IMAGING BIOMARKERS OF PROGRESSION OF MOBILITY IMPAIRMENT IN PD

描述（由申请人提供）： 帕金森病（PD）是一种进行性神经退行性疾病，随着时间的推移会导致严重的运动和非运动残疾。福尔斯在PD中很常见，是最严重的运动障碍。虽然黑质纹状体多巴胺能去神经支配已被认为是一个关键的病理生物学机制，有一个普遍的共识，大多数的姿势控制和步态障碍与福尔斯在PD是耐多巴胺能治疗。因此，有必要进一步探讨帕金森病步态控制的非多巴胺能机制。最近的神经病理学研究表明，PD是一种多系统神经退行性变综合征，也影响多种非多巴胺能递质。例如，脚桥核（PPN），脑干运动中心，也退化的PD和PPN功能障碍已与多巴胺抵抗性运动不能。PPN具有胆碱能和非胆碱能神经元，并向丘脑提供主要的胆碱能输入。我们目前的RR&D项目B4213 R的初步结果表明，胆碱能去神经，特别是丘脑，而不是黑质纹状体多巴胺能去神经的程度与PD的福尔斯有关。除了原发性神经元多巴胺能和非多巴胺能变性，一般皮质功能障碍，特别是额叶，可能会影响PD的步态控制。此外，常见的年龄相关因素，如脑小血管病（BSVD）的存在也可能影响PD的运动功能。BSVD在PD患者中也更常见，可能是由于他们更多的久坐不动的生活方式，并且已被发现独立地导致更高的跌倒风险。BSVD的存在与皮质灌注减少有关，并且可能非选择性地影响皮质神经递质功能。因此，多系统神经退行性变和衰老的一个关键挑战是如何在其他系统同时衰退时在症状的病理生理学中牵连特定系统。纵向研究设计在神经退行性疾病和衰老的研究中具有特别的优势，因为它们允许对多个变量随时间的间隔变化进行独特的受试者内分析，并将其与基线功能相关联。因此，当前提案的总体目标是在项目B4213 R参与者入组研究3.5周年时重复进行脑MRI、全球皮质脑血流量（CBF，来自动态PET成像）、多巴胺能和胆碱能PET成像、临床、活动性、功能和认知评估。从动态PET成像集提取的皮质CBF数据将能够对皮质功能进行全局评估，以研究步态控制中涉及的全局皮质因素。CBF数据还将允许分析整体皮质功能对移动性的影响与可能的特定发射器效应（如果存在）。此外，我们建议在一部分患者中使用[C-11]氟马西尼放射性配体进行GABA能PET成像，以确定丘脑对活动性的可能影响是否特异于丘脑胆碱能去神经支配或代表整体丘脑功能障碍。

DESCRIPTION (provided by applicant): Parkinson disease (PD) is a progressive neurodegenerative condition causing serious motor and non-motor disability over time. Falls are common in PD and represent the most severe motor disability. Although nigrostriatal dopaminergic denervation has been recognized as a key pathobiological mechanism, there is general consensus that the majority of postural control and gait impairments associated with falls in PD are resistant to dopaminergic treatment. Therefore, there is a need to further explore non-dopaminergic mechanisms of gait control in PD. Recent neuropathological studies show that PD is a multi-system neurodegeneration syndrome that also affects multiple non-dopaminergic transmitters. For example, the pedunculopontine nucleus (PPN), a brainstem locomotor center, also degenerates in PD and PPN dysfunction has been associated with dopamine-resistant akinesia. The PPN has cholinergic and non-cholinergic neurons and provides the major cholinergic input to the thalamus. Preliminary results from our current RR&D project B4213R suggest that cholinergic denervation, especially of the thalamus, rather than the degree of nigrostriatal dopaminergic denervation is associated with falls in PD. Apart from primary neuronal dopaminergic and non- dopaminergic degeneration, general cortical dysfunction, especially of the frontal lobe, may affect gait control in PD. Furthermore, the presence of common age-associated factors, such as brain small vessel disease (BSVD) may also affect mobility functions in PD. BSVD is also more common in patients with PD likely due to their more sedentary lifestyle, and has been found to independently contribute to higher fall risk. The presence of BSVD is associated with reduced cortical perfusion and may affect cortical neurotransmitter functions non- selectively. Therefore, a critical challenge in multi-system neurodegeneration and aging is how to implicate a specific system in the pathophysiology of symptoms when other systems simultaneously decline. Longitudinal study designs have a particular advantage in the study of neurodegenerative disorders and aging as they allow a unique within-subject analysis of interval changes of multiple variables over time and relate them to baseline functions. Therefore, the overarching goal of the current proposal is to repeat brain MRI, global cortical cerebral blood flow (CBF, derived from dynamic PET imaging), dopaminergic and cholinergic PET imaging, clinical, mobility, functional and cognitive assessments in project B4213R participants at their 3.5-year anniversary of their enrollment in the study. Cortical CBF data extracted from the dynamic PET imaging set will enable global assessment of cortical function to study global cortical factors involved in gait control. The CBF data will also allow analysis of effects of global cortical function on mobility versus possible specific transmitter effects, if present. In addition, we propose to perform GABAergic PET imaging using the [C-11]Flumazenil radioligand in a subset of patients to determine if possible thalamic effects on mobility are specific for thalamic cholinergic denervation or represent global thalamic dysfunction.