Journal of Cerebral Blood Flow and Metabolism最新文献

Alzheimer's disease (AD), a neurodegenerative disorder with progressive cognitive decline, remains clinically challenging with limited understanding of etiology and interventions. Clinical studies have reported vascular defects prior to other pathological manifestations of AD, leading to the "Vascular Hypothesis" for the disorder. However, in vivo assessments of cerebral vasculature in AD rodent models have been constrained by limited spatiotemporal resolution or field of view of conventional imaging. We herein employed two in vivo imaging technologies, Dual-Wavelength Imaging and Optical Coherence Doppler Tomography, to evaluate cerebrovascular reactivity (CVR) to vasoconstrictive cocaine and vasodilatory hypercapnia challenges and to detect resting 3D cerebral blood flow (CBF) in living transgenic AD mice at capillary resolution. Results showed that CVR to cocaine and hypercapnia was significantly attenuated in 7-10 months old AD mice vs controls, indicating reduced vascular flexibility and reactivity. Additionally, in the AD mice, arterial CBF velocities were slower and the microvascular density in cortex was decreased compared to controls. These results reveal significant vascular impairments including reduced CVR and resting CBF in early-staged AD mice. Hence, this cutting-edge in vivo optical imaging offers an innovative venue for detecting early neurovascular dysfunction in AD brain with translational potential.

Myelin is crucial for neuron health and central nervous system (CNS) function. Recent research by McNamara et al. highlighted microglia's essential role in compacting the myelin sheath during development and their absence leads to aberrant oligodendrocyte clusters and subsequent cognitive impairment. The study revealed that the critical involvement of the TGFβ1-TGFβR1 axis in microglia-oligodendrocyte communication could influence the oligodendrocyte lipid metabolism and thereby regulate myelin integrity. Further exploration is needed to fully elucidate the dual impact of microglia on myelination, and interactions with other glial cells, holding promise for discovering new targets in myelin-related neurodegenerative and CNS disorders.

Intercellular mitochondrial transfer (IMT) is an intriguing biological phenomenon where mitochondria are transferred between different cells and notably, cell types. IMT is physiological, occurring in normal conditions, but also is utilized to deliver healthy mitochondria to cells in distress. Transferred mitochondria can be integrated to improve cellular metabolism, and mitochondrial function. Research on the mitochondrial transfer axis between astrocytes and brain capillaries in vivo is limited by the cellular heterogeneity of the neurovascular unit. To this end, we developed an inducible mouse model that expresses mitochondrial Dendra2 only in astrocytes and then isolated brain capillaries to remove all intact astrocytes. This method allows the visualization of in vivo astrocyte- endothelial cell (EC) and astrocyte-pericyte IMT. We demonstrate evidence of astrocyte-EC and astrocyte-pericyte mitochondrial transfer within brain capillaries. We also show that healthy aging enhances mitochondrial transfer from astrocytes to brain capillaries, revealing a potential link between brain aging and cellular mitochondrial dynamics. Finally, we observe that astrocyte-derived extracellular vesicles transfer mitochondria to brain microvascular endothelial cells, showing the potential route of in vivo IMT. These results represent a breakthrough in our understanding of IMT in the brain and a new target in brain aging and neurovascular metabolism.

Chronic cerebral hypoperfusion (CCH) is an important clinical condition characterized by a prolonged reduction in cerebral blood flow that contributes to several neurodegenerative diseases, including vascular dementia and Alzheimer's disease. A number of rodent models of CCH have been developed that mimic the human pathological conditions of reduced cerebral perfusion. These models have been instrumental in elucidating the molecular and cellular mechanisms involved in CCH-induced brain damage. Oxidative stress is induced by perturbations in cellular pathways caused by CCH, including mitochondrial dysfunction, ion pump dysfunction, and adenosine triphosphate (ATP) depletion. The deleterious stress leads to the accumulation of reactive oxygen species (ROS) and exacerbates damage to neuronal structures, significantly impairing cognitive function. Among the various therapeutic strategies being evaluated, edaravone, a potent antioxidant, is emerging as a promising drug due to its neuroprotective properties against oxidative stress. Initially approved for use in ischemic stroke, research using rodent CCH models has shown that edaravone has significant efficacy in scavenging free radicals and ameliorating oxidative stress-induced neuronal damage under CCH conditions. This mini-review summarizes the current literature on the rodent models of CCH and then discusses the therapeutic potential of edaravone to reduce neuronal and vascular damage caused by CCH-induced oxidative stress.

White matter (WM) free water (FW) is a potential imaging marker for cerebral small vessel disease (CSVD). This study aimed to characterize longitudinal changes in WM FW and investigate factors contributing to its elevation in CSVD. We included 80 CSVD patients and 40 normal controls (NCs) with multi-modality MRI data. Cerebral blood flow (CBF) was measured, and fiber alterations were assessed using total apparent fiber density (AFD_t). FW were extracted from whole WM, white matter hyperintensities (WMH) and normal-appearing WM (NAWM). Baseline and longitudinal FW elevation were compared between patients and NCs, and between WMH and NAWM. We investigated whether baseline vascular risk factor score, CBF, and AFD_t could predict longitudinal FW elevation. Association between cognition and WM FW in CSVD was also assessed. Results shown that FW was higher and increased faster in CSVD compared to NCs and in WMH compared to NAWM. Baseline AFD_t predicted longitudinal FW elevation in CSVD patients, while CBF predicted FW changes only in controls. WM FW was associated with cognitive impairment. These findings suggest that CSVD is associated with a faster increase in WM FW. Hypoperfusion and WM fiber alterations might accelerate FW elevation, which is associated with cognitive decline.

