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

妇女健康倡议(WHI)随机、安慰剂对照的激素疗法(HT)临床试验旨在验证以下假设：结合马类雌激素单独使用(CEE-单独)或与醋酸甲羟孕酮(CEE+MPA)联合使用可防止绝经后妇女患心脏病。WHI Memory研究(WHIMS)是WHI试验的一项辅助研究，该试验由平行的安慰剂对照随机临床试验组成，分别在有子宫或子宫切除后的妇女中每天接受0.625毫克的CEE治疗和不使用2.5毫克/天的甲孕酮。Whims研究了单独服用CEE和CEE+MPA对65岁及以上女性可能患痴呆症和轻度认知损伤的风险的影响，以及这些治疗对整体认知功能的影响。WHI认知老化研究(WHISCA)是Whims的一项辅助研究，旨在调查羟色胺对非痴呆症女性特定领域认知功能的影响。WHISCA在14个Whims网站招募了2305名女性，分布在两个平行的试验中。WHISCA在WHI随机化后平均3年开始，主要结果是HT对认知改变率的影响，并根据随机化以来的时间进行了调整。WHIMS CEE+MPA试验比原计划提前结束(2002年7月)，原因是WHI主要试验的风险对收益的不利情况。随后，WHI CEE单独进行的试验也在早期(2004年2月)终止。Whims试验的结果表明，单独服用CEE或CEE+MPA会增加患痴呆症的风险，并对65岁或以上女性的全球认知产生不利影响。在65岁及以上的女性中，高血压也被证明会增加临床中风的风险。WHISCA研究结果的初步报告显示，与对其他认知领域没有影响的安慰剂相比，CEE+MPA对言语记忆有负面影响(p&lt；0.01)，而对图形记忆有积极影响(p=0.012)。此外，这些效果只有在长期治疗后才明显。CEE+MPA对积极情感、消极情感或抑郁症状没有显著影响。这些发现表明，在不同的认知领域，羟色胺可能有不同的影响。CEE单独试验的结果表明，随着时间的推移，CEE本身并不影响特定领域的认知功能。这些妇女被随机分为CEE组和安慰剂组，这些妇女接受过CEE。WHISCA和WHIMS研究的参与者在经历认知能力下降的风险期时，继续接受电话认知评估。在2011-2015年间，NIA通过一份研究和开发合同，承担了Whims研究套件的主要资金角色。该合同还包括对Whims-Young(Whims-Y)研究中的女性进行持续认知跟踪，这些女性在50-54岁时被随机通过WHI接受激素治疗。Whims-Y研究将检验这一假设，即更年期前后的激素治疗可能有助于晚年的认知功能。 Whims研究套件由维克森林大学进行，该大学也是WHI东南地区中心的所在地，并领导WHI的老龄化、认知和功能地位兴趣小组。 过去一年的出版物包括关于分配到以CEE为基础的治疗对认知功能的长期影响的调查，晚年抑郁症状和局部脑容量之间的关联，以及体重变化和认知变化之间的关联。 在随机临床试验中，基于CEE的激素治疗与总体认知功能和几个特定领域认知功能的小平均相对下降有关，试验后大部分持续到4年。最有力的统计证据是全球认知功能。对于特定领域的分数，平均降幅略小，也不那么显著；与CEE+MPA相比，仅CEE的降幅往往更大。基于CEE的疗法在65岁之后开始，会导致认知功能的小幅广泛下降，并在停止使用后持续存在，但认知功能的差异很小，对女性个体来说不会被检测到，也不会有临床意义。 在第二项调查中，Whims的研究人员显示，抑郁症女性的基线全球认知水平较低，更有可能有激素治疗史。此外，抑郁症状的增加与某些额叶亚区的体积较小有关，但与内侧颞叶结构无关，这表明额叶大脑结构在女性晚年抑郁症状中的重要性。 在对2283名老年绝经后WHI女性的第三次调查中，我们发现保持稳定或体重增加的女性的体重和认知之间缺乏相关性。然而，体重减轻(p&lt；0.05)，很可能是早期疾病的信号，与较低的认知能力有关。认知与腰围的变化无关。

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. Publications over the last year include investigations of long-term effects of assignment to CEE-based therapies on cognitive function, associations between late-life depressive symptoms and regional brain volumes, and associations between weight change and cognitive change. CEE-based hormone therapy was associated with small mean relative decrements in global cognitive function and several domain-specific cognitive functions during the randomized clinical trial, which largely persisted through up to 4 years after the trial. The strongest statistical evidence was for global cognitive function. For domain-specific scores, the mean decrements were slightly smaller and were less significant; these decrements tended to be larger for CEE-alone compared to CEE+MPA. CEE-based therapies, when initiated after the age of 65, produce a small broad-based decrement in cognitive function that persists after their use is stopped, but the differences in cognitive function are small and would not be detectable or have clinical significance for an individual woman. In a second investigation, WHIMS investigators showed that depressed women had lower baseline global cognition and were more likely to have prior hormone therapy history. Moreover, elevated depressive symptoms were associated with smaller volumes in certain frontal lobe subregions but not in the medial temporal lobe structures, suggesting the importance of frontal lobe brain structures in late-life depressive symptoms in women. In a third investigation of 2283 older postmenopausal WHI women, we found a lack of associations between weight and cognition in women who remained stable or gained weight. However, weight loss (p <0.05), most likely signaling incipient disease, was associated with lower cognition. Cognition was not related to changes in waist circumference.