Journal of Cerebral Blood Flow and Metabolism最新文献

White matter hyperintensities (WMH), perivascular spaces (PVS) and lacunes are common MRI features of small vessel disease (SVD). However, no shared underlying pathological mechanism has been identified. We investigated whether SVD burden, in terms of WMH, PVS and lacune status, was related to changes in the cerebral arterial wall by applying global cerebral pulse wave velocity (gcPWV) measurements, a newly described marker of cerebral vascular stiffness. In a population-based cohort of 190 individuals, 66-85 years old, SVD features were estimated from T1-weighted and FLAIR images while gcPWV was estimated from 4D flow MRI data. Additionally, the gcPWV's stability to variations in field-of-view was analyzed. The gcPWV was 10.82 (3.94) m/s and displayed a significant correlation to WMH and white matter PVS volume (r = 0.29, p < 0.001; r = 0.21, p = 0.004 respectively from nonparametric tests) that persisted after adjusting for age, blood pressure variables, body mass index, ApoB/A1 ratio, smoking as well as cerebral pulsatility index, a previously suggested early marker of SVD. The gcPWV displayed satisfactory stability to field-of-view variations. Our results suggest that SVD is accompanied by changes in the cerebral arterial wall that can be captured by considering the velocity of the pulse wave transmission through the cerebral arterial network.

The brain is a highly demanding organ, utilizing mainly glucose but also ketone bodies as sources of energy. Glucose transporter-1 (GLUT1) and monocarboxylates transporter-1 (MCT1) respectively transport glucose and ketone bodies across the blood-brain barrier. While reduced glucose uptake by the brain is one of the earliest signs of Alzheimer's disease (AD), no change in the uptake of ketone bodies has been evidenced yet. To probe for changes in GLUT1 and MCT1, we performed Western immunoblotting in microvessel extracts from the parietal cortex of 60 participants of the Religious Orders Study. Participants clinically diagnosed with AD had lower cerebrovascular levels of GLUT1, whereas MCT1 remained unchanged. GLUT1 reduction was associated with lower cognitive scores. No such association was found for MCT1. GLUT1 was inversely correlated with neuritic plaques and cerebrovascular β-secretase-derived fragment levels. No other significant associations were found between both transporters, markers of Aβ and tau pathologies, sex, age at death or apolipoprotein-ε4 genotype. These results suggest that, while a deficit of GLUT1 may underlie the reduced transport of glucose to the brain in AD, no such impairment occurs for MCT1. This study thus supports the exploration of ketone bodies as an alternative energy source for the aging brain.

Brain glucose metabolism, which can be investigated at the macroscale level with [¹⁸F]FDG PET, displays significant regional variability for reasons that remain unclear. Some of the functional drivers behind this heterogeneity may be captured by resting-state functional magnetic resonance imaging (rs-fMRI). However, the full extent to which an fMRI-based description of the brain's spontaneous activity can describe local metabolism is unknown. Here, using two multimodal datasets of healthy participants, we built a multivariable multilevel model of functional-metabolic associations, assessing multiple functional features, describing the 1) rs-fMRI signal, 2) hemodynamic response, 3) static and 4) time-varying functional connectivity, as predictors of the human brain's metabolic architecture. The full model was trained on one dataset and tested on the other to assess its reproducibility. We found that functional-metabolic spatial coupling is nonlinear and heterogeneous across the brain, and that local measures of rs-fMRI activity and synchrony are more tightly coupled to local metabolism. In the testing dataset, the degree of functional-metabolic spatial coupling was also related to peripheral metabolism. Overall, although a significant proportion of regional metabolic variability can be described by measures of spontaneous activity, additional efforts are needed to explain the remaining variance in the brain's 'dark energy'.

