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。认知能力下降的原因和机制仍不清楚，可能是多方面的（神经，代谢以及血管）。有证据表明，健康的老龄化和疾病对基线血流量以及血管顺应性有影响，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。 虽然传统的（功能性）磁共振成像研究提供了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信号的解释，广泛用于脑映射，是复杂的，因为它是由血流量，容量和氧合的综合变化的结果。此外，血液动力学基线状态（例如，血流和静止时的代谢率）已显示影响功能数据，但通常不在功能成像研究中测量。在异质性人群中，如老年人，基线生理对功能测量的影响，血管网络结构及其在大脑中的密度的变化是数据中受试者间变异性的原因。 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液动力学反应变化的关系，该项目建议首先开发互补光学成像技术的组合，包括：内在光学成像，斑点流成像，多普勒光学相干断层扫描和双光子显微镜。然后，先前提出的生物物理模型区分代谢和血管过程中测得的血流动力学反应的贡献将验证对微观数据在动物模型的老化和高血压。

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.