Journal of Cerebral Blood Flow and Metabolism最新文献

Brain arteriovenous malformations (bAVMs) are a notable cause of intracranial hemorrhage, strongly associated with severe morbidity and mortality. Contemporary treatment options include surgery, stereotactic radiosurgery, and endovascular embolization, each of which has limitations. Hence, development of pharmacological interventions is urgently needed. The recent discovery of the presence of activating Kirsten rat sarcoma (KRAS) viral oncogene homologue mutations in most sporadic bAVMs has opened the door for a more comprehensive understanding of the pathogenesis of bAVMs and has pointed to entirely novel possible therapeutic targets. Herein, we review the status quo of genetics, animal models, and therapeutic approaches in bAVMs.

White matter lesions (WMLs) are prevalent with aging, and higher WML burden has been observed in older adults with vascular diseases. While the physiology underlying the formation of WMLs is not known, various risk factors are associated with high WML burden. Here, we investigated the relationship between vascular risk factors and microvascular physiology (i.e., oxygen supply and oxygen extraction fraction [OEF]) and their association with WML burden. Forty-one typically aging adults (60-80 years) were classified into high or low vascular risk based on common modifiable vascular risk factors (hypertension, diabetes, hyperlipidemia, and overweight). These groups were subdivided into high or low WML burden. Differences in microvascular physiology (oxygen supply and OEF) were then compared between and within groups. Overall, OEF was significantly higher in the high vascular risk group compared to the low vascular risk group (p < 0.01). In the low vascular risk subgroup, OEF was uniquely lower in the individuals with high WML versus low WML burden (p = 0.02), despite no differences in oxygen supply between these subgroups (p = 0.87). The coupling of impaired OEF with the absence of compensatory physiology, such as elevated oxygen supply, may represent an important mechanism underlying WML burden in individuals with low vascular risk factors.

Familial hemiplegic migraine type 2 (FHM2) is linked to Na,K-ATPase α₂ isoform mutations, including that of G301R. Mice heterozygous for this mutation (${\alpha }_2^{+/\text{G3}0\text{1R}}$) show cerebrovascular hypercontractility associated with amplified Src kinase signaling, and exaggerated neurovascular coupling. This study hypothesized that targeting Na,K-ATPase-dependent Src phosphorylation with pNaKtide would normalize cerebral perfusion and neurovascular coupling in ${\alpha }_2^{+/\text{G3}0\text{1R}}$ mice. The effect of pNaKtide on cerebral blood flow and neurovascular coupling was assessed using laser speckle contrast imaging in awake, head-fixed mice with cranial windows in a longitudinal study design. At baseline, compared to wild type, ${\alpha }_2^{+/\text{G3}0\text{1R}}$ mice exhibited increased middle cerebral artery tone; with whisker stimulation leading to an exaggerated increase in sensory cortex blood flow. No difference between genotypes in telemetrically assessed blood pressure occurred. The exaggerated neurovascular coupling in ${\alpha }_2^{+/\text{G3}0\text{1R}}$ mice was associated with increased K_ir2.1 channel expression in cerebrovascular endothelium. Two weeks pNaKtide treatment normalized cerebral artery tone, endothelial K_ir2.1 expression, and neurovascular coupling in ${\alpha }_2^{+/\text{G3}0\text{1R}}$ mice. Inhibition of the Na,K-ATPase-dependent Src kinase signaling with pNaKtide prevented excessive vasoconstriction and disturbances in neurovascular coupling in ${\alpha }_2^{+/\text{G3}0\text{1R}}$ mice. pNaKtide had only minor hypotensive effect similar in both genotypes. These results demonstrate a novel treatment target to normalize cerebral perfusion in FHM2.

