Journal of Cerebral Blood Flow and Metabolism最新文献

Neurofibrillary tangles (NFTs), composed of aggregated tau protein, in the brain is a neuropathological hallmark and feature of Alzheimer's disease (AD) and other tauopathies. One promising approach to prevent tau aggregates is to inhibit O-GlcNAcase (OGA), an enzyme that regulates tau O-GlcNAcylation. [¹¹C]BIO-1819578 has emerged as a promising candidate to determine target occupancy of such OGA inhibitor drugs. The aim of this study was to further evaluate the pharmacokinetic properties of [¹¹C]BIO-1819578 in non-human primates (NHPs) and to estimate its effective dose. Kinetic compartment analyses of [¹¹C]BIO-1819578 binding to OGA in the brain were performed on positron emission tomography (PET) measurements conducted in three cynomolgus NHPs. Whole-body PET measurements were carried out in two NHPs to estimate the effective radiation dose. Both the 1-tissue-compartment (1TCM) and 2-tissue-compartment model (2TCM) could describe the regional time activity curves of [¹¹C]BIO-1819578. The 2TCM was the statistically preferred model. The effective radiation dose was estimated to be 0.0033 mSv/MBq. The results showed that [¹¹C]BIO-1819578 has suitable characteristics for reliable quantification of OGA using full kinetic modelling. The effective dose was on par with other ¹¹C radioligands and is unlikely to pose an issue for human use.

Hyperglycemia in poorly controlled diabetes is widely recognized as detrimental to organ dysfunction. However, the acute effects of hyperglycemia on brain metabolism and function are not fully understood. The potential protective benefit of ketone bodies on mitochondrial function in the brain has also not been well characterized. Here, we evaluated the acute effects of hyperglycemia and β-hydroxybutyrate (BHB) on brain metabolism by employing a novel approach leveraging adenosine triphosphate (ATP)-dependence of bioluminescence originating from luciferin-luciferase activity. Oxygen consumption rate was measured in ex vivo live brain punches to further evaluate mitochondrial function. Our data demonstrate that brain metabolism in mice is affected by acute exposure to high glucose. This short-term effect of glucose exposure was reduced by co-administration with the ketone body BHB. Additionally, we investigated the functional relevance of BHB using an in vivo photothrombotic stroke model to assess its cerebroprotective effects in presence or absence of acute hyperglycemia. BHB significantly reduced infarct size in the brain stroke model, providing functional evidence for its protective role in the brain. These findings suggest that BHB may effectively mitigate the adverse effects of metabolic stress and ischemic events on brain metabolism and function.

The glymphatic system, a vital brain perivascular network for waste clearance, hinges on the functionality of the aquaporin 4 (AQP4) water channel. Alarmingly, AQP4 single nucleotide polymorphisms (SNPs) are linked to impaired glymphatic clearance, or glymphopathy, which contributes to sleep disturbances and various age-related neurodegenerative diseases. Despite the critical role of glymphopathy and sleep disturbances in cerebral small vessel disease (CSVD) - a silent precursor to age-related neurodegenerative disorders - their interplay remains underexplored. CSVD is a major cause of stroke and dementia, yet its pathogenesis is not fully understood. Emerging evidence implicates glymphopathy and sleep disorders as pivotal factors in age-related CSVD, exacerbating the condition by hindering waste removal and compromising blood-brain barrier (BBB) integrity. Advanced imaging techniques promise to enhance diagnosis and monitoring, while lifestyle modifications and personalised medicine present promising treatment avenues. This narrative review underscores the need for a multidisciplinary approach to understanding glymphopathy and sleep disorders in CSVD. By exploring their roles, emphasising the necessity for longitudinal studies, and discussing potential therapeutic interventions, this paper aims to pave the way for new research and therapeutic directions in CSVD management.

Intracranial cardiac impulse propagation along penetrating arterioles is vital for both nutrient supply via blood circulation and waste clearance via CSF circulation. However, current neuroimaging methods are limited to simultaneously detecting impulse propagation at pial arteries, arterioles, and between them. We hypothesized that this propagation could be detected via paravascular CSF dynamics and that it may change with aging. Using dynamic diffusion-weighted imaging (dynDWI), we detected oscillatory CSF motion synchronized with the finger photoplethysmography in the subarachnoid space (SAS) and cerebral cortex, with a delay revealing an impulse propagation pathway from the SAS to the cortex, averaging 84 milliseconds. Data from 70 subjects aged 18 to 85 years showed a bimodal age-related change in the SAS-Cortex travel time: it initially increases with age, peaks around 45 years, then decreases. Computational biomechanical modeling of the cardiovascular system was performed and replicated this 84-millisecond delay. Sensitivity analysis suggests that age-related variations in travel time are primarily driven by changes in arteriolar compliance. These findings support the use of dynDWI for measuring intracranial impulse propagation and highlight its potential in assessing related vascular and waste clearance functions.

