Rating The Months Research - The thesis of this newsletter is that the most important studies deal with the pathophysiology of CFS. Each month is graded according to the following criteria;

B – a difference making paper on CFS pathophysiology plus several important ones

C - several important papers on CFS pathophysiology

This was a big month in CFS research. In one swoop CDC sponsored researchers 14 papers that incorporated the gene expression, laboratory and clinical data gathered from a 2-day study done in Wichita, Kansas were published in the Pharmacogenomics Journal. The CDC believes this effort is a start of a new era in CFS research; one that employs community sampling and that focuses of various stress response systems in the body. This newsletter begins a four part exploration into these studies. The first focuses on the allostatic load studies; the next on the search for subsets in CFS, then comes the gene polymorphism studies, and finally gene expression papers. 

The ‘Natelson Group’ strikes again. Dr. Natelson has been exploring brain functioning in CFS patients for over 10 years now and he is convinced that at least a portion of CFS patients suffer from an encephalopathy – a brain disease. Now he has trained his sights on a timely subject – blood flows in the brains of CFS patients. Dr. Baraniuk’s recent proteome study suggested a condition sometimes associated with low blood flows called amyloidosis (protein aggregation) condition may be occurring in CFS patients brains and several studies have suggested either low blood volume or microcirculatory problems occur in CFS.

Brain blood flow studies in CFS have, however, had mixed results. While some studies have found evidence of hypoperfusion (low blood flow) others have not. These studies employed a technique that measures blood flows across the brain relative to one region of the brain. This works fine if one region has reduced blood flows but it will not work if blood flows across the entire brain are reduced.

Dr. Natelson bypassed this problem by using a technique that measures absolute brain blood flows. As usual he divided his study group up in CFS patients with and without mood disorders and healthy controls. CFS patients without mood disorders have displayed more brain abnormalities in past studies.

Findings – This study found significant reduced blood flows in both the left and right middle cerebral arteries in CFS patients compared to controls (p<.019). Contrary to expectations, while the CFS patients without mood disorders had greater reductions in brain blood flows, both CFS groups had reduced brain blood flows relative to controls. The data was quite striking. The rates of blood flow in the CFS patients were about 25-30 lower than those of the controls (!) (CFS – 45-60 p/m, controls – 65-85 p/m).

Unfortunately there was no speculation as to the cause or the effects of these reduced blood flows but they do fit in with mounting evidence of both vascular and brain problems in CFS. Last year, Dr. Lange found that CFS patients had a brain wide reduction in gray matter volume. The recent Lloyd study that followed infectious mononucleosis patients concluded that central nervous system damage was implicated in the progress of mononucleosis to CFS in some patients. Several studies suggest CFS patients have low blood volume and the researchers at MERGE have found evidence of microcirculatory problems in CFS. Peckerman found evidence of impaired cardiac activity in CFS.

Dr. Natelson suffered through several years underwhelming findings on CFS but seems to have found his footing with this brain research. Hopefully results such as these will lead the NIH to finally fund the cerebrospinal proteome study he’s been trying to get going for several years.

A recent finding that CFS patients displayed increased levels of two substances released during platelet activation and/or coagulation (TGF-b, annexin) prompted these researchers from MERGE to assess the state of blood coagulation in CFS.

Findings – No evidence of hypercoagulation was found in CFS. Neither thrombin, pro-thrombin time, platelet volume nor measures of platelet aggregation were increased in CFS patients relative to controls.

The authors offered several reasons that might explain the disparity between their results and Dr. Berg’s. Uppermost was the possibility that the heterogeneous nature of the disease could have resulted in increased numbers of hypercoagulable patients in Dr. Berg’s sample. Several methodological concerns may also have lead to skewed results in Dr. Berg’s work as well. One study collapsed FMS and CFS patients into one category – a questionable practice given the sometimes different laboratory findings in the two groups. Another study, which Kennedy et. al. believed did not provide sufficient quantitative data, focused on a subset of CFS patients (HHV-6 positive), that may not reflect CFS patients as a whole. This study did not provide a control group or characterize several factors that can affect hypercoagulation including gender, age, cigarette smoker, etc. that could also have affected the findings.

In an end note the authors indicate that the sedentary life most CFS patients will lead tend to reduced levels of platelet activation. This suggests, I believe, that CFS patients should have lower than normal levels of hypercoagulation. Could this mean that even normal levels of hypercoagulation could be considered high??

Allostatic Research: a short history - The theory of allostatic stress is relatively new but studies of the effects of allostatic load (AL) are becoming common; twenty-nine papers were published on AL in 2003, 19 of them studies. Most efforts have attempted to characterize the contributions aging and social/psychological stress play in increasing allostatic loads. Increased levels of psychological stress have been shown to increase allostatic load, but social stress studies have had mixed results. Aging has been shown to be associated with increased allostatic load. This appears to be one of the first studies to characterize levels of allostatic stress in a specific disease.

Increased levels of allostatic load have been associated with increased risk of death, heart disease, cognitive problems and worsened physical functioning in prospective studies. AL was predictive of both physical and cognitive decline in one study.

Altering the Allostatic Stress Response - McEwen cites four ways the stress response can be deregulated (McEwen 2000).

• repeated exposures to stressors (infection, low blood volume, low blood glucose levels, psychological stress, etc) can result in the stress response system being chronically turned on.
• The inability of the body to metabolize or clear stress agents such as hormones or neurotransmitters from its system can lead to the stress response being chronically turned on.
• A overly sensitive stress response system that on a hair trigger can be chronically turned on.
• A stress response that is under-responsive will leave the body vulnerable to the effects of stressors.

