Anti-Viral therapy in Alzheimer's disease

许多病毒会潜伏数十年，然后因压力、免疫受损或其他原因在大脑中重新激活。 其他因素。初次口腔感染后，单纯疱疹病毒 1 (HSV1) 潜伏在三叉神经中 神经节，随后可以通过逆行轴突运输进入大脑，通常针对颞叶。 HSV1还可以通过嗅觉神经元直接进入大脑。 HSV1（口腔疱疹）和 HSV2（生殖器疱疹） 已知会引发淀粉样蛋白聚集，其 DNA 常见于淀粉样蛋白斑块中。抗单纯疱疹病毒 药物可减少受感染小鼠大脑中 Aβ 和 p-tau 的积累。 HSV1 重新激活与 tau 相关 小鼠体内的过度磷酸化可能在 tau 蛋白跨神经元传播中发挥作用。在人类中，反复发生 新产生的 HSV1 颗粒“一滴一滴”地重新激活可能会产生神经元损伤，并最终 导致神经退行性变和阿尔茨海默病 (AD) 病理，部分原因是对淀粉样蛋白和 tau 蛋白的影响。 临床研究表明，不同患者组和不同人群的 HSV 血清阳性患者存在认知障碍。 健康成年人和抗病毒治疗对外周HSV感染显示出强大的功效。我们将进行 有史以来第一个直接解决 AD 长期存在的病毒病因学假说的临床试验，该假说认为 病毒，特别是非常常见的 HSV1 和 HSV2，可能是 AD 的病因或促成其病理学。 对于血清 HSV1 或 HSV2 抗体检测呈阳性的轻度 AD 患者，通用抗病毒药物 伐昔洛韦被重新用作抗 AD 药物，将每天口服 2 至 4 克剂量与匹配的药物进行比较 在一项随机、双盲、为期 78 周的研究中，安慰剂治疗了 130 名患者（65 名伐昔洛韦，65 名安慰剂） 第二阶段概念验证试验。假设接受伐昔洛韦治疗的患者的病情下降幅度较小 与安慰剂相比，认知和功能得到改善，并且使用 18F-Florbetapir PET 成像显示淀粉样蛋白减少 在 78 周的试验中，累积量高于安慰剂。基线载脂蛋白 E 基因型以及变化 结构 MRI 皮质变薄、嗅觉识别缺陷和抗病毒抗体滴度较基线 至 78 周，将在探索性分析中进行评估。对于同意腰椎穿刺的患者，血浆和 将检测脑脊液阿昔洛韦以确定伐昔洛韦在轻度 AD 中的中枢神经系统渗透程度，我们 将获得 CSF Aβ42、tau、p-tau，用于结果测量变化的子集探索性分析。如果这次审判 如果成功，我们将申请资金，使用研究设计进行更大规模的、多中心的 III 期研究 这将通过第二阶段试验的结果得知。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.