Exploring cognitive decline after hematopoietic cell transplant

December 17, 2013 | by

Hematopoietic cell transplant patients who undergo what's known as myeloablative conditioning (that is, high-intensity chemotherapy and radiation) – and who have shorter telomeres (chromosome “end caps”) – may be at greater risk for cognitive impairment after transplant, City of Hope researchers have found.

Their study was presented earlier this month at the American Society of Hematology (ASH) Annual Meeting and Exposition in New Orleans in December. “Our goal was to understand the trajectory of their cognitive functioning after transplantation and also if there are some vulnerable subpopulations at increased risk of cognitive impairment,” said senior author Smita Bhatia, M.D., M.P.H., the Ruth Ziegler Chair in Population Sciences at City of Hope.

The study was featured during a news conference hosted by ASH.

"This is a significant finding," Bhatia told assembled media, noting that patients should be aware of the potential for cognitive impairment. The complication can be particularly frustrating once they return to school or work.

The longitudinal study was based on 242 patients, age 19 to 71 (median age was 49). Sixty-nine percent of patients had acute leukemia, 14 percent had lymphoma and 17 percent had other hematologic malignancies.

Researchers gave neuropsychological tests to patients, measuring the cognitive function before they underwent transplant. They also administered the tests to healthy control subjects, assessing abilities such as verbal fluency and motor strength. They repeated the tests six months, one year and two years later.

“We found there is significant impairment in cognitive functioning in a variety of domains among transplant patients compared to healthy controls," said Bhatia. "We also found that it is primarily those who receive myeloablative transplants who are having these cognitive impairments."

Researchers also sought  a glimpse into what causes cognitive impairment through a biomarker called telomeres: DNA protein structures that cap the ends of chromosomes.

Knowing that patients with severe Alzheimer’s have shorter telomeres, researchers wanted to verify whether shorter telomeres also correlated with cognitive impairment in their study participants.

"Each time a cell divides, a small piece of that telomere is shaved off, and the telomere gets shorter and shorter with each cell division,” explained Bhatia.

“The older a person is, the shorter their telomeres are going to be. What chemotherapy and radiation do is really speed up this attrition of telomere lengths. A 25-year-old who has not had any radiation and chemotherapy has much longer telomeres than a 25-year-old who has had chemotherapy and radiation,” she said.

The study showed that among females, the shorter the telomere length before transplant, the more likely the women were to have cognitive impairment after transplantation. “This finding is also pretty significant in trying to understand what’s going in the brain with respect to cognitive functioning,” Bhatia added.

Alysia Bosworth, the study's first author and clinical research coordinator for City of Hope's Department of Population Sciences,  said the findings should make physicians be on heightened alert when examining patients after transplant.

“We recommend that patients at high risk for cognitive dysfunction, such as those receiving allogeneic transplants, be followed carefully, with prompt attention to intervention for those identified with cognitive dysfunction,” she said.

Bosworth looks forward to delving deeper into the causes of this debilitating complication.

"We need to further explore the reasons for cognitive impairment after transplantation, specifically looking at functional imaging and genetic factors, especially those that are responsible for maintaining telomere length," she added.

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Above, Smita Bhatia, M.D., M.P.H., the Ruth Ziegler Chair in Population Sciences at City of Hope, discusses her latest research, presented recently at the American Society of Hematology Annual Meeting and Exposition.