The primary aims of this study are: 1) to determine whether hormone replacement therapy (HRT: testosterone in men, estrogen in women) enhances cognitive functioning and mood in physically healthy, cognitively intact adults over the age of 65 years. 2) to better understand the neuroanatomical and neurophysiological substrates for the expected changes in cognition and mood by using magnetic resonance imaging (MRI) to measure brain structure and positron emission tomography (PET) and 18-F-Fluorodeoxyglucose (18-F-FDG) to measure regional cerebral glucose metabolism. The hypotheses are: 1) participants will perform better on memory tasks, including both standard neuropsychological tests and the activational memory task, while receiving hormone replacement therapy (HRT) than while receiving placebo. 2) within-subject comparisons of the pattern of regional brain activity will differ during the hormonal treatment phase compared to the treatment phase, with notable differences in brain regions known to subserve memory abilities such as the medial temporal lobe. Background: The effect of aging on cognitive ability varies from one individual to the next. Recent studies suggest that one of the factors influencing individual differences in cognitive aging is the use of hormonal replacement therapy (HRT). For example, recent findings from the Baltimore Longitudinal Study on Aging (BLSA) suggest that the use of estrogen replacement therapy (ERT) protects against age-associated declines in memory and against the development of Alzheimer's Disease. One limitation of such studies is that women who participated in them elected on their own to receive ERT. Research suggests that such women tend to be better educated and to receive better health care than women who do not receive ERT. The bias is termed the """"""""healthy use effect"""""""". To address this bias, we are recruiting postmenopausal women age 65 years and older who are not currently receiving HRT, and we are investigating their cognitive and brain functioning on and off estrogen. We are conducting a parallel study on men, age 65 years and older. Men experience a gradual loss of testosterone, about 1% a year after age 40. Little is known about how testosterone replacement therapy affects cognition in older men, though there is some suggestion that the hormone may enhance spatial abilities. Little is known about the neural underpinnings of the cognitive changes associated with HRT. Recent findings from an observational study in our laboratory indicated that ERT users and nonusers show different patterns of regional brain activation during memory test performance. These differences appear in brain regions subserving memory.
We aim to investigate similar brain functions in a randomized trial in older women and men. Design: the investigation is a double-blind, placebo-controlled, cross-over study wherein we examine brain structure (i.e., MRI), brain function (i.e., PET measures of regional glucose metabolism), and neuropsychological test performance in women on and off estrogen (Premarin/Prempro .625 mg daily) and men on and off testosterone (Delatestryl 200 mg biwekly). The study lasts 9 months per participant. Participants receive hormone replacement therapy (HRT) for 3 months, nothing for 3 months, and a placebo for the other 3 months. To ensure that the cross-over is successful, participants undergo neuropsychological testing four times. Each test session involves 2 hours of neuropsychological tests (e.g., mood, memory) and blood draws. At session 2 and 4, participants undergo neuroimaging and complete a supplemental neuropsychological test battery. The ERT and testosterone replacement therpy (TRT) arms of the study are similar, but will be kept separate for analysis purposes. Goals: By overcoming the healthy user bias of previous studies, we can more strongly support the hypothesis that ERT improves cognitive functioning in women. By extending this area of inquiry to the study of testosterone replacement, we can begin to address whether HRT offers similar benefits to men. Lastly, the neuroimaging component allows us to investigate the neural underpinnings for the expected benefits in cognition.
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