Journal: J Cereb Blood Flow Metab

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Abstract

Integrative analysis of the human brain mural cell transcriptome.

Gastfriend BD, Foreman KL, Katt ME, Palecek SP, Shusta EV
Brain mural cells, including pericytes and vascular smooth muscle cells, are important for vascular development, blood-brain barrier function, and neurovascular coupling, but the molecular characteristics of human brain mural cells are incompletely characterized. Single cell RNA-sequencing (scRNA-seq) is increasingly being applied to assess cellular diversity in the human brain, but the scarcity of mural cells in whole brain samples has limited their molecular profiling. Here, we leverage the combined power of multiple independent human brain scRNA-seq datasets to build a transcriptomic database of human brain mural cells. We use this combined dataset to determine human-mouse species differences in mural cell transcriptomes, culture-induced dedifferentiation of human brain pericytes, and human mural cell organotypicity, with several key findings validated by RNA fluorescence in situ hybridization. Together, this work improves knowledge regarding the molecular constituents of human brain mural cells, serves as a resource for hypothesis generation in understanding brain mural cell function, and will facilitate comparative evaluation of animal and in vitro models.



J Cereb Blood Flow Metab: 30 Oct 2021; 41:3052-3068
Gastfriend BD, Foreman KL, Katt ME, Palecek SP, Shusta EV
J Cereb Blood Flow Metab: 30 Oct 2021; 41:3052-3068 | PMID: 34027687
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Abstract

Association between pre-treatment perfusion profile and cerebral edema after reperfusion therapies in ischemic stroke.

Ng FC, Churilov L, Yassi N, Kleinig TJ, ... Mitchell PJ, Campbell BC
The relationship between reperfusion and edema is unclear, with experimental and clinical data yielding conflicting results. We investigated whether the extent of salvageable and irreversibly-injured tissue at baseline influenced the effect of therapeutic reperfusion on cerebral edema. In a pooled analysis of 415 patients with anterior circulation large vessel occlusion from the Tenecteplase-versus-Alteplase-before-Endovascular-Therapy-for-Ischemic-Stroke (EXTEND-IA TNK) part 1 and 2 trials, associations between core and mismatch volume on pre-treatment CT-Perfusion with cerebral edema at 24-hours, and their interactions with reperfusion were tested. Core volume was associated with increased edema (p < 0.001) with no significant interaction with reperfusion (p = 0.82). In comparison, a significant interaction between reperfusion and mismatch volume (p = 0.03) was observed: Mismatch volume was associated with increased edema in the absence of reperfusion (p = 0.009) but not with reperfusion (p = 0.27). When mismatch volume was dichotomized at the median (102 ml), reperfusion was associated with reduced edema in patients with large mismatch volume (p < 0.001) but not with smaller mismatch volume (p = 0.35). The effect of reperfusion on edema may be variable and dependent on the physiological state of the cerebral tissue. In patients with small to moderate ischemic core volume, the benefit of reperfusion in reducing edema is related to penumbral salvage.



J Cereb Blood Flow Metab: 30 Oct 2021; 41:2887-2896
Ng FC, Churilov L, Yassi N, Kleinig TJ, ... Mitchell PJ, Campbell BC
J Cereb Blood Flow Metab: 30 Oct 2021; 41:2887-2896 | PMID: 33993795
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Abstract

Metabolic MRI with hyperpolarized [1-C]pyruvate separates benign oligemia from infarcting penumbra in porcine stroke.

Bøgh N, Olin RB, Hansen ES, Gordon JW, ... Vigneron DB, Laustsen C
Acute ischemic stroke patients benefit from reperfusion in a short time-window after debut. Later treatment may be indicated if viable brain tissue is demonstrated and this outweighs the inherent risks of late reperfusion. Magnetic resonance imaging (MRI) with hyperpolarized [1-13C]pyruvate is an emerging technology that directly images metabolism. Here, we investigated its potential to detect viable tissue in ischemic stroke. Stroke was induced in pigs by intracerebral injection of endothelin 1. During ischemia, the rate constant of pyruvate-to-lactate conversion, kPL, was 52% larger in penumbra and 85% larger in the infarct compared to the contralateral hemisphere (P = 0.0001). Within the penumbra, the kPL was 50% higher in the regions that later infarcted compared to non-progressing regions (P = 0.026). After reperfusion, measures of pyruvate-to-lactate conversion were slightly decreased in the infarct compared to contralateral. In addition to metabolic imaging, we used hyperpolarized pyruvate for perfusion-weighted imaging. This was consistent with conventional imaging for assessment of infarct size and blood flow. Lastly, we confirmed the translatability of simultaneous assessment of metabolism and perfusion with hyperpolarized MRI in healthy volunteers. In conclusion, hyperpolarized [1-13C]pyruvate may aid penumbral characterization and increase access to reperfusion therapy for late presenting patients.



