Journal of Cerebral Blood Flow and Metabolism最新文献

Neuroinflammation is a promising therapeutic target in intracerebral hemorrhage (ICH), characterized in the brain by microglial activation and blood-brain barrier (BBB) breakdown. In this study, 36 acute, spontaneous, supratentorial ICH patients underwent dynamic contrast-enhanced MRI to measure BBB permeability (K^trans) 1-3 days post-onset and 16 returned for [¹¹C](R)-PK11195 PET to quantify microglial activation (BP_ND), 2-7 days post-onset. We first tested if these markers were increased and co-localized in the perihematomal brain and found that perihematomal K^trans and BP_ND were increased vs. the contralateral brain, but regions of high K^trans and BP_ND only overlapped by a mean of 4.9%. We then tested for associations of perihematomal K^trans and BP_ND with clinical characteristics (age, ICH volume & location, blood pressure), other markers of inflammation (edema, IL-6, and CRP), and long-term functional outcome (90-day mRS). Lower perihematomal BP_ND was associated with increasing age. Lobar hemorrhage was associated with greater K^trans than deep, but K^trans and BP_ND were not associated with ICH volume, or other inflammatory markers. While perihematomal K^trans and BP_NDwere not associated with outcome, contralateral K^trans was significantly associated with greater 90-day mRS. Exploratory analyses demonstrated that blood pressure variability over 72 h was also associated with contralateral K^trans.

Peroxisome proliferator-activated receptor-γ (PPARγ) plays a protective role against brain injury after stroke in mice. However, the relationship between PPARγ gene polymorphisms and the functional outcome of acute ischemic stroke (AIS) remains unknown. 8822 patients from The Third China National Stroke Registry (CNSR-III) after whole-genome sequencing, two functional single nucleotide polymorphisms(SNPs) in PPARγ, rs1801282 C > G and rs3856806 C > T, were further analysed. The primary outcome was neurological functional disability at three months. Of the 8822 patients, 968 (11.0%) and 3497 (39.6%) were carriers of rs1801282 and rs3856806, respectively. Carriers of rs3856806 showed reduced risks for three-month neurological functional disability (OR, 0.84; 95% CI, 0.73-0.98; p = 0.02) and reduced risks for higher infarct volume (OR 0.90, 95% CI, 0.81-0.99, p = 0.04). They also had a reduced risk of neurological functional disability only in case of lower baseline IL-6 levels (OR 0.64, 95% CI 0.48-0.84, P_interaction = 0.01). Carriers of rs1801282 had a reduced risk for three-month neurological functional disability (OR 0.77, 95% CI, 0.61-0.99, p = 0.04). Our study suggested that PPARγ polymorphisms are associated with a reduced risk for neurological functional disability and higher infarct volume in AIS. Therefore, PPARγ can be a potential therapeutic target in AIS.

[¹⁸F]SF51 is a novel radioligand for imaging translocator protein 18 kDa (TSPO) that previously displayed excellent imaging properties in nonhuman primates. This study assessed its performance in human brain and its dosimetry. Seven healthy participants underwent brain PET imaging to measure TSPO binding using a two-tissue compartment model (2TCM) to calculate total distribution volume (V_T). This cohort included two high-affinity binders (HABs), three mixed-affinity binders (MABs), and two low-affinity binders (LABs). Two other participants received whole-body scans to assess radiation exposure. Peak brain radioactivity reached a standardized uptake value (SUV) of 1.4 at 3 minutes post-injection, diminishing to 30% of peak by 120 minutes. The average V_T for all genotype groups was notably low (<1 mL·cm^-3), emphasizing the radioligand's poor binding in brain. [¹⁸F]SF51 remained sensitive to the TSPO polymorphism in vivo, as shown by a two-fold difference in V_T between HABs and LABs. V_T stabilization by 80 minutes post-injection suggested minimal radiometabolite accumulation in brain. The average effective dose was 13.8 ± 0.9 µSv/MBq. Contrary to previously published animal data, [¹⁸F]SF51 showed low binding to human TSPO, with uptake remaining influenced by the rs6971 polymorphism. These findings highlight the challenges of developing TSPO radioligands and underscore the significant species differences that may influence translational outcomes.ClinicalTrials.gov identifier: NCT05564429; registered 10/03/2022.

Variations in cerebral blood flow and blood volume interact with intracranial pressure and cerebrospinal fluid dynamics, all of which play a crucial role in brain homeostasis. A key physiological modulator is respiration, but its impact on cerebral blood flow and volume has not been thoroughly investigated. Here we used 4D flow MRI in a population-based sample of 65 participants (mean age = 75 ± 1) to quantify these effects. Two gating approaches were considered, one using respiratory-phase and the other using respiratory-time (i.e. raw time in the cycle). For both gating methods, the arterial inflow was significantly larger during exhalation compared to inhalation, whereas the venous outflow was significantly larger during inhalation compared to exhalation. The cerebral blood volume variation per respiratory cycle was 0.83 [0.62, 1.13] ml for respiratory-phase gating and 0.78 [0.59, 1.02] ml for respiratory-time gating. For comparison, the volume variation of the cardiac cycle was 1.01 [0.80, 1.30] ml. Taken together, our results clearly demonstrate respiratory influences on cerebral blood flow. The corresponding vascular volume variations appear to be of the same order of magnitude as those of the cardiac cycle, highlighting respiration as an important modulator of cerebral blood flow and blood volume.

Stem cell-based therapies have raised considerable interest to develop regenerative treatment for neurological disorders with high disability. In this review, we focus on recent preclinical and clinical evidence of stem cell therapy in the treatment of degenerative neurological diseases and discuss different cell types, delivery routes and biodistribution of stem cell therapy. In addition, recent advances of mechanistic insights of stem cell therapy, including functional replacement by exogenous cells, immunomodulation and paracrine effects of stem cell therapies are also demonstrated. Finally, we also highlight the adjunction approaches that has been implemented to augment their reparative function, survival and migration to target specific tissue, including stem cell preconditioning, genetical engineering, co-transplantation and combined therapy.

