Advanced magnetic resonance imaging of the human brain in normative aging, cognitive impairment, and dementia

人类大脑在正常衰老、认知障碍和痴呆症中的先进磁共振成像

• 批准号: 10688802
• 负责人: Richard Spencer
• 金额: $ 2.79万
• 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/10688802
• 关键词: 3-Dimensional; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Anoxia; Bayesian Analysis; Bayesian Method; Body mass index; Brain; Brain imaging; Brain region; Cartilage; Cerebrovascular Circulation; Cholesterol; Clinical; Cognition; Cognitive; Cognitive deficits; Craniocerebral Trauma; Data Analyses; Data Set; Dementia; Demyelinations; Deposition; Development; Diffuse; Diffusion; Diffusion Magnetic Resonance Imaging; Echo-Planar Imaging; Edema; Environmental Risk Factor; Equilibrium; Evaluation; Exhibits; Free Radicals; Functional disorder; Funding; Genetic Risk; Genotype; Health; Heterogeneity; Hospitals; Image; Impaired cognition; Impairment; Individual; Inflammation; Investigation; Judgment; Laboratories; Language; Lead; Least-Squares Analysis; Lesion; Life; Magnetic Resonance Imaging; Maps; Mathematics; Measures; Memory; Methodology; Methods; Modeling; Morphologic artifacts; Multiple Sclerosis; Myelin; Myelin Sheath; Nature; Noise; Pathway interactions; Pattern; Performance; Phase; Physiologic pulse; Protocols documentation; Publishing; Recovery; Relaxation; Research; Risk; Role; Scanning; Signal Transduction; Slice; Speed; Stains; Structure; Symptoms; T2 weighted imaging; Techniques; Testing; Therapeutic Intervention; Time; Toxic effect; Water; Work; age related; base; biomarker development; clinical development; cognitive ability; cognitive function; density; experimental study; high dimensionality; human data; human imaging; imaging system; improved; in vivo monitoring; interest; mild cognitive impairment; myelination; pre-clinical; prognostic; remyelination; targeted treatment; treatment response; volunteer; white matter

This work is all based on our Interlaboratory Proposa "Patterns of Myelination in Mild Cognitive Impairment", initially funded in 2015 for 2016, with funding renewed for the following year, and our funded 2017 Interlaboratory proposal, entitled: "Establishing the Relationship Between Myelination Patterns and Regional Cerebral Blood Flow in Normative Aging, Mild Cognitive Impairment, and Dementia" Mild cognitive impairment (MCI) is characterized by a progressive decline in cognitive abilities, including memory, language, and judgment. MCI increases the risk of progression to frank dementia, including Alzheimer's disease (AD). Although the majority of cases of MCI may be due to underlying AD pathology, MCI remains a heterogeneous condition. The development of non-invasive markers for MCI due to AD and, in particular, early pre-symptomatic stages of AD would provide important prognostic information and an opportunity for developing and evaluating targeted therapies. Moreover, such markers would provide important mechanistic information on the brain changes underlying impairment in memory and other cognitive functions. Conventional magnetic resonance imaging (MRI) using transverse relaxation time (T2) and magnetization transfer (MT) have been extensively applied in the evaluation of lesions, including therapeutic response, in multiple sclerosis (MS). Increases in T2 have been interpreted as indicating localized or diffuse edema, inflammation, or demyelination, likely in combination. However, while changes of T2 and MT are often attributed to myelin alteration, they do not directly measure myelin and are influenced by other microstructural changes. More advanced methods of myelin assessment are based on the multicomponent decomposition of the transverse (T2) decay signal. MWF correlates strongly with myelin stain, validating MWF as a measure of myelin density. However, these MR MWF analyses cannot be performed on the whole brain within clinically reasonable acquisition times due to the ill-posed nature of the signal analysis required to estimate MWF. Nevertheless, it is clear that quantification of MWF using quantitative MRI has tremendous potential for in vivo monitoring of demyelination and potential remyelination in response to therapies in MCI and, by extension, AD. We have studied the problem of multi-component relaxation extensively in our laboratory and have made several advances in this analysis. Much of our work has centered on cartilage, but we have successfully transferred this work to brain. An important recent extension of this has been the application of sophisticated Bayesian methods for multi-parameter data analysis using multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT). This method permits whole-brain analysis at the expense of requiring analysis of a high-dimensional signal model, that is, model with several unknown parameters. However, we have specifically