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

基本信息

批准号：
10674733
负责人：
Katrin I. Andreasson
金额：
$ 72.3万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
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/10674733
关键词：
Abbreviations Acceleration Address Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer’s disease biomarker Amplifiers Amyloid Amyloid beta-Protein 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 Early identification Employment Equipment and supply inventories Event Exhibits Family Genetic Hallucinations Health system Impaired cognition Individual Inflammatory Institutionalization Intervention Lewy Bodies Lewy body pathology Magnetic Resonance Imaging Medial Memory Memory Loss Memory impairment Mission Movement Disorders Neurofibrillary Tangles Neurology Neuropsychological Tests Newly Diagnosed PET positivity Parkinson Disease Parkinson&apos 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 impairment in Parkinson&apos 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

项目摘要

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.

项目概要/摘要所有患有帕金森病 (PD) 的人都有出现记忆障碍和痴呆的风险，失业人数显着增加、护理人员压力增大、卫生系统成本增加、患者没有可用的干预措施来防止这种毁灭性的发生。疾病的后果，导致 PD 痴呆 (PDD) 和密切相关的路易体痴呆 (DLB) 迫在眉睫的公共卫生危机在尸检中，不到 40% 的患者仅表现出路易体 (LB) 病理学，尽管 60-80% 的患者表现出混合性 LB 和阿尔茨海默病 (LB/AD) 病理，但很少有 PD 患者。不幸的是，我们在临床诊断时被认为患有 AD 共同病理，但我们对 PD 患者的情况知之甚少。发展 AD 共同病理学，这对开发有效疗法造成障碍：PD 患者没有 AD 共病理将是 α-突触核蛋白靶向治疗的理想候选者，而患有 AD 共病理的 PD 患者病理学可能需要联合治疗。这里提出的实验朝着这一方向迈出了重要一步。通过识别活体患者与其认知进展相关的早期 Tau 病理学，克服了这一障碍。为了进行这些实验，我们将利用同时 PET/MRI 的完美共同配准来识别内侧颞叶中微妙出现的 Tau 病变我们还将确定是否有炎症。骨髓细胞 2 上表达的放大器触发受体 (TREM2) 在接受 Tau PET 治疗的 PD 患者中升高 AD 共同病理学的证据，正如我们的初步数据所表明的那样，最后，我们将确定 AD 共同病理学的影响。 AD 共同病理学对认知进展和神经精神症状（例如精神病）的发生的影响。将利用太平洋尤德尔中心和斯坦福大学阿尔茨海默病中心的联合参与者研究中心，为研究具有明确特征的帕金森病患者群体提供了独特的机会对他们进行纵向跟踪，进行临床评估、生物样本采集，并最终进行尸检 A。斯坦福大学神经科学家合作团队接受过运动障碍神经病学培训，核医学、神经免疫学、生物统计学和病理学将实现这些目标。研究与解决阿尔茨海默病国家计划的使命高度相关，该计划呼吁改善痴呆症诊断并加速阿尔茨海默病及相关疾病治疗方法的开发痴呆症，例如帕金森病痴呆症。