Single-cell RNA sequencing (scRNA-seq) is a high-throughput transcriptomic approach with the power to identify rare cells, discover new cellular subclusters, and describe novel genes. scRNA-seq can simultaneously reveal dynamic shifts in cellular phenotypes and heterogeneities in cellular subtypes. Since the publication of the first protocol on scRNA-seq in 2009, this evolving technology has continued to improve, through the use of cell-specific barcodes, adoption of droplet-based systems, and development of advanced computational methods. Despite induction of the cellular stress response during the tissue dissociation process, scRNA-seq remains a popular technology, and commercially available scRNA-seq methods have been applied to the brain. Recent advances in spatial transcriptomics now allow the researcher to capture the positional context of transcriptional activity, strengthening our knowledge of cellular organization and cell-cell interactions in spatially intact tissues. A combination of spatial transcriptomic data with proteomic, metabolomic, or chromatin accessibility data is a promising direction for future research. Herein, we provide an overview of the workflow, data analyses methods, and pros and cons of scRNA-seq technology. We also summarize the latest achievements of scRNA-seq in stroke and acute traumatic brain injury, and describe future applications of scRNA-seq and spatial transcriptomics.

[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.

Discovery and development of efficacious and safe pharmacological therapies is fraught with challenges. As proteins constitute the majority of drug targets and are encoded by genes, naturally occurring genetic variation within populations can provide valuable insights to inform drug discovery and development efforts. The drug target Mendelian randomization (MR) paradigm leverages these principles to investigate the causal effects of drug targets in humans. This review examines the application of drug target MR in informing the efficacy and development of therapeutics for ischemic stroke prevention and treatment. We consider applications of MR for existing and novel treatment strategies, including targeting blood pressure, lipid metabolism, coagulation, inflammation and glycemic control. Several of these genetically supported targets are under evaluation in late-stage clinical trials. Methodological limitations of drug target MR are addressed, followed by an outline of future research directions. We anticipate that careful application of drug target MR will enhance the efficiency of drug development for ischemic stroke, consequently accelerating the delivery of effective medications to patients.

In the past decade, noble gases have emerged as highly promising neuroprotective agents. Previous studies have demonstrated the efficacy of argon neuroprotection in rodent models of cerebral ischemia. The objective of the present pre-clinical study was to confirm the neuroprotective effect of argon in a non-human primate model of endovascular ischemic stroke. Thirteen adult Macaca mulatta were subjected to a focal cerebral ischemia induced by a transient (90 min) middle cerebral artery occlusion (tMCAO). The monkeys were randomly allocated to a control group (n = 8) and an argon group (n = 5). Pre-mixed gas (40-60 oxygen-argon) was applied 30 min after the onset of tMCAO to 30 min after reperfusion. Infarct volumes were measured from the MRI scans conducted 1 hour and 1 month after the reperfusion. A clinical neurological assessment was performed 24 hours and 1 month after tMCAO. Our results show that Argon dramatically reduced ischemic core volume after ischemia compared to the control group with a long-lasting improvement of post-stroke infarct volume at 1 month. In addition, the neurological scale suggests a better prognosis in argon-treated animals without reaching the significance threshold. These pre-clinical results in gyrencephalic non-human primates support the potential use of this therapeutic approach for future clinical studies.

Familial hemiplegic migraine type 2 (FHM2) is linked to Na,K-ATPase α₂ isoform mutations, including that of G301R. Mice heterozygous for this mutation (${\alpha }_2^{+/\text{G3}0\text{1R}}$) show cerebrovascular hypercontractility associated with amplified Src kinase signaling, and exaggerated neurovascular coupling. This study hypothesized that targeting Na,K-ATPase-dependent Src phosphorylation with pNaKtide would normalize cerebral perfusion and neurovascular coupling in ${\alpha }_2^{+/\text{G3}0\text{1R}}$ mice. The effect of pNaKtide on cerebral blood flow and neurovascular coupling was assessed using laser speckle contrast imaging in awake, head-fixed mice with cranial windows in a longitudinal study design. At baseline, compared to wild type, ${\alpha }_2^{+/\text{G3}0\text{1R}}$ mice exhibited increased middle cerebral artery tone; with whisker stimulation leading to an exaggerated increase in sensory cortex blood flow. No difference between genotypes in telemetrically assessed blood pressure occurred. The exaggerated neurovascular coupling in ${\alpha }_2^{+/\text{G3}0\text{1R}}$ mice was associated with increased K_ir2.1 channel expression in cerebrovascular endothelium. Two weeks pNaKtide treatment normalized cerebral artery tone, endothelial K_ir2.1 expression, and neurovascular coupling in ${\alpha }_2^{+/\text{G3}0\text{1R}}$ mice. Inhibition of the Na,K-ATPase-dependent Src kinase signaling with pNaKtide prevented excessive vasoconstriction and disturbances in neurovascular coupling in ${\alpha }_2^{+/\text{G3}0\text{1R}}$ mice. pNaKtide had only minor hypotensive effect similar in both genotypes. These results demonstrate a novel treatment target to normalize cerebral perfusion in FHM2.