Journal of Cerebral Blood Flow and Metabolism最新文献

We studied the regulation dynamics of cerebral blood velocity (CBv) at middle cerebral arteries (MCA) in response to spontaneous changes of arterial blood pressure (ABP), termed dynamic cerebral autoregulation (dCA), and end-tidal CO₂ as proxy for blood CO₂ tension, termed dynamic vasomotor reactivity (DVR), by analyzing time-series data collected at supine rest from 36 patients with Type-2 Diabetes Mellitus (T2DM) and 22 age/sex-matched non-diabetic controls without arterial hypertension. Our analysis employed a robust dynamic modeling methodology that utilizes Principal Dynamic Modes (PDM) to estimate subject-specific dynamic transformations of spontaneous changes in ABP and end-tidal CO₂ (viewed as two "inputs") into changes of CBv at MCA measured via Transcranial Doppler ultrasound (viewed as the "output"). The quantitative results of PDM analysis indicate significant alterations in T2DM of both DVR and dCA in terms of two specific PDM contributions that rise to significance (p < 0.05). Our results further suggest that the observed DVR and dCA alterations may be due to reduction of cholinergic activity (based on previously published results from cholinergic blockade data) that may disturb the sympatho-vagal balance in T2DM. Combination of these two model-based "physio-markers" differentiated T2DM patients from controls (p = 0.0007), indicating diabetes-related alteration of cerebrovascular regulation, with possible diagnostic implications.

Deranged cerebral autoregulation (CA) is associated with worse outcome in adult brain injury. Strategies for monitoring CA and maintaining the brain at its 'best CA status' have been implemented, however, this approach has not yet developed for the paediatric population. This scoping review aims to find up-to-date evidence on CA assessment in children and neonates with a view to identify patient categories in which CA has been measured so far, CA monitoring methods and its relationship with clinical outcome if any. A literature search was conducted for studies published within 31st December 2022 in 3 bibliographic databases. Out of 494 papers screened, this review includes 135 studies. Our literature search reveals evidence for CA measurement in the paediatric population across different diagnostic categories and age groups. The techniques adopted, indices and thresholds used to assess and define CA are heterogeneous. We discuss the relevance of available evidence for CA assessment in the paediatric population. However, due to small number of studies and heterogeneity of methods used, there is no conclusive evidence to support universal adoption of CA monitoring, technique, and methodology. This calls for further work to understand the clinical impact of CA monitoring in paediatric and neonatal intensive care.

Endothelial blood-brain barrier (BBB) dysfunction is critical in the pathophysiology of brain injury. Rho-associated protein kinase (ROCK) activation disrupts BBB integrity in the injured brain. We aimed to test the efficacy of a novel ROCK2 inhibitor in preserving the BBB after acute brain injury. We characterized the molecular structure and pharmacodynamic and pharmacokinetic properties of a novel selective ROCK2 inhibitor, NRL-1049, and its first metabolite, 1-hydroxy-NRL-1049 (referred to as NRL-2017 hereon) and tested the efficacy of NRL-1049 on the BBB integrity in rodent models of acute brain injury. Our data show that NRL-1049 and NRL-2017 both inhibit ROCK activity and are 44-fold and 17-fold more selective towards ROCK2 than ROCK1, respectively. When tested in a mouse model of cortical cryoinjury, NRL-1049 significantly attenuated the increase in water content. Interestingly, 60% of the mice in the vehicle arm developed seizures within 2 hours after cryoinjury versus none in the NRL-1049 arm. In spontaneously hypertensive rats, NRL-1049 attenuated the dramatic surge in Evans Blue extravasation compared with the vehicle arm after transient middle cerebral artery occlusion. Hemorrhagic transformation was also reduced. We show that NRL-1049, a selective ROCK2 inhibitor, is a promising drug candidate to preserve the BBB after brain injury.

