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。Whims研究套件还包括Whims-Young(Whims-Y)研究中女性的认知跟踪，这些女性在50-54岁时被随机通过WHI接受激素治疗。这项名为Whims-Y的研究测试了一项假设，即绝经前后的激素治疗可能有助于晚年的认知功能。Whims-Y研究的初步结果基于1326名绝经后女性的研究，这些女性在试验结束后平均7.2年接受了有效的电话认知评估电池研究，当时女性的平均年龄为67.2岁。最初的报告包括前两次服用认知电池，并没有显示早期羟色胺对后来的认知功能既没有害处也没有好处。 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。在过去的一年里，我们继续在最初的Whims队列(Whims Expansion Study)中通过电话评估进行认知跟踪评估。Whims-Y研究的结论是，在这个队列中获得了足够的数据来检验研究假设。 在过去的一年里，我们继续调查可能调节老年女性认知和大脑结果的因素。我们使用Whims-MRI研究的数据研究了颗粒物空气污染对脑体积的影响(Casanova等人，2016)。体素线性回归模型被用来检验PM2.5暴露与灰质(GM)和白质(WM)之间的关联，并对潜在的混杂因素进行了调整。PM2.5暴露的增加与皮质GM区和皮质下WM区体积的减少有关。对于GM，联系聚集在双侧额叶上、中、内侧回。对于西医来说，最大的簇在额叶，较小的簇在颞叶、顶叶和枕叶。这些发现表明，长期接触PM2.5可能会加速老年女性GM和WM的丧失。 在第二项研究中，我们调查了AD风险等位基因APOE e4是否影响了颗粒性空气污染物和认知障碍之间的关系(Cciottolo等人，2017年)。我们发现，居住在细颗粒物超过EPA标准的地方，全球认知能力下降和全因痴呆症的风险分别增加了81%和92%，APOE 4/4携带者的不良反应更强。 我们还继续调查了羟色胺对纵向认知轨迹的长期影响(Espeland等人，2017)。使用来自奇思妙想和奇思妙想-Y队列的数据，我们发现，在绝经期(奇思妙想)前后服用羟色胺对多年后测量的纵向认知变化既没有害处，也没有好处。相反，当给65岁以后的老年女性服用羟色胺时，如果对老年女性服用，它会导致几个认知领域的微小下降，并持续多年。 Whims的下一阶段分析将重点放在那些活到80岁以上并在认知方面保持健康和认知韧性的女性。

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. The WHIMS Suite of Studies also includes 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 tested the hypothesis that hormone therapy around the time of the menopause may benefit cognitive function later in life. 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 earlyHT on later cognitive function. 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. The WHIMS-Y study has concluded as sufficient data were obtained in this cohort to test the study hypotheses. Over the last year, we have continued to investigate factors that may modulate cognitive and brain outcomes in older women. We examined the effects of particulate air pollution on brain volumes using data from the WHIMS-MRI Study (Casanova et al, 2016). Voxel-wise linear regression models were used to examine associations between PM2.5 exposure and gray matter (GM) and white matter (WM), with adjustment for potential confounders. Increased PM2.5 exposure was associated with smaller volumes in both cortical GM and subcortical WM areas. For GM, associations were clustered in the bilateral superior, middle, and medial frontal gyri. For WM, the largest clusters were in the frontal lobe, with smaller clusters in the temporal, parietal, and occipital lobes. These findings suggest that long-term PM2.5 exposures may accelerate loss of both GM and WM in older women. In a second study, we investigated whether the AD risk allele APOE e4 influenced the relation between particulate air pollutants and cognitive impairment (Caciottolo et al., 2017). We found that residing in places with fine PM exceeding EPA standards increased the risks for global cognitive decline and all-cause dementia respectively by 81 and 92%, with stronger adverse effects in APOE 4/4 carriers. We also continued to investigate the long-term effects of HT on longitudinal cognitive trajectories (Espeland et al, 2017). Using data from the WHIMS and WHIMS-Y cohorts, we found that HT administered around menopause (WHIMSY) had neither harm nor benefit to longitudinal cognitive change measured years later. In contrast, when administered to older women after the age of 65, HT resulted in small decrements in If administered in older women, it results in small decrements in several cognitive domains that remain for many years. The next phase of the WHIMS analyses are focusing on women who survive to old age (80+) and remain cognitively healthy, cognitive resilience.