Importance Older adults with major depressive disorder (MDD) or mild cognitive impairment (MCI) are at high risk for cognitive decline. Objective To assess the efficacy of cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) targeting the prefrontal cortex in slowing cognitive decline, acutely improving cognition, and reducing progression to MCI or dementia in older adults with remitted MDD (rMDD), MCI, or both. Design, Setting, and Participants This randomized clinical trial was conducted at 5 academic hospitals in Toronto, Ontario, Canada. Participants were older adults who had rMDD (with or without MCI, age ≥65 y) or MCI without rMDD (age ≥60 y). Assessments were made at baseline, month 2, and yearly from baseline for 3 to 7 years. Interventions CR plus tDCS (hereafter, active) or sham plus sham 5 days a week for 8 weeks followed by twice-a-year 5-day boosters and daily at-home CR or sham CR. Main Outcomes and Measures The primary outcome was change in global composite cognitive score. Secondary outcomes included changes in 6 cognitive domains, moderating effect of the diagnosis, moderating effect of APOE ε4 status, change in composite score at month 2, and progression to MCI or dementia over time. Results Of 486 older adults who provided consent, 375 (with rMDD, MCI, or both) received at least 1 intervention session (mean [SD] age, 72.2 [6.4] years; 232 women [62%] and 143 men [38%]). Over a median follow-up of 48.3 months (range, 2.1-85.9), CR and tDCS slowed cognitive decline in older adults with rMDD or MCI (adjusted z score difference [active - sham] at month 60, 0.21; 95% CI, 0.07 to 0.35; likelihood ratio test [LRT] P = .006). In the preplanned primary analysis, CR and tDCS did not improve cognition acutely (adjusted z score difference [active - sham] at month 2, 0.06, 95% CI, -0.006 to 0.12). Similarly, the effect of CR and tDCS on delaying progression from normal cognition to MCI or MCI to dementia was weak and not significant (hazard ratio, 0.66; 95% CI, 0.40 to 1.08; P = .10). Preplanned analyses showed treatment effects for executive function (LRT P = .04) and verbal memory (LRT P = .02) and interactions with diagnosis (P = .01) and APOE ε4 (P < .001) demonstrating a larger effect among those with rMDD and in noncarriers of APOE ε4. Conclusions and Relevance The study showed that CR and tDCS, both targeting the prefrontal cortex, is efficacious in slowing cognitive decline in older adults at risk of cognitive decline, particularly those with rMDD (with or without MCI) and in those at low genetic risk for Alzheimer disease. Trial Registration ClinicalTrials.gov Identifier: NCT02386670.

中文翻译：

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减缓重度抑郁症和轻度认知障碍的认知能力下降：一项随机临床试验。


重要性 患有重度抑郁症 （MDD） 或轻度认知障碍 （MCI） 的老年人认知能力下降的风险很高。目的 评估认知矫正 （CR） 联合针对前额叶皮层的经颅直流电刺激 （tDCS） 在减缓缓解型 MDD （rMDD） 和/或MCI 或两者兼而有之的老年人认知能力下降、急性改善认知和减少进展为 MCI 或痴呆方面的疗效。设计、设置和参与者 这项随机临床试验在加拿大安大略省多伦多市的 5 家学术医院进行。受试者是患有 rMDD （伴或不伴 MCI，年龄 ≥65 岁） 或无 rMDD 的 MCI （年龄 ≥60 岁） 的老年人。在基线、第 2 个月和每年从基线开始进行评估，持续 3 至 7 年。干预措施 CR 加 tDCS（以下简称主动）或假加假手术，每周 5 天，持续 8 周，然后每年两次，5 天加强剂和每日在家 CR 或假 CR。主要结局和措施 主要结局是整体综合认知评分的变化。次要结局包括 6 个认知领域的变化、诊断的调节作用、APOE ε4 状态的调节作用、第 2 个月综合评分的变化以及随着时间的推移进展为 MCI 或痴呆。结果 在 486 名表示同意的老年人中，375 名（患有 rMDD、MCI 或两者兼而有之）接受了至少 1 次干预 （平均 [SD] 年龄，72.2 [6.4] 岁;232 名女性 [62%] 和 143 名男性 [38%]）。在中位随访 48.3 个月 （范围，2.1-85.9） 中，CR 和 tDCS 减缓了患有 rMDD 或 MCI 的老年人的认知能力下降 （第 60 个月调整后的 z 评分差异 [活动 - 假]，0.21;95% CI，0.07 至 0.35;似然比检验 [LRT] P = .006）。 在预先计划的初步分析中，CR 和 tDCS 没有急性改善认知 （第 2 个月调整后的 z 评分差异 [主动 - 假]，0.06,95% CI，-0.006 至 0.12）。同样，CR 和 tDCS 对延迟从正常认知进展到 MCI 或 MCI 进展到痴呆的影响较弱且不显著（风险比，0.66;95% CI，0.40 至 1.08;P = .10）。预先计划的分析显示，执行功能 （LRT， P = .04） 和语言记忆 （LRT， P = .02） 以及与诊断 （P =.01） 和 APOE ε4 （P < .001） 的相互作用的治疗效果，表明在 rMDD 患者和非 APOE ε4 携带者中效果更大。结论和相关性 研究表明，CR 和 tDCS 都针对前额叶皮层，可有效减缓有认知能力下降风险的老年人的认知能力下降，尤其是那些患有 rMDD（伴或不伴 MCI）的人和阿尔茨海默病遗传风险低的人。Trial Registration ClinicalTrials.gov 标识符： NCT02386670.