Ubiquitin C-terminal hydrolase L1 (UCHL1) is a neuronal protein important in maintaining axonal integrity and motor function and may be important in the pathogenesis of many neurological disorders. UCHL1 may ameliorate acute injury and improve recovery after cerebral ischemia. In the current study, the hypothesis that UCHL1's hydrolase activity underlies its effect in maintaining axonal integrity and function is tested after ischemic injury. Hydrolase activity was inhibited by treatment with a UCHL1 hydrolase inhibitor or by employing knockin mice bearing a mutation in the hydrolase active site (C90A). Ischemic injury was induced by oxygen-glucose deprivation (OGD) in brain slice preparations and by transient middle cerebral artery occlusion (tMCAO) surgery in mice. Hydrolase activity inhibition increased restoration time and decreased the amplitude of evoked axonal responses in the corpus callosum after OGD. Mutation of the hydrolase active site exacerbated white matter injury as detected by SMI32 immunohistochemistry, and motor deficits as detected by beam balance and cylinder testing after tMCAO. These results demonstrate that UCHL1 hydrolase activity ameliorates white matter injury and functional deficits after acute ischemic injury and support the hypothesis that UCHL1 activity plays a significant role in preserving white matter integrity and recovery of function after cerebral ischemia.

Perfusion imaging is useful to assess tissue recovery in patients with acute ischemic stroke (AIS); however, it cannot reflect tissue metabolism. We postulated that amide proton transfer (APT) imaging can characterize the tissue status after reperfusion therapy, thus providing prognostic value for 90-day functional outcomes. We included 63 patients with AIS and large-vessel occlusion (LVO). The APT signals, including APT^# and NOE^# (nuclear Overhauser enhancement) were quantified. Ischemic lesions observed on APT^# and diffusion-weighted imaging (DWI) were classified according to their mismatch patterns (APT^# < DWI; APT^# ≥ DWI). Predictors of 90-day good outcomes (modified Rankin scale score 0-2) were evaluated. Patients with successful reperfusion exhibited higher APT^#, smaller percentage change of APT^#, and a greater likelihood of presenting APT^# < DWI compared to those with poor reperfusion (all P < 0.05). The APT^# (odds ratio [OR] = 11.48, P = 0.046) and a mismatch pattern of APT^# < DWI (OR = 7.41, P = 0.020) independently predicted good outcomes besides the clinical parameters. A mismatch pattern of APT^# ≥ DWI was a significant marker of poor outcomes despite successful reperfusion (P = 0.002). Our study provides preliminary evidence that APT may reveal tissue recovery after reperfusion and predict good outcomes at 90 days in patients with AIS and LVO.

This paper describes the preclinical validation of the radioligand [¹¹C]ORM-13070 and its tritiated analog for addressing selectivity and occupancy of the selective alpha-2C adrenergic receptor (α_2CR) antagonist BAY 292 in the cynomolgus brain. BAY 292 is a novel drug candidate being developed for the treatment of obstructive sleep apnea (OSA) via binding to central α_2CR. In vitro autoradiography studies with sections from non-diseased post-mortem human caudate revealed an excellent specific binding window (>80%) using [³H]ORM-13070. BAY 292 bound to the same binding site as [³H]ORM-13070 and generated a good specific binding signal, with greater selectivity for α_2CR. In non-human primates in vivo, [¹¹C]ORM-13070 demonstrated a reversible behavior, with uptake at baseline highest in striatum (putamen, caudate, ventral striatum, and pallidum) and low in the cerebellar cortex, consistent with the known distribution of the α_2CR. A dose dependent increase in receptor occupancy after BAY 292 administration was observed, confirming BBB penetration and target engagement. The estimated EC₅₀ for BAY 292 is 33.39 ± 11.91 ng/mL. This study aimed to demonstrate the suitability of [¹¹C]ORM-13070 as a PET-radioligand for the study of α_2CR in the non-human primate brain, and to pave the way for future clinical PET tracer studies with BAY 292.

