Journal of Cerebral Blood Flow and Metabolism最新文献

Chronic cerebral hypoperfusion (CCH) has been indicated to impair cognitive and diverse brain functions. However, the neural mechanisms linking these cerebrovascular and phenotypic alterations remain unclear. Here, we investigated the effect of CCH on neuronal activity in male mice with unilateral common carotid artery occlusion using optical imaging and MRI. Our examinations revealed enhanced neuronal activity in concurrence with increased glutamate and tissue acidosis up to seven days after occlusion. At 21-28 days after occlusion, neuronal activity decreased below baseline, while the acidotic but not the hyperglutamatergic state persisted. Notably, pharmacological blockade of the N-methyl-D-aspartate-type glutamate receptor, initiated at an early stage of CCH, suppressed the onset of neuronal hyperexcitation and subsequent deficits in neuronal activity. Altogether, we provide experimental evidence that CCH induces a glutamate surge and results in neuronal hyperexcitation at an early phase, which thereafter gives rise to a non-lethal but progressive deterioration of neuronal functions.

Focal stroke leads to complex neurological disturbances with variable recovery. One explanation for this variability is that stroke disrupts local and remote neural circuits via the connectome, termed 'diaschisis'. Past studies have yielded mixed effects of stroke on dendritic structure in distant regions. However, a previous limitation was the lack of sampling specifically from neurons directly connected to those within the infarct. To overcome this, we used retrograde and anterograde trans-synaptic AAVs to examine dendritic spine density in neurons that provide inputs to, or receive outputs (pre- and post-synaptic) from primary forelimb somatosensory cortex at 1 or 6 weeks after stroke. For both pre- and post-synaptic neurons, spine density was generally lower in superficial and deep neurons in peri-infarct and motor cortex at 1 week, which recovered by 6 weeks. By contrast, no changes in spine density were observed in ipsilateral secondary somatosensory (S2) or contralateral primary somatosensory cortex at 1 week, although there was an increase in spines in select S2 neurons at 6 weeks. Our data show that some cortical connections are more disrupted by stroke than others, particularly those in peri-infarct and motor cortex which could serve as an important substrate for stroke recovery and future therapies.

Obstructive sleep apnea (OSA) disrupts the oxygen supply during apneic and hypopneic events. To evaluate the feasibility of concurrently monitoring cerebral metabolic rate of oxygen (CMRO₂) and airway anatomy, a magnetic resonance imaging (MRI) pulse sequence was developed that interleaves measurements of CMRO₂ with anatomic imaging of the upper airway at a temporal resolution of 5 seconds. The sequence was first tested in healthy subjects during wakefulness to detect the effect of volitional breath-hold and swallowing apneas on neuro-metabolic parameters and airway morphology. Subsequently, select patients with diagnosed OSA and healthy reference subjects were scanned during 90 minutes of wakefulness and sleep with concurrent electroencephalographic (EEG) monitoring and airway plethysmography. During non-rapid eye movement sleep, changes in metabolic parameters caused by neurovascular-metabolic uncoupling were detected, resulting in sleep-stage dependent reductions in the CMRO₂. Spontaneous apneas were visible in airway images and confirmed plethysmographically. Recurrent apneas in patients during N1 and N2 sleep led to increased SvO₂ and CBF (hypercapnic-hypoxic response) and decreases in SaO₂ (hypoxemic response from airway closure) resulting in CMRO₂ reductions as large 60%. The results demonstrate the MRI potential of noninvasive assessment of the dynamic changes in airway anatomy and brain metabolism in OSA during sleep.

