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

项目概要/摘要 所有帕金森病（PD）患者都有发生记忆障碍和痴呆的风险， 失业率显著增加，照顾者压力，卫生系统成本增加，患者 制度化，生存率下降。没有任何干预措施可以防止这种破坏性的 疾病的后果，使PD痴呆症（PDD）和密切相关的路易体痴呆症 (DLB)迫在眉睫的公共卫生危机尸检时，不到40%的患者仅表现出路易体（LB）病理， 而60-80%表现出混合的LB和阿尔茨海默病（LB/AD）病理。相反，极少数PD患者 被认为在临床诊断时具有AD共病理。不幸的是，我们对帕金森病患者 发生AD共病，这对有效治疗的开发造成了障碍：PD患者没有 AD共病是α-突触核蛋白靶向治疗的理想候选者，而AD共病的PD患者 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， 通过识别在世患者中与认知进展相关的早期Tau病理来克服这一障碍。 为了进行这些实验，我们将利用同步PET/MRI的完美共配准来识别 内侧颞叶出现了Tau的病变我们还将确定是否有炎症 髓样细胞上表达的放大器触发受体2或TREM 2在患有Tau PET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共同病理学对认知进展和神经精神症状的发作，如精神病。我们 将利用太平洋尤德尔中心和斯坦福大学阿尔茨海默病研究中心的联合参与者 研究中心，提供了一个独特的机会，研究一个充分表征的PD患者人群 他们被纵向跟踪临床评估，生物标本收集，并最终进行尸检。一 斯坦福大学的神经科学家合作团队，他们接受过运动障碍神经病学的培训， 核医学、神经免疫学、生物统计学和病理学将实现这些目标。拟议 这些研究与解决阿尔茨海默病的国家计划的使命高度相关，该计划呼吁 改善痴呆症的诊断，加速阿尔茨海默病及相关疾病治疗的发展 痴呆症，如帕金森氏病痴呆症。

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.