Journal of Cerebral Blood Flow and Metabolism最新文献

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.

Obtaining the arterial input function (AIF) is essential for quantitative regional cerebral perfusion (rCBF) measurements using [¹⁵O]H₂O PET. However, arterial blood sampling is invasive and complicates the scanning procedure. We propose a new non-invasive dual scan technique with an image derived input function (IDIF) from an additional heart scan. Six patients and two healthy subjects underwent [¹⁵O]H₂O PET imaging of 1) heart and brain during baseline, and 2) heart and brain after infusion of acetazolamide. The IDIF was extracted from the left ventricle of the heart and compared to the AIF. The rCBF was compared for six bilateral cortical regions. AIFs and IDIFs showed strong agreement. rCBF with AIF and IDIF showed strong correlation for both baseline rCBF (R² = 0.99, slope = 0.89 CI: [0.87; 0.91], p < 0.0001) and acetazolamide rCBF (R² = 0.98, slope = 0.93, CI:[0.90;0.97], p < 0.0001) but showed a positive bias of 0.047 mL/(g·min) [-0.025; +0.119] for baseline and 0.024 [-1.04, +1.53] mL/(g·min) for acetazolamide. In conclusion, the invasive arterial cannulation can be replaced by an additional scan of the heart with a minor bias of rCBF estimation. The method is applicable to all scanner systems.

Obesity and associated metabolic disturbances worsen brain ischemia outcome. High fat diet (HFD)-fed mice are obese and have cerebrovascular remodeling and worsened brain ischemia outcome. We determined whether HFD-induced cerebrovascular remodeling impaired reperfusion to the ischemic penumbra. Six-week-old C57BL/6J or matrix metalloprotease-9 knockout (MMP-9^-/-) mice were on HFD or regular diet (RD) for 12 to 14 months before a 60-min left middle cerebral arterial occlusion (MCAO). Photoacoustic microscopy was performed at left cerebral frontal cortex. HFD increased cerebrovascular density and tortuosity in C57BL/6J mice but not in MMP-9^-/- mice. Blood flow to the ischemic penumbra slowly recovered but did not reach the baseline 2 h after MCAO in RD-fed mice. Oxygen extraction fraction was increased to maintain cerebral metabolic rate of oxygen (CMRO₂) throughout brain ischemia and reperfusion period. This blood flow recovery was worsened in HFD-fed mice, leading to decreased CMRO₂. MMP-9^-/- attenuated these HFD effects. HFD increased MMP-9 activity and interleukin 1β. Pyrrolidine dithiocarbamate, an anti-inflammatory agent, abolished the HFD effects. Interleukin 1β increased MMP-9 activity. In summary, HFD induces cerebrovascular remodeling, leading to worsened recovery of blood supply to the ischemic penumbra to contribute to poor outcome after brain ischemia. Neuroinflammation may activate MMP-9 in HFD-fed mice.

Delayed cerebral ischemia (DCI) following an aneurysmal subarachnoid hemorrhage (aSAH) significantly impacts mortality, morbidity, and healthcare costs. This study assessed the diagnostic accuracy of Transcranial Doppler (TCD)-derived biomarkers for predicting DCI via a systematic review and meta-analysis. Included studies had to correctly define DCI and report data on sensitivity, specificity, positive predictive value, and negative predictive value. Univariate or bivariate analyses with a random effects model were used, and risk of bias was evaluated with the Quality Assessment of Diagnostic Accuracy Studies. From 23 eligible articles (n = 2371 patients), three biomarker categories were identified: cerebral blood flow velocities (CBFV), cerebral autoregulation, and microembolic signals (MES). The highest sensitivity (0.86, 95% CI 0.71-0.94) and specificity (0.75, 95% CI 0.52-0.94) for DCI prediction were achieved with a mean CBFV of 120 cm/s combined with a Lindegaard ratio. The transient hyperemic response test showed the best performance among autoregulatory biomarkers with a sensitivity of 0.88, (95% CI 0.54-0.98) and specificity of 0.82 (95% CI 0.52-0.94). MES were less effective predictors. Combining CBFV with autoregulatory biomarkers enhanced TCD's predictive value. High heterogeneity and risk of bias were noted, indicating the need for a standardized TCD approach for improved DCI evaluation.

