Assogna Martina, Di Lorenzo Francesco, Bonnì Sonia, Borghi Ilaria, Cerulli Irelli Emanuele, Mencarelli Lucia, Maiella Michele, Minei Marilena, Esposito Romina, Casula Elias P, Pezzopane Valentina, D'Acunto Alessia, Porrazzini Francesco, Candeo Francesca, Ferraresi Matteo, Motta Caterina, Ferrari Clarissa, Caltagirone Carlo, Martorana Alessandro, Koch Giacomo
Department of Clinical and Behavioural Neurology, Santa Lucia Foundation IRCCS, Rome 00179, Italy.
Department of Neurosciences, S. Camillo-Forlanini Hospital, Rome 00152, Italy.
Brain Commun. 2025 Mar 5;7(2):fcaf080. doi: 10.1093/braincomms/fcaf080. eCollection 2025.
Frontotemporal dementia is a devastating neurodegenerative disorder for which no pharmacological treatments have been approved. Neuroinflammation plays a central role in driving the pathogenic mechanisms underlying frontotemporal dementia. In the last few years, co-ultramicronized palmitoylethanolamide combined with luteoline has emerged as a potential therapeutic molecule in neurodegenerative disorders pathogenically related to frontotemporal dementia, for its demonstrated strong anti-inflammatory and neuroprotective properties. Here we wanted to determine whether treatment with co-ultramicronized palmitoylethanolamide combined with luteoline may have a clinical impact in frontotemporal dementia patients. We performed a Phase 2, monocentric, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of co-ultramicronized palmitoylethanolamide combined with luteoline in frontotemporal dementia patients. Forty eight patients with a diagnosis of probable frontotemporal dementia were randomly assign in a 1:1 ratio to receive co-ultramicronized palmitoylethanolamide combined with luteoline oral suspension at the dosage of 700 mg + 70 mg twice/day ( = 25) or placebo twice/day ( = 23) for 24 weeks. The primary efficacy outcome measure was the change at 24-weeks in the Clinical Dementia Rating Dementia Staging Instrument from the National Alzheimer's Coordinating Center and frontotemporal lobar degeneration modules-sum of boxes (CDR plus NACC FTLD-SoB). Secondary outcome measures included the Frontal Assessment Battery, Screening for Aphasia in Neurodegeneration, Alzheimer's Disease Cooperative Study-Activities of Daily Living, Neuropsychiatric Inventory, Mini-Mental State Examination and Addenbrooke's Cognitive Examination Revised. Among 48 patients randomized [mean (SD) age 63.2 (8.4), 23 (47.9%) female], 45 (93%) completed the study. Patients in the co-ultramicronized palmitoylethanolamide combined with luteoline group showed less decline for the primary outcome measure (CDR plus NACC FTLD) as compared with patients treated with placebo. The estimated mean change (W0-W24) in CDR plus NACC FTLD score was 0.53 for the co-ultramicronized palmitoylethanolamide combined with luteoline group [95% confidence interval (0.12-0.94)] and 1.39 for the placebo group [95% confidence interval (0.96-1.82)], with an estimated mean difference between of 0.86 [95% confidence interval (0.28-1.45), = 0.005]. Estimated mean change in Alzheimer's Disease Cooperative Study-Activities of Daily Living score was -1.8 for co-ultramicronized palmitoylethanolamide combined with luteoline (95% confidence interval, -3.67 to 0.06) and -7.39 for placebo (95% confidence interval -9.34 to -5.45). Estimated mean change in screening for Aphasia in neurodegeneration scores was -3.987 for co-ultramicronized palmitoylethanolamide combined with luteoline (95% confidence interval, -7.75 to -0.22) and -10.35 for placebo (95% confidence interval, -14.33 to -6.37). No effect of treatment was found on other secondary outcome measures. Our results demonstrate that co-ultramicronized palmitoylethanolamide combined with luteoline shows promising efficacy in slowing down the progression of cognitive and functional symptoms in frontotemporal dementia patients. These findings warrant further investigation and offer potential for the development of effective therapeutic strategies for frontotemporal dementia.
额颞叶痴呆是一种毁灭性的神经退行性疾病，目前尚无获批的药物治疗方法。神经炎症在驱动额颞叶痴呆的致病机制中起着核心作用。在过去几年中，超微细化棕榈酰乙醇胺与木犀草素联合使用已成为一种潜在的治疗分子，用于治疗与额颞叶痴呆发病机制相关的神经退行性疾病，因其具有强大的抗炎和神经保护特性。在此，我们想确定超微细化棕榈酰乙醇胺与木犀草素联合治疗是否会对额颞叶痴呆患者产生临床影响。我们进行了一项2期、单中心、随机、双盲、安慰剂对照试验，以评估超微细化棕榈酰乙醇胺与木犀草素联合治疗对额颞叶痴呆患者的安全性和疗效。48名被诊断为可能患有额颞叶痴呆的患者以1:1的比例随机分组，分别接受每日两次、剂量为700mg + 70mg的超微细化棕榈酰乙醇胺与木犀草素口服混悬液（n = 25）或每日两次的安慰剂（n = 23），为期24周。主要疗效指标是在24周时，来自国家阿尔茨海默病协调中心的临床痴呆评定痴呆分期工具和额颞叶变性模块 - 方框总和（CDR加NACC FTLD - SoB）的变化。次要疗效指标包括额叶评估量表、神经退行性疾病失语筛查、阿尔茨海默病协作研究 - 日常生活活动量表、神经精神科问卷、简易精神状态检查和修订后的Addenbrooke认知检查。在随机分组的48名患者中[平均（标准差）年龄63.2（8.4）岁，女性23名（47.9%）]，45名（93%）完成了研究。与接受安慰剂治疗的患者相比，超微细化棕榈酰乙醇胺与木犀草素联合治疗组的患者在主要疗效指标（CDR加NACC FTLD）上的下降幅度较小。超微细化棕榈酰乙醇胺与木犀草素联合治疗组CDR加NACC FTLD评分的估计平均变化（W0 - W24）为0.53[95%置信区间（0.12 - 0.94）]，安慰剂组为1.39[95%置信区间（0.96 - 1.82）]，估计平均差异为0.86[95%置信区间（0.28 - 1.45），P = 0.005]。阿尔茨海默病协作研究 - 日常生活活动量表评分的估计平均变化，超微细化棕榈酰乙醇胺与木犀草素联合治疗组为 - 1.8（95%置信区间， - 3.67至0.06），安慰剂组为 - 7.39（95%置信区间 - 9.34至 - 5.45）。神经退行性疾病失语筛查评分的估计平均变化，超微细化棕榈酰乙醇胺与木犀草素联合治疗组为 - 3.987（95%置信区间， - 7.75至 - 0.22），安慰剂组为 - 10.35（95%置信区间， - 14.33至 - 6.37）。在其他次要疗效指标上未发现治疗效果。我们的结果表明，超微细化棕榈酰乙醇胺与木犀草素联合使用在减缓额颞叶痴呆患者认知和功能症状的进展方面显示出有前景的疗效。这些发现值得进一步研究，并为开发有效的额颞叶痴呆治疗策略提供了潜力。
