Benfotiamine in Alzheimer's Disease: A pilot study

描述（由申请人提供）：尽管在早期诊断、神经影像学和生物标志物研究方面取得了重大进展，但阿尔茨海默病（AD）尚无疾病改善疗法。脑葡萄糖代谢降低总是伴随AD，是疾病进展的一个突出的生物标志物。虽然阿尔茨海默病研究的观点是糖代谢的变化是继发于神经元功能减弱和突触丧失，但糖代谢的降低可导致突触功能减弱，包括认知在内的脑功能下降，并导致阿尔茨海默病样病理的发展。因此，增加脑葡萄糖的利用是一个有吸引力的治疗目标。虽然葡萄糖利用率下降的原因尚不清楚，但合理的机制将其与大脑中硫胺素（维生素B1）依赖过程的下降联系起来。硫胺素依赖酶对正常的脑葡萄糖利用至关重要，在阿尔茨海默病中，所有这些酶都随着临床痴呆评分的下降而减少。在人类和/或动物中，硫胺素缺乏会降低脑代谢和认知能力，同时促进AD样病理，包括斑块和缠结。另一方面，提高脑硫胺素能提高人类和动物的脑代谢和认知能力。在AD动物模型中，硫胺素可减少AD样病理。这些发现表明增加脑硫胺素对阿尔茨海默病有益。增加血液和大脑硫胺素最有效的方法是使用硫胺素衍生物苯胺。多中心人体试验表明，苯福胺可以预防糖尿病视网膜病变和周围神经病变，而且是安全的。因此，我们提出了一项概念验证的试点研究，在患有遗忘性轻度认知障碍（AMCI）和轻度AD痴呆的患者中进行，以验证通过给药苯福地胺增加脑硫胺素可用性将延迟FDG-PET显示的葡萄糖利用率降低并减缓认知能力进一步下降的假设。这项随机、双盲、安慰剂对照的临床试验将对76名患者进行为期一年的苯丙胺治疗。拟议的试点临床试验有可能确定一种新的、安全的干预措施，旨在改变阿尔茨海默病进展的生物学和临床过程，从而为更大规模的临床试验提供信息。

DESCRIPTION (provided by applicant): Despite major advances in early diagnosis, neuroimaging, and biomarker research, no disease-modifying therapies are available for Alzheimer's Disease (AD). Reduced brain glucose metabolism always accompanies AD and is an outstanding biomarker of disease progression. While the sentiment in AD research is that the changes in glucose metabolism are secondary to diminished neuronal function and synaptic loss, reduced glucose metabolism can lead to diminished synaptic function, reduced brain function including cognition, and the development of AD like pathology. Thus, increasing brain glucose utilization is an attractive therapeutic target. Although the cause of the decline in glucose utilization is unknown, plausible mechanisms link it to a decline in thiamine (vitamin B1) dependent processes in the brain. Thiamine dependent enzymes are critical to normal brain glucose utilization, and all are diminished in AD in parallel with a decline in clinical dementia rating scores. In humans and/or animals, thiamine deficiency diminishes brain metabolism and cognition, while promoting AD like pathology including plaques and tangles. On the other hand, elevating brain thiamine increases brain metabolism and cognition in humans and animals. In animal models of AD, thiamine diminishes AD-like pathology. These findings suggest that increasing brain thiamine should be beneficial in AD. The most effective way to increase blood and brain thiamine is with the thiamine derivative benfotiamine. Multicenter trials in humans show that benfotiamine prevents diabetic retinopathy and peripheral neuropathy and that it is safe. Thus, we propose a proof of concept pilot study in patients with Amnestic Mild Cognitive Impairment (AMCI) and mild AD dementia to test the hypothesis that increasing brain thiamine availability by administration of benfotiamine will delay the reduction in glucose utilization as shown by FDG-PET and slow further decline in cognition. The proposed randomized, double blind, placebo controlled clinical pilot trial will treat 76 patients with benfotiamine for one yea. The proposed pilot clinical trial has the potential to identify a new, safe intervention aimed at modifying biological and clinical processes of AD progression that could inform a larger clinical trial.