Journal of Cerebral Blood Flow and Metabolism最新文献

Antibody therapy has demonstrated great potential for treating central nervous system (CNS) disorders. Since therapeutic efficacy relies on sufficient exposure in specific brain regions, quantitative understanding of antibody distribution within the brain is crucial. Additionally, insights into antibody brain distribution help elucidate how pathological antibodies accumulate during encephalitis. Accordingly, this study investigated the regional distribution of a non-target-binding antibody (trastuzumab) and a brain-target-binding antibody (anti-NMDAR1) following systemic and intra-CNS administration in rats. After systemic administration, both antibodies showed similar distribution across brain regions, with the olfactory bulb exhibiting significantly higher concentrations. Other regions had comparable exposure, with the striatum or hippocampus showing the lowest exposure. Intra-CSF administration resulted in similar distribution patterns but achieved significantly higher concentrations than systemic administration. In contrast, intra-striatal administration led to diverse distribution, with the highest concentrations near the injection site. Calculations based on striatum and interstitial fluid (ISF) concentrations indicated antibody accumulation in the perivascular space after intra-CNS administration. Target binding influenced distribution primarily after intra-CSF administration, where anti-NMDAR1 showed lower ISF concentrations early and reduced CSF concentrations later. These findings provide valuable quantitative insights for optimizing brain-targeted antibody therapies and understanding pathological antibody distribution in CNS disorders.

Parkinson's disease (PD) is a complex progressive neurodegenerative disorder involving hallmarks such as $\alpha$-Synuclein ($\alpha$Syn) aggregation and dopaminergic dysfunction that affect brain-wide neural activity. Although movement disorders are prominent in PD, sensory impairments also occur relatively early on, mainly in olfactory and, to a lesser extent visual systems. While these deficits have been described mainly at the behavioral and molecular levels, the underlying network-level activity remains poorly understood. Here, we harnessed a human $\alpha$Syn transgenic mouse model of PD with in vivo functional MRI (fMRI) to map evoked activity in the visual and olfactory pathways, along with pseudo-Continuous Arterial Spin Labeling (pCASL) and c-FOS measurements to disentangle vascular from neuronal effects. Upon stimulation with either odors or flickering lights, we found significant decreases in fMRI responses along both olfactory and visual pathways, in multiple cortical and subcortical sensory areas. Average Cerebral Blood Flow rates were decreased by ∼10% in the $\alpha$Syn group, while c-FOS levels were reduced by over 50%, suggesting a strong neural driver for the dysfunction, along with more modest vascular contributions. Our study provides insight into brain-level activity in an $\alpha$Syn-based model, and suggests a novel target for biomarking via quantification of simple sensory evoked responses.

Oxygen Extraction Fraction (OEF) is a critical measure of a tissue's metabolic state post-ischemic stroke. This study investigated OEF changes in stroke-affected tissue compared to healthy tissue, post-reperfusion. OEF maps generated from gradient echo MRI images of 87 ischemic stroke patients at three time points after successful Endovascular Thrombectomy (EVT) were analysed in a prospective longitudinal multicentre study. Regions of interest (ROIs) delineating the infarct areas and corresponding mirror regions were drawn. The MR-derived OEF index values were obtained from the ROIs and compared using Wilcoxon signed rank tests. The cross-sectional comparison of OEF index values revealed lower values in the infarct areas than the corresponding contralateral areas at all three time points after successful EVT, presented as median (interquartile range) [24-72 hours: 20.84 (17.56-26.82)% vs 27.56 (23.22-31.87)%; 3 months: 27.37 (23.28-30.35)% vs 32.55 (28.00-35.81)%; 12 months: 24.38 (22.35-29.77)% vs 29.39 (25.86-34.04)%, p < 0.001 for all three time points]. Longitudinally, relative OEF index values increased gradually over time [24-72 hours: 0.81 (0.67-0.87); 3 months: 0.86 (0.79-0.95); 12 months: 0.88 (0.75-0.95)]. The findings revealed that following successful EVT, OEF in infarct tissue improves over time, indicating potential tissue recovery.Trial registration name and URL: Post-Reperfusion Pathophysiology in Acute Ischemic Stroke https://trialsearch.who.int/Trial2.aspx?TrialID=ACTRN12624000629538.

