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 will test 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, publications have included a number of papers investigating risk factors, especially diabetes, for cognitive decline, brain changes, and dementia. In one study, we examined cognitive function in 179 WHIMS participants with Type 2 diabetes compared to 1984 non-diabetics, followed for an average of 5 years with annual standardized assessments of domain-specific cognitive function. We found that Type 2 diabetes was associated with mean deficits of 0.2-0.4 standard deviations (SD) across follow-up in most cognitive domains. Consistent evidence that rates of decline were accelerated among women with diabetes was evident only for verbal knowledge and verbal memory (p<0.05). Decrements in fine motor speed, but no measure of cognitive function, were greater for women with earlier onset of disease. Through the WHIMS-MRI study, we performed a follow-up study comparing brain and ischemic lesion volume changes in women with and without type 2 diabetes. MRI data were available for 1,366 women, aged 72-89 years, and repeat scans were collected an average of 4.7 years later in 698 women. The 145 women with diabetes (10.6%) at the first MRI had smaller total brain volumes (0.6% less;P = 0.05) and smaller gray matter volumes (1.5% less;P = 0.01), but not white matter volumes, both overall and within major lobes. They also had larger ischemic lesion volumes (21.8% greater;P = 0.02), both overall and in gray matter (27.5% greater;P = 0.06), in white matter (18.8% greater;P = 0.02), and across major lobes. Overall, women with diabetes had slightly (nonsignificant) greater loss of total brain volumes (3.02 cc;P = 0.11) and significant increases in total ischemic lesion volumes (9.7% more;P = 0.05) with time relative to those without diabetes. Diabetes was associated with lower scores in global cognitive function and its subdomains. These relative deficits were only partially accounted for by brain volumes and risk factors for cognitive deficits. In summary, we found that Type 2 diabetes is associated with smaller gray, but not white, matter volumes and that ischemic lesion volumes increased over an approximately 5-year interval. In a third study, we examined cognitive function and brain volumes in WHIMS participants in relation to retinopathy measured in an overlapping sample of 511 women aged 65 and older who had also participated in the Womens Health Initiative Sight Examination Study (WHISE). Retinopathy was assessed using fundus photography (2000-2002) and cognitive performance over time was evaluated using the modified Mini-Mental State Examination (3MSE) (1996-2007). Presence of retinopathy was associated with poorer mental status scores (mean difference = 1.01, SE: 0.43) (p = 0.019) over a 10-year follow-up period and greater ischemic volumes in the total brain (47% larger, p = 0.04) and the parietal lobe (68% larger, p = 0.01). However, retinopathy was not associated with measures of regional brain atrophy. These findings suggest that retinopathy may be a marker of small vessel cerebrovascular disease that may influence cognitive performance and vascular brain changes.

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Korthauer, Laura E; Goveas, Joseph; Espeland, Mark A et al. (2018) Negative Affect Is Associated With Higher Risk of Incident Cognitive Impairment in Nondepressed Postmenopausal Women. J Gerontol A Biol Sci Med Sci 73:506-512
Espeland, Mark A; Chen, Jiu-Chiuan; Weitlauf, Julie et al. (2018) Trajectories of Relative Performance with 2 Measures of Global Cognitive Function. J Am Geriatr Soc 66:1575-1580
Espeland, Mark A; Rapp, Stephen R; Manson, JoAnn E et al. (2017) Long-term Effects on Cognitive Trajectories of Postmenopausal Hormone Therapy in Two Age Groups. J Gerontol A Biol Sci Med Sci 72:838-845
Cacciottolo, M; Wang, X; Driscoll, I et al. (2017) Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models. Transl Psychiatry 7:e1022
Zhang, Tianhao; Casanova, Ramon; Resnick, Susan M et al. (2016) Effects of Hormone Therapy on Brain Volumes Changes of Postmenopausal Women Revealed by Optimally-Discriminative Voxel-Based Morphometry. PLoS One 11:e0150834
Casanova, Ramon; Wang, Xinhui; Reyes, Jeanette et al. (2016) A Voxel-Based Morphometry Study Reveals Local Brain Structural Alterations Associated with Ambient Fine Particles in Older Women. Front Hum Neurosci 10:495
Goveas, Joseph S; Rapp, Stephen R; Hogan, Patricia E et al. (2016) Predictors of Optimal Cognitive Aging in 80+ Women: The Women's Health Initiative Memory Study. J Gerontol A Biol Sci Med Sci 71 Suppl 1:S62-71
Driscoll, Ira; Gaussoin, Sarah A; Wassertheil-Smoller, Sylvia et al. (2016) Obesity and Structural Brain Integrity in Older Women: The Women's Health Initiative Magnetic Resonance Imaging Study. J Gerontol A Biol Sci Med Sci :
Espeland, Mark A; Brinton, Roberta Diaz; Hugenschmidt, Christina et al. (2015) Impact of Type 2 Diabetes and Postmenopausal Hormone Therapy on Incidence of Cognitive Impairment in Older Women. Diabetes Care 38:2316-24
Espeland, Mark A; Brinton, Roberta Diaz; Manson, JoAnn E et al. (2015) Postmenopausal hormone therapy, type 2 diabetes mellitus, and brain volumes. Neurology 85:1131-8

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