Data_Sheet_2_Trajectories of (Bio)markers During the Development of Cognitive Frailty in the Doetinchem Cohort Study.pdf

Background: Long-term changes in (bio)markers for cognitive frailty are not well characterized. Therefore, our aim is to explore (bio)marker trajectories in adults who became cognitively frail compared to age- and sex-matched controls who did not become cognitively frail over a 15 year follow-up. We hypothesize that those who become cognitively frail have more unfavorable trajectories of (bio)markers compared to controls.
Methods: The Doetinchem Cohort Study is a longitudinal population-based study that started in 1987–1991 in men and women aged 20–59 years, with follow-up examinations every 5 years. For the current analyses, we used data of 17 potentially relevant (bio)markers (e.g., body mass index (BMI), urea) from rounds 2 to 5 (1993–2012). A global cognitive functioning score (based on memory, speed, and flexibility) was calculated for each round and transformed into education and examination round-adjusted z-scores. The z-score that corresponded to the 10th percentile in round 5 (z-score = −0.77) was applied as cut-off point for incident cognitive frailty in rounds 2–5. In total, 455 incident cognitively frail cases were identified retrospectively and were compared with 910 age- and sex-matched controls. Trajectories up to 15 years before and 10 years after incident cognitive frailty were analyzed using generalized estimating equations with stratification for sex and adjustment for age and, if appropriate, medication use. Results were further adjusted for level of education, depressive symptoms, BMI, and lifestyle factors.
Results: In men, (bio)marker trajectories did not differ as they ran parallel and the difference in levels was not statistically significant between those who became cognitively frail compared to controls. In women, total cholesterol trajectories first increased and thereafter decreased in cognitively frail women and steadily increased in controls, gamma-glutamyltransferase trajectories were more or less stable in cognitively frail women and increased in controls, and urea trajectories increased in cognitively frail women and remained more or less stable in controls. Results were similar after additional adjustment for potential confounders.
Conclusions: Out of the 17 (bio)markers included in this explorative study, differential trajectories for three biomarkers were observed in women. We do not yet consider any of the studied (bio)markers as promising biomarkers for cognitive frailty.

背景：目前对于认知衰弱（cognitive frailty）相关（生物）标志物的长期变化特征尚缺乏充分阐释。因此，本研究旨在探究在为期15年的随访期间，新发认知衰弱成人与年龄、性别匹配的未发生认知衰弱对照人群的（生物）标志物轨迹变化。我们假设，相较于对照人群，新发认知衰弱者的（生物）标志物轨迹更呈不利趋势。
方法：杜廷赫姆队列研究（Doetinchem Cohort Study）是一项基于人群的纵向研究，于1987–1991年针对20~59岁的男女人群启动，每5年开展一次随访检查。本次分析采用了该队列第2至5轮（1993–2012年）中17项潜在相关（生物）标志物的数据，例如体质量指数（body mass index, BMI）、尿素。每一轮随访均计算整体认知功能评分（基于记忆力、反应速度与认知灵活性），并转换为经教育程度与随访轮次校正的z评分。以第5轮随访中处于10百分位的z评分（z评分=−0.77）作为第2至5轮随访中新发认知衰弱的截断值。最终共回顾性确认455例新发认知衰弱病例，并匹配910例年龄、性别匹配的对照人群。采用广义估计方程（generalized estimating equations）分析新发认知衰弱前后15年至10年的标志物轨迹，按性别进行分层，并校正年龄、必要时校正用药情况。后续分析进一步校正了教育程度、抑郁症状、体质量指数与生活方式因素。
结果：在男性人群中，（生物）标志物轨迹无显著差异：新发认知衰弱者与对照人群的标志物水平变化趋势平行，组间水平差异无统计学意义。在女性人群中，认知衰弱者的总胆固醇轨迹呈先升高后降低趋势，而对照人群则呈持续升高趋势；γ-谷氨酰转移酶（gamma-glutamyltransferase）轨迹在认知衰弱女性中基本保持稳定，而对照人群则呈升高趋势；尿素轨迹在认知衰弱女性中呈升高趋势，而对照人群则基本保持稳定。在校正潜在混杂因素后，上述结果未发生显著改变。
结论：本探索性研究纳入的17项（生物）标志物中，仅在女性人群中观察到3项标志物存在差异化轨迹。目前我们尚未将本次研究涉及的任何一项（生物）标志物认定为认知衰弱的潜在有效生物标志物。