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，但尚无针对阿尔茨海默氏病（AD）的疾病缓解疗法。大脑葡萄糖代谢降低总是伴随着 AD，并且是疾病进展的重要生物标志物。虽然AD研究的观点是，葡萄糖代谢的变化继发于神经元功能减弱和突触损失，但葡萄糖代谢减少会导致突触功能减弱、包括认知在内的大脑功能下降，以及AD样病理的发展。因此，增加脑葡萄糖利用率是一个有吸引力的治疗目标。尽管葡萄糖利用率下降的原因尚不清楚，但可能的机制将其与大脑中硫胺素（维生素 B1）依赖性过程的下降联系起来。硫胺素依赖性酶对于正常的大脑葡萄糖利用至关重要，并且在 AD 中所有酶都随着临床痴呆评分的下降而减少。在人类和/或动物中，硫胺素缺乏会降低大脑代谢和认知能力，同时促进 AD 样病理，包括斑块和缠结。另一方面，提高大脑硫胺素水平会增加人类和动物的大脑新陈代谢和认知能力。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 AD 应该是有益的。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磷硫胺。人体多中心试验表明，苯磷硫胺可预防糖尿病视网膜病变和周围神经病变，并且是安全的。因此，我们提出了一项针对遗忘性轻度认知障碍 (AMCI) 和轻度 AD 痴呆患者的概念验证试点研究，以检验以下假设：通过给予苯磷硫胺增加脑硫胺素的可用性将延迟 FDG-PET 所示的葡萄糖利用率的降低，并减缓认知能力的进一步下降。拟议的随机、双盲、安慰剂对照临床试验将使用苯磷硫胺治疗 76 名患者一年。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 AD 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.