背景:阿尔茨海默病(AD)是一种进行性疾病,多因素,影响>600万美国人的神经退行性疾病。慢性,低度神经炎症,胰岛素抵抗可能导致AD发病。我们探索了NE3107的神经生理学和神经心理学效应,抗炎,胰岛素增敏分子,在AD。
方法:在此阶段2,开放标签研究,23名轻度认知障碍或轻度痴呆患者接受20mg口服NE3107,每天两次,持续3个月。主要终点使用高级神经影像学分析评估神经生理健康和氧化应激(谷胱甘肽水平)相对于基线的变化。次要终点使用认知评估评估神经心理健康相对于基线的变化,包括11项阿尔茨海默病评估量表-认知子量表(ADAS-Cog11),小型精神状态检查(MMSE),蒙特利尔认知评估,临床痴呆评分,快速痴呆症评定量表,阿尔茨海默病综合评分,和全球变化评级(GRC)。探索性终点评估神经炎症生物标志物(肿瘤坏死因子α,TNF-α)和AD(淀粉样蛋白β和磷酸化tau[P-tau])。
结果:NE3107与临床医生评估的脑血流量和脑内功能连接的改善相关。在MMSE≥20(轻度认知障碍至轻度AD;n=17)的患者中,NE3107与定向相关,但统计学上并不显著,大脑谷胱甘肽水平的变化,随着ADAS-Cog11的统计学显着改善(P=0.017),临床痴呆评分(P=.042),快速痴呆量表(P=0.002),阿尔茨海默病综合评分(P=.0094),和临床医生评定的GRC(P<.001),以及脑脊液P-tau水平(P=.034)和P-tau:淀粉样蛋白β42比值(P=.04)。生物标志物分析也证明了方向性,但统计上不显着,血浆TNF-α的变化,符合NE3107的预期机制。重要的是,我们观察到,在基线MMSE≥20的患者中,TNF-α水平的改善与ADAS-Cog11评分(P=0.026)之间存在统计学上显著的相关性(r=0.59).
结论:我们的结果表明,在这项研究中,NE3107与似乎是积极的神经生理学和神经心理学发现有关,以及诊断为痴呆的患者中与神经炎症和AD相关的生物标志物改善的证据。我们的发现与先前的临床前和临床观察一致,并强调了神经炎症在AD发病机制中的核心作用。
BACKGROUND: Alzheimer\'s disease (AD) is a progressive, multifactorial, neurodegenerative disorder affecting >6 million Americans. Chronic, low-grade neuroinflammation, and insulin resistance may drive AD pathogenesis. We explored the neurophysiological and neuropsychological effects of NE3107, an oral, anti-inflammatory, insulin-sensitizing molecule, in AD.
METHODS: In this phase 2, open-label
study, 23 patients with mild cognitive impairment or mild dementia received 20-mg oral NE3107 twice daily for 3 months. Primary endpoints assessed changes from baseline in neurophysiological health and oxidative stress (glutathione level) using advanced neuroimaging analyses. Secondary endpoints evaluated changes from baseline in neuropsychological health using cognitive assessments, including the 11-item Alzheimer\'s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment, Clinical Dementia Rating, Quick Dementia Rating Scale, Alzheimer\'s Disease Composite Score, and Global Rating of Change (GRC). Exploratory endpoints assessed changes from baseline in neuroinflammation biomarkers (tumor necrosis factor alpha, TNF-α) and AD (amyloid beta and phosphorylated tau [P-tau]).
RESULTS: NE3107 was associated with clinician-rated improvements in cerebral blood flow and functional connectivity within the brain. In patients with MMSE ≥ 20 (mild cognitive impairment to mild AD; n = 17), NE3107 was associated with directional, but statistically nonsignificant, changes in brain glutathione levels, along with statistically significant improvements in ADAS-Cog11 (P = .017), Clinical Dementia Rating (P = .042), Quick Dementia Rating Scale (P = .002), Alzheimer\'s Disease Composite Score (P = .0094), and clinician-rated GRC (P < .001), as well as in cerebrospinal fluid P-tau levels (P = .034) and P-tau:amyloid beta 42 ratio (P = .04). Biomarker analyses also demonstrated directional, but statistically non-significant, changes in plasma TNF-α, consistent with the expected mechanism of NE3107. Importantly, we observed a statistically significant correlation (r = 0.59) between improvements in TNF-α levels and ADAS-Cog11 scores (P = .026) in patients with baseline MMSE ≥ 20.
CONCLUSIONS: Our results indicate that in this
study NE3107 was associated with what appear to be positive neurophysiological and neuropsychological findings, as well as evidence of improvement in biomarkers associated with neuroinflammation and AD in patients diagnosed with dementia. Our findings are consistent with previous preclinical and clinical observations and highlight a central role of neuroinflammation in AD pathogenesis.