Wischik Claude M, Staff Roger T, Wischik Damon J, Bentham Peter, Murray Alison D, Storey John M D, Kook Karin A, Harrington Charles R
School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK.
Aberdeen Royal Infirmary, NHS Grampian, Aberdeen, UK.
J Alzheimers Dis. 2015;44(2):705-20. doi: 10.3233/JAD-142874.
As tau aggregation pathology correlates with clinical dementia in Alzheimer's disease (AD), a tau aggregation inhibitor (TAI) could have therapeutic utility. Methylthioninium (MT) acts as a selective TAI in vitro and reduces tau pathology in transgenic mouse models.
To determine the minimum safe and effective dose of MT required to prevent disease progression on clinical and functional molecular imaging outcomes.
An exploratory double-blind, randomized, placebo-controlled, dose-finding trial of MT (69, 138, and 228 mg/day) was conducted in 321 mild/moderate AD subjects. The primary outcome was change on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) at 24 weeks relative to baseline severity. Effect of treatment on regional cerebral blood flow decline was determined in a sub-study in 135 subjects. After 24 weeks, subjects were re-consented to enter sequential 6- and 12-month blinded extension phases. Registered with ClinicalTrials.gov (NCT00515333).
At 24 weeks, there were significant treatment benefits in two independent populations at the 138 mg/day dose: in moderate subjects on the ADAS-cog scale (treatment effect: -5.42 units, corrected p = 0.047) and two other clinical scales; in mild subjects on the more sensitive regional cerebral blood flow measure (treatment effect: 1.97%, corrected p < 0.001). With continued treatment for 50 weeks, benefit was seen on the ADAS-cog scale in both mild and moderate subjects. The delivery of the highest dose was impaired due to dose-dependent dissolution and absorption limitations.
The minimum safe and effective daily MT dose is 138 mg and suggests that further study of MT is warranted in AD.
由于tau蛋白聚集病理与阿尔茨海默病（AD）的临床痴呆相关，tau蛋白聚集抑制剂（TAI）可能具有治疗作用。亚甲蓝（MT）在体外作为一种选择性TAI，并可减少转基因小鼠模型中的tau蛋白病理改变。
确定预防疾病进展在临床和功能分子成像结果方面所需的MT最低安全有效剂量。
对321例轻度/中度AD患者进行了一项探索性双盲、随机、安慰剂对照、剂量探索试验，给予MT（69、138和228mg/天）。主要结局是相对于基线严重程度，24周时阿尔茨海默病评估量表认知子量表（ADAS-cog）的变化。在135例受试者的一项子研究中确定了治疗对局部脑血流下降的影响。24周后，受试者重新签署知情同意书进入连续6个月和12个月的双盲延长期。在ClinicalTrials.gov注册（NCT00515333）。
在24周时，138mg/天剂量组在两个独立人群中具有显著的治疗益处：在中度受试者的ADAS-cog量表上（治疗效果：-5.42分，校正p = 0.047）以及其他两个临床量表上；在轻度受试者中，在更敏感的局部脑血流测量指标上（治疗效果：1.97%，校正p < 0.001）。持续治疗50周后，轻度和中度受试者在ADAS-cog量表上均有获益。由于剂量依赖性溶解和吸收限制，最高剂量的给药受到影响。
MT的最低安全有效日剂量为138mg，提示有必要对MT在AD中的应用进行进一步研究。
