Acclaimed Neuroscientist Featured at Brody Lecture

By Dirk Hoffman

Maiken Nedergaard, MD, DMSc, is Dean’s Professor and co-director of the Center for Translational Neuromedicine in the Department of Neurology at the University of Rochester. She also holds an appointment as professor of glial cell biology in the Center for Neuroscience at the University of Copenhagen.

Harold Brody, MD, PhD, who came to the University at Buffalo in 1954, was a pioneer in studying aging changes in the human brain. In 1963, he became the first UB faculty member to be named a Fulbright fellow, which he spent at the University of Copenhagen continuing his studies on aging in the nervous system.

In his introduction of Nedergaard, Christopher S. Cohan, PhD, SUNY Distinguished Teaching Professor of pathology and anatomical sciences, noted “we are especially grateful to have you with us here today. Your presence reestablishes the connection between Harold Brody and the University of Copenhagen that influenced so much of his life.”

Nedergaard’s research spans from neuron-glia interactions to the role of the glymphatic system in the sleep-wake cycle and in aging, small vessel disease, stroke and traumatic brain injury (TBI).

Her talk, titled “The Glymphatic System,” provided an overview of portions of her groundbreaking research, including describing in 2012 the previously unknown glymphatic system, the brain’s sleep-time cleansing mechanism. The discovery earned her the “Breakthrough of the Year” honor from Science Magazine.

The system’s name is a combination of glia and lymphatic because Nedergaard and her colleagues advanced the idea that cerebrospinal fluid (CSF) could act as an export pathway for proteins from the brain, much like the lymphatic system collects and removes unused nutrients and cellular waste from the rest of the body.

Nedergaard also coined the term “glymphatics,” to describe how astrocytes at surrounding capillaries regulate the flow of CSF through brain tissue and that acts as a clearance system to clear out brain metabolites and toxic molecules that accumulate in the interstitial fluids of the brain.

In rodent studies, Nedergaard and her colleagues observed the glymphatic system was almost 10-fold more active during the sleep state as it conducted a beneficial “brainwashing.”

The researchers also found the brain’s cells reduce in size during sleep, creating space for CSF to wash more freely through brain tissue.

“It was fascinating to find the awake brain is completely capable of suppressing the influx of CSF,” she said. “It is probably happening because you cannot have neurocircuitry working if there is fluid flow because you lose the position of synaptic transmission if glutamate is transported from one synapse to the other, but we do not know for sure.”

Nedergaard’s discoveries, in part, have transformed scientists’ understanding of the biological purposes of sleep and point to new ways to treat neurological disorders.

“Sleep is non-negotiable. We need to sleep,” she said. “The brain is uniquely sensitive to sleep deprivation.”

Studies have shown that sleep deprivation accelerates amyloid-beta accumulation in mice, Nedergaard noted, adding that Alzheimer’s disease and other neurogenerative diseases are all linked to the accumulation of protein.

The researchers have speculated that disrupted sleep which impairs the glymphatic system could be a driver of Alzheimer’s disease.

“Studies have shown that six hours or less of sleep per night increases dementia risk by as much as 30 percent,” Nedergaard said.

Nedergaard also sees glymphatics as a potential therapeutic target for TBI, noting the neurotransmitter noradrenaline is one of the main triggers of cerebral edema.

“Noradrenaline is a master regulator of glymphatic flow and TBI increases noradrenaline for prolonged periods,” she said. “It can often stay high for days or weeks after TBI.”

The researchers noted noradrenaline restricts the movement of fluid in the section of the brain where CSF drains.

To counteract this, they used a combination of alpha- and beta-blockers in mice studies to reopen gates to the lymph nodes, thus relieving pressure and leading to reduced swelling.

Nedergaard says if the inhibitors are given right away after TBI, “you can completely avoid edema.”

Nedergaard received her medical degree from the University of Copenhagen in 1983 and completed residencies in neurology and neurosurgery, also at the University of Copenhagen.

She completed postdoctoral training there as well in physiology and neuropathology.

Nedergaard came to the United States to work at Cornell University Medical School for postdoctoral training in neuroscience, before returning to the University of Copenhagen to receive her doctor of medical science degree in neuroscience.

She has received more than 11 international awards from a variety of countries, including Denmark, Spain, China and the United States. Nedergaard has 10 patents, published over 400 journal articles and she has published one book and 16 book chapters.

In 2023, she received the 21^st Perl-UNC Neuroscience Prize from the UNC School of Medicine. Past winners include six scientists who went on to win the Nobel Prize.

She also won the 2023 Anders Jahre’s Award for Medical Research, honoring outstanding international research.

Prior to the April 12 lecture, John E. Tomaszewski, MD, SUNY Distinguished Professor and Peter A. Nickerson, PhD, Professor and Chair of pathology and anatomical sciences, gave a brief biographical overview of Brody.

“The annual Brody Lecture is held to celebrate the decades of contributions Harold Brody made to UB,” he said. “He left college in 1942 to enlist in the U.S. Army where he became a neurosurgical assistant, which had a profound effect on his career.”

After finishing military service, Brody completed college at Western Reserve University, obtained his doctoral degree at the University of Minnesota and came to the University at Buffalo, joining the Department of Anatomy. While in Buffalo, he earned his medical degree in 1961.

Brody served as professor and chair of the Department of Anatomy from 1971 to 1992. He served as a founding member of the National Advisory Council of the National Institutes of Health on Aging.

“Dr. Brody was known as an outstanding teacher and that is part of the genesis of this lecture series,” Tomaszewski said. “He developed curriculum that is still being used, in part, today in teaching, so he was well ahead of this time.”

Brody lecturers are selected for their contributions to science in general and neuroscience in particular, their practice of medicine, and their community leadership.