How a Rapid Autopsy Program Is Fueling Research Progress in MS

When Cleveland Clinic’s Bruce Trapp, PhD, created one of the first rapid autopsy programs for multiple sclerosis (MS) back in 1994, he was pioneering a novel concept — to collect a pre-consenting patient’s body as soon as possible after death (ideally within a few hours) for advanced MRI studies followed by removal of the brain and spinal cord for pathological analysis. The aim was to study the effects of MS on the brain in a way that was impossible with animal models or available imaging modalities.

Now, more than two decades later, the program is the largest of its kind in the world, with over 160 specimens collected, and it’s been central to Cleveland Clinic’s mounting grant funding to advance understanding of how MS develops and progresses in the human brain. Three grants were awarded in 2015 and 2016:

• $6.97 million from the National Institute of Neurological Disorders and Stroke (NINDS) in support of efforts to use tissues from the rapid autopsy program to identify new therapeutic targets causing axonal and neuronal degeneration in MS. These studies are directed toward developing neuroprotective therapies to delay and possibly reverse permanent neurological disability.
• $1.7 million from the NINDS supporting work to further reveal factors influencing remyelination in MS. The aim is to identify potential regulators of myelin repair in human autopsy tissues and then try to replicate the findings in animal models, reversing the conventional order of biomedical research.
• $460,000 from the National MS Society to leverage the rapid autopsy program to investigate differences between primary progressive and secondary progressive MS with the goal of aiding development of therapies for progressive MS

Building on a legacy of autopsy-enabled discoveries

“One of our program’s goals is to correlate MRI changes with pathological changes (Figure),” explains Dr. Trapp, who is now Chairman of Cleveland Clinic’s Department of Neurosciences. “We’ve uncovered some surprises — some of the MRI changes have been shown to not be what we historically thought they were.”

Figure. Pathology images from normal white matter (top) and white matter with an active MS lesion (bottom), with corresponding MRI findings in the insets. Such pathology-MRI correlation is a central objective of the rapid autopsy program.

One early surprise was the finding that transected axons are common in MS lesions, and that axonal transection may be the key pathology underlying the disease’s irreversible neurologic impairment. Prior to those discoveries, which Dr. Trapp’s team published in New England Journal of Medicine in 1998, myelin destruction had been thought to be the major factor and axons were believed to be spared. “This was an insight into the disease process that contributed to new research,” Dr. Trapp says.

A few years later, through studying autopsy tissues, the Trapp lab showed that cells capable of producing myelin — the “premyelinating” oligodendrocytes — are present in chronic lesions of MS. Those findings, published in New England Journal of Medicine in 2002, suggested that “a therapeutic strategy could perhaps be achieved by transplanting oligodendrocyte-producing cells into the lesions or developing drugs that will promote an MS brain to repair itself,” Dr. Trapp notes.

Currently, close to a dozen grants are funding research that uses tissue from the MS rapid autopsy program, which remains the only such program to employ MRI to study the brains of recently deceased patients. Now Cleveland Clinic has extended the concept beyond MS, with the recent launch of a rapid autopsy program to study amyotrophic lateral sclerosis. Dr. Trapp hopes to create a program for Alzheimer’s disease as well.

Perfect platform for testing MRI sequences

In parallel with Dr. Trapp’s pioneering work, neurologists in Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research are using the rapid autopsy program in ways that promise more immediate impact for patients: testing new MRI sequences and technologies in MS.

“My role is to direct the MRI sequences,” says the rapid autopsy program’s medical director, Daniel Ontaneda, MD. “This is where the program becomes very interesting to me as a clinical researcher.”

By applying newly developed MRI sequences to the cadavers, Mellen Center researchers get an immediate reading on whether the MRI changes observed are suggestive of the underlying brain and spinal cord pathology. Once validated in the postmortem program, the sequences can be applied as outcome measures in some of the Mellen Center’s many clinical trials, with the hope that some can ultimately be brought into clinical practice.

“The postmortem program is the perfect place for incorporating new MRI technologies in MS,” explains Dr. Ontaneda. “The fact that we do MRI on the brains of all participating patients really helps with the translational aspects of our research. We’re directly translating MRI research to pathology, and it accelerates MRI development.”

Most patients are receptive to the rapid autopsy concept, Dr. Ontaneda says, although generally only those already involved in research are approached about it, to streamline the consent process. About 200 patients currently managed at the Mellen Center are enrolled in the program. “Patients see themselves as vehicles of discovery,” Dr. Ontaneda says. “They feel they are helping the next generation of MS patients.”