Multimodal optical imaging investigation of neuronal, metabolic and vascular correlates of aging

随着年龄的增长，认知功能的恶化对加拿大人的生活产生了重大的个人、社会和经济后果，特别是考虑到目前的人口背景。认知衰退的原因和机制尚不清楚，可能是多方面的(神经、代谢和血管)。有证据表明，健康的衰老和疾病对基线血流量和血管顺应性有影响，这表明血流动力学测量与调查和最终诊断年龄相关疾病的相关性。 虽然使用(功能)磁共振成像的传统研究提供了对大脑及其血管系统的高分辨率成像，但没有诊断工具可以告知临床医生某人是否会患上神经退行性疾病。BOLD信号广泛用于脑成像，它的解释很复杂，因为它是血流量、体积和氧合的综合变化的结果。此外，血流动力学基线状态(例如，静息时的血流和代谢率)已被证明影响功能数据，但在功能成像研究中通常不被测量。在老年人等异质人群中，基线生理对功能测量的影响、脑血管网络结构及其密度的变化是数据研究对象间差异的一个原因。 血流动力学测量的这些混淆限制了成像技术作为最终诊断工具的适用性。为了阐明衰老的机制及其与血流动力学反应变化的关系，本项目建议首先开发补充光学成像技术的组合，包括：本征光学成像、散斑流动成像、多普勒光学相干断层成像和双光子显微镜。然后，以前提出的生物物理模型区分代谢过程和血管过程在测量的血流动力学反应中的贡献，将在衰老和高血压动物模型中与显微镜数据进行验证。

Deteriorating cognitive function with aging has significant individual, social and economic consequences on the lives of Canadians, particularly given the current demographic context. The causes and mechanisms of cognitive decline remain unclear and could be manifold (neural, metabolic as well as vascular). There is evidence that healthy aging and disease have effects on baseline blood flow as well as vascular compliance, suggesting the relevance of hemodynamic measurements for investigating and eventually diagnosing age-related conditions. While traditional studies with (functional) magnetic resonance imaging provide high resolution imaging of the brain and its vasculature, no diagnostic tool exists that can inform a clinician on whether someone will develop a neurodegenerative disease. The interpretation of the BOLD signal, vastly used in brain mapping, is complicated as it results from combined changes in blood flow, volume and oxygenation. Furthermore, the hemodynamic baseline state (e.g., blood flow and metabolic rate at rest) has been shown to affect functional data, but is typically not measured in functional imaging studies. In heterogeneous populations such as the elderly, the influence of baseline physiology on functional measurements, changes in the structure of the vascular network and its density in the brain are a cause of inter-subject variability in data. These confounds of hemodynamic measurements limit the applicability of imaging techniques as eventual diagnosis tools. Towards the goal of elucidating the mechanisms of aging and its relation with changes in the hemodynamic response, this projects proposes to first develop a combination of complementary optical imaging techniques including: intrinsic optical imaging, speckle flow imaging, Doppler optical coherence tomography and two photon microscopy. Then, biophysical models previously proposed discriminate the contributions of metabolic and vascular processes in the measured hemodynamic response will be validated against microscopic data in animal models of aging and hypertension.