Blood-brain barrier (BBB) dysfunction occurs in numerous central nervous system disorders. Unfortunately, a limited understanding of the mechanisms governing barrier function hinders the identification and assessment of BBB-targeted therapies. Previously, we found that non-muscle myosin light chain kinase (nmMLCK) negatively regulates the tight junction protein claudin-5 in brain microvascular endothelial cells (BMVECs) under inflammatory conditions. Here, we used complementary animal and primary cell co-culture models to further investigate nmMLCK and claudin-5 during neuroinflammation. We found that nmMLCK-knockout mice resisted experimental autoimmune encephalomyelitis (EAE), including paralysis, demyelination, neutrophil infiltration, and BBB dysfunction. However, transiently silencing claudin-5 culminated in a fulminant disease course. In parallel, we found that neutrophil-secreted factors triggered a biphasic loss in the barrier quality of wild-type BMVEC monolayers, plus pronounced neutrophil migration during the second phase. Conversely, nmMLCK-knockout monolayers resisted barrier dysfunction and neutrophil migration. Lastly, we found an inverse relationship between claudin-5 expression in BMVECs and neutrophil migration. Overall, our findings support a pathogenic role for nmMLCK in BMVECs during EAE that includes BBB dysfunction and neutrophil infiltration, reveal that claudin-5 contributes to the immune barrier properties of BMVECs, and underscore the harmful effects of claudin-5 loss during neuroinflammation.

Acute ischemic stroke (AIS) requires detailed etiology information to guide optimal management. Given the pivotal role of lipids in AIS, we conducted a comprehensive lipidomics analysis of paired thrombi and plasma from AIS patients, correlating the findings with stroke etiology. Patients were recruited across four etiologies: cardioembolism (CE), large artery atherosclerosis (LAA), active cancer (Cancer), and undetermined. Plasma and thrombi were collected before and during endovascular thrombectomy and analyzed using in-house targeted lipidomics. Among 51 patients (37 CE, 7 LAA, 4 Cancer, and 3 undetermined), we identified 37 and 70 lipid species significantly different between thrombi in CE and LAA, and CE and Cancer, respectively (FDR-corrected P < 0.05). No significant differences were observed in plasma. Notably, 21 diacylglycerols and 11 polyunsaturated triacylglycerols were depleted (2.5 to 12 folds) in LAA compared to CE, while 10 ceramides and 57 glycerophospholipids were elevated in Cancer. With 80% validation accuracy, 29 and 59 lipids distinguished LAA and Cancer from CE, respectively. A neural network model using these lipids effectively classified undetermined patients. This study emphasizes the significance of thrombus lipids in distinguishing between LAA, CE, and Cancer etiologies in AIS, enhancing our understanding of stroke pathophysiology and informing future clinical managements.

Zero echo time (zero-TE) pulse sequences provide a quiet and artifact-free alternative to conventional functional magnetic resonance imaging (fMRI) pulse sequences. The fast readouts (<1 ms) utilized in zero-TE fMRI produce an image contrast with negligible contributions from blood oxygenation level-dependent (BOLD) mechanisms, yet the zero-TE contrast is highly sensitive to brain function. However, the precise relationship between the zero-TE contrast and neuronal activity has not been determined. Therefore, we aimed to derive a function to model the temporal dynamics of the zero-TE fMRI signal in response to neuronal activity. Furthermore, we examined the correlation of zero-TE fMRI with neuronal activity across stimulation frequencies. To these ends, we performed simultaneous electrophysiological recordings and zero-TE fMRI in rats subjected to whisker stimulation. The presented impulse response function provides a basis for the statistical modeling of neuronal activity-induced changes in the zero-TE fMRI signal. The temporal characteristics of the zero-TE fMRI response were found to be consistent with the previously postulated non-BOLD hemodynamic origin of the functional contrast. The zero-TE fMRI signal was well predicted by electrophysiological recordings, although systematic stimulation-dependent residuals were also observed, suggesting nonlinearities in neurovascular coupling. We conclude that zero-TE fMRI provides a robust proxy for neuronal activity.