J Cereb Blood Flow Metab: 30 Oct 2021; 41:2916-2927
Bøgh N, Olin RB, Hansen ES, Gordon JW, ... Vigneron DB, Laustsen C
J Cereb Blood Flow Metab: 30 Oct 2021; 41:2916-2927 | PMID: 34013807
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Abstract

The cold receptor TRPM8 activation leads to attenuation of endothelium-dependent cerebral vascular functions during head cooling.

Fedinec AL, Liu J, Zhang R, Harsono M, Pourcyrous M, Parfenova H
Using the cranial window technique, we investigated acute effects of head cooling on cerebral vascular functions in newborn pigs. Head cooling lowered the rectal and extradural brain temperatures to 34.3 ± 0.6°C and 26.1 ± 0.6°C, respectively. During the 3-h hypothermia period, responses of pial arterioles to endothelium-dependent dilators bradykinin and glutamate were reduced, whereas the responses to hypercapnia and an endothelium-independent dilator sodium nitroprusside (SNP) remained intact. All vasodilator responses were restored after rewarming, suggesting that head cooling did not produce endothelial injury. We tested the hypothesis that the cold-sensitive TRPM8 channel is involved in attenuation of cerebrovascular functions. TRPM8 is immunodetected in cerebral vessels and in the brain parenchyma. During normothermia, the TRPM8 agonist icilin produced constriction of pial arterioles that was antagonized by the channel blocker AMTB. Icilin reduced dilation of pial arterioles to bradykinin and glutamate but not to hypercapnia and SNP, thus mimicking the effects of head cooling on vascular functions. AMTB counteracted the impairment of endothelium-dependent vasodilation caused by hypothermia or icilin. Overall, mild hypothermia produced by head cooling leads to acute reversible reduction of selected endothelium-dependent cerebral vasodilator functions via TRPM8 activation, whereas cerebral arteriolar smooth muscle functions are largely preserved.



J Cereb Blood Flow Metab: 30 Oct 2021; 41:2897-2906
Fedinec AL, Liu J, Zhang R, Harsono M, Pourcyrous M, Parfenova H
J Cereb Blood Flow Metab: 30 Oct 2021; 41:2897-2906 | PMID: 34013806
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Abstract

Hemispheric CSF volume ratio quantifies progression and severity of cerebral edema after acute hemispheric stroke.

Dhar R, Hamzehloo A, Kumar A, Chen Y, ... Strbian D, Lee JM
As swelling occurs, CSF is preferentially displaced from the ischemic hemisphere. The ratio of CSF volume in the stroke-affected hemisphere to that in the contralateral hemisphere may quantify the progression of cerebral edema. We automatically segmented CSF from 1,875 routine CTs performed within 96 hours of stroke onset in 924 participants of a stroke cohort study. In 737 subjects with follow-up imaging beyond 24-hours, edema severity was classified as affecting less than one-third of the hemisphere (CED-1), large hemispheric infarction (LHI, over one-third the hemisphere), without midline shift (CED-2) or with midline shift (CED-3). Malignant edema was LHI resulting in deterioration, requiring osmotic therapy, surgery, or resulting in death. Hemispheric CSF ratio was lower on baseline CT in those with LHI (0.91 vs. 0.97, p < 0.0001) and decreased more rapidly in those with LHI who developed midline shift (0.01 per hour for CED-3 vs. 0.004/hour CED-2). The ratio at 24-hours was lower in those with midline shift (0.41, IQR 0.30-0.57 vs. 0.66, 0.56-0.81 for CED-2). A ratio below 0.50 provided 90% sensitivity, 82% specificity for predicting malignant edema among those with LHI (AUC 0.91, 0.85-0.96). This suggests that the hemispheric CSF ratio may provide an accessible early biomarker of edema severity.



J Cereb Blood Flow Metab: 30 Oct 2021; 41:2907-2915
Dhar R, Hamzehloo A, Kumar A, Chen Y, ... Strbian D, Lee JM
J Cereb Blood Flow Metab: 30 Oct 2021; 41:2907-2915 | PMID: 34013805
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Abstract

Early stopping in clinical PET studies: How to reduce expense and exposure.

