Journal of Cerebral Blood Flow and Metabolism最新文献

Angiography is critical for visualizing cerebral blood flow in intracranial steno-occlusive diseases. Current 4D magnetic resonance angiography (MRA) techniques primarily focus on macrovascular structures, yet few have quantified hemodynamic timing. This study introduces a novel model to estimate macrovascular arterial transit time (mATT) derived from arterial spin labeling (ASL)-based 4D-MRA. We provide examples of our method that visualize mATT differences throughout the brain of patients with intracranial steno-occlusive disease (moyamoya), as well as changes in mATT resulting from the cerebrovascular reactivity response to an acetazolamide (ACZ) injection. Furthermore, we present a method that projects sparse arterial signals into a 3D native brain-region atlas space and correlates regional mATT with other hemodynamic parameters of interest, such as tissue transit time and cerebrovascular reactivity. This approach offers a non-invasive, quantitative assessment of macrovascular dynamics, with potential to enhance understanding of large-vessel and tissue-level hemodynamics and augment monitoring of treatment outcomes in steno-occlusive disease patients. Furthermore, it sets the stage for more in-depth investigations of the macrovascular contribution to brain hemodynamics.

Vasoactive signaling from astrocytes is an important contributor to the neurovascular coupling (NVC), which aims at providing energy to neurons during brain activation by increasing blood perfusion in the surrounding vasculature. Pharmacological manipulations have been previously combined with experimental techniques (e.g., transgenic mice, uncaging, and multiphoton microscopy) and stimulation paradigms to isolate in vivo individual pathways of the astrocyte-mediated NVC. Unfortunately, these pathways are highly nonlinear and non-additive. To separate these pathways in a unified framework, we combine a comprehensive biophysical model of vasoactive signaling from astrocytes with a unique optogenetic stimulation method that selectively induces astrocytic Ca²⁺ signaling in a large population of astrocytes. We also use a sensitivity analysis and an optimization technique to estimate key model parameters. Optogenetically-induced Ca²⁺ signals in astrocytes cause a cerebral blood flow (CBF) response with two major components. Component-1 was rapid and smaller (ΔCBF∼13%, 18 seconds), while component-2 was slowest and highest (ΔCBF ∼18%, 45 seconds). The proposed biophysical model was adequate in reproducing component-2, which was validated with a pharmacological manipulation. Model's predictions were not in contradiction with previous studies. Finally, we discussed scenarios accounting for the existence of component-1, which once validated might be included in our model.

Regional blood flow within the brain is tightly coupled to regional neuronal activity, a process known as neurovascular coupling (NVC). In this study, we demonstrate the striking role of SUR2- and Kir6.1-dependent ATP-sensitive potassium (K_ATP) channels in control of NVC in the sensory cortex of conscious mice, in response to mechanical stimuli. We demonstrate that either globally increased (pinacidil-activated) or decreased (glibenclamide-inhibited) K_ATP activity markedly disrupts NVC; pinacidil-activation is capable of completely abolishing stimulus-evoked cortical hemodynamic responses, while glibenclamide slows and reduces the response. The response is similarly slowed and reduced in SUR2 KO animals, while animals expressing gain-of-function (GOF) mutations in Kir6.1, which underlie Cantú syndrome, exhibit baseline reduction of NVC as well as increased sensitivity to pinacidil. In revealing the dramatic effects of either increasing or decreasing SUR2/Kir6.1-dependent K_ATP activity on NVC, whether pharmacologically or genetically induced, the study has important implications both for monogenic K_ATP channel diseases and for more common brain pathologies.

