HMRI Researcher Lights a Path to Understanding Brain Diseases

Neurologist Mike Harrington of Pasadena, California’s Huntington Medical Research Institutes argues that soon we may be able to detect brain disease before symptoms even begin. The secret is in the cerebrospinal fluid, the clear liquid that cushions our brain and spinal cord.

As guest editor for the January 2006 issue of the respected medical journal Disease Markers (Volume 22, Issues 1-2), published by IOS Press, which was themed to the study of neural markers, Harrington edited the issue and co-authored three of the articles himself. He worked with HMRI biochemist Alfred Fonteh and several other scientists.

“Changes in lipids (e.g. cholesterol) and proteins in our cerebrospinal fluid may be linked to various brain conditions,” Harrington says. “Conditions could include any change in normal brain, such as in development, or in diseases such as migraine, Parkinson’s Disease, schizophrenia, Alzheimer’s Disease, depression, multiple sclerosis and some forms of stroke.

A marker is a molecule in the body that’s involved in a disease, for example in the metabolism of a cancer cell. The marker points to a disease like a glove dropped by a cat burglar.

“We suspect that a problem in processing cholesterol in the brain may be at the root of Alzheimer’s disease,” Harrington adds. (A surprise to most people, the brain contains 25 percent of the body’s cholesterol.) Studying the cholesterol in the brain may help provide an earlier diagnosis.

Harrington is known for his discovery of a marker for mad cow disease which advanced the worldwide study of the brain-wasting condition. His current research into migraine markers at HMRI is entering its fourth year of funding from the National Institutes of Health in Washington.

Harrington’s first article in the journal was a review of 131 articles written by scientists who have studied disease markers in spinal fluid. In the past 27 years, there’s been a 50-fold increase in the number of proteins identified in the cerebrospinal fluid – now a total of about 700. However, Harrington says, “The task ahead is enormous. There may be hundreds of thousands of molecules or their fragments that could serve as disease markers if we knew what they were and what they do in the spinal fluid.”

To get where they need to be in their knowledge of proteins, Harrington calls on clinicians who see patients and researchers who mostly study animals to share their knowledge.

“Currently there’s a disagreement between the two groups over what constitutes a breach of the blood-brain barrier,” Harrington says. “Clinicians believe that the barrier is compromised when a few stray molecules are present. Research physiologists have shown for 15 years that’s incorrect.”

“We see a mismatch between the two disciplines,” Harrington says. “Their separate stores of data, if combined, could provide significant insights into a variety of brain disorders.”

Harrington’s second journal article discussed myriad ways to identify molecules in the cerebrospinal fluid (CSF). Lipidomics is the study of interacting groups of lipids or greasy molecules that comprise cell walls and brain structure. Proteomics studies groups of proteins. According to Harrington, “Both will enhance existing knowledge of brain disease.”

The third article edited by Harrington discussed just one of the 700 known protein molecules, known as PGDS (prostaglandin D synthase). PGDS can adopt many forms and even break into pieces, any one of which could become a disease marker. In one study of 98 people with brain disorders, PGDS molecules showed wide variations in their shape and concentrations. Exactly why the changes occurred is not yet known.

Harrington stresses that study of disease markers requires not just powerful tools to detect the protein molecules in the CSF fluid. “It’s also important to understand the way the CSF works,” he noted.

“The CSF is essentially a circulation system that, among several functions, helps take waste matter away from the brain,” Harrington says. “It is refreshed up to five times a day, changing constantly. If cancer cells are growing in the brain, or other bad things are going on with the cell components, these could be markers that would be present in the CSF. Their position, even the time of day they are collected, could vary their meaning.”

“There’s a lot to be learned correlating brain disease with molecular changes in CSF. These journal articles are about the state of the art in the search for disease markers.”

“It should not be beyond our ability to recognize pre-symptom Alzheimer’s disease,” Harrington says. “You’re losing brain tissue. We should be able to see this.”