Svensson JE, Schain M, Knudsen GM, Ogden RT, Plavén-Sigray P
Clinical positron emission tomography (PET) research is costly and entails exposing participants to radioactivity. Researchers should therefore aim to include just the number of subjects needed to fulfill the purpose of the study. In this tutorial we show how to apply sequential Bayes Factor testing in order to stop the recruitment of subjects in a clinical PET study as soon as enough data have been collected to make a conclusion. By using simulations, we demonstrate that it is possible to stop a study early, while keeping the number of erroneous conclusions low. We then apply sequential Bayes Factor testing to a real PET data set and show that it is possible to obtain support in favor of an effect while simultaneously reducing the sample size with 30%. Using this procedure allows researchers to reduce expense and radioactivity exposure for a range of effect sizes relevant for PET research.



J Cereb Blood Flow Metab: 30 Oct 2021; 41:2805-2819
Svensson JE, Schain M, Knudsen GM, Ogden RT, Plavén-Sigray P
J Cereb Blood Flow Metab: 30 Oct 2021; 41:2805-2819 | PMID: 34018825
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Abstract

Dynamic alterations in the central glutamatergic status following food and glucose intake: multimodal assessments in humans and animal models.

Kubota M, Kimura Y, Shimojo M, Takado Y, ... Suhara T, Higuchi M
Fluctuations of neuronal activities in the brain may underlie relatively slow components of neurofunctional alterations, which can be modulated by food intake and related systemic metabolic statuses. Glutamatergic neurotransmission plays a major role in the regulation of excitatory tones in the central nervous system, although just how dietary elements contribute to the tuning of this system remains elusive. Here, we provide the first demonstration by bimodal positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) that metabotropic glutamate receptor subtype 5 (mGluR5) ligand binding and glutamate levels in human brains are dynamically altered in a manner dependent on food intake and consequent changes in plasma glucose levels. The brain-wide modulations of central mGluR5 ligand binding and glutamate levels and profound neuronal activations following systemic glucose administration were further proven by PET, MRS, and intravital two-photon microscopy, respectively, in living rodents. The present findings consistently support the notion that food-associated glucose intake is mechanistically linked to glutamatergic tones in the brain, which are translationally accessible in vivo by bimodal PET and MRS measurements in both clinical and non-clinical settings.



J Cereb Blood Flow Metab: 30 Oct 2021; 41:2928-2943
Kubota M, Kimura Y, Shimojo M, Takado Y, ... Suhara T, Higuchi M
J Cereb Blood Flow Metab: 30 Oct 2021; 41:2928-2943 | PMID: 34039039
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Abstract

Perfusion and permeability as diagnostic biomarkers of cavernous angioma with symptomatic hemorrhage.

Sone JY, Li Y, Hobson N, Romanos SG, ... Girard R, Awad IA
Cavernous angiomas with symptomatic hemorrhage (CASH) have a high risk of rebleeding, and hence an accurate diagnosis is needed. With blood flow and vascular leak as established mechanisms, we analyzed perfusion and permeability derivations of dynamic contrast-enhanced quantitative perfusion (DCEQP) MRI in 745 lesions of 205 consecutive patients. Thirteen respective derivations of lesional perfusion and permeability were compared between lesions that bled within a year prior to imaging (N = 86), versus non-CASH (N = 659) using machine learning and univariate analyses. Based on logistic regression and minimizing the Bayesian information criterion (BIC), the best diagnostic biomarker of CASH within the prior year included brainstem lesion location, sporadic genotype, perfusion skewness, and high-perfusion cluster area (BIC = 414.9, sensitivity = 74%, specificity = 87%). Adding a diagnostic plasma protein biomarker enhanced sensitivity to 100% and specificity to 85%. A slightly modified derivation achieved similar accuracy (BIC = 321.6, sensitivity = 80%, specificity = 82%) in the cohort where CASH occurred 3-12 months prior to imaging after signs of hemorrhage would have disappeared on conventional MRI sequences. Adding the same plasma biomarker enhanced sensitivity to 100% and specificity to 87%. Lesional blood flow on DCEQP may distinguish CASH after hemorrhagic signs on conventional MRI have disappeared and are enhanced in combination with a plasma biomarker.



J Cereb Blood Flow Metab: 30 Oct 2021; 41:2944-2956
Sone JY, Li Y, Hobson N, Romanos SG, ... Girard R, Awad IA
J Cereb Blood Flow Metab: 30 Oct 2021; 41:2944-2956 | PMID: 34039038
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Abstract

Functional dynamics of dopamine synthesis during monetary reward and punishment processing.