A potential two-way passage of cells and substances between the brain and skull bone marrow may open for new insights into neurological disease. The arachnoid membrane was traditionally considered to restrict cells and larger molecules in CSF from entering the dura and bone marrow directly. However, new data on exchange between brain and skull bone marrow have recently emerged. Here, we conducted a systematic literature to answer the question: What is the current evidence regarding the movement of cells and molecules between the brain and skull bone marrow, spanning CSF and meninges? We excluded studies related to head or skull trauma, cranial fractures or defects, cancer invasion, CSF leakage, spontaneous intracranial hypotension, spinal dura mater, and studies solely focusing on meningeal lymphatic vessels or the passage of substances from CSF to meningeal lymphatic vessels. The review identified 16 studies that provide evidence of communication between the brain, meninges and skull bone marrow. Cells (such as B and T cells and neutrophils), bacteria, and substances (tracers, drug compounds) have been reported to pass between the brain and skull bone. However, most studies are performed in rodents, emphasizing the need for translation to humans.

Current metabolomics technologies can measure hundreds of chemical entities in tissue extracts with good reliability. However, long-recognized requirements to halt enzyme activities during the initial moments of sample preparation are usually overlooked, allowing marked postmortem shifts in levels of labile metabolites representing diverse pathways. In brain many such changes occur in a matter of seconds. These comments overview the concern, contrast representative studies, and specify approaches to consider as standards in the field going forward. Comparison with established metabolite signatures of in vivo brain is an essential validation step when implementing any collection method.

To what extent sildenafil, a selective inhibitor of the type-5 phosphodiesterase modulates systemic redox status and cerebrovascular function during acute exposure to hypoxia remains unknown. To address this, 12 healthy males (aged 24 ± 3 y) participated in a randomized, placebo-controlled crossover study involving exposure to both normoxia and acute (60 min) hypoxia (Fi${\text{O}}_2$ = 0.14), followed by oral administration of 50 mg sildenafil and placebo (double-blinded). Venous blood was sampled for the ascorbate radical (A^•-: electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (NO: ozone-based chemiluminescence). Transcranial Doppler ultrasound was employed to determine middle cerebral artery velocity (MCAv), cerebral delivery of oxygen ${\text{(CDO}}_2\text{),}$ dynamic cerebral autoregulation (dCA) and cerebrovascular reactivity to hypo/hypercapnia (CVR_{CO2HYPO/HYPER}). Cortical oxyhemoglobin (cO₂Hb) and oxygenation index (OI) were assessed using pulsed continuous wave near infra-red spectroscopy. Hypoxia decreased total plasma NO (P = 0.008), ${\text{CDO}}_2$ (P = <0.001) and cO₂Hb (P = 0.005). In hypoxia, sildenafil selectively reduced A^•- (P = 0.018) and MCA_V (P = 0.018), and increased dCA metrics of low-frequency phase (P = 0.029) and CVR_CO2HYPER (P = 0.007) compared to hypoxia-placebo. Collectively, these findings provide evidence for a PDE-5 inhibitory pathway that enhances select aspects of cerebrovascular function in hypoxia subsequent to a systemic improvement in redox homeostasis and independent of altered vascular NO bioavailability.

Hyperpolarized-¹³C magnetic resonance imaging (HP-¹³C MRI) was used to image changes in ¹³C-lactate signal during a visual stimulus condition in comparison to an eyes-closed control condition. Whole-brain ¹³C-pyruvate, ¹³C-lactate and ¹³C-bicarbonate production was imaged in healthy volunteers (N = 6, ages 24-33) for the two conditions using two separate hyperpolarized ¹³C-pyruvate injections. BOLD-fMRI scans were used to delineate regions of functional activation. ¹³C-metabolite signal was normalized by ¹³C-metabolite signal from the brainstem and the percentage change in ¹³C-metabolite signal conditions was calculated. A one-way Wilcoxon signed-rank test showed a significant increase in ¹³C-lactate in regions of activation when compared to the remainder of the brain ($p=0.02$). No significant increase was observed in ¹³C-pyruvate signal ($p=0.11$) or ¹³C-bicarbonate signal ($p=0.95$). The results show an increase in ¹³C-lactate production in activated regions that is measurable with HP-¹³C MRI.

Therapeutic drug development for central nervous system injuries, such as traumatic brain injury (TBI), presents significant challenges. TBI results in primary mechanical damage followed by secondary injury, leading to cognitive dysfunction and memory loss. Our recent study demonstrated the potential of carbon monoxide-releasing molecules (CORMs) to improve TBI recovery by enhancing neurogenesis. However, a comprehensive TBI recovery strategy requires not only neurogenesis but also oligodendrogenesis. In this study, we elucidate the critical role of A-kinase anchor protein 12 (AKAP12), a scaffolding protein predominantly expressed by intact pericytes, in oligodendrocyte regeneration during CO therapy for TBI. CORM treatment increased AKAP12 expression, which enhanced myelin intensity and mitigated TBI-induced oligodendrocyte loss. In addition, CO promotes the generation of new oligodendrocytes, a process that is impaired by AKAP12 deficiency. Notably, even after TBI, cognitive function was restored in wild-type mice following CORM treatment, but this effect was absent in Akap12 knockout mice. These findings highlight the importance of CO-induced AKAP12 upregulation, particularly in pericytes, in supporting oligodendrogenesis and cognitive recovery after TBI. Understanding these mechanisms holds promise for the development of targeted therapies to address TBI-associated impairments.