The Aging Brain and the Cognition-Mobility Interface in Clinically Normal Older Adults

 描述(由申请人提供)：这项以患者为导向的研究职业发展奖(K23)申请书旨在通过研究三种主要脑部疾病(淀粉样变性、神经变性和小血管疾病)对老年人认知-活动界面的影响，使候选人Neelesh Nadkarni，MD，PhD，FRCPC成为一名独立的研究员。Nadkarni博士是一名有执照的老年医生，在美国和加拿大接受了内科、老年医学、老年神经病学和认知神经学以及医院医学方面的住院医师和研究员培训。在完成临床培训后，纳德卡尼博士还获得了医学和神经科学博士学位。这项K23奖项将培训Nadkarni博士发展应用先进神经成像技术研究大脑淀粉样变性和神经退行性变的研究技能，并增强他在小血管疾病成像方面的知识。它还将训练他通过改进双任务(步态认知任务)的协议来开发认知-移动接口(组合)。K23研究应用程序将测试淀粉样变性、神经变性和小血管疾病与联合治疗有关的假设，该联合治疗可以预测临床正常老年人(这里定义为那些没有认知或行动能力障碍的人)即将出现的认知和/或行动能力下降。这一应用的前提是，在临床正常的老年人中，由认知或行动能力下降引起的进行性功能损害是始于认知和/或行动能力障碍的连续体。行走时同时完成认知任务可以评估这种结合，这可以作为大脑的“压力测试”。与年龄相关的病理性疾病负担对认知或行动过程重要的大脑区域，在临床正常的老年人中可表现为联合功能缺陷。这项研究将通过在正电子发射断层扫描(PET)上测量匹兹堡B配体的滞留来量化淀粉样变性，通过在磁共振成像(MRI)上测量白质高信号的体积来测量小血管疾病，通过在PET上测量氟-2-脱氧葡萄糖摄取来测量神经变性。这项研究将评估120名认知正常的老年人中影响合并的三种病理之间的关系，这些老年人将从正在进行的脑淀粉样蛋白沉积的纵向研究中招募(RF1 AG025516；PI：KUNK)。这项研究的发现可以为早期发现老年人认知和行动能力下降的机制和临床方法提供新的见解，最终导致预防老龄化不良后果的干预措施的新靶点。这一K23培训和研究应用涉及痴呆症、PET和MRI神经成像、神经心理学、运动测量、统计学、认知和运动老化、姿势控制和老年病学等领域的一流多学科专家团队。这个由知名领导人组成的团队致力于在整个奖项期限内为候选人提供定期指导和咨询。与K23相关的培训和研究活动将在匹兹堡大学进行，这是理想的 适合承担这项工作的。这项K23奖项最终将使这位老年医生候选人成为一名进行以患者为导向的研究的独立调查员，并成为大脑老化和认知-运动接口方面的领导者。

 DESCRIPTION (provided by applicant):This Mentored Patient-Oriented Research Career Development Award (K23) application is designed to enable the candidate, Neelesh Nadkarni, MD, PhD, FRCPC, to become an independent investigator through the study of the influence of three major brain pathologies (amyloidosis, neurodegeneration and small-vessel disease) on the cognition-mobility interface in older adults. Dr. Nadkarni is a licensed practicing geriatricia with residency and fellowship training acquired in the United States and Canada in internal medicine, geriatric medicine, geriatric and cognitive neurology, and hospital medicine. Dr. Nadkarni also completed a PhD in medical sciences and neurosciences following completion of his clinical training. This K23 award will train Dr. Nadkarni to develop research skills in the application of advanced neuroimaging to study brain amyloidosis and neurodegeneration and enhance his knowledge of small-vessel disease imaging. It will also train him to develop the cognition-mobility interface (COMBINE) through the refinement of a protocol of dual-tasks (gait- cognition tasks). The K23 research application will test the hypothesis that amyloidosis, neurodegeneration and small-vessel disease are related to the COMBINE, which can predict impending cognitive and/or mobility decline in clinically normal older adults (defined here as those without cognitive or mobility impairment). This application is based on the premise that in clinically normal older adults, progressive functional impairment stemming from cognitive or mobility decline is a continuum that commences with deficits in cognition and/or mobility. Concurrent performance of cognitive tasks while walking assesses the COMBINE, which can serve as "stress tests" of the brain. Pathological age-related disease burden in brain regions important to cognitive or mobility processes, can manifest as deficits in the COMBINE in clinically normal older adults. This study will quantify amyloidosis by measuring Pittsburgh B ligand retention on Positron Emission Tomography (PET), small-vessel disease by determining volume of white matter hyperintensities on magnetic resonance imaging (MRI), and neurodegeneration by measuring fluoro-2-deoxy-glucose uptake on PET. The study will evaluate the relationships between the three pathologies affecting the COMBINE in 120 cognitively normal older adults, who will be recruited from an ongoing longitudinal study of brain amyloid deposition (RF1 AG025516; PI: Klunk). The findings from this research can provide new insights into mechanisms and clinical approaches for early detection of cognitive and mobility decline in older adults, ultimately leading to novel targets for interventions to prevent adverse outcomes of aging. This K23 training and research application involves a stellar multidisciplinary team of experts in dementia, PET and MRI neuroimaging, neuropsychology, locomotion measurement, statistics, cognitive and motor aging, postural control and geriatrics. This team of renowned leaders is committed to provide the candidate with mentorship and consultation on a regular basis through the entire duration of this award. The K23 related training and research activities will be conducted at the University of Pittsburgh which is ideally suited to undertake this work. This K23 award will ultimately enable the geriatrician-candidate to become an independent investigator conducting patient-oriented research and a leader in brain aging and the cognition-mobility interface.