By Benjamin H. Natelson, MD
Director, Pain & Fatigue Study Center, Beth Israel Medical Center
Professor of Neurology, Albert Einstein College of Medicine
An exciting study published in February (2011) in the journal PLoS One by Schutzer et al revealed that a group of CFS patients had more than 700 unique proteins in their spinal fluid as compared to patients with Lyme disease and normal controls. Long-time CFS clinician and researcher Dr. Benjamin Natelson was a member of that research team, and Research1st asked him to comment on the study’s next steps.
All of the work in my group is based on the understanding that any clinical syndrome is comprised of subgroups of patients – each with its own pathophysiological cause for the same syndromic presentation. Because of the lack of a commonly acknowledged biomarker, we have used clinical differences among patients with chronic fatigue syndrome (CFS) to establish subgroups to test this basic assumption.
The method of splitting patients into subgroups that has produced the most promising results to date uses the presence or absence of co-morbid psychiatric diagnosis, usually major depressive disorder, as its basis. Over the course of the last 15 years, my colleagues and I have found that the “no-psych” group had more problems with neuropsychological testing, more abnormalities on brain magnetic resonance imaging, more abnormalities in spinal fluid and higher levels of cerebroventricular lactate than patients who had psychiatric comorbidity.
These results lead us to hypothesize the existence of a “neurological” group, that is, a group of patients with brain pathology as the cause of their illness. While this hypothesis was strengthened by our repeatedly finding more neurological abnormalities in the no-psych group compared to the psych group, a problem existed – namely that each was done independently of the other, with different groups of patients participating in the different studies. We thought that an important next step would be to do all these studies on the same patient volunteer.
That idea has been supported by our successful application for an NIH grant to do precisely this. Thus, we will use a structured clinical diagnostic interview for psychiatric illness to determine if a patient falls into the psych or no-psych groups. Then we will assess neuropsychological function using tests of executive motor capacity such as complex reaction time performance and ability to repeat numbers forwards and backwards. We will also do brain imaging, in which we will quantify cerebroventricular lactate and determine if the scan is normal or shows an anatomic abnormality. Finally, we will perform lumbar puncture on our patients to determine if the no-psych group continues to show taps with higher white cell counts or higher protein concentration than patients in the psych group.
We expect to find higher rates of abnormalities in the CFS-no psych group than in the CFS-psych group. That finding would strongly support brain dysfunction as the cause of fatigue in this patient subgroup and will lead to new studies to explore the pathophysiology underlying these findings.
The one requisite for patients volunteering for this study is that they be off any (central nervous system) CNS-active medication for at least 10 days. Thus, to complete this study, we will need the cooperation of physicians in the New York-New Jersey area to consider referring patients to us for study.
While we feel this approach, based on clinical differences between patients, will be helpful in moving our knowledge ahead, we are very excited by the outcome of our collaborative work on the spinal fluid proteome. The method uses high through-put mass spectroscopy to identify all the proteins in one sample. In the one study done to date, we pooled spinal fluid from CFS patients and compared its protein constitution, that is, its proteome, to that of patients with similar symptoms but a known cause – Lyme infection.
Importantly, we found a large number of proteins discrete to each of the fatiguing illnesses. Finding these proteins suggest they may be useful as biomarkers of each illness.
However, there are important next steps waiting to be done. First, using samples of spinal fluid from patients not previously studied, we have to determine if we can replicate finding a set of unique proteins that would allow the identification of CFS patients relative to healthy controls. Because of improvements in technique, we will be able to do this on an individual patient basis rather than having to pool samples in order to get the volume needed for assay. Moving from pooled to individual samples will certainly allow us to determine which patients are positive for a diagnostic marker comprised of several uniquely occurring spinal fluid proteins.
And of equal importance, we hope to do additional spectroscopic studies to determine if and how the proteome of the CFS no-psych patient differs from that of the CFS psych patient. If, as we expect, proteomic differences exist between these two subgroups of CFS, we will be well on our way to hewing out a group of patients – those with apparent brain dysfunction – for specific therapeutic trials based on information provided in their proteome as to the possible metabolic pathways affected.
Benjamin H. Natelson received his bachelor’s and medical degrees at the University of Pennsylvania in Philadelphia and then did his neurology residency at the Albert Einstein College of Medicine in New York City. Following that, he did two postdoctoral fellowships, one in behavioral neurosciences at the Cornell University Medical Center in White Plains, N.Y.; and the other in physiological psychology at the Walter Reed Army Institute of Research in Washington, D.C. Dr. Natelson moved to the New Jersey Medical School in Newark and the Veterans Administration Medical Center in East Orange. He rose through the ranks, becoming professor of neurosciences in 1981 and leaving in 2008 as an emeritus professor. He had continual funding from the VA through 1999 for his experimental work on stress and chronobiology. With the award of a federally funded research center to explore the causes of CFS in 1991, Dr. Natelson shifted his research to studies of humans with CFS, and more recently has extended those studies to include those with fibromyalgia. He has served as president of the Pavlovian Society and of the Academy of Behavioral Medicine Research. He has over 230 papers published in peer-reviewed journals and has authored three books. In 2008, Dr. Natelson has moved his activities to the department of pain and palliative care at the Beth Israel Medical Center in Manhattan, where he directs the Pain & Fatigue Study Center. In that capacity, he also serves as a professor of neurology at the Albert Einstein College of Medicine.