The patented WINDOW INTO THE BRAIN™ test panel offers a real-time view of pathological processes and disease activity in the brain. Often referred to as a “non-invasive brain biopsy,” it includes leukocyte transmigration, neurodegenerative, and demyelination biomarkers. MSDx’s assays can be tested individually or as a panel. Cost effective, reliable, blood-based biomarkers can aid in disease detection and monitoring providing critical data for assessing a patient’s condition throughout his or her lifetime
MSDx’s first patent was issued for its WINDOW INTO THE BRAIN™ technology, describing methods of detecting a neurological condition via analysis of circulating phagocytes. The WINDOW INTO THE BRAIN™ test panel offers a real-time view of pathological processes and disease activity in the brain. Often referred to as a “non-invasive brain biopsy,” it includes demyelination, neurodegenerative, and leukocyte transmigration biomarkers. MSDx’s second patent was issued for a method of detection of a high molecular weight protein complex referred to as MSDx Complex-1. This biomarker is thought to be generated by the process by which leukocytes cross the blood-brain barrier. Monitoring breakdown products of the process of leukocyte trafficking is an innovative strategy for monitoring disease activity in neuroinflammatory diseases.
MSDx’s assays can be tested individually or as a panel. Though initially focused on Multiple Sclerosis (MS), this technology may be applied to other neurological disorders such as Parkinson’s disease (PD) and Traumatic Brain Injury (TBI).
Blood Based Biochemical Monitoring of Major Diseases of the CNS
In the vast majority of diseases of the CNS there are no blood tests to aid in the diagnosis and long-term management of patients. Consequently, there is a pressing clinical need for inexpensive blood tests that allow the physician to closely monitor the physiological status of patients with CNS disease/injury and their response to disease-modifying therapies. To produce tests that provide critical and timely information requires biomarkers that are involved in the disease mechanism. That requires an understanding of how the disease process evolves over time so that key processes can be monitored. Diseases such as Alzheimer’s disease, Parkinson’s disease Multiple Sclerosis and the sequelae of mild (closed cranium) Traumatic Brain Injury (Sports concussion, military overpressure injury (bomb blast)) are the principle areas of need!
Exploiting Immunophysiology to retrieve information
When an organ or tissue is injured an inflammatory response is initiated to begin wound healing regardless of the cause of the injury. White blood cells are recruited to the site of injury to aid in repair and in the case of infection to kill and remove infectious agents, in cancer to kill and remove cancerous cells. In chronic diseases such as autoimmune diseases the initiating insult may have been eradicated but for reasons that are still not known the inflammatory response is not turned off and even escalates. In other chronic diseases such as atherosclerosis the insult is persistent over time (ie persistently elevated blood lipids). A common feature of inflammation in all of these scenarios is that phagocytic cells (monocytes/macrophages) are recruited to the site of damage and they engulf and clear the debris of damaged and dead cells. We discovered that some of these debris laden phagocytes re-enter the blood circulation. Consequently, they can be removed by a simple blood draw and be examined for the type of debris present in the phagocytes.
The process by which white blood cells are recruited into an area of damage is complex. The following description is a simplification that allows an understanding of how the biomarkers we measure are generated and their relevance to monitoring disease activity. Molecular signals (eg chemokines) generated at the site of injury attract white blood cells to the site of injury. To get to the site of injury, white blood cells travel in the blood and travel towards these signals (illustration 1). To get to the site of injury the white blood cells must cross the blood vessel wall. First they must pass through or between the endothelial cells of the blood vessel wall (diapedesis).
Once through the endothelium, they encounter the endothelial basement membrane. This may be considered to be like a chain link fence. It is a physical barrier that must be breached. The endothelial basement membrane is made of several proteins and is breached by the white blood cells by secretion of enzymes that cut these proteins (illustration 2).
In breaching the basement membrane these proteins (fibronectin) are released and enter the blood circulation. Now the white blood cell has to move through the protein matrix that supports the cells of the brain, the extracellular matrix (ECM). Similarly, to move through the ECM enzymes that cut proteins are employed which release Fibulin-1from the matrix surrounding the nerves. Some Fibulin-1 is also released into the blood supply. We discovered that fibronectin and fibulin-1 bind to each other and to fibrinogen B in the blood-forming extremely large protein complexes that we can measure. We call this complex MSDx complex-1 and have found that it is elevated in multiple sclerosis and Parkinson’s disease and other neuroinflammatory conditions.
Having penetrated the ECM and reached the dead and dying nerves, the phagocytes proceed to engulf the debris and clear the site for repair (illustration 3). These debris laden cells may stay in the brain or exit into the lymphatic system or the blood supply (illustration 4). Because the job of the phagocytes is to degrade and recycle the debris, it quickly disappears. Also, phagocytes in the blood are short lived. Consequently, detection of brain-specific debris in circulating phagocytes is an indicator of recent damage and may be usable as a marker of active neurodegeneration. It can be viewed as a kind of brain biopsy as we get information about what is happening in the brain. We call this approach Window into the BrainTM.
By doing a normal blood draw we can obtain both the white blood cells and the liquid part of the blood (plasma). The plasma contains MSDx complex-1 and the white blood cells contain the debris laden phagocytes. These can be measured in a lab. Measuring substances that would normally only be found in nerve cells or myelin cells in these blood phagocytes is a novel strategy for monitoring disease. The results may be useful for neurologists as an aid to monitor patients.
MSDx’s panel of biomarkers to measure disease processes.