Researchers are making headway toward finding evidence of chronic fatigue syndrome and how it may change the brain.
Ronald W. Davis, a Stanford University genetics researcher who was instrumental in the Human Genome Project, is heading up a new research center at Stanford University, which is rapidly becoming a nexus for chronic fatigue research.
Davis -- whose son, Whitney Dafoe, has severe chronic fatigue syndrome -- believes the answers lie in finding molecular biomarkers, which are characteristics or substances that indicate the person has a particular biological condition or disease. A specific marker might lead to a blood test that can definitively diagnose and potentially treat chronic fatigue, Davis said. So far, chronic fatigue has not shown its face through conventional blood markers that indicate inflammation in the body or that show the presence of a specific infection.
Davis and his team plan to use technologies developed for the Human Genome Project to sequence the entire genome of chronic fatigue patients, including 1,600 mitochondrial genes, more than 20,000 other genes and control regions that regulate genes. They hope to identify proteins that are found in immune cells, blood and spinal fluid; search for infectious agents in blood, bone marrow, spinal fluid and saliva and changes to gastrointestinal tract flora; and find evidence of autoimmune responses. The research could reveal DNA sequences that are altered in chronic fatigue patients.
The detailed approach is more comprehensive than that of other research, which has only looked at a fraction of the genes, according to the center's website.
The center's research will also focus on a large number of the most severely ill patients, who often have disruptions to multiple body systems where a pathogen or genetic alteration may be lurking, Davis said. The research will look at patients who have responded positively to drug treatments and those who have failed to respond, he said.
Researchers have known for many years that the onset of chronic fatigue is often preceded by a viral or infection-like illness, according to the Stanford University School of Medicine's Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Initiative, another university research arm.
The disease may have multiple causes. Two main theories are that the disease is caused by a pathogen or by an immune-system reaction to a pathogen, according to a Stanford research team led by Dr. Jose G. Montoya, professor of medicine in the Division of Infectious Diseases. Montoya has studied chronic fatigue patients for seven years through the ME/CFS Initiative.
Focusing on organs and body systems most likely to be involved in the disease, Montoya and his team work with researchers and physicians in departments such as immunology, brain research, cardiology, genetics and pathogen discovery to pursue clues, he said.
In one study, Montoya and lead researcher Mady Hornig of Columbia University looked at 298 chronic fatigue patients and 348 people without the disease, and what they found was surprising: inflammation
Patients in the early stages of chronic fatigue had elevated levels of certain cytokines -- chemical messengers that regulate inflammation. The most prevalent cytokine was interferon gamma, which has been associated with fatigue from viral infections, including mononucleosis.
Patients who had the disease for three years or less had the elevated immune molecules, but persons with the disease for more than three years showed low levels of the cytokines, which could be evidence that the immune system is exhausted, according to the research.
Finding the cytokines provided proof that chronic fatigue is biological and not merely psychological, and it offers hope that early treatment might affect the outcome of the disease.
In a separate study, Montoya and Michael Zeineh, Stanford associate professor of radiology, found significant differences between the brains of chronic fatigue patients and persons without the disease. Brain-imaging studies showed that overall "white matter" -- long nerves that carry signals to the "gray matter" parts of the brain, which process information -- were abnormal. Chronic fatigue syndrome appeared to involve chronic inflammation, according to their research.
The abnormality was located in the right hemisphere of the brain, which connects to the frontal and temporal lobes. The amount of abnormality also correlated to the severity of the patient's condition, they said.
The gray matter in those areas of the brain was also thickened, according to their Oct. 29, 2014, study, which was published in the journal Radiology.
But Montoya said they do not know if the left side of the brain is also inflamed, and the right-side aberrations are thickened because of a compensatory reaction, he said.
There are also two schools of thought regarding whether chronic fatigue is caused by a single disease that causes multiple symptoms or if there are subsets of patients afflicted by are variety of agents, he said.
"With AIDS, there are different manifestations of the disease, but they are all caused by a single virus," he said by way of example.
Several infectious diseases have been associated with the onset of chronic fatigue in some patients, including Epstein-Barr virus (glandular fever), which is associated with mononucleosis, Coxiella burnett (Q fever), enteroviruses (which affect the gastrointestinal tract) and Herpesvirus 6. Montoya said he has had several patients whose chronic fatigue started with the H1N1 influenza.
"There's no question that different agents have been found," he said.
Montoya and Dr. Andreas Kogelnik of the Open Medicine Institute in Mountain View have also looked at the use of anti-viral medications in some chronic fatigue patients. Their 2012 study of 61 patients given the anti-viral drug valganciclovir found that 52 percent experienced at least a 30 percent improvement in physical or cognitive functioning. Among these, 59 percent had physical improvements and 81 percent improved cognitively.
Their 2013 double-blind study with valganciclovir against a placebo involved 30 chronic fatigue patients who had elevated antibodies against human herpesvirus 6 and Epstein-Barr, found that patients who received the drug had a greater improvement in mental fatigue, fatigue severity and cognitive function within the first three months. The benefits continued for the remaining nine months. The patients' white blood cells and other immune-system responses also improved, according to the study, which was published in the Journal of Medical Virology.
Davis is working with numerous collaborators across many fields, hoping the collaborative effort will attract the best minds in their fields.
"This is probably one of the last major diseases we know nothing about. This is your last chance to be a pioneer," he said.