In patients with acute brain injury (ABI), optimizing cerebral perfusion parameters relies on multimodal monitoring. This include data from systemic monitoring-mean arterial pressure (MAP), arterial carbon dioxide tension (PaCO₂), arterial oxygen saturation (SaO₂), hemoglobin levels (Hb), and temperature-as well as neurological monitoring-intracranial pressure (ICP), cerebral perfusion pressure (CPP), and transcranial Doppler (TCD) velocities. We hypothesized that these parameters alone were not sufficient to assess the risk of cerebral ischemia. We conducted a retrospective, single-center study of patients admitted in our ICU between 2015 and 2021. Patients with ABI and multimodal neuromonitoring were included. ABI included traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracranial hemorrhage and ischemic stroke. The relationship between jugular venous oxygen saturation (SjvO₂) and cerebral perfusion parameters was analyzed. Patients were categorized into two groups based on SjvO₂, with a threshold of 60% used to define cerebral ischemia. We compared the parameters used to optimize cerebral perfusion between groups and their diagnosis accuracy for cerebral ischemia was evaluated. Univariable and multivariable analyses were performed to assess the association between the guideline-recommended therapeutic targets and the risk of cerebral ischemia. 601 evaluations from 96 patients with simultaneous ICP, SjvO₂ and TCD were analyzed. Poor relationships were found between SjvO₂ and the parameters of cerebral perfusion. TCD flow velocities and PaCO₂ were lower in the cerebral ischemia group while MAP, ICP and CPP were not different between groups. Most ischemic episodes occurred despite ICP < 22 mmHg and CPP ≥ 60 mmHg. For the diagnosis of cerebral ischemia, only TCD parameters and PaCO₂ were associated with an area under the curve (AUC) > 0.5 but with a low accuracy. In multivariable analysis, the only guideline-recommended therapeutic target associated with a reduction of cerebral ischemia was a diastolic flow velocity (FV) > 20 cm.s^-1.

Therapeutic drug development for central nervous system injuries, such as traumatic brain injury (TBI), presents significant challenges. TBI results in primary mechanical damage followed by secondary injury, leading to cognitive dysfunction and memory loss. Our recent study demonstrated the potential of carbon monoxide-releasing molecules (CORMs) to improve TBI recovery by enhancing neurogenesis. However, a comprehensive TBI recovery strategy requires not only neurogenesis but also oligodendrogenesis. In this study, we elucidate the critical role of A-kinase anchor protein 12 (AKAP12), a scaffolding protein predominantly expressed by intact pericytes, in oligodendrocyte regeneration during CO therapy for TBI. CORM treatment increased AKAP12 expression, which enhanced myelin intensity and mitigated TBI-induced oligodendrocyte loss. In addition, CO promotes the generation of new oligodendrocytes, a process that is impaired by AKAP12 deficiency. Notably, even after TBI, cognitive function was restored in wild-type mice following CORM treatment, but this effect was absent in Akap12 knockout mice. These findings highlight the importance of CO-induced AKAP12 upregulation, particularly in pericytes, in supporting oligodendrogenesis and cognitive recovery after TBI. Understanding these mechanisms holds promise for the development of targeted therapies to address TBI-associated impairments.

Cardiac arrest (CA) is a life-threatening condition that requires immediate medical attention. Considerable advances in resuscitation have led to an increasing number of patients who survive the initial arrest event. However, among this growing patient population, morbidity and mortality rates remain strikingly high. This has been attributed to post-CA syndrome of which an imbalanced immune response is a crucial component. Using a murine CA model, we have shown that a profound immunosuppressive phase, characterized by severe lymphopenia, ensues following the initial pro-inflammatory response after CA. In the current study, we found that T and B lymphopoiesis was greatly impaired, as evidenced by the rapid and marked depletion of double-positive T cells and pre-B cells in the thymus and bone marrow, respectively. Our data then demonstrated that pharmacologic suppression of glucocorticoid signaling after CA significantly attenuated lymphopoiesis impairment, thereby mitigating post-CA lymphopenia. Lastly, we showed that specific deletion of the glucocorticoid receptor in T or B cells largely prevented the CA-induced depletion of immature lymphocyte populations in the thymus or bone marrow, respectively. Together, our findings indicate that glucocorticoid signaling mediates post-CA impairment of lymphopoiesis, a key contributor to post-CA immunosuppression.