Methods - The authors of this report wanted to know if a) CFS patients demonstrated indications of increased allostatic load and b) if it was present which systems it was present in.

Findings - This study found that CFS patients expressed a trend towards having higher levels of allostatic load than the controls (P<.06).  Statistically speaking this number is not particularly strong; the lowest level of probability deemed ‘significant’ is p<.05. It indicates there is a 6% chance that CFS patients do not have increased allostatic load relative to the controls. What researchers really like to see is a level of probability that is a magnitude or more greater (i.e. p<.005).

This study found that three components of allostatic load, waist/hip ratio, aldosterone and urinary cortisol best differentiated CFS patients from the controls. The increased waist/hip ratio suggested impaired metabolic functioning. The altered aldosterone/cortisol levels suggested problems with the energy ‘set point’ of the body.

This theory, which is quite complicated, posits that a disrupted stress response can cause the brain to either pull too much or too little energy (glucose) from the body. In the case of CFS, these researchers believe the lowered cortisol levels caused by chronic stress due to infection, psychological stress, etc. may have caused the brain to under-respond to its own energy deficiencies. This low energy ‘set point’ would cause decreased glucose metabolism in the brain, disrupted signaling of the main neurotransmitter in the brain, glutamate, and increased body mass due to increased glucose allocation and appetite. One way the brain tries to get more glucose is to activate the feeding centers of the brain.

The Future - Despite its relatively poor performance statistically the CDC was impressed enough with the results that a larger study with more extensive cardiovascular measures is planned.

We will apparently know sooner rather than latter whether our brains are selfish or not. The authors end up the article by stating that ‘in the near future we will determine the usefulness of this model in determining the pathophysiology of CFS’ and suggest their results could lead to a biomarker for CFS.

If a biomarker is found it will likely be a simple and relatively cheap one to determine as it appears it will consist of a formula that describes levels of commonly measured substances such as cortisol, aldosterone, etc.

The Maloney paper found that CFS patients demonstrated a higher allostatic load than did healthy age, sex, race and body mass index controls. Often the next step with a finding like this is to see if it is correlated with debility. If allostatic load is a real factor in CFS then patients with more severe CFS should have higher allostatic loads and those who are healthier should have lower allostatic loads.

This study used statistical tests to determine if indices of debility in three areas (fatigue, pain, general symptom intensity/frequency using three self-scored tests (SF-36, MFI, SI)) were correlated with measures of allostatic load (waist/hip ratio, aldosterone, blood pressure, cortisol, etc.). They did this by comparing the scores of CFS patients with high levels of fatigue with low levels of fatigue, etc.

This study found allostatic load did not correlate, interestingly enough, with fatigue but was very significantly correlated with body pain (p<.009), and moderately correlated with physical functioning (activity levels) (p<.02) and symptom severity (p<.05). This suggested that allostatic load does contribute to these symptoms but not to fatigue.

The researchers then used a different statistical technique to determine which measures of allostatic load contributed most to each kind of debility. They found that high levels of c-reactive protein, a marker of inflammation, were the best predictors of body pain; that increased levels of two sympathetic nervous system catecholamines, norepinephrine and epinephrine and diastolic blood pressure best predicted impaired physical functioning. All three of these are involved in maintaining blood flows to the tissues during exercise.

Two markers of cardiovascular functioning, systolic blood pressure and aldosterone, best predicted high symptom severity. The authors noted that (way back in 1993) one study found evidence of increased levels of angiotensin converting enzyme (ACE) activity were found in CFS patients. Like so many other promising studies no followup studies were ever done. They cite another paper in this volume that found altered R-R intervals. For some reason they do not cite Naschitz’s similar findings or Peckerman’s papers on cardiovascular functioning.

One of the key vasoconstricters in the body, norepinephrine (NE), helps determines the amount of blood flow to the tissues. Intriguingly given its possible role in impairing physical functioning in CFS patients it is secreted in response to physical stress and low blood pressure. Epinephrine (E), on the other hand, regulates heart rate and the force of the hearts contraction, the relaxation of bronchial and intestinal tissues and various metabolic activities. Increased SNS activity, not surprisingly, plays a major role in heart disease. Neither NE nor E have been well studied in CFS. Aldosterone effects blood volume and is implicated in hypertension and heart disease. That both systolic and diastolic blood pressure showed up in this analysis further suggests a cardiovascular component to CFS. Raised c-reactive protein levels are commonly found in inflammatory diseases and are considered a risk factor for heart disease.

Not surprisingly, given the target placed on cardiovascular functioning in CFS by these findings, the authors state they will look more closely at the cardiovascular system in future studies.

Significant or Not? – It is unclear how significant these findings are. Yes, there are indications of increased allostatic load in CFS. Yes, they occur in two systems of interest in CFS, the cardiovascular and metabolic systems. The question is how much of the debility found in CFS they can account for. While CFS patients do exhibit several characteristics one would expect to show up in a disease characterized by a disturbed stress response, namely low cortisol levels and signs of immune activation, the cortisol levels in CFS are only ‘mildly’ low (and not infrequently normal), and the results of cytokine studies have been inconsistent as well. We haven’t seen thus far a level of aberration that can in any way account for the debility seen in CFS. Of course these allostatic load studies are preliminary; they focused on broad measures of allostatic load spread across several systems. The next studies that focus more on specific systems should be the really important ones; they should begin to tell us whether these studies will be the beginnings of something really significant for CFS or whether they are merely the signs of a disease that is stressful in so many ways.