Molecular mechanisms underlying disruptions in brain glucose uptake and metabolism, linked with cognitive decline in Alzheimer's disease (AD) patients, are only partially understood. This study investigated how soluble amyloid beta (sAβ) peptides affect glucose transport at the blood-brain barrier (BBB), the primary portal for glucose entry into the brain. We demonstrated that [¹⁸F]-fluorodeoxyglucose (¹⁸FDG) uptake is reduced in sAβ overproducing APP,PS1 transgenic mice compared to wild-type mice. Moreover, the influx rate of ¹⁸FDG decreased in sAβ40 or sAβ42 pre-infused mice, highlighting the inhibitory effect of sAβ peptides on glucose transport at the BBB. Consistently, the expression of GLUT1, the primary glucose transporter at the BBB, is reduced in polarized human cerebral microvascular endothelial cell (hCMEC/D3) monolayers upon exposure to sAβ peptides and in Aβ-laden cerebral vasculature in vivo. The study further examined the influence of sAβ on the insulin-AKT pathway, known to regulate glucose uptake through modulation of thioredoxin-interacting protein (TXNIP) expression. Results showed that sAβ peptides suppress AKT phosphorylation and reduce GLUT1 expression by upregulating TXNIP levels in hCMEC/D3 monolayers. Co-incubation of resveratrol with sAβ peptides reduced TXNIP expression and rectified reductions in GLUT1 expression. In summary, toxic sAβ impairs BBB glucose transport by disrupting the insulin/AKT/TXNIP axis.

Intracerebral hemorrhage (ICH) is a stroke subtype with no effective treatment despite high morbidity and mortality rates. The delineation of the mechanisms of brain damage after ICH is critical to identifying novel molecular targets for therapeutic intervention. Apart from the augmented expression of 18 kDa translocator protein (TSPO) in microglia/macrophages post-ICH and its potential to track neuroinflammation, the precise function of TSPO after brain damage remains largely enigmatic. In the present study, we employed transgenic animal models, such as global and myeloid-specific conditional knockouts, to elucidate the functional role of TSPO in ICH-induced acute brain damage. Neurological deficits, neurodegeneration, and neuroinflammation were assessed at 3-days post-ICH in male and female mice. Male TSPO global knockout and conditional knockout exhibited enhanced neurobehavioral deficits with a concomitant increase in neurodegeneration and neuroinflammation compared to their respective controls. Interestingly, their female counterparts did not exhibit augmented brain damage compared to the respective controls. Mechanistically, studies employing RNA-Seq and subsequent functional validation demonstrate that TSPO could regulate brain cholesterol efflux, which could partly be responsible for enhanced brain damage in TSPO KO male mice after ICH, warranting further investigation.

Functional Positron Emission Tomography (fPET) is an effective tool for studying dynamic processes in glucose metabolism and neurotransmitter action, providing insights into brain function and disease progression. However, optimizing signal processing to extract stimulation-specific information remains challenging. This study systematically evaluates state-of-the-art filtering techniques for fPET imaging. Forty healthy participants performed a cognitive task (Tetris®) during [¹⁸F]FDG PET/MR scans. Seven filtering techniques and multiple hyperparameters were tested: including 3D and 4D Gaussian smoothing, highly constrained backprojection (HYPR), iterative HYPR (IHYPR4D), MRI-Markov Random Field (MRI-MRF) filters, and dynamic/extended dynamic Non-Local Means (dNLM/edNLM). Filters were assessed based on test-retest reliability, task signal identifiability (temporal signal-to-noise ratio, tSNR), spatial task-based activation, and sample size calculations were assessed. Compared to 3D Gaussian smoothing, edNLM, dNLM, MRI-MRF L = 10, and IHYPR4D filters improved tSNR, while edNLM and HYPR enhanced test-retest reliability. Spatial task-based activation was enhanced by NLM filters and MRI-MRF approaches. The edNLM filter reduced the required sample size by 15.4%. Simulations supported these findings. This study highlights the strengths and limitations of fPET filtering techniques, emphasizing how hyperparamter adjustments affect outcome parameters. The edNLM filter shows promise with improved performance across all metrics, but filter selection should consider specific study objectives and resource constraints.

Neurovascular coupling is the temporal relationship between neuronal activity and regional blood flow changes presumably to meet the high metabolic demands of the brain. Prior fMRI studies have reported excitatory synaptic transmission as more metabolically demanding than neuronal spiking, thus correlating better with cerebral hemodynamics. To investigate this finding with newer optical imaging techniques, we used fluorescent markers for extracellular synaptic glutamate and intracellular neuronal calcium to directly measure relationships between synaptic and spiking activities on local vascular changes in awake mice under evoked and spontaneous conditions. To determine which signal better predicts hemodynamic responses, we used a linear convolution model. Using wide field optical imaging (WFOI), we observed peak fluorescence values of 0.38% and 5.60% in synaptic glutamate and neuronal calcium, respectively, to whisker stimulation, and values of 3.13% and 35.77%, respectively, using two-photon microscopy (2PM). Following whisker stimulation, mean R² values were 0.64 and 0.79 for synaptic glutamate and neuronal calcium, respectively, with WFOI and 0.67 and 0.56, respectively, with 2PM. From WFOI resting-state, mean R² values were 0.73 and 0.68 for synaptic glutamate and neuronal calcium, respectively. Altogether, both signals perform similarly in predicting hemodynamic responses, with no significant differences in their prediction efficacy.

