Cerebral Microstructure in Aging and Dementia using Advanced Quantitative MRI

使用先进定量 MRI 观察衰老和痴呆症中的大脑微观结构

• 批准号: 10688787
• 负责人: Mustapha Bouhrara
• 金额: $ 7.82万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688787
• 关键词: Action Potentials; Adult; Age; Aging; Agitation; Alleles; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Animals; Autopsy; Axon; Blood flow; Brain; Brain Stem; Brain region; Cardiac; Cells; Central Nervous System; Central Nervous System Degenerative Diseases; Cerebrovascular Circulation; Cerebrum; Cholesterol; Cognition; Cognitive; Confusion; Dementia; Demyelinations; Deposition; Desire for food; Development; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Emotional; Emotions; Event; Excision; Exhibits; Failure; Foundations; Free Radicals; Functional disorder; Genes; Genetic; Goals; Homeostasis; Human; Hypoxia; Image; Impaired cognition; Impairment; Intervention; Investigation; Iron; Ischemia; Lead; Life Cycle Stages; Link; Magnetic Resonance Imaging; Maintenance; Measurement; Mental Depression; Metabolic; Metabolism; Methods; Modeling; Moods; Motor; Multiple Sclerosis; Myelin; Myelin Proteolipid Protein; Nature; Nerve Degeneration; Nervous System Physiology; Neurodegenerative Disorders; Neurons; Neurotoxins; Oligodendroglia; Parkinson Disease; Participant; Pathogenesis; Phase; Play; Predisposition; Process; Production; Proxy; Reference Values; Regulation; Research; Risk Factors; Role; Sampling; Senile Plaques; Shapes; Sleep; Structure; Techniques; Variant; Vascular Dementia; Vascular blood supply; Vasomotor; Water; Work; abeta accumulation; age difference; age related; alertness; brain tissue; cohort; density; functional disability; functional outcomes; gray matter; hypoperfusion; imaging modality; improved; insight; lipid metabolism; middle age; mild cognitive impairment; myelin degeneration; myelination; neurodegenerative dementia; neuropathology; neuropsychiatric symptom; new therapeutic target; normal aging; novel marker; pain sensation; progression marker; repaired; respiratory; response; tau Proteins; tau aggregation; theories; therapeutic target; trend; white matter

As indicated in the Goals and Objectives section, the main goals of this research initiative is to further expand our current research to investigate the relationship of myelination and axonal density in the brain to cognitive and functional outcomes, as well as the interplay of iron deposition, local myelination, and axonal density, using myelin water fraction (MWF) metrics for myelin quantification, multi-shell diffusion tensor imaging (MSDTI) for axonal density mapping, and susceptibility imaging (SWI) for local iron content quantification. A further important correlate to these studies is the vulnerability of oligodendrocyte metabolism and axonal density to local cerebral blood flow (CBF) through combined MRI measurements of MWF, MSDTI, SWI, and CBF, in the setting of normative aging (NA), mild cognitive impairment (MCI), and dementia. Further, in addition to cognitive decline, dementia is accompanied by neuropsychiatric symptoms including disturbances in mood, emotion and sleep, as well as confusion, agitation and depression. All of this suggests significant brainstem involvement in the development of dementia. This region is remarkably understudied in the investigation of cognitive impairment and dementia. Significant progress has been achieved during the last fiscal year. Using our advanced MRI techniques for MWF and CBF quantifications: 1- We demonstrated a quadratic, inverted U-shape, relationship between MWF and age in all brain regions investigated, suggesting that myelination continues until middle age followed by decreases at older ages. We also observed that these age-related differences vary across different brain regions, as expected. Finally, our results provide reference values for MWF values in normative aging. This work was motivated by the fact that age is the main risk factor for degenerative central nervous system (CNS) disease and associated cognitive and functional impairment. It is therefore crucial to characterize microstructural changes in the brain that occur with normal aging to distinguish them from changes caused by disease. Postmortem studies have shown that myelin degeneration is among the main sequelae of aging and may be associated with concomitant motor and cognitive decline, as well as likely being closely linked to a number of age-associated neurodegenerative disorders and dementias. Myelin, an electrical insulator essential for action potential conduction and for transporting trophic support to the neuronal axons of the CNS, is crucial for higher-order integrative functions of the brain. Our results provide evidence for nonlinear associations between age and myelin in a large sample of well-characterized adults, using a direct myelin content imaging method. 