons with the apoE4 gene variant.  Omega-3 FA levels is clearly one of them.  If someone is genetically predisposed to Alzheimer’s disease, development of it is not a given and it can be prevented with careful lifestyle management.

Nock et al.  Carriers of an apolipoprotein E epsilon 4 allele are more vulnerable to a dietary deficiency in omega-3 fatty acids and cognitive decline.  Molecular and Cell Biology of Lipids, 2017:1862;1068–1078.

Thursday, November 30, 2017

Why Is Exercise an Important Part of the Bredesen Protocol™?

Exercise is largely the modern day substitute for work/survival associated with intense physical activity.  This activity was not only essential for survival providing access to food and other essential resources but also has been important in optimizing physiologic functioning essential to survival.

Physical activity activates the expression of “neurotrophic factors” in the brain.  Most noted of this family of signaling factors is brain derived neurotrophic factor, or BDNFNeurotrophic is defined by the two words it is derived from.  Neuro refers to nervous system cells including brain neurons. Trophic refers to growth and function stimulation.  Neurotrophism is an ongoing process needed to maintain brain cell health and function.

A recent study randomized 95 adults to an exercise training group, a cognitive training group, a combined exercise and cognitive training group and a control group who did not participate in either training.  Exercise training produced significant memory improvements as did the cognitive training compared to the controls.  The combined exercise and cognitive training group improved memory function to an even greater extent than either the exercise alone or cognitive training alone groups.

The images to the left show differences in brain activity on functional MRIs in subjects regularly exercising versus those who are sedentary.  Exercise induces stimulus to the brain to increase activity and synaptic formation, the formation of connections that allow neurons to communicate with each other.  These increased connections translate to higher levels of function such as memory processing.

The effect of exercise correlated with increased BDNF levels.  The researchers concluded that both cognitive training and exercise training improve memory function.  Combining the two has an even greater effect which appears to be the result of stimulating the neurotrophic factor BDNF.

The study relates to important points in the Bredesen Protocol for Alzheimer’s.  The protocol derived its success from the fact that it combines multiple treatments that have synergistic effects on brain restoration.  This is in sharp contrast to the typical drug treatments that focus on one mechanism resulting in no significant effect on the disease outcome.  The disease is multifactorial in origin, and treatment needs to be approached similarly.

The second point relevant to the Bredesen Protocol is that the disease has to be approached from two different areas.  The first is to find and treat the factors that drive the disease.  These are diverse and are addressed in the extensive testing that precedes treatment.  Once the factors that are responsible for injuring the brain are corrected, brain volume and function must be rebuilt using a broad program of neurofeedback, cognitive training, exercise and sleep restoration.

There is a tendency to question if daily exercise is essential.  Our ancestors of long ago were thought to be physically active in pursuit of food and other survival essentials for 12 or more hours daily.  While modern humans are more than 99% genetically identical to these ancestors and therefore share their same activity dependent physiology, our physical activity levels have diminished to only a fraction of our predecessors.  This has not been without serious health impacts including on brain health.

Attention to lifelong exercise is ideal.  However, if that has not been the case, properly managing exercise once brain dysfunction and disease have developed can help in restoring function.
Heisz et al.  The Effects of Physical Exercise and Cognitive Training on Memory and Neurotrophic Factors .  Journal of Cognitive Neuroscience, 2017:29;1895-1907.

Wednesday, November 29, 2017

If We Had This Drug, I Would Be on It

One of the largest studies on the reduction of chronic disease risk and mortality was recently published in The Lancet.  The study looked at the use of a particular treatment and the reduction of cardiovascular disease risk, stroke risk, as well as the risks of cardiovascular, non-cardiovascular and overall mortality.  The study was very comprehensive involving 135,335 individuals aged 35 to 70 years without cardiovascular disease from 613 communities in 18 low-income, middle-income, and high-income countries in seven geographical regions: North America and Europe, South America, The Middle East, South Asia, China, Southeast Asia, and Africa.

The results shown to the left were fairly striking with the treatment reducing the risks uniformly for all of the followed measures.  The vertical black line is the risk in the non-treatment group.  That is arbitrarily called “1” in a comparative study.

