Sick and tired of being sick and tired

Weill Cornell, Mount Sinai and Beth Israel researchers set sights on biomarkers for chronic fatigue syndrome

Amy Swinderman
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NEW YORK—Boosted by a $1.9-million grant from the U.S.National Institute of Mental Health, a multidisciplinary clinical researcheffort seeks to discover novel biomarkers in patients with chronic fatiguesyndrome (CFS), which would represent a major paradigm shift in the criteriaused to diagnose patients with what has been called a "medically mysterious"illness.
A four-year, innovative study to be conducted by WeillCornell Medical College, the Icahn School of Medicine at Mount Sinai and BethIsrael Medical Center aims to expand the scientific understanding of CFS andimprove diagnostics for the condition—which eventually may lead to theidentification of new and more effective treatment targets.
A complex, multisystem disorder, CFS is often misdiagnosed,misunderstood and mistreated. National health organizations have estimated morethan 1 million Americans and approximately a quarter of a million people in theUnited Kingdom have CFS.
Diagnosing CFS is as serious a problem as prevalence of thecondition. The "official," or most widely used, diagnostic criteria for CFScome from the 1994 research guidelines proposed by the International ChronicFatigue Syndrome Study Group, which was led by the Centers for Disease Controland Prevention (CDC). The CDC criteria specifies that the following basicconditions must be met: that the condition is of new or definite onset (has notbeen lifelong); is not the result of ongoing exertion; is not substantiallyalleviated by rest; and results in substantial reduction in previous levels ofoccupational, educational, social or personal activities.
Differentiation of CFS and neuropsychiatric illnesses, suchas major depressive disorder (MDD), can be daunting and is a continuingchallenge, notes Dr. Dikoma Shungu, a professor of physics in radiology andchief of the Laboratory for Advanced Magnetic Resonance Spectroscopy Researchat Weill Cornell Medical College—and a principal investigator of the study.
"Right now, a diagnosis of CFS is a diagnosis by exclusion,"Shungu says. "The million-dollar question is: how do you differ CFS from otherco-morbid diseases? For example, a lot of people with CFS show signs ofdepression, anxiety or pain. It's very difficult to define, and has verydifferent causes in different patients."
Because of these challenges, research funding for CFS hasbeen historically limited, Shungu notes.
"A lot of physicians don't believe that CFS is a distinctdisease from depression. If you don't believe that something is a real disease,people are reluctant to invest money in research," he says. "This large,generous NIH award will allow us to accelerate in-depth, novel clinicalresearch for CFS to make the significant strides we vitally need for researchdiscovery and clinical care."
The grant will be used to advance seven years of researchconducted by the partnering institutions. Using neuroimaging and a battery ofclinical tests, a pilot study suggested that the key culprit in CFS may beincreased and sustained oxidative stress. Levels of cortical glutathione(GSH)—the most abundant and one of the most important antioxidants in livingtissue—decreased by 36 percent in CFS patients. This novel cortical GSH deficitfinding was also correlated with those patients with increased levels of bloodmarkers of oxidative stress and symptoms of CFS. Study results also show CFSpatients have significantly elevated ventricular cerebrospinal fluid lactateand decreased regional cerebral blood flow.
However, because the researchers also found in their pilotstudy that the abnormalities identified in CFS patients were similar to theabnormalities witnessed in patients with MDD, the researchers hope to givevalidity to the oxidative stress hypothesis, but they must first distinguishbetween the two conditions.
"The reason these disorders probably overlap so much isbecause they have the same biological abnormalities," says Shungu. "What weneed to do is not treat MDD or CFS as distinct entities, but to find drugs fordifferent sub-groups of CFS and MDD, and focus on them."

Shungu clarifies that neither CFS nor MDD are distinct entities within their respective disease categories.

"That is, MDD is not one clean diseaseentity because it is highly heterogeneous; there is treatment-resistantdepression, atypical depression, depression with melancholic oranhedonic features. This heterogeneity needs to be considered, and we need to nottreat 'depression' as just one thing," he explains.

The same holds true for CFS, which is known to be highly heterogeneous, even in its mode of onset, he adds.

"CFS has rheumatologic, infectious or psychiatric features that need to besorted out in order to really begin to know what CFS is," Shungu says. "I suspect thatwe will find that CFS consists of different subtypes. It could then bethat each subtype of CFS may be diagnosed by specific biomarkers orrespond a specific treatment. The implication is not that MDD and CFSare not distinct medical entities. Our primary hypothesis, in fact, isthat they are distinct. However, to achieve a clearer distinction, which our research is designed to accomplish, will require that we look atsubtypes of both CFS and MDD to minimize their inherent heterogeneity,which might also minimize the overlap of their symptoms."
For this study, the researchers plan to enroll 40 patientswith CFS, 40 MDD patients and 20 healthy controls. Beth Israel will evaluateand enroll patients in the study. Mount Sinai will screen and characterize thepeople with depression, and all of the actual measurements will be done atWeill Cornell.
"We will do a spinal tap to look at abnormalities in thecerebral spinal fluid biochemically, rather than doing imaging," says Shungu. 
Ultimately, the discovery of specific biomarkers that candifferentiate CFS from similarly presenting psychiatric disorders will have aprofound impact for how the disorder is perceived, managed, diagnosed and forthe development of objective diagnostic tests, therapeutic targets and advancedscientific understanding of this debilitating illness, he says. Shungu addsthat the researchers may also apply some of what is learned for other relateddiseases like fibromyalgia, another chronic pain condition that is difficult todiagnose and treat.
"We must find objective biomarkers for these diseases. Whenyou have biomarkers, people don't argue," he concludes.
Other study investigators include Dr. Benjamin Natelson ofBeth Israel and Dr. Dan Iosifescu of Mount Sinai.

Amy Swinderman

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