Homeostatic modeling of functional neuroimaging data in humans: a novel methodology to obtain brain maps of tissue pCO2, pO2 and pH in aging

Project Summary Altered cerebrovascular health is strongly associated with aging. PET and MRI studies have found age dependent reductions in resting cerebral blood flow (CBF) and neurovascular coupling (NVC) that correlate with poorer cognitive function and higher risk of dementia. Yet paradoxically, brain energy consumption is close to normal. If there is sufficient O2 delivery to support metabolism, how do reduced CBF and neurovascular coupling impact function? Answering this question is critical for interpreting MRI data available via research efforts such as the Human Connectome Project on Aging (HCP-A), and for developing novel in vivo MRI metrics of brain health. To address this question, we recently developed and validated a novel computational Homeostatic Modeling (HoMod), which integrates for the first time NVC with neurometabolic coupling (NMC) – i.e., the increase in proton and lactate production from glucose and glycogen metabolism. Using MRI or PET data, HoMod allows calculation of regional brain tissue and capillary blood levels of not just fuels (glucose, O2), but also metabolic waste products (pH, CO2, lactate). Extensive behavioral and EEG/MEG studies have found cognitive function is highly dependent on homeostasis of these products. Using HoMod we showed for the first time that, in healthy young adults, both resting state CBF and the large increase in NVC during activation, are crucial for maintaining homeostasis of pCO2, pO2, and pH. Motivated by these findings, our objective is to use HoMod to test our general hypothesis: reduced resting CBF and NVC in the elderly impair brain function via loss of pCO2, pO2, and pH homeostasis. Preliminary findings from human brain PET and MRI group datasets strongly support this hypothesis, however same subject measurements of OEF, NVC, and NMC are needed for validation and extension to resting state fluctuations. Our approach pursues prospective calibrated fMRI and fMRS studies in young and elderly subjects, and extends and further validates HoMod, through the following aims. Aim 1: Use HoMod to calculate pCO2, pO2, and pH maps in young and elderly subjects from resting awake OEF maps measured with calibrated fMRI at 3T to determine if there is loss of homeostasis in elderly subjects. Aim 2: Use fMRS and calibrated fMRI at 7T to determine if there are age associated reductions in NMC and NVC during visual stimulation, and use HoMod to assess impact on homeostasis. Exploratory Aim: Measure amplitude of calibrated fMRI resting state fluctuations at 3T, calculate NVC, and estimate possible age associated homeostasis alterations during fluctuations. Achieving these aims is highly impactful for brain aging research and beyond because HoMod is an emerging methodology that allows for the first time assessing whether abnormal NMC and NVC lead to loss of pCO2, pO2, and pH homeostasis. Such an opportunity is potentially critical to determine the impact of homeostasis on brain cognitive health in aging, as well as to guide potential interventions to improve or preserve brain health in aging and in other neurological conditions such as dementia, stroke, traumatic brain injury and cancer.