Modeling of dynamic cerebrovascular reactivity to spontaneous and externally induced CO2 fluctuations in the human brain using BOLD-fMRI

In this work, we investigate the regional characteristics of the dynamic interactions between arterial CO2 and BOLD (dynamic cerebrovascular reactivity - dCVR) during normal breathing and hypercapnic, externally induced step CO2 challenges. To obtain dCVR curves at each voxel, we use a custom set of basis functions based on the Laguerre and gamma basis sets. This allows us to obtain robust dCVR estimates both in larger regions of interest (ROIs), as well as in individual voxels. We also implement classification schemes to identify brain regions with similar dCVR characteristics. Our results reveal considerable variability of dCVR across different brain regions, as well as during different experimental conditions (normal breathing and hypercapnic challenges), suggesting a differential response of cerebral vasculature to spontaneous CO2 fluctuations and larger, externally induced CO2 changes that are possibly associated with the underlying differences in mean arterial CO2 levels. The clustering results suggest that anatomically distinct brain regions are characterized by different dCVR curves that in some cases do not exhibit the standard, positive valued curves that have been previously reported. They also reveal a consistent set of dCVR cluster shapes for resting and forcing conditions, which exhibit different distribution patterns across brain voxels

Estimation of voxel-wise dynamic cerebrovascular reactivity curves from resting-state fMRI data

In this work, we investigate the linear dynamic interactions between fluctuations in arterial CO2 that occur during normal breathing, and the BOLD fMRI signal. We cast this problem within a systems-theoretic framework, where we employ functional expansions for the estimation of the impulse responses in large regions of interest, as well as in individual voxels. We also implement classification schemes in order to identify different brain regions with similar cerebrovascular reactivity characteristics. Our results reveal that it is feasible to obtain reliable estimates of cerebrovascular reactivity curves from resting-state data and that these curves exhibit considerable variability across different brain regions that may be related to the underlying anatomy

Association of Novelty-Related Locus Coeruleus Function With Entorhinal Tau Deposition and Memory Decline in Preclinical Alzheimer Disease

BACKGROUND AND OBJECTIVES: The predictable Braak staging scheme suggests that cortical tau progression may be related to synaptically connected neurons. Animal and human neuroimaging studies demonstrated that changes in neuronal activity contribute to tau spreading. Whether similar mechanisms explain tau progression from the locus coeruleus (LC), a tiny noradrenergic brainstem nucleus involved in novelty, learning, and memory and among the earliest regions to accumulate tau, has not yet been established. We aimed to investigate whether novelty-related LC activity was associated with the accumulation of cortical tau and its implications for cognitive decline. METHODS: We combined functional MRI data of a novel versus repeated face-name learning paradigm, [ F]-FTP-PET, [ C]-PiB-PET, and longitudinal cognitive data from 92 well-characterized older individuals in the Harvard Aging Brain Study. We related novelty versus repetition LC activity to cortical tau deposition, and to longitudinal decline in memory, executive function, and the Preclinical Alzheimer's Disease Cognitive Composite (version 5; PACC5). Structural equation modeling was used to examine whether entorhinal cortical (EC) tau mediated the relationship between LC activity and cognitive decline and whether this depended on beta-amyloid deposition. RESULTS: The participants' average age at baseline was 69.67 ± 10.14 years. 51 participants were female. 91 participants were cognitively normal (CDR global=0), and one had MCI (CDR global=0.5) at baseline. Lower novelty-related LC activity was specifically related to greater tau deposition in the medial-lateral temporal cortex and steeper memory decline. LC activity during novelty versus repetition was not related to executive dysfunction or decline on the PACC5. The relationship between LC activity and memory decline was partially mediated by EC tau, particularly in individuals with elevated beta-amyloid deposition. DISCUSSION: Our results suggested that lower novelty-related LC activity is associated with the emergence of EC tau and that the downstream effects of this LC-EC pathway on memory decline also require the presence of elevated beta-amyloid. Longitudinal studies are required to investigate whether optimal LC activity has the potential to delay tau spread and memory decline, which may have implications for designing targeted interventions promoting resilience