Cerebral infarct growth rate (IGR) varies widely in ischemic stroke, and this has important clinical implications. In their recent article, Lin et al. explored IGR characteristics and treatment modification in so-called "ultrafast progressors". We comment on the study's methodology for calculating IGR and its interpretation, arguing that perfusion-derived metrics should probably not be adjusted for the time between symptom onset and imaging. Time-independent metrics may better characterize ultrafast progressors by avoiding assumptions about the linearity of infarct growth curves. These results could inform future studies, as ultrafast progressors might benefit the most from neuroprotection interventions.

Functional magnetic resonance imaging time-series are conventionally processed by linear modelling the evoked response as the convolution of the experimental conditions with a stereotyped hemodynamic response function (HRF). However, the neural signal in response to a stimulus can vary according to task, brain region, and subject-specific conditions. Moreover, HRF shape has been suggested to carry physiological information. The BOLD signal across a range of sensorial and cognitive tasks was fitted using a sine series expansion, and modelled signals were deconvolved, thus giving rise to a task-specific deconvolved HRF (dHRF), which was characterized in terms of amplitude, latency, time-to-peak and full-width at half maximum for each task. We found that the BOLD response shape changes not only across activated regions and tasks, but also across subjects despite the age homogeneity of the cohort. Largest variabilities were observed in mean amplitude and latency across tasks and regions, while time-to-peak and full width at half maximum were relatively more consistent. Additionally, the dHRF was found to deviate from canonicity in several brain regions. Our results suggest that the choice of a standard, uniform HRF may be not optimal for all fMRI analyses and may lead to model misspecifications and statistical bias.

Type 2 diabetes mellitus (T2DM) is associated with impaired leptomeningeal collateral compensation and poor stroke outcome. Neutrophils tethering and rolling on endothelium after stroke can also independently reduce flow velocity. However, the chronology and topological changes in collateral circulation in T2DM is not yet defined. Here, we describe the spatial and temporal blood flow dynamics and vessel diameter changes in pial arteries and veins and leukocyte-endothelial adhesion following middle cerebral artery (MCA) stroke using two-photon microscopy in awake control and T2DM mice. Relative to control mice, T2DM mice already exhibited smaller pial vessels with reduced flow velocity prior to stroke. Following stroke, T2DM mice displayed persistently reduced blood flow in pial arteries and veins, resulting in a poor recovery of downstream penetrating arterial flow and a sustained deficit in microvascular flow. There was also persistent increase of leukocyte adhesion to the endothelium of veins, coincided with elevated neutrophils infiltration into brain parenchyma in T2DM mice compared to control mice after stroke. Our data suggest that T2DM-induced increase in inflammation and chronic remodeling of leptomeningeal vessels may contribute to the observed hemodynamics deficiency after stroke and subsequent poor stroke outcome.

The brain's resting-state energy consumption is expected to be driven by spontaneous activity. We previously used 50 resting-state fMRI (rs-fMRI) features to predict [¹⁸F]FDG SUVR as a proxy of glucose metabolism. Here, we expanded on our effort by estimating [¹⁸F]FDG kinetic parameters K_i (irreversible uptake), K₁ (delivery), k₃ (phosphorylation) in a large healthy control group (n = 47). Describing the parameters' spatial distribution at high resolution (216 regions), we showed that K₁ is the least redundant (strong posteromedial pattern), and K_i and k₃ have relevant differences (occipital cortices, cerebellum, thalamus). Using multilevel modeling, we investigated how much spatial variance of [¹⁸F]FDG parameters could be explained by a combination of a) rs-fMRI variables, b) cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO₂) from ¹⁵O PET. Rs-fMRI-only models explained part of the individual variance in K_i (35%), K₁ (14%), k₃ (21%), while combining rs-fMRI and CMRO₂ led to satisfactory description of K_i (46%) especially. K_i was sensitive to both local rs-fMRI variables (ReHo) and CMRO₂, k₃ to ReHo, K₁ to CMRO₂. This work represents a comprehensive assessment of the complex underpinnings of brain glucose consumption, and highlights links between 1) glucose phosphorylation and local brain activity, 2) glucose delivery and oxygen consumption.

