Introduction Low-frequency oscillations (LFOs) are emerging as key drivers of brain fluid dynamics, and through functional MRI (fMRI) studies, systemic LFOs (sLFOs) have been identified as endogenous contrast agents that track cerebral blood flow. However, their cerebral propagation has largely been interpreted as reflecting slow blood flow, potentially overlooking a faster pressure transmission mechanism. In this work, we propose a comprehensive physiological framework for the propagation of cerebral vascular sLFOs, leveraging both blood-oxygen-level-dependent (BOLD) and non-BOLD fMRI signal components to capture flow- and velocity-driven dynamics. Methods Cerebral artery and superior sagittal sinus (SSS) sLFOs (0.01-0.15 Hz) were extracted from fMRI and time-locked to gray matter (GM) sLFOs to characterize their temporal coupling and transmission patterns. Results In 605 subjects, artery-GM-SSS sLFOs exhibited strong temporal coupling, revealing two distinct pathways: a rapid, millisecond-scale pressure transmission route reflecting intracranial pulse transmission (~100 milliseconds), and a slower, second-scale route consistent with artery-to-capillary-to-venous blood flow transit (~5 seconds). Discussion These findings distinguish the pressure- and flow-driven components of sLFOs, revealing distinct propagation pathways with different timescales, providing a comprehensive characterization of their underlying physiology, enabling new approaches to investigate cerebrovascular health using fMRI.
The advent of optogenetics has revolutionized neuroscience by enabling precise manipulation of neural circuits, solidifying a neuron-centric view of brain function. This perspective has increasingly expanded to encompass non-neuronal cells, with the optogenetic control of astrocytes, microglia, and pericytes revealing their active roles in information processing. Yet the vascular endothelium long regarded as a passive conduit has remained largely unexplored through this lens. Here we discuss the emerging field of endothelial optogenetics, which seeks to isolate the cell-autonomous signaling capacity of brain endothelial cells, distinct from their hemodynamic functions. We explore the hypothesis that targeted optical stimulation of these cells may evoke calcium-dependent release of angiocrine factors, establishing a vasculature-to-parenchyma signaling axis that directly modulates neuronal activity and behavior. This approach not only challenges the traditional neurovascular coupling paradigm but also offers transformative potential for reinterpreting neuroimaging data and developing novel therapies for neuropsychiatric and neurodegenerative disorders. By elevating the endothelium to the status of an active computational element, endothelial optogenetics promises to reshape our understanding of the brain as an integrated hemo-neural system.
Background: Alzheimer’s disease (AD) is characterized by alterations in brain glucose metabolism, classically showing [18F]FDG-PET hypometabolism in later stages. However, emerging evidence suggests a transient phase of glucose hypermetabolism early in the disease, for which biological basis remains unclear. Methods: We combined longitudinal and cross-sectional approaches in TgF344-AD rats and wild-type controls at 3, 6, 9, and 12 months. Longitudinal assessments included [ 1 8 F]FDG-microPET imaging, behavioral testing, and cerebrospinal fluid biomarker analysis. Cross-sectional analyses included amyloid histopathology, western blot and ex vivo glutamate uptake measurements. Results: TgF344-AD rats exhibited increased cerebral glucose metabolism at 9mo, predominantly in cortical regions. This phase coincided with emerging cognitive impairment and early amyloid deposition. CSF analyses showed increased GFAP at 9–12mo and reduced S100B at 9mo, while microglial/inflammatory markers remained unchanged. WB confirmed region-specific GFAP alterations without changes in neuronal or synaptic markers. Glutamate uptake was increased in the cortex and hippocampus at 9mo. Conclusion: These findings identify a transient phase of increased glucose metabolism early in disease progression, associated with astrocyte-related changes, suggesting that early hypermetabolism may reflect non-neuronal processes. This has implications for the interpretation of [18F]FDG-PET as a biomarker in early AD and for understanding early physiological responses to AD pathology.
Background: Cerebral small vessel disease (CSVD) is linked to cognitive impairment. This study examined associations of autonomic function and cerebral hemodynamics with cognitive function in patients with CSVD. Methods: In this cross-sectional study, patients with white matter hyperintensity and recent subcortical small infarction were recruited from January 2020 to March 2022. Cognitive function was assessed using education-adjusted Montreal Cognitive Assessment (MoCA), autonomic function using heart rate variability (HRV), and cerebral hemodynamics including cerebral autoregulation (CA), cerebrovascular reactivity, and neurovascular coupling (NVC). Logistic and linear regression and ROC analyses were performed. Results: Among 206 patients (median age 63 years; 130 men), 167 (81.1%) had cognitive impairment. Patients with cognitive impairment showed reduced HRV and impaired cerebral hemodynamics, including dynamic CA and NVC. Mean Holding LF Phase and Mean Holding CBFv remained significantly associated with cognitive impairment in multivariable models. Hemodynamics-based models showed AUCs of 0.776–0.850 for LF Phase-based models and 0.917–0.924 for CBFv-based models. In sensitivity analyses excluding HFnu, Mean Holding CBFv remained significantly associated with cognitive impairment. Conclusions: Impaired autonomic function and cerebral hemodynamic responses may contribute to cognitive dysfunction in CSVD. Assessing parasympathetic function and cerebral hemodynamics may help identify cognitive impairment.
Background: Perivascular spaces (PVS) are MRI-visible markers of cerebrovascular and glymphatic function, but their regional determinants in preclinical Alzheimer's disease (AD), regarding sex and AD biomarkers, remain poorly understood. Methods: We studied 1,199 cognitively unimpaired ALFA study participants (aged 54–65 years), genetically enriched for AD risk, with CSF biomarker phenotyping in 296 participants. PVS were automatically quantified in basal ganglia, centrum semiovale, hippocampus, and midbrain on 3T MRI. Counts were modelled using Poisson or negative binomial regression, adjusting for demographics, cardiometabolic, lifestyle, and genetic factors, with effect modification by sex and amyloid/tau (AT) status. Results: PVS showed marked regional specificity. Centrum semiovale PVS were associated with age, male sex, and cardiometabolic factors, whereas hippocampal and midbrain PVS were more closely related to AD biomarker status and sleep or psychological measures. Men exhibited higher centrum semiovale burden while women showed higher counts in hippocampus, midbrain, and basal ganglia. Associations were stronger in amyloid-positive individuals with concurrent tau pathology. Polygenic scores for lipid and metabolic traits contributed modestly to regional PVS variation. Conclusions: PVS burden is associated with multidomain determinants in preclinical AD with regional, sex-specific, and biomarker-dependent patterns, supporting PVS as accessible MRI markers for risk stratification and precision prevention.
