Exploratory imaging outcomes of a phase 1b/2a clinical trial of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: Structural effects and functional connectivity outcomes.
Exploratory imaging outcomes of a phase 1b/2a clinical trial of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: Structural effects and functional connectivity outcomes.
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DOI：
10.1002/trc2.12258
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Brinton RD
中科院分区：
文献类型：
--
作者：
Raikes AC;Hernandez GD;Matthews DC;Lukic AS;Law M;Shi Y;Schneider LS;Brinton RD
Allopregnanolone (ALLO) 是一种内源性神经类固醇，可促进阿尔茨海默病 (AD) 动物模型的神经发生和寡发生并恢复认知功能。基于这些发现研究结果，我们在早期 AD 患者中进行了 ALLO 的随机对照 1b/2a 期多次递增剂量试验 (NCT02221622)，以评估安全性、耐受性和药代动力学。报告了探索性影像学结果，以确定 ALLO 是否影响海马结构、白质完整性和功能连接。 24 名受试者参加了该试验（n = 6 名安慰剂；n = 18 ALLO），并在治疗 12 周之前和之后接受了脑部磁共振成像 (MRI)。海马萎缩率通过体积 MRI 确定，计算为变化率，并在 ALLO 和安慰剂性别、载脂蛋白 E (APOE) ε4 等位基因和 ALLO 剂量亚组之间进行定性评估。使用分数和定量各向异性 (QA) 比较安慰剂和 ALLO 之间的白质微观结构完整性。还使用静息态功能 MRI 比较了各组之间局部、区域间和网络级功能连接的变化。与安慰剂组相比，ALLO 组的海马体积下降速度减慢，在某些情况下甚至逆转。 APOE ε4 携带者的海马体积增加很明显（范围：海马体积增加 0.6% 至 7.8%）。白质完整性的多种测量表明完整性得到保留或改善。 ALLO 显着增加了 690 个纤维束中的 690 个纤维束的分数各向异性 (FA) 和 1888 个纤维束中的 1416 个纤维束的 QA，这些纤维束主要位于胼胝体、双侧丘脑辐射和双侧皮质脊髓束。与结构变化一致，ALLO 增强了 AD 易受影响区域的局部、区域间和网络水平的功能连接，包括楔前叶和后扣带回，以及默认模式网络和边缘系统之间的网络连接。之前临床前研究的再生指标以及来自该 1b/2a 期临床队列的这些基于 MRI 的探索性结果支持进展为 ALLO 作为轻度 AD 再生疗法的 2 期概念验证疗效临床试验（REGEN-BRAIN 研究；NCT04838301）。
Allopregnanolone (ALLO), an endogenous neurosteroid, promoted neurogenesis and oligogenesis and restored cognitive function in animal models of Alzheimer's disease (AD). Based on these discovery research findings, we conducted a randomized‐controlled phase 1b/2a multiple ascending dose trial of ALLO in persons with early AD (NCT02221622) to assess safety, tolerability, and pharmacokinetics. Exploratory imaging outcomes to determine whether ALLO impacted hippocampal structure, white matter integrity, and functional connectivity are reported. Twenty‐four individuals participated in the trial (n = 6 placebo; n = 18 ALLO) and underwent brain magnetic resonance imaging (MRI) before and after 12 weeks of treatment. Hippocampal atrophy rate was determined from volumetric MRI, computed as rate of change, and qualitatively assessed between ALLO and placebo sex, apolipoprotein E (APOE) ε4 allele, and ALLO dose subgroups. White matter microstructural integrity was compared between placebo and ALLO using fractional and quantitative anisotropy (QA). Changes in local, inter‐regional, and network‐level functional connectivity were also compared between groups using resting‐state functional MRI. Rate of decline in hippocampal volume was slowed, and in some cases reversed, in the ALLO group compared to placebo. Gain of hippocampal volume was evident in APOE ε4 carriers (range: 0.6% to 7.8% increased hippocampal volume). Multiple measures of white matter integrity indicated evidence of preserved or improved integrity. ALLO significantly increased fractional anisotropy (FA) in 690 of 690 and QA in 1416 of 1888 fiber tracts, located primarily in the corpus callosum, bilateral thalamic radiations, and bilateral corticospinal tracts. Consistent with structural changes, ALLO strengthened local, inter‐regional, and network level functional connectivity in AD‐vulnerable regions, including the precuneus and posterior cingulate, and network connections between the default mode network and limbic system. Indicators of regeneration from previous preclinical studies and these exploratory MRI‐based outcomes from this phase 1b/2a clinical cohort support advancement to a phase 2 proof‐of‐concept efficacy clinical trial of ALLO as a regenerative therapeutic for mild AD (REGEN‐BRAIN study; NCT04838301).
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影响因子：
6.7
作者：
Irwin, Ronald W.;Brinton, Roberta Diaz
通讯作者：
Brinton, Roberta Diaz
影响因子：
3.7
作者：
Chen S;Wang JM;Irwin RW;Yao J;Liu L;Brinton RD
通讯作者：
Brinton RD
影响因子：
5.2
作者：
Irwin RW;Wang JM;Chen S;Brinton RD
通讯作者：
Brinton RD
DOI：
10.1073/pnas.0308627101
发表时间：
2004-03-30
影响因子：
11.1
作者：
Greicius, MD;Srivastava, G;Menon, V
通讯作者：
Menon, V
影响因子：
5.7
作者：
Chen, Shuhua;Wang, Tian;Brinton, Roberta Diaz
通讯作者：
Brinton, Roberta Diaz