Functional MRI Biomarkers Predicting Cognitive Progression in PD

帕金森病(PD)是一种神经退行性疾病，最初的运动症状归因于 黑质纹状体多巴胺耗竭，但随着人们对非运动性症状复合体的认识增加。多巴胺 替代疗法(DRT)是最有效的治疗运动功能的方法，但不能有效地治疗非 运动特征，如认知缺陷。事实上，DRT会对注意力和记忆力产生有害影响， 这表明，这些早期的认知缺陷可能不是未来认知进步的可靠标志。温和的 帕金森病的认知障碍(MCI)很常见，可以以不同的速度发展到痴呆症，但最终 导致大多数患者残疾和生活质量下降。弥漫性路易体病可能是主要的 帕金森病患者认知功能下降的病理基础，尽管可靠的生物标志物可以预测病理负担 转化为痴呆症的风险尚未确定。帕金森病患者的视力亚组 幻觉可在2.5年内发展为痴呆症，有证据表明与之相关的后部皮质萎缩和 代谢不足。然而，由于视觉幻觉的发生率很低，额外敏感的区域 视知觉功能障碍的标记物可能是病理密度和 分发。这项应用的长期目标是研究早期认知的预测有效性 帕金森病的缺陷，以及功能神经成像标志物的识别，信号更快地转化为 痴呆症。我们的假设是，基于病理分期模型，早期累及后部 皮质区域以及背侧和腹侧视觉通路(有或没有视觉存在 幻觉)是认知进步的可靠信号。我们会达致以下具体目标：(一) 利用前瞻性纵向队列评价PD-MCI亚型在预测风险中的预后价值 导致痴呆症的进展。将对轻度帕金森病患者进行为期4年的系列神经心理评估 以确定视觉操作缺陷是否可以预测认知进展。探索性遗传分析 α-突触核蛋白、微管相关tau蛋白和载脂蛋白E如何影响 将进行认知进展。(2)评价任务激活型fMRI作为脑功能检测指标的价值。 在临床表现之前，通过研究改变的后皮质网络来研究认知进展。一个 物体识别记忆的事件相关fMRI范式将测量背外侧的大胆反应 帕金森病患者(伴有和不伴有MCI)的前额、内侧和枕顶颞区 基线。(3)确定预测认知功能的解剖和局部脑激活模式。 进步。在基线和每年4年的结构和功能磁共振成像将显示解剖特征 而神经网络改变了对进展的预测。具有早期敏感性的生物标志物的鉴定 预测和评估转化为痴呆症的风险将为有效的干预铺平道路 在治疗影响最大的关键阶段进行神经保护治疗。

Parkinson’s disease (PD) is a neurodegenerative disease with initial motor symptoms attributed to nigrostriatal dopamine depletion, but with increasing awareness of a non-motor symptom complex. Dopamine replacement therapy (DRT) is the most effective treatment for motor features, but fails to effectively treat non- motor features such as cognitive deficits. In fact, DRT can have a deleterious effect on attention and memory, suggesting that these early cognitive deficits may be unreliable markers for future cognitive progression. Mild cognitive impairment (MCI) in PD is common, and can progress at variable rates to dementia, but eventually results in disability and poor quality of life for most patients. Diffuse Lewy body disease is likely the primary pathological substrate for cognitive decline in PD, although reliable biomarkers predicting pathologic burden and risk of conversion to dementia have not been identified. The subgroup of PD patients experiencing visual hallucinations can develop dementia in 2.5 years, with evidence for associated posterior cortical atrophy and hypometabolism. However, since the incidence of visual hallucinations is low, additional sensitive regional markers of visuoperceptual dysfunction may potentially serve as cardinal signs of pathologic density and distribution. The long-term objective of this application is the study of the predictive validity of early cognitive deficits in PD, and identification of functional neuroimaging markers signaling more rapid conversion to dementia. Our hypothesis, based on models of pathologic staging, is that earlier involvement of posterior cortical regions and the dorsal and ventral visual pathways (with or without the presence of visual hallucinations) are reliable signals for cognitive progression. We will pursue the following specific aims: (1) To utilize a prospective longitudinal cohort to evaluate the prognostic value of PD-MCI subtypes in predicting risk for progression to dementia. Serial neuropsychological evaluations will be given across 4 years to mild PD patients to determine if visuoperceptual deficits predict cognitive progression. An exploratory genetic analysis of how SNCA (α-synuclein), MAPT (microtubule associated tau) and APOE (apolipoprotein E) might influence cognitive progression will be conducted. (2) To evaluate the utility of task-activated fMRI as a probe for cognitive progression by investigating altered posterior cortical networks prior to clinical manifestation. An event-related fMRI paradigm of object recognition memory will measure BOLD response in dorsolateral prefrontal, medial temporal and occipito-parieto-temporal regions in PD patients (with and without MCI) at baseline. (3) To determine the anatomical and regional brain activation patterns predictive of cognitive progression. Structural and functional MRI at baseline and annually for 4 years will characterize anatomical and neural network changes predictive of progression. Identification of biomarkers with sensitivity for early prediction and estimation of risk for conversion to dementia will pave the way for effective intervention with neuroprotective therapies during the critical stage when treatment has the greatest impact.