Blood-brain barrier (BBB) damage significantly affects the prognosis of ischemic stroke patients. This project employed multi-omics analysis to identify key factors regulating BBB disruption during cerebral ischemia-reperfusion. An integrated analysis of three transcriptome sequencing datasets from mouse middle cerebral artery occlusion/reperfusion (MCAO/R) models identified eight downregulated genes in endothelial cells. Additionally, transcriptome analysis of BBB (cortex) and non-BBB (lung) endothelium of E13.5 mice revealed 2,102 upregulated genes potentially associated with BBB integrity. The eight downregulated genes were intersected with the 2,102 BBB-related genes and mapped using single-cell RNA sequencing data, revealing that solute carrier family 22 member 8 (Slc22a8) is specifically expressed in endothelial cells and pericytes and significantly decreases after MCAO/R. This finding was validated in the mouse MCAO/R model at both protein and mRNA levels in this study. External overexpression of Slc22a8 using a lentivirus carrying Tie2 improved Slc22a8 and tight junction protein levels and reduced BBB leakage after MCAO/R, accompanied by Wnt/β-catenin signaling activation. In conclusion, this study suggested that MCAO/R-induced downregulation of Slc22a8 expression may be a crucial mechanism underlying BBB disruption. Interventions that promote Slc22a8 expression or enhance its function hold promise for improving the prognosis of patients with cerebral ischemia.

After stroke onset, ischemic brain tissue will progress to infarction unless blood flow is restored. Core growth rate measures the infarction speed from stroke onset. This multicenter cohort study aimed to explore whether core growth rate influences benefit from the reperfusion treatment of endovascular thrombectomy in large ischemic core stroke patients. It identified 134 patients with large core volume >70 mL assessed on brain perfusion image within 9 hours of stroke onset. Of 134 patients, 71 received endovascular thrombectomy and 63 did not receive the treatment. Overall, poor outcomes were frequent, with 3-month severed disability or death rate at 56% in treatment group and 68% in no treatment group (p = 0.156). Patients were then stratified by core growth rate. For patients with 'ultrafast core growth' of >70 mL/hour, rates of poor outcome were especially high in patients without endovascular thrombectomy (n = 13/14, 93%) and relatively lower in patients received the treatment (n = 12/20, 60%, p = 0.033). In contrast, for patients with core growth rate <70 mL/hour, there was not a large difference in poor outcomes between patients with and without the treatment (55% vs. 61%, p = 0.522). Therefore, patients with 'ultrafast core growth' might stand to benefit the most from endovascular treatment.

We discuss two potential non-invasive MRI methods to study phenomena related to subarachnoid cerebrospinal fluid (CSF) motion and perivascular fluid transport, and their association with sleep and aging. We apply diffusion-based intravoxel incoherent motion (IVIM) imaging to evaluate pseudodiffusion coefficient, D*, or CSF movement across large spaces like the subarachnoid space (SAS). We also performed perfusion-based multi-echo, Hadamard encoded arterial spin labeling (ASL) to evaluate whole brain cortical cerebral blood flow (CBF) and trans-endothelial exchange (T_ex) of water from the vasculature into the perivascular space and parenchyma. Both methods were used in young adults (N = 9, 6 F, 23 ± 3 years old) in the setting of sleep and sleep deprivation. To study aging, 10 older adults (6 F, 67 ± 3 years old) were imaged after a night of normal sleep and compared with the young adults. D* in SAS was significantly (p < 0.05) reduced with sleep deprivation (0.016 ± 0.001 mm²/s) compared to normal sleep (0.018 ± 0.001 mm²/s) and marginally reduced with aging (0.017 ± 0.001 mm²/s, p = 0.029). Cortical CBF and T_ex were unchanged with sleep deprivation but significantly lower in older adults (37 ± 3 ml/100 g/min, 578 ± 61 ms) than in young adults (42 ± 2 ml/100 g/min, 696 ± 62 ms). IVIM was sensitive to sleep physiology and aging, and multi-echo, multi-delay ASL was sensitive to aging.

