Journal of Cerebral Blood Flow and Metabolism最新文献

This investigation explored the impact of partial pressure of end-tidal carbon dioxide (P_ETCO₂) alterations on temporal neurovascular coupling (NVC) responses across the cardiac cycle and the influence of biological sex via a complex visual scene-search task ("Where's Waldo?"). 10 females and 10 males completed five puzzles, each with 40 seconds of eyes open and 20 seconds of eyes closed, under P_ETCO₂ clamped at ∼40 mmHg (eucapnia), ∼55 mmHg (hypercapnia), and ∼25 mmHg (hypocapnia). Cerebral blood velocity (CBv) in the middle and posterior cerebral arteries (MCAv, PCAv) were measured via Transcranial Doppler ultrasound. Linear mixed-effects models with participants as a random effect analyzed NVC metrics, including baseline and peak CBv, relative increase, and area-under-the-curve (AUC30). During hypercapnic trials, reductions in PCAv and MCAv AUC30 were noted across the cardiac cycle (all p < 0.001). Hypocapnic PCAv AUC30 was reduced (all p < 0.012), as was systolic MCAv AUC30 (p = 0.003). Females displayed greater baseline PCA diastole (p = 0.048). No other biological sex differences were observed across conditions in baseline (all p > 0.050), peak (all p > 0.054), relative increase (all p > 0.511), and AUC30 metrics (all p > 0.514). Despite differences in responses to hypercapnic and hypocapnic stimuli, NVC responses to complex visual tasks remain robust, across the physiological CO₂ range.

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.

The glymphatic system regulates cerebrospinal fluid (CSF) transport and brain waste clearance. Focused ultrasound combined with microbubbles (FUSMB) has shown feasibility for manipulating glymphatic transport, yet its mechanisms remain poorly understood. In this work, we used in vivo two-photon microscopy to reveal how FUSMB manipulates the CSF tracer transport in the mouse brain. A FUS transducer was confocally aligned with the objective of a two-photon microscope. Fluorescently labeled albumin was infused into the CSF via cisterna magna. FUS sonication was applied following an intravenous injection of microbubbles. Dynamic imaging was performed through a cranial window to record local changes in vessel and tracer dynamics. The fluorescence intensity of the CSF tracer within the treated region decreased rapidly upon FUSMB treatment. Concurrently, vessel deformation was observed, and the fastest diameter changes were observed during FUSMB treatment. A linear correlation was identified between the rate of vessel diameter change and the rate of tracer intensity change. Moreover, given the same rate of vessel diameter change, the tracer intensity changed faster around larger vessels than smaller vessels. These findings offer insight into the potential biophysical mechanism of FUSMB-mediated glymphatic transport.

Glucose metabolic dysfunction is a hallmark of Alzheimer's disease (AD) pathology and is used to diagnose the disease or predict imminent cognitive decline. The main method to measure brain metabolism in vivo is positron emission tomography with 2-Deoxy-2-[¹⁸F]fluoroglucose ([¹⁸F]FDG-PET). The cellular origin of changes in the [¹⁸F]FDG-PET signal in AD is controversial. We addressed this by combining [¹⁸F]FDG-PET with subsequent cell-sorting and γ-counting of [¹⁸F]FDG-accumulation in sorted cell populations. 7-month-old male TgF344-AD rats and wild-type controls (n = 24/group) received sham or ceftriaxone (200 mg/kg) injection prior to [¹⁸F]FDG-PET imaging to increase glutamate uptake and glucose utilisation. The same animals were injected again one week later, and radiolabelled brains were dissected, with hippocampi taken for magnetically-activated cell sorting of radioligand-treated tissues (MACS-RTT). Radioactivity in sorted cell populations was measured to quantify cell-specific [¹⁸F]FDG uptake. Transcriptional analyses of metabolic enzymes/transporters were also performed. Hypometabolism in the frontal association cortex of TgF344-AD rats was identified using [¹⁸F]FDG-PET, whereas hypermetabolism was identified in the hippocampus using MACS-RTT. Hypermetabolism was primarily driven by GLAST+ cells. This was supported by transcriptional analyses which showed alteration to metabolic apparatus, including upregulation of hexokinase 2 and altered expression of glucose/lactate transporters. See Figure 1 for summary.

