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Functional MRI Biomarkers Predicting Cognitive Progression in PD

预测 PD 认知进展的功能 MRI 生物标志物

基本信息

批准号：
10165841
负责人：
Brenda Hanna-Pladdy
金额：
$ 47.36万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165841
关键词：
Alzheimer&apos s disease pathology Amyloid beta-Protein Anatomy Apolipoprotein E Atrophic Attention Awareness Biological Markers Brain Clinical Clinical Trials Cognitive Cognitive deficits Complex Corpus striatum structure Data Dementia Detection Development Diagnosis Diffuse Lewy Body Disease Disease Dopamine Dorsal Dose Early Intervention Early identification Evaluation Event Evolution Follow-Up Studies Foundations Fractals Functional Magnetic Resonance Imaging Functional disorder Future Genes Genetic Markers Genetic Variation Idiopathic Parkinson Disease Image Impaired cognition Impairment Incidence Inclusion Bodies Intervention Investigation Lewy Bodies Longitudinal cohort Longitudinal prospective study Magnetic Resonance Imaging Measures Medial Memory Microtubules Modeling Motor Neurobiology Neurodegenerative Disorders Neuropsychology Outcome Parkinson Disease Parkinson&apos s Dementia Pathologic Pathological Staging Pathology Patients Pattern Performance Prefrontal Cortex Process Quality of life Relative Risks Rest Risk Signal Transduction Staging Structure Subgroup Symptoms Thick Thinness Variant Visual Hallucination Visual Pathways Visuospatial alpha synuclein base biomarker identification blood oxygenation level dependent response cerebral atrophy cognitive impairment in Parkinson&apos s density disability dopamine replacement therapy effective intervention effective therapy experience genetic analysis improved indexing memory recognition mild cognitive impairment morphometry motor symptom neocortical neural network neuroimaging marker non-demented non-motor symptom novel object recognition predictive marker prognostic value prospective receptor density relating to nervous system tau Proteins

项目摘要

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.

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，但随着非运动综合征意识的增强。多巴胺替代疗法（DRT）是对运动功能最有效的治疗，但不能有效治疗非运动功能障碍。运动功能，如认知缺陷。事实上，DRT会对注意力和记忆力产生有害影响，提示这些早期认知缺陷可能是未来认知进展的不可靠标志。轻度 PD中的认知障碍（MCI）很常见，并且可以以不同的速度进展为痴呆，但最终导致大多数患者残疾和生活质量差。弥漫性路易体病很可能是 PD中认知下降的病理学底物，尽管可靠的生物标志物预测病理学负荷和转变为痴呆症的风险尚未确定。发生视觉障碍的PD患者亚组幻觉可以在2.5年内发展成痴呆，有证据表明与此相关的后皮质萎缩，代谢减退然而，由于幻视的发生率低，额外的敏感区域视知觉功能障碍的标志物可能作为病理密度的主要标志，分布本申请的长期目标是研究早期认知的预测有效性， PD缺陷，以及识别功能性神经影像学标记物，这些标记物信号更快地转化为痴呆基于病理分期模型，我们的假设是，皮层区域和背侧和腹侧视觉通路（有或没有视觉通路）幻觉）是认知进展的可靠信号。我们的具体目标如下：（1）利用前瞻性纵向队列评估PD-MCI亚型在预测风险中的预后价值发展成痴呆症将在4年内对轻度PD进行一系列神经心理学评估患者以确定视觉感知缺陷是否预测认知进展。探索性遗传分析 SNCA（α-突触核蛋白）、MAPT（微管相关tau蛋白）和APOE（载脂蛋白E）如何影响将进行认知进展。(2)评价任务激活功能磁共振成像作为一种探针的实用性，通过在临床表现之前研究改变的后皮质网络来评估认知进展。一个物体再认记忆的事件相关fMRI范式将测量背外侧区的BOLD反应 PD患者（伴和不伴MCI）的前额、内侧颞和枕顶颞区，基线。(3)为了确定解剖学和局部脑激活模式，进展基线时和4年内每年一次的结构和功能MRI将表征解剖结构和神经网络变化预测进展。鉴定具有早期诊断敏感性的生物标志物预测和估计转化为痴呆症的风险将为有效干预铺平道路，在治疗效果最大的关键阶段进行神经保护疗法。