Cognition in Parkinson's Disease

帕金森病的认知

• 批准号: 8842872
• 负责人: DEBORAH Lynn HARRINGTON
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842872
• 关键词: Alzheimer' s Disease; Atrophic; Attention; Award; Basal Ganglia; Biological Markers; Brain; Brain region; Classification; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Communication; Deltastab; Dementia; Development; Diffusion Magnetic Resonance Imaging; Disease; Dorsal; Early Diagnosis; Evolution; Fiber; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Gray unit of radiation dose; Healthcare; Healthcare Systems; Image; Impaired cognition; Incidence; Individual Differences; Intervention; Knowledge; Lateral; Lead; Magnetic Resonance Imaging; Measures; Motor; Multimodal Imaging; Neurodegenerative Disorders; Neuropsychological Tests; Outcomes Research; Parkinson Disease; Pathology; Pathway interactions; Patients; Performance; Phenotype; Prefrontal Cortex; Process; Relative (related person); Research; Risk; Sensitivity and Specificity; Short-Term Memory; Signal Transduction; Staging; Symptoms; System; Testing; Therapeutic Intervention; Time; Tissues; Veterans; Visuospatial; base; blood oxygen level dependent; clinically significant; cognitive change; cognitive function; cognitive task; gray matter; high risk; mild cognitive impairment; neuroimaging; normal aging; prognostic; public health relevance; relating to nervous system; research clinical testing; targeted treatment; white matter

DESCRIPTION (provided by applicant): Parkinson's disease (PD) leads to cognitive deficits that can be more disturbing to patients than the motor symptoms, yet these symptoms are overlooked and untreated despite their high frequency in early disease stages and the high risk for future mild cognitive impairment or dementia. Most PD patients eventually develop dementia, which is up to five times more prevalent than in normal aging. With emerging applications of functional magnetic resonance imaging (fMRI), there is mounting evidence of abnormal brain functioning in PD even when performance is normal on clinical testing. Early structural changes in gray- and white-matter tissue also are associated with subtle changes in cognition in PD patients without dementia. Prediction of cognitive changes before clinical symptoms manifest is vital since optimal interventions will ultimately depend on early detection. The primary goal of this proposal is to identify early multimodal signatures of brain dysfunction in different networks implicated in the development of cognitive impairment in PD. The neural bases of subtle cognitive changes in early stages of PD are not well understood. This has been hampered by a paucity of studies that probe for dysfunction in different brain networks implicated in the development of different types of cognitive impairment. Changes in some networks may be more prognostic of the risk for dementia than changes in others. Moreover, most studies focus on disease-related changes in the amount of brain activation, which is insensitive to communications among brain regions. Since brain regions interact to fulfill a cognitive function, it is essential to study their functional connectivity, which may be a more significant intermediat phenotype of early pathology. It is also critical to consider that the functionality of brain netwoks may depend partly on the structural integrity of grey- and white-matter tissue, yet this also has not been studied in PD. To this end, the proposed project will identify abnormal functional connectivity in different brain networks as measured from the blood oxygen level dependent (BOLD) signal during task-activated fMRI. We will then determine if abnormal functional connectivity in each brain network is related to a loss in white- matter tract integrity or gray-matter volume using diffusion tensor imaging (DTI) and structural MRI (sMRI). PD patients and healthy control subjects will undergo fMRI as they perform three cognitive tasks that probe for functioning in brain networks implicated in the development of cognitive impairment, namely tests of temporal integration, visuospatial working memory, and inhibitory control. Aim 1 will identify disease-related functional changes in the connectivity of brain circuits that govern each cognitive function. The main hypotheses are that functional connectivity in PD will be altered in brain circuits that govern temporal integration (cortico-basal ganglia thalamocortical system), visuospatial working memory (dorsolateral prefrontal cortex circuit, dorsal and ventral attention networks), and inhibitory control (ventral lateral orbitofrontal circuit). Aim 2 will then determin if abnormal functional connectivity of the different brain networks identified by fMRI is associated with a loss in white-matter fiber-tract integrity using DTI tractography. The main hypothesis is that abnormal functional connectivity in brain networks that govern processing in each cognitive domain will best correlate with abnormal tissue diffusivity in the same pathways. For Aim 3, sMRI analyses will be conducted to determine if abnormal functional connectivity of the different brain networks correlates with volume loss. The main hypothesis is that abnormal functional connectivity in brain networks that govern processing in each cognitive domain will correlate with frontostriatal and/or temporal atrophy. Our multimodal inquiry into identifying neuroimaging markers of cognitive changes in distinct brain networks, before clinically significant symptoms manifest, be the first of its kind in PD and will promote a new understanding of pathological mechanisms of cognitive dysfunction. Ultimately, outcomes from this research may inform the selection of surrogate measures for evaluating therapeutic interventions.