2- We investigated myelin differences with normal aging within the brainstem. In our cross-sectional investigation, we studied a large cohort of cognitively unimpaired participants spanning a wide age range and found a decrease in myelination with age in most brainstem regions studied, with several regions exhibiting a quadratic association between myelin and age. Little work has been conducted to investigate age differences in the myelin content of brainstem structures. In addition to functioning as a relay and integrative brain center, the brainstem plays an important role in motor function and pain sensation, alertness, and regulation of cardiac, respiratory, and vasomotor functions. Multiple studies suggest significant brainstem involvement in the early development of Alzheimers and Parkinsons diseases with accompanying neuropsychiatric symptoms including disturbances in mood, emotion, appetite, and sleep, as well as confusion, agitation, and depression. Therefore, characterizing age differences in brainstem microstructure could provide important insights into the functional, emotional, and motor alterations that accompany normative aging and neurodegeneration. Our study is the first investigation of MWF differences with normative aging in the adult brainstem. Our work also provides reference MWF values for the main substructures of the brainstem, providing a baseline for investigations of neurodegenerative diseases, such as Alzheimers and Parkinsons diseases. 3- We provided the first demonstration of the association between local blood supply and myelin integrity, and found that myelin content declines with CBF across a wide age range of cognitively normal subjects. Indeed, production and maintenance of myelin integrity through oligodendrocytes is critical for saltatory conduction and normal axonal function. Indeed, accumulating evidence is establishing a close relationship between myelin degeneration and several neuropathologies, including multiple sclerosis and dementia. In animal studies, it has been shown that oligodendrocytes are vulnerable to blood flow deficits, and loss of these cells may occur rapidly in response to reductions in blood flow. Indeed, myelin maintenance through oligodendrocyte metabolism is an energy- intensive process, so that myelin homeostasis is particularly sensitive to hypoxia, hypo-perfusion or ischemia. In addition to substrate delivery, adequate cerebral blood flow (CBF) is crucial for removal of metabolic by- products and neurotoxins. The oligodendrocyte cells and myelin sheets are vulnerable to various insults, including iron accumulation as well as aggregations of tau and amyloid- beta proteins. Aside from potential neuronal damage, these insults can lead to loss of oligodendrocytes or impairment of their myelin synthetic capacity; this may result in deficits in myelin production and repair during turnover, or frank demyelination. Our cross-sectional findings suggest that blood supply may significantly impact white matter integrity, specifically myelin content. We expect that this work may lay the foundation for further longitudinal investigations to establish this link and to clarify the nature of myelin damage in neurodegeneration, including Alzheimers disease. These studies may lead to new markers for disease progression as well as to therapeutic targets. 4- We provided the first demonstration of the association between cerebral iron accumuand myelin integrity, and found that iron content if higher with lower myelin content. This indicate that iron accumulation in the brain is also driven by myelin and oligodendrocytes, cells that incoporate a substential amount of iron for myelin synthesis, breakdown. 5-We found that variation of the APOE gene is correlated with myelin content in several key brain regions. Our analysis indicates that adult carriers of the 2 allele exhibit significantly higher myelin content as compared to noncarriers in several cerebral regions evaluated, while carriers of the 4 allele exhibit regional trends toward lower myelin content as compared to noncarriers with significance observed in various brain structures. This exploratory study provides further evidence of a relationship between genetic background and life-course brain myelination.

