Toxicodietary and genetic determinants of susceptibility to neurodegeneration

总结 理由。拟议的项目寻求预防和阐明神经认知生物标志物的方法， 运动缺陷与长期饮食依赖生氰木薯有关，生氰木薯是一种主食作物， 六亿人生活在热带地区。目标1将实现一种新的木薯加工方法（润湿 方法，WTM），安全地去除氰化合物从木薯粉之前，人类消费， 分层村群随机非劣效性试验，以比较同行领导的 干预（妇女培训其他妇女参加妇女培训运动）和社区保健工作者专家（2名）的干预 干预训练武器）。我们假设同伴主导的WTM干预不劣于 在2年干预期结束时和1年随访时进行专家主导的干预。任务转移到 同行领导的WTM培训如果证明是有效的，将提供更具成本效益的， 可持续意味着在全社区一级推广这一干预措施。主要成果将是 由受训母亲产生的木薯生氰含量（每个干预组N = 200）和尿 在她的konzo和非konzo同胞子女5至12岁的硫氰酸盐（U-SCN）浓度。 次要结果将是儿童的神经心理学表现评分， 考夫曼儿童认知成套评估（KABC-II）和Bruininks/Oseretsky测验（BOT-2） 运动能力的测试目标2将确定干预后木薯氰含量是否减少 和儿童U-SCN与木薯神经毒性生物标志物的变化有关，特别是8，12-异 iPF 2 α-VI异前列烷（氧化剂标记物）、氨甲酰化白蛋白片段KVPQVSTPTLVEVSR（残基 438-452）和LDELRDEGKASSAK（残基206-219），或高瓜氨酸（氨甲酰化标记），和 在KABC-II和BOT-2测试中得分。我们假设：1）较低的木薯生氰含量和U- 在整个两年干预期和一年随访时，SCN与较低的 氧化剂和氨甲酰化标记物，但KABC-II和BOT-2测试得分较高; 在1年随访时持续; 2）较高水平的氧化和氨甲酰化将与 神经心理学表现较差。将在血清（侵入性）、干血斑中监测生物标志物 (DBS)（微创）或尿液（非侵入性）使用组学方法，长期目标是开发 实地快速测试，以监测木薯相关神经发育缺陷的风险。目标3将提高 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.