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

项目摘要/摘要 所有帕金森氏症(PD)患者都有发展为记忆障碍和痴呆症的风险， 显著增加的失业，照顾者的压力，增加的医疗系统和患者的成本 制度化，存活率下降。没有可用的干预措施来防止这种毁灭性的 疾病的后果，使帕金森病痴呆(PDD)和与路易体密切相关的痴呆 (DLB)迫在眉睫的公共卫生危机。在尸检中，只有不到40%的患者只表现出路易体(LB型)病理， 而60-80%的患者表现为混合的LB和阿尔茨海默病(LB/AD)病理。相反，极少数帕金森病患者 在临床诊断时被认为是AD的共同病理。不幸的是，我们对帕金森病患者 发展AD的共同病理，这为开发有效的治疗方法创造了障碍：没有 AD共同病理将是α-突触核蛋白靶向治疗的理想候选者，而PD患者合并AD- 病理学可能需要联合治疗。这里提出的实验迈出了重要的一步， 通过确定活体患者的早期Tau病理与他们的认知进展相关来克服这一障碍。 为了进行这些实验，我们将利用同步PET/MRI的完美联合配准来识别 内侧颞叶出现微妙的Tau病理改变。我们还将确定炎症性疾病是否 帕金森病患者Tau-PET患者髓系细胞2或TREM2上表达的放大器触发受体升高 AD共同病理的证据，正如我们的初步数据所表明的那样。最后，我们将确定 AD共同病理学关于认知进展和神经精神症状的出现，如精神病。我们 将利用太平洋尤德尔中心和斯坦福阿尔茨海默病的联合参与者 研究中心，它提供了一个独特的机会来研究具有良好特征的帕金森病患者群体 他们被纵向跟踪进行临床评估、生物标本收集，并最终进行尸检。一个 斯坦福大学神经科学家合作团队，接受运动障碍神经学方面的培训， 核医学、神经免疫学、生物统计学和病理学将实现这些目标。建议数 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 提高痴呆症诊断水平，加快阿尔茨海默病及其相关治疗方法的发展 痴呆症，如帕金森氏症痴呆症。

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.