During pregnancy, the fetus is subject to complex interactions of biological and environmental factors that can influence developmental trajectories even into adulthood. Although several factors, such as maternal malnutrition and substance abuse, have been associated with offspring development, the mechanisms through which short- and long-term effects manifest in the fetus are not well understood. To this end, positron emission tomography (PET) imaging using preclinical models has been a promising and underutilized technique for investigating fetal exposure and physiology in utero with minimal invasiveness. Herein, we review the application of PET imaging to fetal medicine and survey the limitations and opportunities for future longitudinal studies of development. Over the past two decades, several studies have utilized preclinical PET in quantitative studies of maternal-fetal exchange dynamics of pharmaceuticals, environmental toxins, or drugs of abuse. Another application has shown [¹⁸F]FDG PET to be a potential biomarker for fetal glucose transport, hypoxia, and brain function in utero. In contrast, only a few studies have employed reversibly binding radioligands to quantify protein markers of dopaminergic signaling and synaptic density in the fetal brain. As PET technology continues to improve, our review highlights a future role for PET in longitudinal studies of fetal health and development.

Microsomal epoxide hydrolase (mEH), first identified as detoxifying enzyme, can hydrolyze epoxyeicosatrienoic acids (EETs) to less active diols (DHETs). EETs are potent vasodilatory and pro-angiogenic lipids, also implicated in neurovascular coupling. In mouse brain, mEH is strongly expressed in vascular and perivascular cells in contrast to the related soluble epoxide hydrolase (sEH), predominantly found in astrocytes. While sEH inhibition in stroke has demonstrated neuroprotective effects and increases cerebral blood flow (CBF), data regarding the role of mEH in brain are scarce. Here, we explored the function of mEH in cerebral vasculature by comparing mEH-KO, sEH-KO and WT mice. Basal cerebral volume (CBV₀) was significantly higher in various mEH-KO brain areas compared to WT and sEH-KO. In line, quantification of cerebral vasculature in cortex and thalamus revealed a higher capillary density in mEH-KO, but not in sEH-KO brain. Whisker-stimulated CBF changes were by factor two higher in both mEH-KO and sEH-KO. In acutely isolated cerebral endothelial cells the loss of mEH, but not of sEH, augmented total EET levels and decreased the DHET:EET ratio. Collectively, these data suggest an important function of mEH in the regulation of cerebral vasculature and activity-modulated CBF, presumably by controlling local levels of endothelial-derived EETs.

Antibody therapy has demonstrated great potential for treating central nervous system (CNS) disorders. Since therapeutic efficacy relies on sufficient exposure in specific brain regions, quantitative understanding of antibody distribution within the brain is crucial. Additionally, insights into antibody brain distribution help elucidate how pathological antibodies accumulate during encephalitis. Accordingly, this study investigated the regional distribution of a non-target-binding antibody (trastuzumab) and a brain-target-binding antibody (anti-NMDAR1) following systemic and intra-CNS administration in rats. After systemic administration, both antibodies showed similar distribution across brain regions, with the olfactory bulb exhibiting significantly higher concentrations. Other regions had comparable exposure, with the striatum or hippocampus showing the lowest exposure. Intra-CSF administration resulted in similar distribution patterns but achieved significantly higher concentrations than systemic administration. In contrast, intra-striatal administration led to diverse distribution, with the highest concentrations near the injection site. Calculations based on striatum and interstitial fluid (ISF) concentrations indicated antibody accumulation in the perivascular space after intra-CNS administration. Target binding influenced distribution primarily after intra-CSF administration, where anti-NMDAR1 showed lower ISF concentrations early and reduced CSF concentrations later. These findings provide valuable quantitative insights for optimizing brain-targeted antibody therapies and understanding pathological antibody distribution in CNS disorders.