Futile recanalization hampers prognoses for ischemic stroke patients despite successful recanalization therapy. Allegedly, hypertension and reperfusion deficits contribute, but a better understanding is needed of how they interact and mediate disease outcome. We reassessed data from spontaneously hypertensive and normotensive Wistar-Kyoto rats (male, n = 6-7/group) that were subjected to two-hour embolic middle cerebral artery occlusion and thrombolysis in preclinical trials. Serial MRI allowed lesion monitoring and parcellation of regions-of-interest that represented infarcted (core) or recovered (perilesional) tissue. Imaging markers of hemodynamics and blood-brain barrier (BBB) status were related to tissue fate and neurological outcome. Despite comparable ischemic severity during occlusion between groups, hypertensive rats temporarily developed larger lesions after recanalization, with permanently aggravated vasogenic edema and BBB permeability. One day post-stroke, cerebral blood flow (CBF) was variably restored, but blood transit times were consistently prolonged in hypertensives. Compared to the core, perilesional CBF was normo-to-hyperperfused in both groups, yet this pattern reversed after seven days. Volumes of hypo- and hyperperfusion developed irrespective of strain, differentially associating with final infarct volume and behavioral outcome. Incomplete reperfusion and cerebral injury after thrombolysis were augmented in hypertensive rats. One day after thrombolysis, fractional volumes of hypoperfusion associated with worsened outcomes, while fractional volumes of hyperperfusion appeared beneficial or benign.

This study presents the first in vivo measurement of transcytolemmal water exchange in the brain using a novel Magnetic Resonance technique. We extend previous applications of Chemical Exchange Saturation Transfer (CEST) to examine water exchange across cellular membranes in late-stage chicken embryo brains. The immature blood-brain barrier at this stage allows Gadolinium-Based Contrast Agents (GBCAs) to penetrate the brain's interstitial space, sensitizing the CEST effect to water exchange between intra- and extracellular environments. Exchange rates were measured in the awake brain and under different anaesthetic regimens, including isoflurane and ketamine/xylazine. Results show that brain water exchange is dominated by activity-dependent mechanisms, with anaesthesia reducing exchange rates by over an order of magnitude. These findings suggest that anaesthetics may impact neuronal and glial function by interfering with active transport mechanisms, potentially altering brain water homeostasis. This study highlights the utility of CEST MRI for studying dynamic biological processes in vivo.

Current techniques for inducing intraluminal filamentous middle cerebral artery occlusion (fMCAo) in mice produce highly variable results and often cause additional infarcts in the posterior cerebral artery (PCA) territory. The aim of the current study was to develop a novel procedure to overcome these shortcomings. Male C57BL/6 mice were subjected to 60 min of fMCAo with cerebral blood flow monitored by laser Doppler flowmetry. The influence of the length of the occlusion filament coating and the combination of common carotid artery (CCA) or pterygopalatine artery (PPA) ligation on lesion volume and functional outcome 24 h after reperfusion was evaluated. The use of appropriate filament and PPA ligation while maintaining CCA perfusion prevented the development of infarcts in the PCA area, resulted in pure MCA infarcts (68.3 ± 14.5 mm³) and reduced the variability of infarct volumes by more than half (from 26-38% to 14% standard deviation/mean). Using an improved fMCAo procedure, we were able to produce PCA area-unaffected reproducible (PURE) infarcts exclusively in the MCA territory. Thus PURE-MCAo reduced outcome variability by more than 50%. Our results may thus help to reduce the number of animals in preclinical stroke research and to increase the reproducibility of the fMCAo model.

Photobiomodulation (PBM) therapy stands as an innovative neurostimulation modality that has demonstrated both efficacy and safety in improving brain function. This therapy exerts multifaceted influences on neurons, blood vessels, and their intricate interplay known as neurovascular coupling (NVC). Growing evidence indicates that NVC may present a promising target for PBM intervention. However, the detailed mechanisms underlying its therapeutic benefits remain to be fully understood. This review aims to elucidate the potential metabolic pathways and signaling cascades involved in the modulatory effects of PBM, while also exploring the extensive repertoire of PBM applications in neurologic and psychiatric conditions. The prospects of PBM within the realm of NVC investigation are intensively considered, providing deeper insights into the powerful capabilities of PBM therapy and its potential to revolutionize neurostimulation treatments.

