The impact of early Tau pathology on cognitive progression and neuropsychiatric symptoms in Parkinson's disease

早期 Tau 病理学对帕金森病认知进展和神经精神症状的影响

• 批准号: 10468837
• 负责人: Katrin I. Andreasson
• 金额: $ 74.7万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468837
• 关键词: Abbreviations; Address; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amplifiers; Amyloid; Amyloid beta-42; Autopsy; Award; Behavioral; Biological Markers; Biometry; Brain; Cause of Death; Cerebrospinal Fluid; Cessation of life; Clinical assessments; Clinical dementia rating scale; Cognitive; Collection; Combined Modality Therapy; Data; Dementia; Dementia with Lewy Bodies; Development; Diagnosis; Discipline of Nuclear Medicine; Disease; Employment; Equipment and supply inventories; Event; Exhibits; Family; Genetic; Hallucinations; Health system; Impaired cognition; Individual; Inflammatory; Institutionalization; Intervention; Lewy Bodies; Lewy Body Dementia; Lewy body pathology; Magnetic Resonance Imaging; Medial; Memory; Memory Loss; Memory impairment; Mission; Movement Disorders; Neurofibrillary Tangles; Neurology; Neuropsychological Tests; Newly Diagnosed; Parkinson Disease; Parkinson' s Dementia; Participant; Pathology; Patients; Performance; Persons; Population; Positron-Emission Tomography; Prognosis; Protocols documentation; Psychoses; Public Health; Research; Resources; Risk; Spinal Puncture; Surrogate Markers; TREM2 gene; Temporal Lobe; Testing; Therapeutic; Time; Training; Uncertainty; Universities; Verbal Learning; Work; advanced disease; alpha synuclein; amnestic mild cognitive impairment; behavior measurement; caregiver stress; clinical diagnosis; cognitive development; cognitive impairment in Parkinson' s; cognitive testing; cost; disability; disability-adjusted life years; effective therapy; experimental study; improved; innovation; innovative technologies; neuroimmunology; neuropathology; neuropsychiatric symptom; neuropsychiatry; next generation; novel; prevent; progression marker; psychotic symptoms; targeted treatment; tau Proteins; tau-1; therapeutic development; therapeutically effective; therapy development

Project Summary/Abstract All individuals with Parkinson’s disease (PD) are at risk for developing memory impairment and dementia, markedly increasing loss of employment, caregiver stress, increased cost to health systems, patient institutionalization, and decreased survival. There are no interventions available to prevent this devastating consequence of disease, making both PD Dementia (PDD) and the closely related Dementia with Lewy Bodies (DLB) a looming public health crisis. At autopsy, less than 40% of patients exhibit only Lewy body (LB) pathology, whereas 60-80% exhibit mixed LB and Alzheimer’s disease (LB/AD) pathology. Conversely, very few PD patients are thought to have AD co-pathology at clinical diagnosis. Unfortunately, we know little about when PD patients develop AD co-pathology, which creates a barrier to the development of effective therapies: PD patients without AD co-pathology would be ideal candidates for α-synuclein targeted therapies, whereas PD patients with AD co- pathology likely would require combination therapy. Experiments proposed here take a significant step toward overcoming this barrier by identifying early Tau pathology in living patients relative to their cognitive progression. To perform these experiments, we will leverage the perfect co-registration of simultaneous PET/MRI to identify subtlely emerging Tau pathology in the medial temporal lobe. We will also determine whether the inflammatory amplifier Triggering Receptor Expressed on Myeloid Cells 2, or TREM2, is elevated in PD patients with Tau PET evidence of AD co-pathology, as is suggested by our preliminary data. Finally, we will determine the impact of AD co-pathology on cognitive progression and the onset of neuropsychiatric symptoms, such as psychosis. We will leverage the combined participants of the Pacific Udall Center and the Stanford Alzheimer’s disease Research Center, which provides a unique opportunity to study a well-characterized population of PD patients who are followed longitudinally with clinical assessments, biospecimen collection, and, ultimately, autopsy. A collaborative team of neuroscientists at Stanford University with training in Movement Disorders Neurology, Nuclear Medicine, Neuroimmunology, Biostatistics and Pathology will carry out these aims. The proposed studies are highly relevant to the mission of the National Plan to Address Alzheimer's Disease, which calls to improve dementia diagnosis and accelerate the development of treatments for Alzheimer's disease and related dementias, such as Parkinson’s disease dementia.

项目摘要/摘要 所有患有帕金森氏病（PD）的人都有发展记忆力障碍和痴呆的风险， 明显增加了就业损失，护理人员压力，增加了卫生系统的成本，患者 制度化并改善了生存。没有可用的干预措施来防止这种毁灭性 疾病的后果，使PD痴呆（PDD）和与Lewy身体紧密相关的痴呆 （DLB）迫在眉睫的公共卫生危机。在尸检时，只有不到40％的患者仅表现出Lewy身体（LB）病理学， 而60-80％暴露了混合LB和阿尔茨海默氏病（LB/AD）病理学。相反，很少有PD患者 人们认为在临床诊断方面具有AD竞争病理学。不幸的是，我们对PD患者何时了解 开发AD共同病理学，这为开发有效疗法的开发造成了障碍：没有PD患者 AD辅助病理学将是α-突触核蛋白靶向疗法的理想候选者，而PD患者均具有 病理可能需要组合疗法。这里提出的实验朝着迈出了重要一步 通过确定活着的患者相对于认知进展，克服这种障碍。 要执行这些实验，我们将利用简单宠物/MRI的完美共同注册来识别 内侧临时叶中的细微出现的tau病理。我们还将确定炎症是否 在tau PET患者的PD患者中，在髓样细胞2或TREM2上表达的放大器触发受体升高 正如我们的初步数据所暗示的那样，AD共同病理学的证据。最后，我们将确定 AD关于认知进展和神经精神症状（例如精神病）发作的共同病理学。我们 将利用太平洋乌德尔中心和斯坦福阿尔茨海默氏病的合并参与者 研究中心提供了一个独特的机会来研究良好的PD患者人群 纵向进行临床评估，生物测定收集以及最终尸检的人。一个 斯坦福大学神经科学家合作团队，并接受运动障碍培训神经病学培训 核医学，神经免疫学，生物统计学和病理学将执行这些目标。提议 研究与国家计划解决阿尔茨海默氏病的任务高度相关，该计划呼吁 改善痴呆症诊断并加速阿尔茨海默氏病及相关治疗的疗法 痴呆症，例如帕金森氏病痴呆症。