Aircraft cabins are routinely pressurized to the equivalent of 8000 ft altitude. Exposure of lab animals to aeromedical evacuation relevant hypobaria after traumatic brain injury worsens neurological outcomes, which is paradoxically exacerbated by hyperoxia. This study tested the hypothesis that exposure of rats to hypobaria following cortical impact reduces cerebral blood flow, increases neuroinflammation, and alters brain neurochemistry. Rats were exposed to simulated ground (normobaric) or air (hypobaric 8000 ft) transport, under normoxia or hyperoxia, 24 hr after trauma. Hypobaria exposure resulted in lower cerebral blood flow to the contralateral cortex and bilateral thalamus during flight and increased delayed cortical inflammation (ED1 immunoreactivity) at 14 days post injury. Impacted rats exposed to hypobaria had higher cortical creatine levels compared rats maintained at sea level. Exposure to the combination of hyperoxia and hypobaria resulted in the greatest reduction in cortical blood flow and total creatine during flight which persisted up to two weeks. In conclusion, hypoperfusion during hypobaria exposure could contribute to worsening of neuroinflammation and neurochemical imbalances. The presence of excessive O₂ during hypobaria results in long-term suppression of cerebral blood flow, indicating that supplemental O₂ should be titrated during hypobaria to maintain normoxia.

Mid-life vascular risk factors predict late-life cerebrovascular diseases and poor global brain health. Although endothelial dysfunction is hypothesized to contribute to this process, evidence of impaired neurovascular function in early stages remains limited. In this cross-sectional study of 31,934 middle-aged individuals from UK Biobank without established cerebrovascular disease, the overall 10-year risk of cardiovascular events was associated with reduced neurovascular coupling (p < 2 × 10^-16) during a visual task with functional MRI, including in participants with no clinically apparent brain injury on MRI. Diabetes, smoking, waist-hip ratio, and hypertension were each strongly associated with decreased neurovascular coupling with the strongest relationships for diabetes and smoking, whilst in older adults there was an inverted U-shaped relationship with DBP, peaking at 70-80 mmHg DBP. These findings indicate that mid-life vascular risk factors are associated with impaired cerebral endothelial-dependent neurovascular function in the absence of overt brain injury. Neurovascular dysfunction, measured by neurovascular coupling, may play a role in the development of late-life cerebrovascular disease, underscoring the need for further longitudinal studies to explore its potential as a mediator of long-term cerebrovascular risk.

White matter (WM) free water (FW) is a potential imaging marker for cerebral small vessel disease (CSVD). This study aimed to characterize longitudinal changes in WM FW and investigate factors contributing to its elevation in CSVD. We included 80 CSVD patients and 40 normal controls (NCs) with multi-modality MRI data. Cerebral blood flow (CBF) was measured, and fiber alterations were assessed using total apparent fiber density (AFD_t). FW were extracted from whole WM, white matter hyperintensities (WMH) and normal-appearing WM (NAWM). Baseline and longitudinal FW elevation were compared between patients and NCs, and between WMH and NAWM. We investigated whether baseline vascular risk factor score, CBF, and AFD_t could predict longitudinal FW elevation. Association between cognition and WM FW in CSVD was also assessed. Results shown that FW was higher and increased faster in CSVD compared to NCs and in WMH compared to NAWM. Baseline AFD_t predicted longitudinal FW elevation in CSVD patients, while CBF predicted FW changes only in controls. WM FW was associated with cognitive impairment. These findings suggest that CSVD is associated with a faster increase in WM FW. Hypoperfusion and WM fiber alterations might accelerate FW elevation, which is associated with cognitive decline.