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

妇女健康倡议（WHI）随机、安慰剂对照的激素治疗（HT）临床试验旨在验证结合马雌激素单独（CEE- alone）或与醋酸甲羟孕酮（CEE+MPA）联合保护绝经后妇女免受心脏病发展的假设。WHI记忆研究（WHIMS）是WHI试验的一项辅助研究，该研究包括平行安慰剂对照随机临床试验，分别在子宫切除或子宫切除术后妇女中使用0.625 mg/天CEE治疗和不使用2.5 mg/天MPA。WHIMS研究了CEE单独和CEE+MPA对65岁及以上女性可能发生痴呆和轻度认知障碍风险的影响，以及这些治疗对整体认知功能的影响。WHI认知衰老研究（WHISCA）是WHIMS的一项辅助研究，旨在研究HT对无痴呆女性特定领域认知功能的影响。WHISCA在14个WHIMS站点招募了2305名女性，分布在两个平行试验中。WHISCA在WHI随机化后平均3年开始，主要结局是HT对认知改变率的影响，随机化后调整时间。WHIMS CEE+MPA试验比原计划（2002年7月）提前终止，原因是主要WHI试验的风险-收益对比不利。随后，WHI cee单独试验也提前终止（2004年2月）。WHIMS试验的结果显示，CEE-单独或CEE+MPA会增加65岁及以上女性患痴呆的风险，并对全球认知产生不利影响。HT也被证明会增加65岁及以上女性临床中风的风险。WHISCA的初步研究结果显示，与安慰剂相比，CEE + MPA对言语记忆有负向影响（p < 0.01），对图形记忆有正向影响（p = 0.012），但对其他认知领域没有影响。此外，这些效果仅在长期治疗后才明显。CEE + MPA对积极情绪、消极情绪或抑郁症状无显著影响。这些发现表明，HT可能在不同的认知领域有不同的影响。在既往子宫切除术的妇女中，CEE单独试验的结果显示，CEE单独试验不会随着时间的推移影响特定领域的认知功能。WHISCA和WHIMS研究的参与者继续通过电话进行认知评估，直到他们度过认知能力下降的危险期。在2011-2015年期间，NIA通过研发合同承担了WHIMS研究套件的主要资助角色。该合同还包括对WHIMS-Younger （WHIMS-Y）研究中妇女的持续认知随访，这些妇女在50-54岁时通过WHI随机接受激素治疗。WHIMS-Y研究将检验一个假设，即更年期前后的激素治疗可能有益于以后的认知功能。

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.