ARTICLE IN BRIEF
Daniel S. Reich, MD, PhD, the recipient of the American Neurological Association's 2015 Derek Denny-Brown Young Neurological Award in Clinical Science, discusses the personal and professional influences and events that shaped his career.
In September, Daniel S. Reich, MD, PhD, chief of the Translational Neuroradiology Unit at the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) and an attending neurologist in the NIH Clinical Center in Bethesda, MD, received the 2015 Derek Denny-Brown Young Neurological Award in Clinical Science at the annual meeting of the American Neurological Association in Chicago. The award recognizes neurologists and neuroscientists in the first 10 years of their career who have made outstanding clinical and scientific advances toward the prevention, diagnosis, treatment, and cure of neurologic diseases. Dr. Reich spoke with Neurology Today about the personal and professional influences and events that have shaped his career.
Dr. Reich studied and worked diligently for many years before rising to his current role at the NINDS — but in terms of actual mileage, he hasn't traveled very far. “I grew up about three miles from the NIH,” he told Neurology Today. His father, a psychiatrist, worked for 20 years at the National Institute of Mental Health, studying, among other things, the psychiatric abuse of political dissidents in the former Soviet Union (who were often declared “mentally unstable” and hastily locked away).
Reich and his two siblings shared their father's passion for science from an early age and often joked that they would “all become psychiatrists, go into practice with my father, and my mother would be the patient.” (His mother, a novelist, has no need for four psychiatrists, mercifully.)
While attending Yale in pursuit of a degree in mathematics and physics, Reich spent time at the NINDS as a summer student, where he worked on computational modeling of neural circuits. He also spent a summer at the Weizmann Institute in Israel and several at Rockefeller University in New York, studying information processing in the brain. “I got hooked on this question of how the brain processes sensory information, how we understand what we see,” he said. That ultimately became the focus of his PhD research.
As he approached the end of his MD-PhD at Cornell and Rockefeller, Reich became fascinated by advances in brain imaging, and decided to enroll in the short-lived combined residency program in neurology and radiology at Johns Hopkins, one of only two such programs in the country. “I had not intended to go into radiology. I was always pretty sure I was going to be totally a neurologist,” he said. “But then I got really excited about the imaging, and the Hopkins program was designed to train people who were interested in developing a scientific career that involved imaging of neurological disease. It was right up my alley.”
With his background in physiology, Dr. Reich thought that he might specialize in epilepsy after completing his residency. But “seeing MS patients turned out to be really fascinating,” he said. And then he met Peter A. Calabresi, MD, FAAN, FANA, who had just arrived at Hopkins. Dr. Calabresi, who is now a professor of neurology, director of the Johns Hopkins Multiple Sclerosis Center, and director of the Richard T. Johnson Division of Neuroimmunology and Neurological Infections at Hopkins, quickly became his mentor. Together, they embarked on a research collaboration that resulted in more than 30 coauthored papers investigating pathological changes in the brain in human and animal models of MS. (Dr. Calabresi also recommended Dr. Reich for the 2015 ANA award.)
At Hopkins, Dr. Reich began pioneering techniques for quantitative imaging of MS. His early work used diffusion tensor imaging (DTI) to link diffusion parameters within visual pathways in the white matter to visual outcomes in MS patients, ultimately “developing some of the methodology that's still used today for interrogating these various functional systems separately,” he said.
BUILDING A LAB AT NIH
At the end of his fellowship at Hopkins in 2009, Dr. Reich received a K99/R00 Pathway to Independence Award from the NINDS — only the third MD to receive funding through this mechanism. He then accepted a position at the NINDS, where he established the Translational Neuroradiology Unit, developing imaging techniques that would help uncover the events that lead to the development of focal lesions in brain tissue and the effects of these lesions on axons and myelin.
Working with Steven Jacobson, PhD, another NINDS investigator, and Luca Massacesi, MD, an Italian neurologist who spent a sabbatical at the NIH, Dr. Reich began investigating lesion development in the marmoset model of experimental autoimmune encephalomyelitis (EAE) — a model that Dr. Massacesi had originally helped develop.
“That led to a series of studies on the development of focal inflammatory lesions or plaques that have changed the way we think about the relationships between inflammation and the blood-brain barrier and damage and repair in the disease,” he said.
One of Dr. Reich's seminal findings at NIH has been that the pattern of blood-brain barrier opening in and around new MS lesions is more dynamic than previously thought. Using 7T gadolinium-enhanced MRI, Dr. Reich and his colleagues determined that “how the blood-brain barrier is opened is a highly dynamic process, and where it's opened changes over the course of a lesion's development.
“Early in the life of a lesion, gadolinium seems to leak out right from the center of the lesion, which we know is where there is an inflamed small vein,” he said. “But very rapidly, as the lesion enlarges, the area where the blood-brain barrier is open changes to the periphery of the lesion. Our hypothesis is that what we're seeing is not necessarily a pathogenic opening of the blood brain-barrier, but rather perhaps part of the wound-healing response that occurs whenever tissue is damaged.”
Now, he said, “we're trying to pursue that [hypothesis] much more deeply,” using these advanced MRI techniques both in the primate model and in patients. In the case of patients, he added, these techniques will “hopefully [be used] in the context of a drug trial.”
PIONEERING POSTMORTEM MRI
Of all his contributions to the field, however, Dr. Reich's most buzzed-about work may be his development of postmortem MRI to evaluate MS pathology in truly unprecedented detail. This began with the discovery, published in Neurology in July, of gadolinium enhancement in the meninges. “We started seeing areas of gadolinium enhancement not in the brain but around the brain, in the meninges, that hadn't been described before,” he said. Furthermore, he and his colleagues found that this leptomeningeal contrast enhancement was nearly twice as common in progressive MS as in early relapsing MS.
Dr. Reich and his colleagues hypothesized that this enhancement was indicative of inflammation in the meninges. But in order to confirm the findings on pathology — findings that were “about a millimeter or so in size” on MRI — they would need to develop an extremely detailed and precise technique for imaging, modeling, and autopsying the brain.
“We realized that MRI could be incredibly valuable as a tool for guiding pathology,” Dr. Reich said. So he and his colleagues developed a method of imaging the brain after fixation in formalin, leaving it in the NIH scanner for hours or days in order to “get down to a tenth of a millimeter on the edge of a pixel.”
Once those highly detailed images had been generated, Dr. Reich and his colleagues used 3D printing technology to create an exact mold of the brain, placing grooves in the mold at regular intervals to enable precise slicing. And because of the match-up between the MRI scan and the mold, they were able to tell the pathologist exactly where to cut in order to examine these inflamed areas in the membranes covering the brain.
The result? Dr. Reich and his colleagues were able to demonstrate in two autopsied brains that the leptomeningeal enhancement on MRI did in fact correspond to the type of inflammation that has been observed in cortical lesions.
Now, Dr. Reich and his colleagues at the NIH have established a long-term brain donation program in which patients can visit the NIH clinic on a regular basis for imaging studies, then donate their brains at death “so we can really understand how things change over time within a patient, from the imaging while they're alive to the pathology after death.” The researchers are hoping to enroll 50 to 60 patients of all ages into the program.
Dr. Reich said he has high hopes in the translational potential of his imaging research, particularly for developing new approaches for conducting clinical trials of drug therapies. “Understanding the biology of MS is as thrilling as anything can be, but when you sit in this translational place, you'd really like to find new ways of making significant differences in how the disease is treated,” he said. “We haven't done it yet, but we're moving in that direction.”