Alzheimer's disease (AD), a neurodegenerative disorder with progressive cognitive decline, remains clinically challenging with limited understanding of etiology and interventions. Clinical studies have reported vascular defects prior to other pathological manifestations of AD, leading to the "Vascular Hypothesis" for the disorder. However, in vivo assessments of cerebral vasculature in AD rodent models have been constrained by limited spatiotemporal resolution or field of view of conventional imaging. We herein employed two in vivo imaging technologies, Dual-Wavelength Imaging and Optical Coherence Doppler Tomography, to evaluate cerebrovascular reactivity (CVR) to vasoconstrictive cocaine and vasodilatory hypercapnia challenges and to detect resting 3D cerebral blood flow (CBF) in living transgenic AD mice at capillary resolution. Results showed that CVR to cocaine and hypercapnia was significantly attenuated in 7-10 months old AD mice vs controls, indicating reduced vascular flexibility and reactivity. Additionally, in the AD mice, arterial CBF velocities were slower and the microvascular density in cortex was decreased compared to controls. These results reveal significant vascular impairments including reduced CVR and resting CBF in early-staged AD mice. Hence, this cutting-edge in vivo optical imaging offers an innovative venue for detecting early neurovascular dysfunction in AD brain with translational potential.

Synaptic vesicle protein 2A (SV2A) is ubiquitously expressed in presynaptic terminals where it functions as a neurotransmission regulator protein. Synaptopathy has been reported during healthy ageing and in a variety of neurodegenerative diseases. Positron emission tomography (PET) imaging of SV2A can be used to evaluate synaptic density. The PET ligand [¹¹C]UCB-J has high binding affinity and selectivity for SV2A but has a short physical half-life due to the ¹¹C isotope. Here we report the characterization and validation of its ¹⁸F-labeled equivalent, [¹⁸F]UCB-J, in terms of specificity, reproducibility and stability in C57BL/6J mice. Plasma analysis revealed at least one polar radiometabolite. Kinetic modelling was performed using a population-based metabolite corrected image-derived input function (IDIF). [¹⁸F]UCB-J showed relatively fast kinetics and a reliable measure of the IDIF-based volume of distribution (V_T(IDIF)). [¹⁸F]UCB-J specificity for SV2A was confirmed through a levetiracetam blocking assay (50 to 200 mg/kg). Reproducibility of the V_T(IDIF) was determined through test-retest analysis, revealing significant correlation (r² = 0.773, p < 0.0001). Time-stability analyses indicate a scan duration of 60 min to be sufficient to obtain a reliable V_T(IDIF). In conclusion, [¹⁸F]UCB-J is a selective SV2A ligand with optimal kinetics in mice. Further investigation is warranted for (pre)clinical applicability of [¹⁸F]UCB-J in synaptopathies.

Understanding neuromodulatory effects of serotonin 2A receptor (5-HT_2AR) agonists with diverse pharmacological profiles is relevant to advancing psychedelic-related drug applications. We performed simultaneous positron emission tomography (PET) and pharmacological magnetic resonance imaging (phMRI) in anesthetized nonhuman primates (NHP; N = 3) to examine partial agonists with varying 5-HT_2AR affinities and selectivity profiles: psilocybin (30, 60, and 90 µg/kg), lisuride (5 µg/kg), and 25CN-NBOH (15 µg/kg). Receptor occupancy was assessed with [¹¹C]MDL-100907 PET, and cerebral blood volume (CBV) changes were measured with phMRI. Mixed partial agonists psilocybin and lisuride evoked biphasic CBV responses, whereas the selective 25CN-NBOH produced monophasic CBV increases. Cortical occupancy for psilocybin plateaued at 60 µg/kg (32%), whereas a lower dose of lisuride (5 µg/kg) resulted in similar occupancy (31%). Administration of 25CN-NBOH resulted in lower occupancy (7%) but larger changes in CBV compared to psilocybin and lisuride. The associations between CBV and 5-HT_2AR occupancy appear linear for lisuride and 25CN-NBOH, but not for psilocybin. We speculate that the temporal and spatial differences in hemodynamic responses of the three agonists could stem from mixed affinity profiles. This work provides an understanding of pharmacological impacts of mixed serotonergic agonists being pursued as therapeutics for psychiatric conditions, offering valuable insights for future drug applications and development strategies.