如目标和目标部分所示，本研究计划的主要目标是进一步扩展我们当前的研究，以调查大脑中髓鞘形成和轴突密度与认知和功能结果的关系，以及铁沉积、局部髓鞘形成和轴突密度的相互作用，使用髓鞘质水分数 (MWF) 指标进行髓鞘质定量、多壳扩散张量成像 （MSDTI）用于轴突密度图，磁敏成像（SWI）用于局部铁含量定量。与这些研究相关的另一个重要关联是，在正常衰老 (NA)、轻度认知障碍 (MCI) 和痴呆的情况下，通过 MWF、MSDTI、SWI 和 CBF 的组合 MRI 测量，少突胶质细胞代谢和轴突密度对局部脑血流 (CBF) 的脆弱性。此外，除了认知能力下降外，痴呆症还伴有神经精神症状，包括心境、情绪和睡眠障碍，以及混乱、烦躁和抑郁。所有这些都表明脑干与痴呆症的发展密切相关。在认知障碍和痴呆症的研究中，该区域的研究明显不足。 上一财年取得了重大进展。使用我们先进的 MRI 技术进行 MWF 和 CBF 定量： 1- 我们在所有研究的大脑区域中证明了 MWF 与年龄之间存在二次倒 U 形关系，表明髓鞘形成持续到中年，然后在老年时减少。我们还观察到，正如预期的那样，这些与年龄相关的差异在不同的大脑区域中有所不同。最后，我们的结果为规范老化中的MWF值提供了参考价值。这项工作的动机是年龄是退行性中枢神经系统（CNS）疾病以及相关认知和功能障碍的主要危险因素。因此，表征正常衰老过程中发生的大脑微观结构变化至关重要，以将其与疾病引起的变化区分开来。尸检研究表明，髓磷脂变性是衰老的主要后遗症之一，可能与伴随的运动和认知能力下降有关，并且可能与许多与年龄相关的神经退行性疾病和痴呆症密切相关。髓磷脂是一种电绝缘体，对于动作电位传导和向中枢神经系统神经元轴突输送营养支持至关重要，对于大脑的高级整合功能至关重要。我们的结果使用直接髓磷脂含量成像方法，为大量特征明确的成年人样本中年龄与髓磷脂之间的非线性关联提供了证据。 2- 我们研究了脑干内髓磷脂与正常衰老的差异。在我们的横断面调查中，我们研究了一大群年龄范围广泛的认知未受损的参与者，发现大多数研究的脑干区域的髓鞘形成随着年龄的增长而减少，其中一些区域表现出髓磷脂与年龄之间的二次相关性。很少有人研究脑干结构髓磷脂含量的年龄差异。除了作为中继和综合大脑中枢外，脑干还在运动功能和痛觉、警觉性以及心脏、呼吸和血管舒缩功能的调节中发挥着重要作用。多项研究表明，脑干与阿尔茨海默病和帕金森病的早期发展密切相关，并伴有神经精神症状，包括情绪、情绪、食欲和睡眠障碍，以及混乱、激动和抑郁。因此，表征脑干微观结构的年龄差异可以为伴随正常衰老和神经退行性变的功能、情绪和运动改变提供重要的见解。我们的研究是首次调查 MWF 与成人脑干正常衰老的差异。我们的工作还提供了脑干主要亚结构的参考 MWF 值，为阿尔茨海默病和帕金森病等神经退行性疾病的研究提供了基线。 3- 我们首次证明了局部血液供应与髓磷脂完整性之间的关联，并发现在大范围认知正常受试者中，髓磷脂含量随着 CBF 的增加而下降。事实上，通过少突胶质细胞产生和维持髓磷脂完整性对于跳跃传导和正常轴突功能至关重要。事实上，越来越多的证据正在证实髓磷脂变性与多种神经病理学（包括多发性硬化症和痴呆症）之间存在密切关系。动物研究表明，少突胶质细胞很容易受到血流不足的影响，并且这些细胞可能会因血流减少而迅速丧失。事实上，通过少突胶质细胞代谢维持髓磷脂是一个能量密集型过程，因此髓磷脂稳态对缺氧、低灌注或缺血特别敏感。除了底物输送外，充足的脑血流量（CBF）对于代谢副产物和神经毒素的清除也至关重要。少突胶质细胞和髓磷脂片很容易受到各种损伤，包括铁积累以及 tau 蛋白和淀粉样β蛋白的聚集。除了潜在的神经元损伤外，这些损伤还可能导致少突胶质细胞损失或髓磷脂合成能力受损；这可能会导致周转期间髓磷脂生成和修复的缺陷，或直接脱髓鞘。我们的横断面研究结果表明，血液供应可能会显着影响白质完整性，特别是髓磷脂含量。我们预计这项工作可能为进一步的纵向研究奠定基础，以建立这种联系并阐明神经退行性变（包括阿尔茨海默病）中髓磷脂损伤的性质。这些研究可能会产生疾病进展的新标志物以及治疗靶点。 4-我们首次证明了脑铁积累与髓磷脂完整性之间的关联，并发现铁含量越高，髓磷脂含量越低。这表明大脑中铁的积累也是由髓磷脂和少突胶质细胞驱动的，这些细胞掺入大量铁以促进髓磷脂的合成和分解。 5-我们发现 APOE 基因的变异与几个关键大脑区域的髓磷脂含量相关。我们的分析表明，与非携带者相比，2 等位基因的成年携带者在评估的几个大脑区域表现出明显更高的髓磷脂含量，而与非携带者相比，4 等位基因的携带者表现出区域髓磷脂含量较低的趋势，在各种大脑结构中观察到显着性。这项探索性研究提供了遗传背景与生命全程脑髓鞘形成之间关系的进一步证据。