Cerebral small vessel disease (SVD) is diagnosed through imaging hallmarks like white matter hyperintensities (WMH). Novel hypotheses imply that endothelial dysfunction, blood-brain barrier (BBB) disruption and neurovascular inflammation contribute to conversion of normal-appearing white matter (NAWM) into WMH in hypertensive individuals. Aiming to unravel the association between chronic hypertension and the earliest WMH pathogenesis, we characterized microvascular pathology in periventricular NAWM into WMH in post-mortem brains of individuals with and without hypertension. Our second aim was to delineate the NAWM-WMH transition from NAWM towards the center of WMH using deep learning, refining WMH segmentation capturing increases in FLAIR signal. Finally, we aimed to demonstrate whether these processes may synergistically contribute to WMH pathogenesis by performing voxel-wise correlations between MRI and microvascular pathology. Larger endothelium disruption, BBB damage and neurovascular inflammation were observed in individuals with hypertension. We did not observe gradual BBB damage nor neurovascular inflammation along the NAWM-WMH transition. We found a strong correlation between BBB damage and neurovascular inflammation in all individuals in both periventricular NAWM and WMH. These novel findings suggest that endothelium disruption, BBB damage and neurovascular inflammation are major contributors to SVD progression, but being already present in NAWM in hypertension.

Stroke is the leading cause of physical disability and death among adults in most Western countries. Consecutive to a vascular occlusion, cells face a brutal reduction in supply of oxygen and glucose and thus an energy failure, which in turn triggers cell death mechanisms. Among brain cells, neurons are the most susceptible to ischemia because of their high metabolic demand and low reservoir of energy substrates. In neurons, glycolysis uses glucose coming from blood or from glycogen stored in astrocytes, underlying the deep astrocyte-neuron metabolic cooperation. During ischemia, both the aerobic and anaerobic pathways and thus energy production are compromised, which disrupts proper cell functioning, notably Na⁺/K⁺ ATPase and mitochondria. This results in altered Ca²⁺ homeostasis and overproduction of ROS, the latter being further exacerbated during the reperfusion phase. Consequently, glucose metabolism in the different brain cell populations plays a central role in injury and recovery after stroke, and has recently emerged as a promising target for therapeutic intervention. In this context, the overall objective of this article is to review the interconnections between stroke and brain glucose metabolism and to explore how its targeting may offer new therapeutic opportunities in addressing the global stroke epidemic.

The Circle of Willis (CW), visualized via Magnetic Resonance Angiography (MRA), is crucial for assessing cerebral circulation. Accurate artery identification is essential not only for detecting stenosis and pathological changes but also for understanding vascular adaptations in healthy aging. Manual CW assessment is time-consuming, necessitating automated alternatives. This study evaluates intracranial artery diameter estimations from the Express IntraCranial Arteries Breakdown (eICAB) toolbox against manual measurements. eICAB was tested on 631 participants from the Northern Manhattan Study (NOMAS) with 1.5T MRA images (0.293 × 0.293 × 1 mm resolution). We analyzed eICAB's detection and diameter estimation accuracy of the Internal Carotid (ICA), Basilar (BA), Anterior Cerebral (ACA), Middle Cerebral (MCA), Posterior Cerebral (PCA), and Posterior Communicating (PCom). eICAB showed over 95% accuracy in detecting major arteries except for PCA and PCom (∼80%). Diameter discrepancies were generally ≤0.5 mm, with ICA and BA reaching 1 mm. Spearman correlation (p ≪ 0.05) confirmed strong agreement between automated and manual measurements. Resampling at 0.2083 mm improved precision. eICAB accurately identifies CW arteries and estimates diameters, demonstrating strong clinical and research potential.