描述（由申请人提供）：帕金森氏病（PD）会导致认知缺陷，这可能比患者更令人不安，但尽管在早期疾病阶段频率很高，并且对未来轻度认知障碍或痴呆症的高风险，但这些症状仍被忽视和未治疗。大多数PD患者最终患有痴呆症，其流行程度是正常衰老的五倍。随着功能磁共振成像（fMRI）的新兴应用，即使在临床测试中表现正常，PD的脑功能异常也有越来越多的证据。灰色 - 和白色组织组织的早期结构变化也与无痴呆症患者的认知发生细微变化有关。临床症状之前的认知变化预测至关重要，因为最佳干预措施最终将取决于早期检测。该提案的主要目标是确定不同网络中脑功能障碍的早期多模式特征 与PD认知障碍的发展有关。在PD早期阶段，微妙的认知变化的神经基础尚不清楚。在不同类型的认知障碍发展的不同大脑网络中探测功能障碍的研究削弱了这一点。某些网络的变化可能比其他网络的变化更为预后。此外，大多数研究都集中在与疾病相关的大脑激活量的变化上，这对大脑区域之间的通信不敏感。由于大脑区域相互作用以实现认知功能，因此必须研究其功能连通性，这可能是早期病理学的更重要的中间表型。考虑到脑网的功能可能部分取决于灰质和白色物质组织的结构完整性，但这也尚未在PD中进行研究，这也至关重要。为此，提出的项目将在任务激活的fMRI期间根据血氧水平依赖性信号（BOLD）信号来鉴定不同大脑网络中的异常功能连通性。然后，我们将确定每个大脑网络中的异常功能连接性是否与使用扩散张量成像（DTI）和结构MRI（SMRI）相关的白质图完整性或灰色 - 毛线体积的损失有关。 PD患者和健康对照受试者将执行三个认知任务，以探测与认知障碍发展有关的脑网络中功能的认知任务，即对时间整合，视觉空间工作记忆和抑制控制的测试。 AIM 1将确定控制每个认知功能的脑回路连通性的功能变化。主要的假设是，在控制时间整合的脑电路（Cortico-Basal神经节丘脑皮层系统），视觉空间工作记忆（背侧前额叶皮层皮质电路，背侧和腹侧注意网络）和抑制性对照（腹侧偏侧或横向偏侧循环）中，PD的功能连通性将改变。然后，AIM 2将确定fMRI鉴定的不同大脑网络的异常功能连通性是否与使用DTI拖拉术损失的白种纤维完整性损失有关。主要的假设是，在每个认知领域进行处理的大脑网络中的异常功能连通性将最好与同一途径中的异常组织扩散率相关。对于AIM 3，将进行SMRI分析，以确定不同大脑网络的异常功能连通性是否与体积损失相关。主要的假设是，在每个认知领域处理处理的大脑网络中的异常功能连通性将与额叶和/或时间萎缩相关。我们在识别不同脑网络中认知变化的神经影像学标记的多模式调查（在临床意义上的症状都表现出来）中是PD中的第一个，并将促进对认知功能障碍的病理机制的新理解。最终，这项研究的结果可能会为评估治疗干预措施的替代措施的选择提供信息。