Increases in mean lesional iron content by quantitative susceptibility mapping (QSM) by ≥6% and/or vascular permeability by dynamic contrast enhanced quantitative perfusion (DCEQP) by ≥40% on MRI have been associated with new symptomatic hemorrhage (SH) in cerebral cavernous malformations (CCMs). It is not known if plasma biomarkers can reflect these changes within the lesion proper. This cohort study enrolled 46 CCM patients with SH in the prior year. Plasma samples, QSM and DCEQP were simultaneously acquired at the beginning and end of 60 one-year epochs of prospective follow-up. Plasma levels of 16 proteins and 12 metabolites linked to CCM hemorrhage were assessed by enzyme-linked immunosorbent assay and liquid-chromatography mass spectrometry, respectively. A weighted model combining the percent changes in plasma levels in roundabout guidance receptor-4, cluster of differentiation 14, thrombomodulin and acetyl-L-carnitine reflected a mean increase in QSM ≥ 6% (97.2% and 100% specificity/sensitivity, p = 3.1 × 10^-13). A weighted combination of percent changes in plasma levels of endoglin, pipecolic acid, arachidonic acid and hypoxanthine correlated with an increase in mean DCEQP ≥40% (99.6% specificity and 100% sensitivity, p = 4.1 × 10^-17). This is a first report linking with great accuracy changes of circulating molecules to imaging changes reflecting new SH during prospective follow-up of CCMs.

Collateral blood vessels are unique, naturally occurring endogenous bypass vessels that provide alternative pathways for oxygen delivery in obstructive arterial conditions and diseases. Surprisingly however, the capacity of the collateral circulation to provide protection varies greatly among individuals, resulting in a significant fraction having poor collateral circulation in their tissues. We recently reviewed evidence that the presence of naturally-occurring polymorphisms in genes that determine the number and diameter of collaterals that form during development (ie, genetic background), is a major contributor to this variation. The purpose of this review is to summarize current understanding of the other determinants of collateral blood flow, drawing on both animal and human studies. These include the level of smooth muscle tone in collaterals, hemodynamic forces, how collaterals form during development (collaterogenesis), de novo formation of additional new collaterals during adulthood, loss of collaterals with aging and cardiovascular risk factor presence (rarefaction), and collateral remodeling (structural lumen enlargement). We also review emerging evidence that collaterals not only provide protection in ischemic conditions but may also serve a physiological function in healthy individuals. Primary focus is on studies conducted in brain, however relevant findings in other tissues are also reviewed, as are questions for future investigation.

Human primary (hpBMEC) and induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial-like cells (hiBMEC) are interchangeably used in blood-brain barrier models to study neurological diseases and drug delivery. Both hpBMEC and hiBMEC use glutamine as a source of carbon and nitrogen to produce metabolites and build proteins essential to cell function and communication. We used metabolomic, transcriptomic, and computational methods to examine how hpBMEC and hiBMEC metabolize glutamine, which may impact their utility in modeling the blood-brain barrier. We found that glutamine metabolism was systemically different between the two cell types. hpBMEC had a higher metabolic rate and produced more glutamate and GABA, while hiBMEC rerouted glutamine to produce more glutathione, fatty acids, and asparagine. Higher glutathione production in hiBMEC correlated with higher oxidative stress compared to hpBMEC. α-ketoglutarate (α-KG) supplementation increased glutamate secretion from hiBMEC to match that of hpBMEC; however, α-KG also decreased hiBMEC glycolytic rate. These fundamental metabolic differences between BMEC types may impact in vitro blood-brain barrier model function, particularly communication between BMEC and surrounding cells, and emphasize the importance of evaluating the metabolic impacts of iPSC-derived cells in disease models.

Rho-associated protein kinase (ROCK) inhibitors are therapeutic candidates in ischemic stroke and subarachnoid hemorrhage. However, their efficacy in intracerebral hemorrhage (ICH) is unknown. Here, we tested the efficacy of fasudil (10 mg/kg), an isoform-nonselective ROCK inhibitor, and NRL-1049 (10 mg/kg), a novel inhibitor with 43-fold higher selectivity for ROCK2 isoform compared with ROCK1, in a collagenase-induced ICH model in mice. Both short (1-3 days) and prolonged (14 days) therapeutic paradigms were tested using robust sample sizes in both males and females and in active and inactive circadian stages. Outcome readouts included weight loss, mortality, hematoma volume, hemispheric swelling, brain water content, BBB permeability to large molecules, and sensorimotor and cognitive function. We found the treatments safe but not efficacious in improving the hematoma volume, BBB disruption, or neurological deficits in this collagenase-induced ICH model. Intriguingly, however, induction of ICH during the active circadian stage was associated with worse tissue and behavioral outcomes compared with the inactive stage.