A recent publication in JCBFM, "Static autoregulation in humans" gives rise to critical comments. Autoregulation of cerebral blood flow implies that flow is rather constant within a certain blood pressure (BP) range with a lower and an upper pressure limit. The physiology at the two limits is very different, making comparison of the brain's vulnerability at the limits questionable. The recent publication in JCBFM claims a narrow autoregulatory range based on pooling of data from several studies. However, we argue that such pooling blurs the autoregulatory limits. We summarize the classical literature, therefrom we argue for a broad autoregulatory range.

Stroke is one of the leading causes of death and disability, yet the cellular response to the ischemic insult is poorly understood limiting therapeutic options. Brain pericytes are crucial for maintaining blood-brain barrier (BBB) integrity and are known to be one of the first responders to ischemic stroke. The exact timeline of cellular events after stroke, however, remains elusive. Using the permanent middle cerebral artery occlusion stroke model, we established a detailed timeline of microvascular events after experimental stroke. Our results show that pericytes respond already within 1 hour after the ischemic insult. We find that approximately 30% of the pericyte population dies as early as 1 hour after stroke, while ca 50% express markers that indicate activation. A decrease of endothelial tight junctions, signs of endothelial cell death and reduction in blood vessel length are only detected at time points after the initial pericyte response. Consistently, markers of BBB leakage are observed several hours after pericyte cell death and/or vascular detachment. Our results suggest that the pericyte response to stroke occurs early and precedes both the endothelial response and the BBB breakdown. This highlights pericytes as an important target cell type to develop new diagnostic and therapeutic tools.

Mitochondrial function is tightly linked to morphology, and fragmentation of dendritic mitochondria during noxious conditions suggests loss of function. In the normoxic cortex, spreading depolarization (SD) is a phenomenon underlying migraine aura. It is unknown whether mitochondria structure is affected by normoxic SD. In vivo two-photon imaging followed by quantitative serial section electron microscopy (ssEM) was used to monitor dendritic mitochondria in the normoxic cortex of urethane-anesthetized mature male and female mice during and after SD initiated by focal KCl microinjection. Structural dynamics of dendrites and their mitochondria were visualized by transfecting excitatory, glutamatergic neurons of the somatosensory cortex with bicistronic AAV, which induced tdTomoto labeling in neuronal cytoplasm and mitochondria labeling with roGFP. Normoxic SD triggered rapidly reversible fragmentation of dendritic mitochondria alongside dendritic beading; however, mitochondria took significantly longer to recover. Several rounds of SD resulted in transient mitochondrial fragmentation and dendritic beading without accumulating injury, as both recovered. SsEM corroborated normoxic SD-elicited dendritic and mitochondrial swelling and transformation of the filamentous mitochondrial network into shorter, swollen tubular, and globular structures. Our results revealed normoxic SD-induced disruption of the dendritic mitochondrial structure that might impact mitochondrial bioenergetics during migraine with aura.

Cerebral hyperperfusion (CHP) occurred frequently after direct superficial temporal artery-middle cerebral artery (STA-MCA) bypass surgery for moyamoya disease (MMD). We analyzed cortical microvascular density (CMD) and the change of cerebral blood flow (LΔCBF) using intraoperative laser speckle contrast imaging (LSCI) on 130 hemispheres of 95 consecutive adult patients with MMD. The demographic characteristics, cortical hemodynamic sources, bypass methods, intraoperative blood flow data, and relative CBF changes on single-photon emission computed tomography (SPECT) examination (SΔrCBF) were compared between the groups with and without CHP. The median values for CMD, LΔCBF, and SΔrCBF were significantly higher in the CHP group than in the non-CHP group (CMD 0.240 vs 0.206, P = 0.004; LΔCBF 2.285 vs 1.870, P < 0.001; SΔCBF 1.535 vs 1.260, P < 0.001). Multivariate analysis revealed that hemodynamic sources of recipient parasylvian cortical arteries from MCA (M-PSCAs), end-to-side (E-S) bypass method, CMD ≥ 0.217, and LΔCBF ≥ 1.985 were the risk factors for CHP. Intraoperative LSCI was useful for evaluating hemodynamics and predicting CHP in patients with MMD.