Endovascular thrombectomy has a recanalization rate over 80%; however, approximately 50% of ischemic stroke patients still experience dependency or mortality. Recently, clinical trials demonstrated the benefits of administering neuroprotective agents prior to endovascular thrombectomy. Additionally, recent studies showed neuroprotective effects of mild hypercapnia in patients resuscitated after cardiac arrest. However, its efficacy in ischemic stroke remains unclear. We aimed to investigate whether carbon dioxide (CO₂) per-conditioning has neuroprotective effects in rat models with middle cerebral artery occlusion (MCAO). Rat models received intermittent inhalation of mixed gas during the MCAO period. After surgery, behavioral assessments, infarct size measurement, immunohistochemistry, and western blot analysis were performed. We found CO₂ per-conditioning reduced infarct size and neurological deficit. The number of 8-hydroxy-2-deoxyguanosine (8-OHdG) positive cells and matrix metalloproteinase 9 (MMP-9)/platelet derived growth factor receptor beta (PDGFRβ) double positive cells were significantly decreased after CO₂ per-conditioning. The expressions of tight junction protein and pericytes survival were preserved. This study underscores mild hypercapnia before reperfusion not only reduces neurologic deficit and infarct size, but also maintains the integrity of the blood-brain barrier and neurovascular unit, alongside mitigating oxidative stress in hyperacute stroke rat models. Therapeutic mild hypercapnia before reperfusion is promising and requires further clinical application.

While the concept of pericyte heterogeneity in the brain microvasculature is becoming more widely accepted, little is known about how they arise, or their functional contributions to the blood-brain barrier (BBB). We therefore set out to examine the distribution of subtypes of pericytes at the BBB and sought to elucidate some of their functional characteristics by examining their unique mRNA expression patterns. We demonstrate that type-1 pericytes (PC1) that are associated with young healthy brains and BBB homeostasis, can transition into type-2 pericytes (PC2) that are associated with disease and BBB breakdown, both in vitro and in vivo, in the presence of both endogenous and disease associated ligands. We identified PC1 and PC2 in single-cell RNA-sequencing from vascular enriched mouse brain and identified transcriptional differences between PC1 and PC2. PC2 showed increased expression of genes associated with phagocytosis and peripheral immune cell infiltration. On the contrary, PC1 displayed increased expression of genes involved in hedgehog signaling, which is known to promote tight junction formation at the BBB. Our data support the PC1-to-PC2 transition as an origin of PC diversity and suggest a functional role for PC1 in maintaining BBB homeostasis and PC2 in responding to pathological conditions.

The increasing prevalence of pathological cerebrovascular conditions, including stroke, hypertensive encephalopathy, and chronic disorders, underscores the importance of anesthetic considerations for affected patients. Preserving cerebral oxygenation and blood flow during anesthesia is paramount to prevent neurological deterioration. Furthermore, protecting vulnerable neurons from damage is crucial for optimal outcomes. Recent research suggests that anesthetic agents may provide a potentially therapeutic approach for managing pathological cerebrovascular conditions. Anesthetics target neural mechanisms underlying cerebrovascular dysfunction, thereby modulating neuroinflammation, protecting neurons against ischemic injury, and improving cerebral hemodynamics. However, optimal strategies regarding mechanisms, dosage, and indications remain uncertain. This review aims to clarify the physiological effects, mechanisms of action, and reported neuroprotective benefits of anesthetics in patients with various pathological cerebrovascular conditions. Investigating anesthetic effects in cerebrovascular disease holds promise for developing novel therapeutic strategies.

Early imaging-based detection of acute ischemic stroke (AIS) has improved in the era of reperfusion therapy. Despite of this, prognosis of outcome after AIS remains a challenge. Therefore, parameters that support clinical decision making are sought. Blood-based biomarkers have the potential to provide valuable information in addition to the established prognostic factors. Neuronal biomarkers of acute or degenerative neuronal injury have shown to be reliably detected in plasma. These biomarkers are well-established in neurodegenerative pathology, such as Alzheimer's disease. In this study, we explored the association between stroke diameter and plasma biomarkers for neuronal injury and tau pathophysiology (brain-derived tau [BD-tau], phosphorylated-tau-217 [p-tau21] and neurofilament light [NfL]) in patients (n = 193) admitted to the acute ward, Akershus University Hospital. All patients received a final diagnosis of AIS, transient ischemic attack or stroke mimics. Blood samples were obtained the day after admission. We find that levels of BD-tau (p = .004) and NfL (p = .011) were higher after AIS than in patients with stroke mimics. The cortical stroke diameter correlated with BD-tau (tau-b = 0.64, p < .001) and p-tau217 (tau-b = 0.36, p = .003). Linear regression confirmed BD-tau to be the strongest variable associated with stroke diameter, pointing to the potential clinical value of plasma BD-tau in outcome prediction after AIS.