Finding a Treatment for Postoperative Cognitive Dysfunction

For those caring for elderly parents or grandparents, this scene may be familiar: Grandma falls and fractures her hip. Grandma has surgery to repair the broken hip. Grandma comes out of surgery delirious and confused; she can’t remember simple things, or focus on more than one thing at a time.

 

More than half of older adults suffer from delirium after surgery that may progress to dementia, a condition called postoperative cognitive dysfunction (POCD). There are no good treatments for postoperative cognitive dysfunction, which is associated with increased illness and death. Estimates suggest that caring for patients with POCD costs more than $150 billion a year.

A team of researchers from the University of Rochester Medical Center (URMC) and Duke University Medical Center is addressing the problem, with the help of a five-year, $2.8 million grant from the National Institutes of Aging at the National Institutes of Health.   

 

What causes postoperative cognitive dysfunction is not entirely understood, but the body’s immune response to surgery and subsequent inflammation throughout the body – including in the brain – likely play a role. The team, led by Niccolo Terrando, Ph.D. at Duke, will test in animal models a drug developed in the laboratory of Harris A. “Handy” Gelbard, M.D., Ph.D. at URMC. Called URMC-099, the drug tamps down the body’s immune response and reduces inflammation.

 

Earlier studies yielded promising results. Mice received anesthesia and underwent surgery, mimicking the process in humans. Untreated, they showed a buildup of activated microglia, immune cells in the brain that were “turned on” in response to surgery. Activated microglia are a hallmark of postoperative cognitive dysfunction and the mice exhibited cognitive impairment.

Treatment with URMC-099 completely reversed the activation of microglia. With the new grant, the teams at URMC and Duke will continue to test URMC-099’s ability to protect the brain during and following surgery.

 

In amyotrophic lateral sclerosis (ALS), immune cells in the brain and spinal cord are in overdrive, leading to inflammation. Nerve cells in the spinal cord eventually die, limiting muscle control and movement. Damage to cells in the brain leads to memory loss, thinking problems and other symptoms associated with dementia, a syndrome called frontotemporal dementia.  While the two drugs available to treat ALS, riluzole and edaravone, may slow the progression of the disease, they do little to prevent the ultimate outcome, which is death.

 

With a $100,000 award from the UR Ventures Technology Development Fund, Gelbard will study URMC-099’s influence in a mouse model of ALS. In addition to postoperative cognitive dysfunction, the drug has been shown to reduce immune cell activation and inflammation in brain diseases like multiple sclerosis, HIV-associated neurocognitive disorder and Alzheimer’s disease. The work will be conducted in partnership with Charles Thornton, M.D. at URMC and Laura Ranum, Ph.D. at the University of Florida.

Gelbard, director of the Center for Neurotherapeutics Discovery at URMC, is optimistic that these new disease targets will further increase the potential uses for URMC-099 and related drugs.

 

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