Anti-Viral therapy in Alzheimer's disease

许多病毒潜伏了几十年，然后在大脑中被压力、免疫妥协或其他因素重新激活。 其他因素在最初的口腔感染后，单纯疱疹病毒-1（HSV 1）在三叉神经中潜伏 神经节，然后可以通过逆行轴突运输进入大脑，通常以颞叶为目标。 HSV-1也可以通过嗅觉神经元直接进入大脑。HSV 1（口腔疱疹）和HSV 2（生殖器疱疹） 已知会引发淀粉样蛋白聚集，并且它们的DNA通常存在于淀粉样蛋白斑块中。抗hsv 药物减少了Aβ和p-tau在感染小鼠脑中的积累。HSV 1再激活与tau蛋白相关 在小鼠中，tau蛋白可能是过度磷酸化的，并且可能在tau蛋白跨神经元的传播中起作用。在人类中， 用新产生的HSV 1颗粒“一滴一滴”重新激活，可能会造成神经元损伤， 导致神经变性和阿尔茨海默病（AD）病理学，部分原因是对淀粉样蛋白和tau蛋白影响。 临床研究表明，不同患者组和不同年龄组的HSV血清阳性患者存在认知障碍。 健康成年人，并且抗病毒治疗显示出针对外周HSV感染的稳健功效。我们会进行 这是有史以来第一次直接解决AD长期存在的病毒病因学假设的临床试验，该假设认为， 病毒，特别是非常常见的HSV 1和HSV 2，可能是AD的病因或促成AD的病理。 在血清HSV 1或HSV 2抗体检测阳性的轻度AD患者中， 伐昔洛韦，作为一种抗AD药物，将在口服剂量为2至4克，每天与匹配 安慰剂治疗130例患者（65例伐昔洛韦，65例安慰剂），在一个随机，双盲，78周 第二阶段概念验证试验。假设接受伐昔洛韦治疗的患者的血糖下降幅度较小 与安慰剂相比，使用18F-Florbetapir PET成像显示淀粉样蛋白减少， 在78周的试验中，与安慰剂相比，基线时载脂蛋白E基因型以及变化 在结构MRI、嗅觉识别缺陷和抗病毒抗体滴度方面， 至78周，将在探索性分析中进行评价。在同意腰椎穿刺的患者中，血浆和 将测定CSF阿昔洛韦以确定轻度AD患者伐昔洛韦的CNS渗透程度， 将获得CSF Aβ42、tau、p-tau，用于结局指标变化的子集探索性分析。如果这次试验 如果成功，我们将申请资金，使用研究设计进行更大规模的多中心III期研究。 这将是第二阶段试验的结果。这一创新的第二阶段概念验证试验清楚地表明， 对于治疗AD具有极高的潜在回报。

Many viruses are latent for decades before being reactivated in the brain by stress, immune compromise, or other factors. After the initial oral infection, herpes simplex virus-1 (HSV1) becomes latent in the trigeminal ganglion and can later enter the brain via retrograde axonal transport, often targeting the temporal lobes. HSV1 can also enter the brain via olfactory neurons directly. HSV1 (oral herpes) and HSV2 (genital herpes) are known to trigger amyloid aggregation and their DNA is commonly found in amyloid plaques. Anti-HSV drugs reduce Aβ and p-tau accumulation in brains of infected mice. HSV1 reactivation is associated with tau hyperphosphorylation in mice and may play a role in tau propagation across neurons. In humans, recurrent reactivation with newly produced HSV1 particles, 'drop by drop,' may produce neuronal damage and eventually lead to neurodegeneration and Alzheimer's disease (AD) pathology, partly due to effects on amyloid and tau. Clinical studies show cognitive impairment in HSV seropositive patients in different patient groups and in healthy adults, and antiviral treatments show robust efficacy against peripheral HSV infection. We will conduct the first-ever clinical trial to directly address the long-standing viral etiology hypothesis of AD which posits that viruses, particularly the very common HSV1 and HSV2, may be etiologic or contribute to the pathology of AD. In patients with mild AD who test positive for serum antibodies to HSV1 or HSV2, the generic antiviral drug valacyclovir, repurposed as an anti-AD drug, will be compared at oral doses of 2 to 4 g per day to matching placebo in the treatment of 130 patients (65 valacyclovir, 65 placebo) in a randomized, double-blind, 78-week Phase II proof of concept trial. Patients treated with valacyclovir are hypothesized to show smaller decline in cognition and functioning compared to placebo, and, using 18F-Florbetapir PET imaging, to show less amyloid accumulation than placebo over the 78-week trial. Apolipoprotein E genotype at baseline, as well as changes in cortical thinning on structural MRI, olfactory identification deficits, and antiviral antibody titers from baseline to 78 weeks, will be evaluated in exploratory analyses. In patients who agree to lumbar puncture, plasma and CSF acyclovir will be assayed to establish the degree of CNS penetration of valacyclovir in mild AD, and we will obtain CSF Aβ42, tau, p-tau for subset exploratory analyses with changes in outcome measures. If this trial is successful, we will apply for funding to conduct a larger, multicenter, Phase III study using a study design that will be informed by the results of this Phase II trial. This innovative Phase II proof of concept trial clearly has exceptionally high reward potential for the treatment of AD.