Laboratory Alzheimer's Neuroimaging & Epidemiology, IRCCS Istituto Centro San Giovanni Di Dio Fatebenefratelli, Brescia, Italy.
Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni Di Dio Fatebenefratelli, Brescia, Italy.
Nutr J. 2024 Nov 1;23(1):135. doi: 10.1186/s12937-024-01039-8.
Developing interventions for older adults with subjective cognitive decline (SCD) has the potential to prevent dementia in this at-risk group. Preclinical models indicate that Citrus-derived phytochemicals could benefit cognition and inflammatory processes, but results from clinical trials are still preliminary. The aim of this study is to determine the effects of long-term supplementation with Citrus peel extract on cognitive performance and inflammation in individuals with SCD.
Eighty participants were randomly assigned to active treatment (400 mg of Citrus peel extract containing 3.0 mg of naringenin and 0.1 mg of auraptene) or placebo at 1:1 ratio for 36 weeks. The primary endpoint was the change in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score across the 36-week trial period. Other cognitive outcomes included tests and scales evaluating verbal memory, attention, executive and visuospatial functions, and memory concerns. The secondary endpoint was the change of interleukin-8 (IL-8) levels over the 36-week trial period in a subsample of 60 consecutive participants. An Intention-to-treat approach with generalized linear mixed models was used for data analysis.
The RBANS total score showed significant improvement in both Citrus peel extract and placebo groups at 36 weeks (p for time < .001, d = 0.36, p time x treatment = .910). Significant time effects were also found in cognitive domains of short- and long-term verbal memory (p < .001) and scales of subjective memory (p < .01), with no significant time x treatment interaction. The largest effect sizes were observed in verbal memory in the placebo group (d = 0.69 in short-term, and d = 0.78 in long-term verbal memory). Increased IL-8 levels were found at 36-week follow-up in both Citrus peel extract and placebo groups (p for time = .010, d = 0.21, p time x treatment = .772). Adverse events were balanced between groups.
In this randomized clinical trial, long-term Citrus peel extract supplementation did not show cognitive benefits over placebo in participants with SCD, possibly due to high placebo response. These findings might have specific implications for designing future nutraceutical trials in individuals experiencing SCD.
The trial has been registered at the United States National Library of Medicine at the National Institutes of Health Registry of Clinical Trials under the code NCT04744922 on February 9th, 2021 ( https://www.
gov/ct2/show/NCT04744922 ).
为有主观认知下降（SCD）的老年人开发干预措施有可能预防该高危人群的痴呆症。临床前模型表明，源自柑橘的植物化学物质可能有益于认知和炎症过程，但临床试验的结果仍初步。本研究的目的是确定长期补充柑橘果皮提取物对 SCD 个体认知表现和炎症的影响。
80 名参与者按 1:1 的比例随机分为活性治疗组（400mg 柑橘果皮提取物，含 3.0mg 柚皮苷和 0.1mg 川陈皮素）或安慰剂组，共 36 周。主要终点是 36 周试验期间重复神经心理状态评估电池（RBANS）总分的变化。其他认知结果包括评估言语记忆、注意力、执行和视空间功能以及记忆问题的测试和量表。次要终点是在连续 60 名参与者的亚组中，36 周试验期间白细胞介素-8（IL-8）水平的变化。采用广义线性混合模型的意向治疗方法进行数据分析。
柑橘果皮提取物组和安慰剂组在 36 周时 RBANS 总分均显著改善（时间点 p < 0.001，d = 0.36，p 时间 x 治疗 = 0.910）。认知领域的短期和长期言语记忆（p < 0.001）和主观记忆量表（p < 0.01）也显示出显著的时间效应，无时间 x 治疗的交互作用。安慰剂组在言语记忆方面观察到的效应量最大（短期 d = 0.69，长期言语记忆 d = 0.78）。柑橘果皮提取物组和安慰剂组在 36 周随访时均发现 IL-8 水平升高（时间点 p = 0.010，d = 0.21，p 时间 x 治疗 = 0.772）。两组间不良反应平衡。
在这项随机临床试验中，长期补充柑橘果皮提取物对 SCD 患者的认知表现没有优于安慰剂的效果，这可能是由于安慰剂反应较高。这些发现可能对设计处于 SCD 经历的个体的未来营养临床试验具有特定意义。
该试验于 2021 年 2 月 9 日在美国国立卫生研究院注册中心美国国家医学图书馆注册，注册号为 NCT04744922（https://www.clinicaltrials.gov/ct2/show/NCT04744922）。
NCT04744922
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