Hahn A, Reed MB, Pichler V, Michenthaler P, ... Hacker M, Lanzenberger R
The assessment of dopamine release with the PET competition model is thoroughly validated but entails disadvantages for the investigation of cognitive processes. We introduce a novel approach incorporating 6-[18F]FDOPA uptake as index of the dynamic regulation of dopamine synthesis enzymes by neuronal firing. The feasibility of this approach is demonstrated by assessing widely described sex differences in dopamine neurotransmission. Reward processing was behaviorally investigated in 36 healthy participants, of whom 16 completed fPET and fMRI during the monetary incentive delay task. A single 50 min fPET acquisition with 6-[18F]FDOPA served to quantify task-specific changes in dopamine synthesis. In men monetary gain induced stronger increases in ventral striatum dopamine synthesis than loss. Interestingly, the opposite effect was discovered in women. These changes were further associated with reward (men) and punishment sensitivity (women). As expected, fMRI showed robust task-specific neuronal activation but no sex difference. Our findings provide a neurobiological basis for known behavioral sex differences in reward and punishment processing, with important implications in psychiatric disorders showing sex-specific prevalence, altered reward processing and dopamine signaling. The high temporal resolution and magnitude of task-specific changes make fPET a promising tool to investigate functional neurotransmitter dynamics during cognitive processing and in brain disorders.



J Cereb Blood Flow Metab: 30 Oct 2021; 41:2973-2985
Hahn A, Reed MB, Pichler V, Michenthaler P, ... Hacker M, Lanzenberger R
J Cereb Blood Flow Metab: 30 Oct 2021; 41:2973-2985 | PMID: 34053336
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Abstract

Evidence of cerebral hemodynamic dysregulation in middle-aged APOE ε4 carriers: The PREVENT-Dementia study.

Dounavi ME, Low A, McKiernan EF, Mak E, ... Su L, O\'Brien JT
Accumulating evidence suggests vascular dysregulation in preclinical Alzheimer\'s disease. In this study, cerebral hemodynamics and their coupling with cognition in middle-aged apolipoprotein ε4 carriers (APOEε4+) were investigated. Longitudinal 3 T T1-weighted and arterial spin labelling MRI data from 158 participants (40-59 years old) in the PREVENT-Dementia study were analysed (125 two-year follow-up). Cognition was evaluated using the COGNITO battery. Cerebral blood flow (CBF) and cerebrovascular resistance index (CVRi) were quantified for the flow territories of the anterior, middle and posterior cerebral arteries. CBF was corrected for underlying atrophy and individual hematocrit. Hemodynamic measures were the dependent variables in linear regression models, with age, sex, years of education and APOEε4 carriership as predictors. Further analyses were conducted with cognitive outcomes as dependent variables, using the same model as before with additional APOEε4 × hemodynamics interactions. At baseline, APOEε4+ showed increased CBF and decreased CVRi compared to non-carriers in the anterior and middle cerebral arteries, suggestive of potential vasodilation. Hemodynamic changes were similar between groups. Interaction analysis revealed positive associations between CBF changes and performance changes in delayed recall (for APOEε4 non-carriers) and verbal fluency (for APOEε4 carriers) cognitive tests. These observations are consistent with neurovascular dysregulation in middle-aged APOEε4+.



J Cereb Blood Flow Metab: 30 Oct 2021; 41:2844-2855
Dounavi ME, Low A, McKiernan EF, Mak E, ... Su L, O'Brien JT
J Cereb Blood Flow Metab: 30 Oct 2021; 41:2844-2855 | PMID: 34078163
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Abstract

Reliability of task-specific neuronal activation assessed with functional PET, ASL and BOLD imaging.

Rischka L, Godbersen GM, Pichler V, Michenthaler P, ... Lanzenberger R, Hahn A
Mapping the neuronal response during cognitive processing is of crucial importance to gain new insights into human brain function. BOLD imaging and ASL are established MRI methods in this endeavor. Recently, the novel approach of functional PET (fPET) was introduced, enabling absolute quantification of glucose metabolism at rest and during task execution in a single measurement. Here, we report test-retest reliability of fPET in direct comparison to BOLD imaging and ASL. Twenty healthy subjects underwent two PET/MRI measurements, providing estimates of glucose metabolism, cerebral blood flow (CBF) and blood oxygenation. A cognitive task was employed with different levels of difficulty requiring visual-motor coordination. Task-specific neuronal activation was robustly detected with all three imaging approaches. The highest reliability was obtained for glucose metabolism at rest. Although this dropped during task performance it was still comparable to that of CBF. In contrast, BOLD imaging yielded high performance only for qualitative spatial overlap of task effects but not for quantitative comparison. Hence, the combined assessment of fPET and ASL offers reliable and simultaneous absolute quantification of glucose metabolism and CBF at rest and task.



