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Oxford-Harrington Rare Disease Scholar Award
For all the failed efforts to treat Alzheimer’s disease, there is one therapy that is known to actually work: physical exercise. A decline in brain blood flow is a root cause of Alzheimer’s; however, improvement in blood flow can prevent cognitive decline. The idea behind aerobic exercise is that it increases blood flow in the brain, and researchers have shown exercise to be beneficial in the prevention and progression of Alzheimer’s. However, how much exercise is not well understood.
“As a nation, we are exercising blindly,” explains Jonathan S. Stamler, MD, President, Harrington Discovery Institute at UH, Robert S. and Sylvia K. Reitman Family Foundation Distinguished Professor of Cardiovascular Innovation, and Professor of Medicine and Biochemistry at UH and Case Western Reserve School of Medicine. “We know through clinical studies that aerobic exercise is beneficial in preventing and slowing the progression of Alzheimer’s; however, how much and what form of exercise is unclear.” We have no marker of productive exercise.
Dr. Stamler and his research team discovered that a molecule called Nitric Oxide (NO) is released from hemoglobin in red blood cells to dilate small blood vessels and improve brain blood flow. The primary stimulus to release nitric oxide in the brain is actually exercise -- NO then opens small blood vessels so that red blood cells can enter tissues and deliver oxygen.
Further, in an animal model study, Dr. Stamler and his team showed that mice lacking NO can’t increase brain blood flow, and have cognitive impairment. For example, the mice in the study failed to recognize new objects.
“It stands to reason then that if we could increase the amount of NO released from red blood cells, we could better oxygenate and nourish the brain,” explained Dr. Stamler. “But we currently have no way to measure NO in tissues non-invasively.”
Dr. Stamler and his team are currently developing the first device and mobile app prototype to measure NO released from blood cells in real-time during physical exercise.
“While exercise generates Nitric Oxide, not all exercises are equal,” emphasizes Dr. Stamler. “The higher the NO the better – more Nitric Oxide from red blood cells leads to better blood flow to the brain, heart and muscles. You should want a peloton instructor that increases blood flow to your brain.”
Currently, the gold standard for fitness in medicine is a measurement of VO2 max – the amount of oxygen consumed by a person during exercise. This is measured in a lab using sophisticated equipment. Patients who have Alzheimer’s have decreased VO2 max, but the reason for this is still unknown. Dr. Stamler and his research team have developed a Nitric Oxide-based algorithm called “useable oxygen” (UO2) to precisely track VO2 and naturally predict VO2 max using a wearable device.
Dr. Stamler explains that moving forward, exercise protocols should be optimized to maximize NO and NO-targeted exercise may benefit Alzheimer’s patients, and all people, as they age. Individualizing workouts and spending less time on what doesn’t work will help to reduce dementia risk. Next steps for the research team involve finalizing the exercise device and mobile app prototype.
Funding for this research has been provided by University Hospitals, Harrington Discovery Institute at UH, an award from the American Heart Association-Allen Initiative in Brain Health and Cognitive Impairment and NHLBI. Dr. Stamler has an equity interest in NNOXX, which develops NO-based technology, and in SNO-bio, which is developing S-nitrosylation based therapeutics.
University Hospitals - Cleveland