Women's Health Initiative Memory Study Suite of Studies - Extension Study

National Institute On Aging

Investigators

Linked publications & trials

Abstract

The Womens Health Initiative (WHI) randomized, placebo-controlled clinical trials of hormone therapy (HT) were designed to test the hypothesis that conjugated equine estrogens alone (CEE-Alone) or in combination with medroxyprogesterone acetate (CEE+MPA) protected postmenopausal women against the development of heart disease. The WHI Memory Study (WHIMS) was an ancillary study to the WHI trials, which consisted of parallel placebo-controlled randomized clinical trials of 0.625 mg/day CEE therapy with and without 2.5 mg/day MPA in women with a uterus or post-hysterectomy, respectively. WHIMS investigated the effect of CEE-Alone and CEE+MPA on risk for probable dementia and mild cognitive impairment in women age 65 and older, as well as the effects of these treatments on global cognitive function. The WHI Study of Cognitive Aging (WHISCA), an ancillary study to WHIMS, was developed to investigate the effects of HT on domain-specific cognitive function in women without dementia. WHISCA enrolled 2305 women at 14 of the WHIMS sites, distributed across the two parallel trials. WHISCA was initiated on average 3 years after WHI randomization and the primary outcome was the effect of HT on rates of cognitive change, adjusted for time since randomization. The WHIMS CEE+MPA trial terminated earlier than planned (July, 2002) due to an adverse risk-to-benefit profile in the main WHI trial. Subsequently, the WHI CEE-Alone Trial also was terminated early (February, 2004). Results from the WHIMS trials showed that CEE-Alone or CEE+MPA increase the risk of dementia and have adverse effects on global cognition in women aged 65 years or older. HT also has been shown to increase the risk of clinical stroke in women 65 years and older. The initial report of WHISCA findings showed that CEE + MPA had a negative impact on verbal memory (p < 0.01) and a trend to a positive impact on figural memory (p = 0.012) over time compared with placebo with no effect on other cognitive domains. In addition, these effects were evident only after long-term therapy. CEE + MPA did not significantly influence positive affect, negative affect, or depressive symptoms. These findings suggest that HT may have different effects across different cognitive domains. The findings from the CEE-Alone Trial in women with prior hysterectomy who were randomized to CEE or placebo show that CEE alone did not affect domain-specific cognitive function over time. Participants in the WHISCA and WHIMS studies continue to be followed through telephone cognitive assessments as they pass through the risk period for cognitive decline. Over the 2011-2015 period the NIA is assuming the primary funding role for the WHIMS Suite of Studies through a Research and Development Contract. This contract also includes continued cognitive follow-up of women in the WHIMS-Younger (WHIMS-Y) study, who were randomized to hormone therapy through the WHI when aged 50-54 years. The WHIMS-Y study tests the hypothesis that hormone therapy around the time of the menopause may benefit cognitive function later in life. The WHIMS Suite of Studies is conducted by Wake Forest University, which is also the site for the Southeast Regional Center for WHI and leads the Aging, Cognition and Functional Status interest group for the WHI. Over the last year, we have continued to perform cognitive follow-up evaluations through telephone assessments in the original WHIMS cohort (WHIMS extension study) and in the more recently established WHIMS-Y study of women randomized to HT versus placebo when aged 50-55. Initial results from the WHIMS-Y study were based on 1326 postmenopausal women studied with a validated telephone cognitive assessment battery an average of 7.2 years after the trials ended, when women had a mean age of 67.2 years. The initial report included the first two administrations of the cognitive battery and showed neither harm nor benefit of early HT on later cognitive function. Annual assessments continue and these analyses will be repeated upon completion of the follow-up period. Over the last year, we have continued to examine the association of elevated depressive symptoms with domain-specific cognitive changes and the moderating role of cardiovascular risk factor severity and cardiovascular disease. We found that women with elevated depressive symptoms showed baseline multidomain cognitive deficits but longitudinal declines in global cognition only. Persistent depressive symptoms were related to greater global cognition, verbal knowledge and fluency, and memory declines. In addition, significant cross-sectional interactions were observed between cardiovascular disease and subclinical depressive symptoms. In other work, we investigated whether educational attainment, a proxy for cognitive reserve, is correlated with cognitive decline, brain lesion volume, and total brain atrophy. After adjustment for total lesion and total brain volumes (atrophy), higher educational attainment predicted better cognitive performance (p < 0.001). Following conversion to dementia or mild cognitive impairment, higher education predicted steeper declines in cognitive function (p < 0.001). Thus, higher educational attainment was associated with a delay in diagnosis of dementia/mild cognitive impairment in the face of a growing neuropathological load. We also published the follow-up WHIMS-MRI study in a subset of 729 of the approximately 1400 women who received an initial MRI study. Conjugated equine estrogen-based postmenopausal HT, previously assigned at WHI baseline, did not affect rates of decline in brain volumes or increases in brain lesion volumes during the 4.7 years between the initial and follow-up WHIMS-MRI studies. Smaller frontal lobe volumes were observed as persistent group differences among women assigned to active HT compared with placebo. Women with a history of cardiovascular disease treated with active HT, compared with placebo, had higher rates of accumulation in white matter lesion volume and total brain lesion volume. Cognitive assessments continue in the WHIMS Suite of Studies and will continue to provide important information on factors associated with cognitive decline and impairment as well as those that promote the maintenance of cognitive health in late-life.