In an ongoing randomized trial, Dr. Daniel H.S. Silverman, Dr. Natalie L. Rasgon, and their colleagues are examining the effects of both endogenous and exogenous estrogen exposure on regional cerebral metabolism in women who were on hormone therapy (HT) at the time of recruitment and had an increased risk of Alzheimer's disease. These women either stopped or continued HT and then underwent fluorine-18 FDG-PET imaging at baseline and at 2 years. Dr. Silverman, head of the neuronuclear imaging section of the Ahmanson Biological Imaging Division at the University of California, Los Angeles, presented data at the San Antonio Breast Cancer Symposium on the first 25 women to complete the protocol.
Endogenous estrogen exposure was positively correlated most significantly with the metabolism of the precuneus area of the posterior medial cortex. “That's a part of the brain in which blood flow is decreased most significantly in early stages of Alzheimer's disease,” he said.
Two years after discontinuation of HT, those women exhibited a highly significant negative correlation between the duration of endogenous exposure and the metabolism of the anterior medial cortex. “That's part of the brain that we know is affected most significantly by normal aging of the brain,” he said. In contrast, women who continued on HT during the trial demonstrated a relative increase in the most anterior portion of the medial prefrontal cortex after 2 years.
In women who stopped HT, “there were two things that we saw. First of all, they didn't have that preservation of the frontal area that declines with normal aging. In addition, they experienced a significant decrease in metabolism in the inferior parietal cortex, a part of the brain that is affected very early in incipient Alzheimer's disease,” he said.
In a parallel but unrelated trial, Dr. Silverman, along with UCLA oncologist Dr. Patti Ganz and UCLA neuropsychologist Steve Castellon, Ph.D., set out to determine the cognitive effects of chemotherapy on breast cancer patients. They conducted PET scans in 16 women who had been exposed to adjuvant chemotherapy for breast cancer—and to tamoxifen in the majority of cases. The women were studied 5-10 years after their last dose of chemotherapy and were compared with age-matched controls, who had not been exposed to chemotherapy.
Controversy exists over how much of the neurocognitive impairment that follows chemotherapy exposure (chemobrain) is directly associated with chemotherapy and how much is attributable to related factors, such as the cancer itself and precipitous menopause.
“Those who had cognitive impairment after having been exposed to chemotherapy had significantly decreased metabolism [in the inferior frontal cortex] at mental rest and substantially increased activation when performing short-term memory tasks. … these are people who start off with lower metabolism or lower activity in that part of the brain, so to perform the same task, that area of the brain has to work a lot harder to get to the same level,” he said.
Women on continual hormone therapy had increased metabolism in both sides of the medial prefrontal cortex. Images courtesy Dr. Daniel Silverman