Toxicodietary and genetic determinants of susceptibility to neurodegeneration

摘要 基本原理。拟议的项目寻求方法来预防和阐明神经认知和 与长期饮食依赖氰化木薯有关的运动障碍，木薯是一种主食作物，超过 生活在热带地区的6亿人。AIM 1将实施一种新的木薯加工方法(湿化 方法，WTM)，在人类食用前安全地去除木薯粉中的含氰化合物 分层整群随机非劣势试验以比较同伴领导的有效性 干预(妇女在WTM培训其他妇女)与社区卫生工作者专家的干预(2 干预训练部队)。我们假设，同行主导的WTM干预并不比 在两年干预期结束时和一年随访时由专家领导的干预。任务转移到 同行主导的WTM培训如果被证明是有效的，将提供更具成本效益和 可持续的手段，使这种干预在全社区范围内扩大规模。主要结果将是 实习生母亲产生的木薯氰化物(每个干预臂N=200)和尿液 她5至12岁的兄弟姐妹中的硫氰酸盐(U-SCN)浓度。 次要结果将是使用 考夫曼儿童认知成套测验(KABC-II)和Bruinks/Oseretsky测验(BOT-2) 以提高运动能力。目标2将确定干预后木薯氰化物含量的减少 和儿童U-SCN与木薯神经毒性的生物标记物的变化有关，特别是8，12-iso- IPF2α-VI异前列腺素(氧化标记物)、氨基甲酰化白蛋白片段KVPQVSTPTLVEVSR(残留物 438-452)和LDELRDEGKASSAK(残基206-219)，或高瓜氨酸(氨基甲酰标记物)，以及 KABC-II和BOT-2测试的分数。我们假设1)降低木薯的氰化物含量和U- 在整个两年干预期和一年的随访期内，SCN将与较低的 氧化剂和氨基甲酰化标记物，但KABC-II和BOT-2测试分数较高；类似的模式将是 持续1年的随访；和2)更高水平的氧化和氨甲酰化将与 神经心理表现较差。将监测血清(有创)、干血斑点中的生物标记物 (DBS)(侵入性较小)，或尿液(非侵入性)，使用基因组方法，长期目标是开发 用于监测木薯相关神经发育缺陷风险的现场快速测试。目标3将增强 受Konzo影响的刚果民主共和国的研究人员。

SUMMARY Rationale. The proposed project seeks methods to prevent and elucidate biomarkers of neurocognition and motor deficits associated with chronic dietary reliance on cyanogenic cassava, a staple food crop for more than 600 millions of people living in the tropics. Aim 1 will implement a novel cassava processing method (wetting method, WTM) that safely removes cyanogenic compounds from cassava flour prior to human consumption in a stratified village-cluster randomized non-inferiority trial so as to compare the effectiveness of a peer-led intervention (women training other women in the WTM) with that by community-health worker specialists (2 intervention training arms). We hypothesize that the peer-led WTM intervention is non-inferior to the specialist-led intervention at the end of the 2-year intervention period and at 1-year follow-up. Task shifting to peer-led training for WTM should it prove to be effective, would provide for a more cost-effective and sustainable means to bring this intervention to scale at a community-wide level. Primary outcomes will be the cassava cyanogenic content produced by the trainee mother (N = 200 in each intervention arm) and urinary concentrations of thiocyanate (U-SCN) in her konzo and non-konzo sibling children 5 to 12 years of age. Secondary outcomes will be the neuropsychological performance scores of children assessed using the Kaufman Assessment Battery for Children (KABC-II) for cognition and the Bruininks/Oseretsky Test (BOT-2) for motor proficiency. Aim 2 will determine whether post-intervention reductions in cassava cyanogenic content and child U-SCN are associated with changes in biomarkers of cassava neurotoxicity particularly 8,12-iso- iPF2α-VI isoprostane (oxidant marker), carbamoylated albumin fragments KVPQVSTPTLVEVSR (residues 438-452) and LDELRDEGKASSAK (residues 206-219), or homocitrulline (carbamoylating markers), and scores at the KABC-II and BOT-2 testing. We hypothesize that 1) lower cassava cyanogenic content and U- SCN throughout the two-year intervention period and at one-year follow-up, will be associated with lower oxidant and carbamoylating markers but higher KABC-II and BOT-2 testing scores; and a similar pattern will be sustained at 1-year follow-up; and 2) higher levels of oxidation and carbamoylation will be associated with poorer neuropsychological performance. Biomarkers will be monitored in serum (invasive), dried blood spots (DBS) (less invasive), or urine (non-invasive) using omic methodologies with the long-term goal of developing field-based rapid tests to monitor risk for cassava associated neurodevelopmental deficits. Aim 3 will enhance the research manpower of the konzo-affected Democratic Republic of Congo.