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

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