developed and applied Bayesian analysis methods to the mcDESPOT experiment, permitting whole-brain analysis with high-quality parameter estimates with acquisition times of only 30 - 45 minutes. Further decreases in acquisition time are possible with more advanced hardware. We anticipate that the currently proposed study may lead to a much larger initiative in understanding the role of myelin trajectory in cognitive function, including dementia. As one important direction, these studies may help distinguish cognitively normal A positive individuals who will ultimately develop cognitive impairment from those who will maintain cognitive health, i.e. remain resilient. Indeed, MWF changes even in pre-symptomatic stages of the pathway to cognitive impairment may serve as important biomarkers for development of clinical symptoms and has the potential to greatly facilitate development of early therapeutic interventions. We have evaluated the performance of our analytic technique applied to mcDESPOT over wide ranges of SNR and underlying input parameter values, and experimentally from MR imaging data of human brain obtained through use of different protocols reflectingdifferent noise levels. The accuracy and precision in the estimation of MWF obtained with our Bayesian Monte Carlo analysis showed substantial improvements over the currently used nonlinear least-squares methods. All volunteers undergo the following MRI protocol on the 3T Philips MRI system at Harbor Hospital: - MWF mapping using BMC-mcDESPOT analysis: spoiled recalled gradient echo (SPGR) and balanced steady-state free precession (bSSFP) brain datasets obtained at eight different flip angles and a TR of 8 ms will be acquired. In order to correct for off-resonance artifacts, bSSFP datasets will be acquired with two different phase increments of 00 and 180o. Inversion-recovery SPGR (IR-SPGR) images will also be acquired to be combined with the SPGR dataset in order to correct for flip angle heterogeneity. The total acquisition time is estimated to be approximately 30 minutes for whole brain coverage. Following acquisition, 3D MWF maps will be generated using the BMC-mcDESPOT analysis as indicated above. These methods have all been developed in Dr. Spencer's group. - Multiexponential relaxation mapping: Multi-spin-echo imaging will be used to acquire T2-weighted images at 32 echo-times increasing linearly from 9 to 288 ms, with TR fixed to 2000 ms. Through our published Bayesian analysis and conventional nonnegative least squares, MWF and transverse relaxation times maps will be generated. Results will be compared to those derived through the BMC-mcDESPOT analysis. Given the lengthy acquisition time required for this scan, only localized slices will be obtained instead of whole brain coverage. Additional conventional, non-specific, measures of myelination will also be applied: - Magnetization transfer (MT) mapping: two spin echo images will be obtained, with and without on-resonance saturating pre-pulses. MT maps will be generated through the calculated ratio between those two images. Given the long acquisition time required for this scan, only localized slices will be obtained instead of whole brain coverage. - Apparent diffusion coefficient (ADC) mapping: a single-shot spin-echo echo planar imaging sequence will be used to acquire up to three diffusion-weighted images at diffusion-sensitizing b-values of 0, 500 and 1000 s/mm2, with TR fixed to 2500 ms. Given the long acquisition time required for this scan, only localized slices will be obtained instead of whole brain coverage. EXPECTED OUTCOMES 1) We expect to obtain high-quality myelin water fraction maps from all subjects. While we have demonstrated this methodology in published work, the current proposal will provide the opportunity to test the approach in individuals across a wide range of age and cognition status. 2) We expect to obtain results that will correspond qualitatively to the conventional methods currently employed for white matter assessment, although with greatly improved speed, accuracy, and whole-brain coverage. 3) With age some myelin sheaths exhibit degenerative changes. We expect to find differences in myelin content between healthy young subjects and healthy old subjects in distinct brain regions. 4) We expect to find differences in myelin content between old subjects without cognitive impairment and old subjects with MCI in distinct brain regions. This is our principal hypothesis as detailed above. 5) We expect to determine quantitative associations between MWF and degree of cognitive impairment. Overall, our interest is in the relationship of myelination to MCI and preclinical AD, and the relationship between local cerebral blood flow and myelin deficits. Other relationships, such as with ApeE genotype and BMI, are also under investigation.

