There is growing interest in clinical neurosciences in the identification of biomarkers that can support early disease diagnosis as well as monitoring of disease progression and evaluation of new therapies. In the absence of clear morphological modifications in age-related conditions, functional imaging is expected to provide important insights into cerebral pathophysiology that may lead to sensitive biomarkers of brain disease. In particular, small vessel diseases (SVD) are one of the most prevalent causes of dementia and even a low load of associated white matter (morphological) lesions may reflect significant (functional) disruption of the cerebral microvasculature, metabolism and function. Changes in cerebral metabolism and blood supply have also been associated with age-related cognitive decline. CADASIL (Cerebral Autosomic Dominant Arteriopathy With Subcortical Infarcts and Leucoencephalopathy) is considered a model of vascular dementia, usually in the presence of only minor age-related changes, and it may therefore help clarify the key roles of such physiological parameters in SVD and normal aging.

The critical physiological parameters cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) can in principle be measured by Positron Emission Tomography (PET) using 15O-labelled water and oxygen. However, the requirement of an onsite cyclotron, extremely high costs and use of ionizing radiation severely limit the clinical applicability of this technique. Magnetic Resonance Imaging (MRI), on the other hand, provides a number of non-invasive and accessible methods for assessing cerebral physiology, but their predominantly indirect and non-quantitative nature has hampered their translation into clinical applications. In this Project, we propose to overcome current methodological limitations and develop completely noninvasive and quantitative MRI techniques for fast and reliable evaluation of cerebral physiology in clinical applications.

The baseline regional CBF and associated arterial transit times will be measured across the brain using an optimized Arterial Spin Labeling (ASL) technique previously developed by the team. The ASL technique will then be combined with the acquisition of Blood Oxygenation Level Dependent (BOLD) data, in order to assess dynamic physiological parameters, based on preliminary work by the team. Firstly, cerebrovascular reactivity (CVR) and associated vascular delays, describing the ability of blood vessels to dilate and contract, will be mapped by measuring the BOLD and CBF responses to noninvasive respiratory challenges inducing hypercapnia or hypocapnia. Secondly, CMRO2 changes associated with well-established neuronal stimulation paradigms will be mapped based on the calibration of the BOLD and CBF responses by those to the respiratory challenges.

The functional imaging protocols will first be optimized and a test-retest study will then be conducted on a group of healthy control subjects, in order to determine the intra- and inter-subject variability of the measurements. In parallel, improved models of the ASL and BOLD signals as a function of the relevant physiological parameters will be developed, and appropriate estimation methodologies will be implemented within a Bayesian framework, incorporating prior knowledge about the physiological parameters as well as their spatial distributions. In an effort to enhance their clinical applicability, developed algorithms will be incorporated into a plug-in for an open-source medical image analysis software, enabling an end-user to define the options of interest and visualize the resulting physiological maps.

The proposed methodology will then be applied to the study of a healthy cohort covering an age-span of 20-80 years old and two groups of SVD patients: CADASIL and sporadic SVD, one of the most important vascular phenotypes implicated in age-related impairment. Each patient will be studied at two time points, including imaging investigation, clinical examination and application of a battery of neuropsychological tests to assess cognitive and motor impairment. A gender and age-matched control group will be selected from the healthy cohort. Multivariate analysis of the data will be performed in order to identify age-related changes in the measured cerebral physiology maps, and to assess the potential of such measures to provide new functional imaging biomarkers that are sensitive to disease progression and can be used for early differential diagnosis.

In summary, we expect to develop a completely non-invasive, quantitative and reliable protocol for imaging key parameters of cerebral physiology, by introducing methodological improvements to enhance its feasibility in clinical applications, and by demonstrating its applicability in the study of age-related changes and the identification of a biomarker for SVD progression.