The graphic shows the risk reductions circled in red compared to those not taking the treatment regularly.  The red line shows the risk reduction to 0.7 which means a 30% reduction.  For cardiovascular events (CV disease) the reductions were all about 20%.  The mortality reductions were more dramatic, all being more than 30%.

The conclusion is that this treatment resulted in broad reductions in disease rates and deaths for the leading cause in developed and less developed countries.  The results occurred regardless of age, income status or country of residence.

Participation in this treatment would not take much persuasion if this drug existed, was widely available and relatively inexpensive.  While it meets all of those criteria, it has been and continues to be a hard sell to the population at large.  This is because the “drug” used in the study was actually “more than 3 servings per day of fruits, vegetables and legumes”. 

To give some perspective on these results, the results of similar clinical trials using statin drugs on total cardiovascular mortality have found risk reductions varying between 0 and 12%.  Seems like one could do twice as much just by eating enough fruits and vegetables daily.

The irony of all of this is that virtually every guideline out there supports this “therapy”, yet the minority of the population follow this in practice.  The breakdown seems to occur for many reasons.  Medical practice has become largely “this drug for that problem” with insufficient time spent or emphasis on implementing this very effective prevention.  This is driven by time restraints in patient care, patients preferring a pill over lifestyle change, and intense pharmaceutical advertising biasing opinions.

The bottom line is that you can’t fight data and in this case, it is convincing.  We are in the era of chronic lifestyle related disease and the biggest piece of lifestyle appears to be diet.

Thursday, November 16, 2017

Chronic Inflammation as a Risk Factor for Alzheimer’s Disease

Acute or short-term inflammation is a protective response that occurs in injury or infection to help the body defend itself and begin repair.  It is one of the tools the immune system uses to attack whatever is injuring us.  It is, however, a nonselective response taking a toll on us as well. While this is OK when fighting a virus for a week, it causes important damage to the body if continued over very long periods of time.

Chronic inflammation is involved in virtually all chronic degenerative disease.  It has long been established as an important mechanism of degenerative brain disease, especially Alzheimer’s disease.  Over 5400 studies discussing both “Alzheimer’s” and “Inflammation” appear in a search of PubMed, the search engine of the National Library of Medicine.

While the data linking chronic inflammation to Alzheimer’s disease has been growing, one of the strongest links has recently been found.  The study examined the presence of midlife inflammatory markers and the presence of one of the important diagnostic indicators of Alzheimer’s disease, loss of volume or physical size in key brain areas involved in memory processing and storage.

The study population involved 1633 subjects with a mean age of 53 years. Two- thirds were women reflecting the female predominance seen in the disease. Five inflammatory markers were used to create an "inflammatory composite score". Volumetric MRI scans which accurately digitize the volume of each brain area were used to compare brain volume losses.

The images show the loss of volume in the key memory areas typical of Alzheimer’s disease.  The gray areas are areas of brain cells, while the black is cerebrospinal fluid that fills empty areas. The image on the left shows the loss of volume in the hippocampus (pink area in green circle) and temporal lobe (red circle), key areas in memory function.  It also shows increased volume of CSF fluid in the ventricles (black area in the white circle) which results from gray matter/brain cell loss.

Follow-up testing was done 24 years later. The results of the study were striking.  For every 1 standard deviation higher inflammatory composite score at midlife, there was a 110 mm3 loss in hippocampal volume, and 532 mm3 loss in the total region where Alzheimer’s affects the brain. There was also a 1788 mm3 increase in the ventricle volume representing cell loss at the center of the brain.

In addition to the brain volume changes correlating to level of midlife inflammation the researchers also correlated changes in episodic memory which is the memory of events including when, where, what and other details.  Episodic memory decline paralleled with brain volume loss connecting loss of memory function with brain volume loss driven by chronic inflammation.
There were also trends for the correlations being stronger in whites and in those of younger age at the beginning of the study.  The latter suggests that the longer inflammation has to work on the brain, the more damage it will do by the typical age of onset of Alzheimer’s disease.

