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

项目概要/摘要 认知功能障碍是恶性血液病（HM）生存者接受治疗的公认不良结局 有或没有血液或骨髓移植（BMT）。认知障碍严重挑战幸存者的 独立性和重返工作岗位的能力，此外还降低了他们接受复杂治疗的能力 管理计划，这与老年HM患者的生存结局较差有关。在一个大 在对接受BMT治疗的HM患者进行的前瞻性研究中，我们发现总体认知障碍的患病率很高（高达36%）， 赤字，持续了3年。年龄较大、男性、受教育程度和收入较低、认知储备较低， 以及血脑屏障、端粒稳态和DNA修复基因的遗传变异相关 会增加认知障碍的风险为了满足减轻认知缺陷风险的需要， 我们进行了一项研究，以检查12周的可行性，以家庭为基础，认知训练干预HM 接受同种异体BMT治疗的患者。到目前为止，我们已经招募了43名可评估的患者，获得了60.4%的同意 随机化率为77.3%，随机化后脱落率为20.7%，中位干预依从性为83.3%。 初步结果显示，干预对改善患者的处理速度（p = 0.006）有影响。 基线损伤然而，认知功能是一个复杂的表型，最好涉及几个领域。 使用多成分方法解决，包括补偿（例如认知训练）和 增强分子途径（例如营养性酮病）机制。生酮干预具有 在包括患者在内的非肿瘤领域中，早在6 - 8周就持续显示出认知改善 患有轻度认知障碍、阿尔茨海默病和痴呆症。虽然大脑利用葡萄糖作为 能量来源随着老化而减少;循环血浆酮体是一种有效的替代方法， 水溶性和穿过血脑屏障的能力。此外，营养性酮症上调DNA修复 通路，增强突触可塑性，并减少炎症。这些对HM认知结果的影响 幸存者没有被发现。我们的目的是探索整合外源性生酮的可行性， 补充现有的12周认知训练干预，使用 客观地测量认知功能，并检查多成分干预的持续效果。 本研究将由具有干预经验的合格多学科研究者团队进行 以及伯明翰的亚拉巴马大学的癌症生存研究。我们确定的可行性， 在认知训练干预中招募幸存者提供了测试这些目标所需的基础设施， 未来的目标是在HM中实施一项明确的多组分认知随机临床试验 幸存者

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.