Ischemic stroke is a devastating neurological disease. Brain ischemia impairs systemic immune responses and heightens susceptibility to infections, though the underlying mechanisms remain incompletely understood. Natural killer (NK) cells exhibited decreased frequency and compromised function after acute stage of stroke, resulting in NK cell-associated immune deficiency and increased risk of infection. MicroRNAs (miRNAs) are post-transcriptional molecular modulators. Our previous study revealed a significant upregulation of miR-451a in circulating NK cells from patients with ischemic stroke, but its effects and precise mechanism on immune defense remain elusive. In this study, we observed a substantial elevation of miR-451a level in brain and splenic NK cells in murine model of ischemic stroke miR-451a mimics suppressed NK cell activation and cytotoxicity within the ischemic brain and periphery, including a downregulation of activation marker CD69, and reduced production of effector molecules IFN-γ and perforin. Conversely, miR-451a inhibitor preserved NK cell activation and cytotoxicity, rescuing local inflammation, and reducing bacterial burden in the lung. Pharmacological inhibition of Akt-mTOR pathway with AZD8055 effectively blocked the impacts of miR-451a on NK cell functions. Collectively, these findings suggest miR-451a negatively regulates NK cell cytotoxicity in both the brain and periphery, which could be re-addressed by modulating the Akt-mTOR signaling pathway.

Cerebrovascular morphology plays a critical role in brain health, influencing cerebral blood flow (CBF) and contributing to the pathogenesis of various neurological diseases. This review examines the anatomical structure of the cerebrovascular network and its variations in healthy and diseased populations and highlights age-related changes and their implications in various neurological conditions. Normal variations, including the completeness and anatomical anomalies of the Circle of Willis and collateral circulation, are discussed in relation to their impact on CBF and susceptibility to ischemic events. Age-related changes in the cerebrovascular system, such as alterations in vessel geometry and density, are explored for their contributions to age-related neurological disorders, including Alzheimer's disease and vascular dementia. Advances in medical imaging and computational methods have enabled automatic quantitative assessment of cerebrovascular structures, facilitating the identification of pathological changes in both acute and chronic cerebrovascular disorders. Emerging technologies, including machine learning and computational fluid dynamics, offer new tools for predicting disease risk and patient outcomes based on vascular morphology. This review underscores the importance of understanding cerebrovascular remodeling for early diagnosis and the development of novel therapeutic approaches in brain diseases.

Vascular comorbidities complicate stroke pathophysiology, worsen outcomes, and delay recovery. Obesity, in particular, significantly increases stroke-induced brain edema, a fatal complication during infarction, which leads to worsened long-term recovery. Treatment of aflibercept, a VEGF-trap, has been shown to reduce stroke-induced brain edema and attenuate acute neurological deficits in obese mice. However, the effect of aflibercept on long-term stroke recovery is unknown. We found that treating obese stroke mice with aflibercept at 3 hours displayed significantly improved long-term motor and cognitive function. Notably, VEGFR2 expression was upregulated at 3- and 7-days post-stroke, indicating sustained VEGF signaling in obese subjects. Unlike acute treatment of aflibercept at 3 hours post-stroke, delayed treatment (3-day) worsened stroke recovery. While the improved long-term stroke recovery in mice treated aflibercept 3 hours is associated with the upregulated Pecam-1 and Angiopoietin-1 mRNAs and vessel densities in peri-infarct area at 3 months post-stroke, the delayed treatment led to a reduction in both angiogenic marker expression and vessel density. These findings highlight the importance of early intervention with VEGF signaling in obese mice to promote subsequent vascular remodeling during the stroke recovery phase and indicate a critical therapeutic window for VEGF inhibition to treat stroke in subjects with vascular comorbidities.

Stroke-associated mood disorders are less recognised than sensorimotor impairment, despite their high prevalence. Similarly, few experimental stroke studies assess non-sensorimotor functions. This study examined the prevalence and implementation of non-sensorimotor tests in three stroke-focused journals over the last twenty years. Of 965 experimental ischaemic stroke papers which used behavioural testing in rodents, 932 included sensorimotor testing, while 137 used non-sensorimotor tests (most commonly the Morris water maze, open field, Y-maze, and novel object recognition tests, but with a more diverse range of tests introduced in recent years). Cognition, anxiety and depression were assessed in 70%, 27% and 3% of these 137 papers. Non-sensorimotor deficits were typically observed after recovery of sensorimotor function. Potential confounding factors and challenges for data interpretation were identified in the most prevalent tests. More generally, experimental rigor (a priori power calculation, randomisation, blinding, and pre-defined inclusion/exclusion) improved over the years, but remained unsatisfactory with only 26% of studies providing some evidence of adequate statistical power. Furthermore, most studies focused on male animals, limiting external validity. This review confirms the disparity between sensorimotor and non-sensorimotor testing in experimental stroke but shows that the share of the studies including the latter is increasing. It is essential that research into the neuropsychiatric sequalae of stroke addresses methodological issues noted and continues to expand to improve patient outcomes post-stroke.

