A multi-component non-pharmacological intervention to improve cognitive outcomes in hematologic cancer survivors

一种多成分非药物干预措施，可改善血液癌症幸存者的认知结果

• 批准号: 10626850
• 负责人: Noha Sharafeldin
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-24 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10626850
• 关键词: Address; Adherence; Affect; Aging; Alabama; Allogenic; Alzheimer' s Disease; Appointment; Area; Attention; Autologous; Blood; Blood - brain barrier anatomy; Bone Marrow Transplantation; Brain; Cancer Survivor; Cancer Survivorship; Cognition; Cognitive; Cognitive deficits; Complex; Consent; DNA Repair Gene; DNA Repair Pathway; Data; Dementia; Education; Educational Intervention; Elderly; Energy-Generating Resources; Enrollment; Evaluable Disease; Fatigue; Future; General Population; Glucose; Goals; Hematologic Neoplasms; High Prevalence; Home; Homeostasis; Impaired cognition; Impairment; Income; Inflammation; Infrastructure; Intervention; Ketone Bodies; Ketoses; Ketosis; Learning; Malignant Neoplasms; Measures; Memory; Metabolic; Metabolic Pathway; Molecular; Morbidity - disease rate; Nutritional; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pilot Projects; Plasma; Population; Prospective Studies; Qualifying; Quality of life; Randomized; Research; Research Personnel; Risk; Self Management; Short-Term Memory; Standardization; Supplementation; Survivors; Synaptic plasticity; Testing; Transplant Recipients; Treatment Efficacy; Universities; Waiting Lists; Work; adverse outcome; arm; blood-brain barrier crossing; cancer therapy; cellular targeting; cognitive function; cognitive reserve; cognitive testing; cognitive training; comparison intervention; computerized; efficacy evaluation; executive function; experience; future implementation; genetic variant; high risk; human old age (65+); improved; interest; intervention effect; intervention program; ketogentic; longitudinal, prospective study; male; mild cognitive impairment; mortality; multi-component intervention; multidisciplinary; novel; phase III trial; processing speed; programs; randomized, clinical trials; risk mitigation; sex; survival outcome; telomere; treatment arm; treatment effect; trial design; water solubility

PROJECT SUMMARY / ABSTRACT Cognitive impairment is a well-established adverse outcome in survivors of hematologic malignancy (HM) treated with and without blood or marrow transplantation (BMT). Cognitive impairment significantly challenges survivors’ independence and ability to return to work, in addition to reducing their ability to follow complex treatment management plans which has been associated with worse survival outcomes in older adults with HM. In a large prospective study of HM patients treated with BMT, we found a high prevalence (up to 36%) of global cognitive deficits, which persisted up to 3y. Older age, male sex, lower education and income, lower cognitive reserve, as well as genetic variants on blood brain barrier, telomere homeostasis, and DNA repair genes were associated with increased risk of cognitive impairment. In order to address the need to mitigate the risk of cognitive deficits, we conducted a study to examine the feasibility of a 12-week, home-based, cognitive training intervention in HM patients treated with allogeneic BMT. To date, we have enrolled 43 evaluable patients, achieving 60.4% consent rate, 77.3% randomization rate, 20.7% post-randomization attrition and median intervention adherence of 83.3%. Preliminary results show an intervention effect in improved processing speed (p=0.006) among patients with baseline impairment. Cognitive function, however, is a complex phenotype involving several domains best tackled using a multi-component approach that involves both compensatory (e.g. cognitive training) and enhancement of molecular pathways (e.g. nutritional ketosis) mechanisms. Ketogenic interventions have consistently shown cognitive improvements as early as 6-8 weeks in the non-oncology space including patients with mild cognitive impairment, Alzheimer's disease and dementia. While the brain's ability to use glucose as an energy source is reduced with aging; circulating plasma ketone bodies are an effective alternative due to their water solubility and ability to cross the blood brain barrier. In addition, nutritional ketosis upregulates DNA repair pathways, enhances synaptic plasticity, and reduces inflammation. These effects on cognitive outcomes in HM survivors have not been explored. We aim to explore the feasibility of integrating exogenous ketogenic supplementation to the existing 12-week cognitive training intervention, examine intervention effects using objectively measured cognitive function, and examine the sustained effects of the multi-component intervention. The study will be conducted by a qualified multidisciplinary team of investigators with experience in intervention and cancer survivorship research at the University of Alabama at Birmingham. Our established feasibility of enrolling survivors in the cognitive training intervention provides the needed infrastructure to test these aims with the future goal of implementation of a definitive multi-component cognitive randomized clinical trial in HM survivors.

项目摘要 /摘要 认知障碍是治疗的血液恶性肿瘤（HM）生存中的良好不利结果 有和没有血液或骨髓移植（BMT）。认知障碍极大地挑战了生存 独立性和恢复工作的能力除了降低其遵循复杂治疗的能力外 与HM老年人的生存结果差有关的管理计划。大 对接受BMT治疗的HM患者的前瞻性研究，我们发现全球认知的患病率很高（高达36％） 缺陷，持续到3岁。年龄较大，男性性别，较低的教育和收入，较低的认知储备为 以及血液脑屏障，端粒稳态和DNA修复基因的遗传变异与 随着认知障碍的风险增加。为了解决减轻认知缺陷风险的需求， 我们进行了一项研究，以研究HM中为12周的，基于家庭的，基于家庭的认知训练干预措施 用同种异体BMT治疗的患者。迄今为止，我们已经招募了43名可评估患者，达到60.4％的同意 速率为77.3％的随机化率，随机损耗后20.7％，中位干预措施依从性为83.3％。 初步结果表明，患者的处理速度提高了处理速度（P = 0.006）的干预效果 基线障碍。但是，认知功能是一个涉及多个领域的复杂表型 使用涉及补偿性（例如认知培训）和 分子途径（例如营养酮症）机制的增强。生酮干预措施 在非肿瘤空间中，在6-8周内一直表现出认知的改善，包括患者 有轻度的认知障碍，阿尔茨海默氏病和痴呆症。而大脑将葡萄糖用作的能力 衰老会减少能源。循环等离子体酮体是一种有效的替代方法 水溶性和越过血脑屏障的能力。此外，营养酮症会上调DNA修复 途径，增强突触可塑性并减少感染。这些对HM认知结果的影响 尚未探索幸存者。我们旨在探索整合外源性基因的可行性 补充现有的12周认知训练干预措施，使用 客观地测量认知功能，并检查多组分干预的持续影响。 该研究将由具有干预经验的合格多学科研究人员进行 以及伯明翰阿拉巴马大学的癌症生存研究。我们确定的可行性 在认知训练干预中注册生存提供了所需的基础设施，以测试这些目标 在HM中实施确定的多组分认知随机临床试验的未来目标 幸存者。