New approach to studying white matter aging: symmetric multimodal fusion of MRI techniques targeting different biophysical properties of white matter

描述 其中一个缺失的部分，对发展成功的治疗， 认知能力下降和阿尔茨海默病及相关痴呆症（ADRD）可能是 对白色物质（WM）的理解。多年来，人们对WM老化的研究几乎 仅使用扩散MRI（dMRI），并且主要使用扩散张量成像。的 dMRI的局限性导致了WM完整性与认知的不一致关联， 大脑功能，以及对WM在成人神经可塑性中的作用的低估。的目标 这一建议为研究活体WM微结构提供了一种新的多模态方法 人类我们的方法结合了几种先进的定量MRI技术，对 髓鞘和轴突的不同生物物理特性。因为没有单一的MRI技术-即使是 最先进的-可以充分表征WM组织，我们将使用对称融合分析， 利用每种技术的优势并克服其局限性。具体来说，我们将 采用多集典型相关分析和联合独立成分分析 (mCCA+jICA）来提取模态共享和模态唯一独立分量（IC） 区分年轻人和老年人的WM。我们的样本将包括认知和 神经健康的年轻人（n=35，20- 30岁）和老年人（n=50，60- 80岁）。45分钟 扫描将包括神经突方向密度和弥散成像以量化轴突密度， 纤维定向分散和细胞外体积，基于T1的髓鞘水成像， 对髓鞘脂质双层中捕获的水敏感，以及定量磁化转移， 对与髓磷脂大分子的磁化交换敏感。目标1将测试 多模态方法证实了在后期发展的WM中对老化的选择性脆弱性 地区目的2将测试年龄相关的髓鞘和轴突损失的多模式测量是否 与记忆、处理速度、执行功能和流体能力相关， 弗吉尼亚认知老化项目电池和美国国立卫生研究院的电池。探索性分析将测试 在上述目标上存在性别差异。总之，我们新颖的多模式方法将带来更多 稳健和公正的表征老化WM微观结构，并提供新的证据 关于认知老化的激烈争论一旦建立，我们的方法将得到验证， 认知能力下降的动物模型，扩展到更多样化的样本，并结合 功能磁共振成像。我们的最终目标是确定ADRD治疗的新WM靶点， 诊断症状前痴呆，以便早期干预，并确定保护性措施， 和WM老化的危险因素。

DESCRIPTION One of the missing pieces of the puzzle towards development of successful treatments against cognitive decline and Alzheimer’s Disease and Related Dementias (ADRD) may be understanding of the white matter (WM). For many years, WM aging has been studied almost solely using diffusion MRI (dMRI), and predominantly with diffusion tensor imaging. The limitations of dMRI have lead to inconsistent associations of WM integrity with cognition and brain function, and an underappreciation of the role of WM in adult neuroplasticity. The goal of this proposal is to provide a new multimodal approach for studying WM microstructure in living humans. Our approach combines several advanced quantitative MRI techniques sensitive to different biophysical properties of myelin and axons. As no single MRI technique – even the most advanced – can fully characterize WM tissue, we will use symmetric fusion analysis to capitalize on the strengths and overcome the limitations of each technique. Specifically, we will use the multiset Canonical Correlation Analysis with joint Independent Component Analysis (mCCA+jICA) to extract modality-shared and modality-unique independent components (IC) differentiating the WM of younger from older adults. Our sample will include cognitively and neurologically healthy younger (n=35, 20-30y) and older adults (n=50 60-80y). The 45min-long scan will include Neurite Orientation Density and DIspersion Imaging to quantify axonal density, fiber orientational dispersion, and extracellular volume, a T1-based myelin water imaging, sensitive to water trapped in myelin lipid bilayers, and quantitative magnetization transfer, sensitive to the exchange of magnetization with myelin macromolecules. Aim 1 will test whether the multimodal approach confirms the selective vulnerability to aging in late-developing WM regions. Aim 2 will test whether the multimodal measure of age-related myelin and axonal loss correlates with memory, processing speed, executive function and fluid abilities, measured with the Virginia Cognitive Aging Project battery and the NIH Toolbox®. Exploratory analyses will test sex differences in the above aims. Together, our novel multimodal approach will lead to a more robust and unbiased characterization of the aging WM microstructure and provide new evidence for hotly debated models of cognitive aging. Once established, our approach will be validated in animal models of cognitive decline, extended to more diverse samples, and combined with fMRI. Our ultimate aim is to identify new WM targets for treatments for ADRD, to improve diagnosis of pre-symptomatic dementia to allow early interventions, and to identify protective and risk factors for WM aging.