Rajji Tarek K, Bowie Christopher R, Herrmann Nathan, Pollock Bruce G, Lanctôt Krista L, Kumar Sanjeev, Flint Alastair J, Mah Linda, Fischer Corinne E, Butters Meryl A, Bikson Marom, Kennedy James L, Blumberger Daniel M, Daskalakis Zafiris J, Gallagher Damien, Rapoport Mark J, Verhoeff Nicolaas P L G Paul, Golas Angela C, Graff-Guerrero Ariel, Vieira Erica, Voineskos Aristotle N, Brooks Heather, Melichercik Ashley, Thorpe Kevin E, Mulsant Benoit H
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Department of Psychiatry and Toronto Dementia Research Alliance, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
JAMA Psychiatry. 2025 Jan 1;82(1):12-21. doi: 10.1001/jamapsychiatry.2024.3241.
Older adults with major depressive disorder (MDD) or mild cognitive impairment (MCI) are at high risk for cognitive decline.
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.
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.
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.
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.
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.
ClinicalTrials.gov Identifier: NCT02386670.
患有重度抑郁症（MDD）或轻度认知障碍（MCI）的老年人认知功能下降风险很高。
评估认知康复（CR）联合经颅直流电刺激（tDCS）靶向额叶前皮质在减缓认知功能下降、急性改善认知以及减少缓解期MDD（rMDD）、MCI或二者皆有的老年人进展为MCI或痴呆方面的疗效。
设计、背景和参与者：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。参与者为患有rMDD（无论有无MCI，年龄≥65岁）或无rMDD的MCI（年龄≥60岁）的老年人。在基线、第2个月以及从基线开始每年进行评估，为期3至7年。
CR联合tDCS（以下简称“活性治疗组”）或假刺激联合假刺激，每周5天，共8周，随后每年进行两次为期5天的强化治疗，以及每日在家进行CR或假CR。
主要结局为总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个月时综合评分的变化以及随时间进展为MCI或痴呆的情况。
在486名同意参与的老年人中，375名（患有rMDD、MCI或二者皆有）接受了至少1次干预治疗（平均[标准差]年龄，72.2[6.4]岁；女性232名[62%]，男性143名[38%]）。在中位随访48.3个月（范围2.1 - 85.9个月）期间，CR和tDCS减缓了患有rMDD或MCI的老年人的认知功能下降（第60个月时调整后的z评分差异[活性治疗组 - 假刺激组]为0.21；95%置信区间，0.07至0.35；似然比检验[LRT]P = 0.006）。在预先计划的主要分析中，CR和tDCS未急性改善认知功能（第2个月时调整后的z评分差异[活性治疗组 - 假刺激组]为0.06，95%置信区间， - 0.006至0.12）。同样，CR和tDCS在延迟从正常认知进展为MCI或从MCI进展为痴呆方面的作用微弱且不显著（风险比，0.66；95%置信区间，0.40至1.08；P = 0.10）。预先计划的分析显示在执行功能方面有治疗效果（LRT P = 0.04）以及言语记忆方面（LRT P = 0.02），并且与诊断存在交互作用（P = 0.01）以及与APOE ε4存在交互作用（P < 0.001），表明在患有rMDD的人群以及APOE ε4非携带者中效果更大。
该研究表明，靶向额叶前皮质的CR和tDCS在减缓有认知功能下降风险的老年人，特别是那些患有rMDD（无论有无MCI）以及阿尔茨海默病遗传风险较低的老年人的认知功能下降方面是有效的。
ClinicalTrials.gov标识符：NCT02386670。
