Journal of Cerebral Blood Flow and Metabolism最新文献

This study measured the relationship between pial collateral (leptomeningeal anastomoses, LMA) flow, intraparenchymal cortical cerebral blood flow (cCBF) and brain tissue oxygenation (btO₂) during acute ischemic stroke to investigate how pial flow translates to downstream cCBF and btO₂ and examined how this relationship is altered in hypertension. Proximal transient middle cerebral artery occlusion (tMCAO) was performed in male Wistar (n = 8/group) and Spontaneously Hypertensive Rats (SHR, n = 8/group). A combination laser Doppler-oxygen probe was placed within the expected cortical peri-infarct in addition to a surface laser doppler probe which measured LMA flow. Phenylephrine (PE) was infused 30 minutes into tMCAO to increase blood pressure (BP) by 30% for 10 minutes and assessed CBF autoregulation. During the initial 30-minute period of tMCAO, btO₂ and cCBF were lower in SHR compared to Wistar rats (btO₂: 11.5 ± 10.5 vs 17.5 ± 10.8 mmHg and cCBF: -29.7 ± 23.3% vs -17.8 ± 41.9%); however, LMA flow was similar between groups. The relationship between LMA flow, cCBF and btO₂ were interdependent in Wistar rats. However, this relationship was disrupted in SHR rats and partially restored by induced hypertension. This study provides evidence that cCBF and btO₂ were diminished during tMCAO in chronic hypertension, and that induced hypertension was beneficial regardless of hypertensive status.

This paper describes pharmacokinetic analyses of the monoamine-oxidase-B (MAO-B) radiotracer [¹⁸F](S)-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ([¹⁸F]SMBT-1) for positron emission tomography (PET) brain imaging. Brain MAO-B expression is widespread, predominantly within astrocytes. Reactive astrogliosis in response to neurodegenerative disease pathology is associated with MAO-B overexpression. Fourteen elderly subjects (8 control, 5 mild cognitive impairment, 1 Alzheimer's disease) with amyloid ([¹¹C]PiB) and tau ([¹⁸F]flortaucipir) imaging assessments underwent dynamic [¹⁸F]SMBT-1 PET imaging with arterial input function determination. [¹⁸F]SMBT-1 showed high brain uptake and a retention pattern consistent with the known MAO-B distribution. A two-tissue compartment (2TC) model where the K₁/k₂ ratio was fixed to a whole brain value best described [¹⁸F]SMBT-1 kinetics. The 2TC total volume of distribution (V_T) was well identified and highly correlated (r²∼0.8) with post-mortem MAO-B indices. Cerebellar grey matter (CGM) showed the lowest mean V_T of any region and is considered the optimal pseudo-reference region. Simplified analysis methods including reference tissue models, non-compartmental models, and standard uptake value ratios (SUVR) agreed with 2TC outcomes (r² > 0.9) but with varying bias. We found the CGM-normalized 70-90 min SUVR to be highly correlated (r² = 0.93) with the 2TC distribution volume ratio (DVR) with acceptable bias (∼10%), representing a practical alternative for [¹⁸F]SMBT-1 analyses.

Electroencephalogram (EEG) alpha-band oscillations may reflect executive and processing function in patients with cerebral small vessel disease (CSVD). We aimed to assess such association and its relationship with CSVD severity, and to identify specific alpha-band parameters and the cut-off values for cognitive screening. We analysed the dispersion of amplitude-frequency characteristics of EEG alpha-band and different alpha-band parameters (PFα , ΔPFα , PPα , NCL) in different brain locations. We also assessed patients' executive and processing functions using verbal fluency test (VFT) and color trails test (CTT), and CSVD severity using total burden and Fazekas scores. 129 patients were recruited in the study. After adjusting for age, gender and education, PFα(F3), PFα(F4) and NCL were significantly associated with VFT-composite performance (p < 0.05). CTT-1 time and error were associated with PFα(F3), PFα(F4), ΔPFα(O1;F3) and CSVD severity (p < 0.05), whereas CTT-2 time was only associated with CSVD severity. Moreover, the correlations between alpha-band oscillations and cognitive function were higher in low than in high disease-severity group (ρ: -0.58 vs. -0.38, p < 0.05). The AUC of selected alpha-band parameters were higher than 0.8 for VFT and CTT. Specific alpha-band parameters in the frontal lobe were identified to correspond to executive and processing function. Assessing EEG alpha-band oscillations may assist in screening cognitive impairment.

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.

Intra-vital visualization of deep cerebrovascular structures and blood flow in the aging brain has been a difficult challenge in the field of neurovascular research, especially when considering the key role played by the cerebrovasculature in the pathogenesis of both vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). Traditional imaging methods face difficulties with the thicker skull of older brains, making high-resolution imaging and cerebral blood flow (CBF) assessment challenging. However, functional ultrasound (fUS) imaging, an emerging non-invasive technique, provides real-time CBF insights with notable spatial-temporal resolution. This study introduces an enhanced longitudinal fUS method for aging brains. Using elderly (24-month C57BL/6) mice, we detail replacing the skull with a polymethylpentene window for consistent fUS imaging over extended periods. Ultrasound localization mapping (ULM), involving the injection of a microbubble (<<10 μm) suspension allows for recording of high-resolution microvascular vessels and flows. ULM relies on the localization and tracking of single circulating microbubbles in the blood flow. A FIJI-based analysis interprets these high-quality ULM visuals. Testing on older mouse brains, our method successfully unveils intricate vascular specifics even in-depth, showcasing its utility for longitudinal studies that require ongoing evaluations of CBF and vascular aspects in aging-focused research.

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.