A major emphasis of the Bredesen or ReCode Protocol for the treatment of Alzheimer’s is measuring inflammatory markers and using intense treatment efforts to reduce them.  Of course, the best time to address inflammation would be in prevention but as Dr. Bredesen has shown, it is an important piece of reversing early stages of the disease itself if coordinated with all other contributing disease mechanisms.

Walker et al.  Midlife systemic inflammatory markers are associated with late-life brain volume: The ARIC study.   Neurology, 2017 ePub

Thursday, October 26, 2017

New Research Findings on Alzheimer’s Disease

Omega-3 fatty acids

Neurons or brain cells contain high amounts of omega-3 fatty acids particularly DHA.  This fatty acid plays several important roles in brain health including controlling inflammation (a known driver of neurodegeneration), influencing brain blood flow, helping lower brain deposition of the toxic protein β-amyloid and maintaining brain volume.

How Much Omega-3 FAs are Enough?

There is broad agreement that the omega-3 FAs in our diet have declined progressively.  Our ancient hunter/gather ancestors were estimated to consume 12-15 grams each day, while the current intake is 0.5-1.0 grams.  As the importance of these FAs to brain health are appreciated, a question becomes how much is adequate supplementation to restore brain health?  Two studies have addressed this question recently.

While it would be ideal to measure these FAs in brain cells directly, this is not possible.  Typically, the levels in red blood cells are measured and thought to closely reflect brain cell levels.  The first study compared SPECT scans which show brain perfusion or blood delivery to different brain areas compared to the red blood cell levels of omega-3 FAs.(1)  Higher red blood cell omega-3 levels correlated with higher profusion of several brain areas involved in cognitive processing. 

The study went a step further also correlating the omega-3 levels in red blood cells to neuropsychological testing.  Higher red blood cell levels of omega-3 FAs correlated with better scores on measures of depressive tendencies.  This is important as depressive tendencies both are a risk factors for Alzheimer’s, and they are also caused by the disease itself.

Another recent study also compared red blood cell omega-3 FA content in subjects with minor cognitive impairment (MCI) or Pre-Alzheimer’s disease to similar aged cognitively normal individuals.(3)  The MCI group had lower levels of total omega-3 FAS and particularly of DHA.  The researchers concluded that the lower omega-3 FA levels might be predictive of the development of MCI or Pre-Alzheimer’s given this relationship.

While multiple studies have found that higher levels of omega-3 FAs correlate with improved brain function and cognition, perhaps the most striking finding has been that omega-3 FA levels directly correlate with the loss of brain volume associated with Alzheimer’s disease.  Many of the pathological changes in the brain that are associated with Alzheimer’s disease such as the build-up of the toxic protein β-amyloid show up many years before cognitive function declines resulting in the symptoms such as memory loss.  The one finding that is the exception to this is brain volume.  Symptoms typically correlate with the loss of brain volume as seen on MRI examination.

Two studies have looked at omega-3 FA levels in older adults compared to brain volume loss.(2, 4)  In a study of 1100 postmenopausal women it was found that for each 1 standard deviation higher of red blood cell omega-3 FA levels, the key brain memory area called the hippocampus was 50 mm3 greater. Women in the lowest 20% of omega-3 levels had hippocampal volumes 159 mmsmaller than those in the highest 20% of the group.

So, how much omega-3 FA intake is enough?  This is best determined by a simple test measuring red blood cell levels.   The data indicates that the omega-3 FAs should account for >10% of the total red blood cell fatty acid levels.  Because of variations of absorption of fatty acids in the digestive tract and transport into cell membranes, different persons will require different supplemental amounts.

The process should begin with a red blood cell omega-3 test.  A targeted level of supplementation is started, and the test is redone in about 4 months.  Supplementation levels are then adjusted from there to obtain and maintain the >10% level.

An important fact not to get lost here is that the best time to give attention to omega-3 FA levels is prior to the development of the disease as it appears to be preventative.  However, even when symptoms have developed optimizing levels of these important fatty acids is an essential part of treatment.