这项工作都是基于我们的实验室间提议“轻度认知障碍的髓鞘形式”，最初于2015年为2016年提供资金，第二年的资金恢复了，我们资助的2017年经验培训提案的题为：“确定了在髓鞘和区域性流体之间的关系：” 轻度认知障碍（MCI）的特征是认知能力的逐步下降，包括记忆，语言和判断力。 MCI增加了包括阿尔茨海默氏病（AD）在内的弗兰克痴呆症的风险。尽管大多数MCI病例可能是由于潜在的AD病理而引起的，但MCI仍然是一种异质状况。由于AD，尤其是AD的早期症状阶段而引起的MCI非侵入性标记的开发将提供重要的预后信息，并有机会开发和评估目标疗法。此外，此类标记将提供有关记忆和其他认知功能中大脑变化的重要机械信息。 使用横向松弛时间（T2）和磁化转移（MT）的常规磁共振成像（MRI）已广泛应用于多发性硬化症（MS）中的病变，包括治疗反应。 T2中的增加已被解释为表明可能结合的局部或弥漫性水肿，炎症或脱髓鞘。但是，尽管T2和MT的变化通常归因于髓磷脂的改变，但它们并未直接测量髓磷脂，并且受其他微结构变化的影响。 髓磷脂评估的更先进的方法基于横向（T2）衰减信号的多组分分解。 MWF与髓磷脂染色密切相关，将MWF验证为髓磷脂密度的量度。但是，由于估计MWF所需的信号分析的性质，这些MR MWF分析无法在临床合理的获取时间内对整个大脑进行。然而，很明显，使用定量MRI对MWF进行定量具有巨大的体内监测脱髓鞘和潜在的透明度的潜力，以响应MCI的疗法，并扩展为AD。 我们已经在实验室中广泛研究了多组分放松的问题，并在此分析中取得了一些进步。我们的大部分工作都集中在软骨上，但我们已经成功地将这项工作转移到了大脑上。最新扩展的是，使用多组分驱动的平衡单脉冲观察T1和T2（McDespot）应用了复杂的贝叶斯方法在多参数数据分析中的应用。这种方法允许全脑分析，而牺牲了需要分析高维信号模型的，即具有几个未知参数的模型。 但是，我们已将贝叶斯分析方法专门开发并应用于McDespot实验，从而允许使用高质量参数估计的全脑分析，而获取时间仅为30-45分钟。通过更高级的硬件，可以进一步减少采集时间。 我们预计，当前提出的研究可能会导致更大的举措，以了解髓磷脂轨迹在包括痴呆在内的认知功能中的作用。作为一个重要的方向，这些研究可能有助于区分正常的正常人，他们将对那些维持认知健康的人最终发展认知障碍，即保持韧性。 实际上，即使在认知障碍途径的症状前阶段，MWF也会变化，这可能是发展临床症状的重要生物标志物，并有可能极大地促进早期治疗干预措施的发展。 我们已经评估了在SNR和基础输入参数值的宽范围内应用于McDespot的分析技术的性能，并通过使用反映不同方案的不同协议获得的人类大脑的MR成像数据进行了实验。通过我们的贝叶斯蒙特卡洛分析获得的MWF估计的准确性和精度表明，与当前使用的非线性最小二乘方法相比，有了很大的改善。 所有志愿者都在Harbour Hospital的3T Philips MRI系统上遵守以下MRI协议： - 使用BMC-MCDESPOT分析的MWF映射：将在八个不同的翻盖角度获得的损坏的召回梯度回声（SPGR）和平衡的稳态自由进液（BSSFP）脑数据集，将获取8 ms的TR。为了纠正异子伪影，将以两个不同的阶段增量为00和180o获取BSSFP数据集。反转重新发现SPGR（IR-SPGR）图像也将与SPGR数据集相结合，以纠正翻转角度异质性。对于整个大脑覆盖率，估计总采集时间约为30分钟。获取后，将使用上述BMC-MCDESPOT分析生成3D MWF地图。这些方法均已在Spencer博士的小组中开发。 - 多型弛豫映射：多自动回波成像将用于以32次回声时的T2加权图像从9到288 ms线性增加，而TR固定为2000毫秒。通过我们发表的贝叶斯分析和常规的非负方块，将生成MWF和横向松弛时间地图。结果将与通过BMC-MCDESPOT分析得出的结果进行比较。鉴于此扫描所需的冗长获取时间，仅将获得局部切片而不是全脑覆盖范围。 还将采用其他常规，非特异性的髓鞘措施： - 磁化转移（MT）映射：将获得两个自旋回波图像，并且有和不进行谐振饱和的前脉冲。 MT地图将通过这两个图像之间的计算比率生成。鉴于此扫描所需的较长获取时间，仅将获得局部切片而不是全脑覆盖范围。 - 表观扩散系数（ADC）映射：单发旋转回声回声平面成像序列将用于在扩散敏感的B值为0、500和1000 s/mm2的B值下最多三个扩散加权图像，并以TR固定为2500毫秒。鉴于此扫描所需的较长获取时间，仅将获得局部切片而不是全脑覆盖范围。 预期的结果 1）我们希望从所有受试者获得高质量的髓磷脂水分位图。尽管我们已经在已发表的工作中证明了这种方法，但当前的提案将为测试各个年龄和认知状况的个人的方法提供机会。 2）我们期望获得与当前用于白质评估的常规方法对应的结果，尽管速度，准确性和全脑覆盖范围有很大提高。 3）随着年龄的增长，一些髓鞘会显示出变化的变化。 我们希望在不同大脑区域中健康的年轻受试者和健康的老受试者之间发现髓磷脂含量的差异。 4）我们期望在不同的大脑区域中没有认知障碍的旧受试者和具有MCI的旧受试者之间的髓磷脂含量差异。这是我们的主要假设，如上所述。 5）我们希望确定MWF与认知障碍程度之间的定量关联。 总体而言，我们的兴趣是髓鞘化与MCI和临床前AD的关系，以及局部脑血流与髓磷脂缺陷之间的关系。 其他关系，例如与APEE基因型和BMI，也正在研究中。