Buzz – October: Each month we scour the Internet to bring you a summary of news articles, blogs and research publications we think you’ll find interesting for our What’s the Buzz post.
This month, Suzanne D. Vernon, PhD, BHC Research Liaison, highlights and summarize two recent research publications for you:
The Importance of Measuring Symptoms
ME/CFS is characterized by 6 months or more of profound fatigue debilitating enough to make even the simplest daily tasks monumental feats. Other symptoms including unrefreshing sleep, orthostatic intolerance, pain, and cognitive impairment accompany the extreme fatigue. The hallmark symptom of ME/CFS is post-exertional malaise where following physical or mental exertion all symptoms are exacerbated causing the individual to “crash” as if all the body’s energy is completely sucked dry.
Knowing what the specific symptoms are and being able to measure them are important outcome measures. Clinical trials test a treatment by measuring the effect of a drug or intervention on improving a disease symptom or biomarker. This outcome measure is specific for the disease or optimized for the disease if the symptom or biomarker is not specific. This helps avoid measurement challenges like the ceiling effect wherein a drug or intervention has some benefit (moves the needle just a bit towards improving a symptom) yet may not be detected because of the ceiling effect. For example, in treatment of pain relief some kinds of analgesic drugs have no further effect on pain above a particular dosage level.
Dr. Xin Shelley Wang at Department of Symptom Research, The University of Texas, MD Anderson Cancer Center and her team published a paper titled, “The utility of patient-reported outcome measures among patients with myalgic encephalomyelitis chronic fatigue syndrome”. They analyzed the responses of 240 ME/CFS patients and controls to three self-report symptom questionnaires commonly used in ME/CFS research, 1) the Multidimensional Fatigue Inventory (MFI), 2) the RAND SF-36 and 3) the DePaul Symptom Questionnaire (DSQ). Only the DSQ was developed specifically for ME/CFS. There were significant ceiling effects in both the MFI and RAND SF-36 for measuring fatigue and physical health. (Reminder – because of this ceiling effect a beneficial response to treatment targeting the fatigue may not be detected!). The measures of autonomic/neuroendocrine/immune, cognitive, post-exertional malaise, and sleep of the DePaul Symptom Questionnaire all showed excellent reliability and no ceiling effect. Importantly, the post-exertional malaise subscale has excellent sensitivity and specificity indicating that it can differentiate ME/CFS from people in the general population and could be a useful outcome measure for ME/CFS clinical trials.
This paper represents exactly what the FDA asked the research community to do: identify outcome measures that can be used in clinical trials. The Bateman Horne Center Research Ready Army has completed the DSQ and will continue collaborating with Dr. Xin Shelley Wang to develop an ME/CFS specific outcome measure of fatigue, fatigability, and post-exertional malaise among ME/CFS patients.
More Evidence for Altered Metabolism in ME/CFS
Metabolism is the process of converting food and drink into energy to keep our body’s cells alive. Disturbances in metabolism results in too much or not enough of the substances needed for these vital chemical reactions. This can affect the function of organs- including the brain – and even the ability of the mitochondria to produce energy. Mass spectrometry is a sensitive technique used to analyze the metabolites and chemicals in a sample.
In a paper published this month in Scientific Reports, the research team led by Professors Kataoka and Watanabe at RIKEN Center for Life Science Technologies in Kobe Japan provides strong evidence for altered metabolism in ME/CFS. The title is “Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles”. The study included Japanese adults ages 20-60 years including 67 ME/CFS patients and 66 healthy controls. A total of 47 ME/CFS patients and 46 healthy controls were assigned to the training set, while 20 CFS patients and 20 healthy controls were used in the validation set. A fasting blood sample was collected from these individuals and the plasma analyzed by capillary electrophoresis time-of-flight mass spectroscopy (CE-TOFMS).
The chemicals of glycolysis, the TCA cycle, the urea cycle and glutamine metabolism were analyzed. The TCA cycle and the urea cycle were abnormal in ME/CFS.
- In the TCA cycle the amount of citrate, isocitrate and malate were significantly lower in ME/CFS patients.
- In the urea cycle citrulline was (highly) significantly lower in ME/CFS while ornithine was significantly higher in ME/CFS patients.
- There were no differences in glycolysis and glutamine metabolism between healthy and ME/CFS.
In analyzing the differences, the researchers were able to distinguish between ME/CFS and healthy controls.
The TCA cycle (also known as the Krebs cycle) occurs in the mitochondria where through a series of chemical reactions energy is produced in the form of ATP. The results from this study indicate that ME/CFS patients have a deficiency in ATP production. The urea cycle produces urea – which is excreted – from ammonia (NH3) which is toxic if not metabolized by the body. The urea cycle is an essential detoxification projects that takes place predominately in the liver. Problems in the urea cycle result in the build up of toxic chemicals that can affect the function of the liver as well as other cells and organs.
The Bateman Horne Center of Excellence is working with the team at RIKEN to confirm these results. We sent several hundred samples to Japan last month and testing is currently underway. Should these results be confirmed, these metabolite markers could be developed into a clinical diagnostic tool as well as guide potential therapeutic interventions.
You can read the full text of this important research here: https://www.ncbi.nlm.nih.gov/pubmed/27725700