Quantification of dopamine transporter (DAT) with [¹⁸F]FE-PE2I PET is an important progression marker for Parkinson's disease (PD). This study aimed to validate a novel correction (SUVRc) for a less-biased estimate of SUVR by accounting for [¹⁸F]FE-PE2I clearance-rate, in independent cross-sectional (38 PD, 38 controls), test-retest (9 PD) and longitudinal cohorts (21 PD). SUVRc was calculated as $\frac{\mathrm{SUVR}}{1 - \frac{{\beta }_{\mathrm{ref}}}{k_{2,\mathrm{ref}}} +{\beta }_{\mathrm{tar}}\frac{\mathrm{SUVR}}{k_{2,\mathrm{ref}}{R}_1}}$. β_tar and β_ref are the clearance rates from the target and reference tissues. Bias relative to DVR, discriminative power, test-retest variability (TRV) and annual longitudinal change (ALC) were used to compare SUVR_50-80 min, SUVRc_50-80 min, SUVR_15-45 min and DVR. SUVR_50-80 min showed high bias across all regions (HC: mean: 48.31 ± 20.49% [range: 28.32-53.80%]; PD: 29.91 ± 13.95% [20.45-39.80%]) that was corrected by SUVRc_50-80 min (HC: -0.80 ± 12.72% [-9.69-11.64%]; PD: -0.13 ± 7.41% [-5.04-2.97%]), p < 0.001 for both groups compared to mean bias of SUVR_50-80 min, similar to SUVR_15-45 min. For the striatum, Cohen's d was similar for all measures. TRV were 3.2 ± 2.5% (DVR), 6.4 ± 5.7% (SUVR_50-80 min), 6.8 ± 5.9% (SUVRc_50-80 min) and 3.9 ± 3.2% (SUVR_15-45 min). Higher TRV of SUVRc_50-80 min was due to TRV of 9.2 ± 5.1% [1.1-19.4] for β_tar. ALC was 4.5 ± 4.2% (DVR), 5.2 ± 6.5% (SUVR_50-80 min), 4.4 ± 4.1% (SUVRc_50-80 min) and 4.2 ± 4.1% (SUVR_15-45 min). SUVRc_50-80 min reduced bias compared to SUVR_50-80 min, as previously reported. SUVRc_50-80 min was sensitive to small changes of β_tar, with higher TRV compared to DVR, but with similar ALC, suggesting that it can reliably assess longitudinal DAT changes.

Neurovascular coupling (NVC) is the link between local neuronal activity and regional cerebral blood flow. High altitude (HA) ascent induces acute hypoxic vasodilation of the cerebral vasculature, with associated changes in CO₂ and acid-base status. We aimed to characterise the effects of (a) acute removal of the HA-induced vasodilation and (b) rapid ascent to and residency at HA on NVC responses. In twelve healthy participants (7 M/5F), arterial blood gases and NVC were measured at baseline (1130 m) and on days two (<24 h at HA) and nine (post-acclimatisation) at 3800 m. Acute gas challenges were performed using end-tidal forcing, with (a) normoxia and isocapnic hypoxia at 1130 m and (b) poikilocapnic hypoxia and isocapnic hyperoxia on days two and nine at 3800 m. Posterior cerebral artery velocity (PCAv) was measured using transcranial Doppler ultrasound in each condition and time-point. NVC was assessed via a standardized 30 s intermittent strobe light visual stimulus (VS), and quantified as the peak and mean change from baseline in PCAv. No significant differences were observed for any NVC metric across all conditions and time points. Our results reveal remarkable stability of the NVC response following (a) acute removal of HA-induced hypoxic vasodilation and (b) rapid ascent to and residency at 3800 m.