In hypertension-associated arteriolosclerosis cerebral small vessel disease (CSVD), various studies have shown that MRI-detected lesions-such as lacunes, white matter hyperintensities, enlarged perivascular spaces, and cerebral microbleeds-are more prevalent in deep brain regions (DBR) than in the cortex. However, the underlying mechanisms remain poorly understood. We propose that differential vascular remodeling between DBR small vessels and superficial cortical branches contributes to this heterogeneity. Using a stroke-prone renovascular hypertensive rat (RHRsp) model, we observed pronounced changes in vessel density, diameter, extracellular matrix deposition, and smooth muscle cell alterations in DBR small arteries compared to that of the cortex. These findings were further confirmed in human brain tissue of our study. Additionally, our mathematical modeling indicated greater hemodynamic alterations in DBR vessels, with increased shear and circumferential stress under hypertension conditions. Overall, our study highlights more severe vascular remodeling and hemodynamic changes in the deep brain regions, where CSVD-associated MRI lesions are frequently detected.

Brain aging leads to reduced cerebral blood flow and cognitive decline, but how normal aging affects neurovascular coupling (NVC) in the awake brain is unclear. Here, we investigated NVC in relation to calcium changes in vascular mural cells (VMCs) in awake adult and aged mice. We show that NVC responses are reduced and prolonged in the aged brain and that this is more pronounced at the capillary level than in arterioles. However, the overall NVC response, measured as the time integral of vasodilation, is the same in the two age groups. In adult, but not in aged mice, the NVC response correlated with Ca2+ signaling in VMCs, while the overall Ca2+ kinetics were slower in aged than in adult mice. In particular, the rate of Ca2+ transport, and the Ca2+ sensitivity of VMCs were reduced in aged mice, explaining the reduced and prolonged vasodilation. Spontaneous locomotion was less frequent and reduced in aged mice as compared to young adult mice, and this was reflected in the 'slow but prolonged' NVC and vascular Ca2+ responses. Taken together, our data characterize the NVC in the aged, awake brain as slow but prolonged, highlighting the remodeling processes associated with aging.

Psilocin, the active metabolite of psilocybin, is a psychedelic and agonist at the serotonin 2A receptor (5-HT2AR) that has shown positive therapeutic effects for brain disorders such as depression. To elucidate the brain effects of psilocybin, we directly compared the acute effects of 5-HT2AR agonist (psilocybin) and antagonist (ketanserin) on cerebral blood flow (CBF) using pseudo-continuous arterial spin labeling magnetic resonance imaging (MRI) in a single-blind, cross-over study in 28 healthy participants. We evaluated associations between plasma psilocin level (PPL) or subjective drug intensity (SDI) and CBF. We also evaluated drug effects on internal carotid artery (ICA) diameter using time-of-flight MRI angiography. PPL and SDI were significantly negatively associated with regional and global CBF (∼11.6% at peak drug effect, p < 0.0001). CBF did not significantly change following ketanserin (2.3%, p = 0.35). Psilocybin induced a significantly greater decrease in CBF compared to ketanserin in the parietal cortex (p_FWER < 0.0001). ICA diameter was significantly decreased following psilocybin (10.5%, p < 0.0001) but not ketanserin (-0.02%, p = 0.99). Our data support an asymmetric 5-HT2AR modulatory effect on CBF and provide the first in vivo human evidence that psilocybin constricts the ICA, which has important implications for understanding the neurophysiological mechanisms underlying its acute effects.

Metabolism is fundamental to functional brain imaging. While functional MRI (fMRI) has greatly benefited neuroscience, ¹³C-MRS measures coupling between neuroenergetics and neurotransmission. However, a hyperpolarized ¹³C-MRI study in human brain shows increased ¹³C-lactate (i.e., cytosolic aerobic glycolysis) with no ¹³C-bicarbonate change (i.e., mitochondrial oxidation) within fMRI-defined activated areas. We discuss (dis)advantages of hyperpolarized vs. non-hyperpolarized ¹³C experiments and metabolic implications regarding the lactate increase: Is lactate a fuel for oligodendrocytes, astrocytes, or neurons? Is lactate a neuromodulator or a vasomodulator? Is lactate a byproduct of astrocytic glycogenolysis? Caveats aside, there is great enthusiasm for hyperpolarized ¹³C-fMRI.

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.

Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system that involves immune-mediated demyelination and axonal degeneration. Clinical imaging techniques play a critical role in diagnosing and assessing the prognosis of MS. Magnetic resonance imaging has been most frequently used to visualize demyelination and detect acute and chronic active lesions, which are key indicators of clinical course of illness. Previous research has also highlighted the effectiveness of translocator protein 18-kDa (TSPO) positron emission tomography (PET) imaging for identifying chronic active lesions and progressive pathology. Building on this work, the present study used PET imaging to explore the role of cyclooxygenase-1 and -2 (COX-1 and COX-2)-key enzymes involved in neuroinflammation-in individuals with MS. Five participants with MS were recruited, and lesions were identified using 7 Tesla MRI. No significant differences in COX radioligand binding were observed in the co-registered PET images between lesioned areas and normal-appearing brain tissues, nor between individuals with MS and healthy volunteers. The negative findings underscore the complexity of MS pathology and raise several important considerations for planning future studies using COX PET for imaging in MS.