J Cereb Blood Flow Metab: 30 Oct 2021; 41:2986-2999
Rischka L, Godbersen GM, Pichler V, Michenthaler P, ... Lanzenberger R, Hahn A
J Cereb Blood Flow Metab: 30 Oct 2021; 41:2986-2999 | PMID: 34078145
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Abstract

Impact of sex and ε4 on age-related cerebral perfusion trajectories in cognitively asymptomatic middle-aged and older adults: A longitudinal study.

Wang R, Oh JM, Motovylyak A, Ma Y, ... Eisenmenger L, Okonkwo OC
Cerebral hypoperfusion is thought to contribute to cognitive decline in Alzheimer\'s disease, but the natural trajectory of cerebral perfusion in cognitively healthy adults has not been well-studied. This longitudinal study is consisted of 950 participants (40-89 years), who were cognitively unimpaired at their first visit. We investigated the age-related changes in cerebral perfusion, and their associations with APOE-genotype, biological sex, and cardiometabolic measurements. During the follow-up period (range 0.13-8.24 years), increasing age was significantly associated with decreasing cerebral perfusion, in total gray-matter (β=-1.43), hippocampus (-1.25), superior frontal gyrus (-1.70), middle frontal gyrus (-1.99), posterior cingulate (-2.46), and precuneus (-2.14), with all P-values < 0.01. Compared with male-ɛ4 carriers, female-ɛ4 carriers showed a faster decline in global and regional cerebral perfusion with increasing age, whereas the age-related decline in cerebral perfusion was similar between male- and female-ɛ4 non-carriers. Worse cardiometabolic profile (i.e., increased blood pressure, body mass index, total cholesterol, and blood glucose) was associated with lower cerebral perfusion at all the visits. When time-varying cardiometabolic measurements were adjusted in the model, the synergistic effect of sex and APOE-ɛ4 on age-related cerebral perfusion-trajectories became largely attenuated. Our findings demonstrate that APOE-genotype and sex interactively impact cerebral perfusion-trajectories in mid- to late-life. This effect may be partially explained by cardiometabolic alterations.



J Cereb Blood Flow Metab: 30 Oct 2021; 41:3016-3027
Wang R, Oh JM, Motovylyak A, Ma Y, ... Eisenmenger L, Okonkwo OC
J Cereb Blood Flow Metab: 30 Oct 2021; 41:3016-3027 | PMID: 34102919
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Abstract

Deep learning-based identification of acute ischemic core and deficit from non-contrast CT and CTA.

Wang C, Shi Z, Yang M, Huang L, ... Ding J, Wang H
The accurate identification of irreversible infarction and salvageable tissue is important in planning the treatments for acute ischemic stroke (AIS) patients. Computed tomographic perfusion (CTP) can be used to evaluate the ischemic core and deficit, covering most of the territories of anterior circulation, but many community hospitals and primary stroke centers do not have the capability to perform CTP scan in emergency situation. This study aimed to identify AIS lesions from widely available non-contrast computed tomography (NCCT) and CT angiography (CTA) using deep learning. A total of 345AIS patients from our emergency department were included. A multi-scale 3D convolutional neural network (CNN) was used as the predictive model with inputs of NCCT, CTA, and CTA+ (8 s delay after CTA) images. An external cohort with 108 patients was included to further validate the generalization performance of the proposed model. Strong correlations with CTP-RAPID segmentations (r = 0.84 for core, r = 0.83 for deficit) were observed when NCCT, CTA, and CTA+ images were all used in the model. The diagnostic decisions according to DEFUSE3 showed high accuracy when using NCCT, CTA, and CTA+ (0.90±0.04), followed by the combination of NCCT and CTA (0.87±0.04), CTA-alone (0.76±0.06), and NCCT-alone (0.53±0.09).



J Cereb Blood Flow Metab: 30 Oct 2021; 41:3028-3038
Wang C, Shi Z, Yang M, Huang L, ... Ding J, Wang H
J Cereb Blood Flow Metab: 30 Oct 2021; 41:3028-3038 | PMID: 34102912
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Abstract

Long-term monitoring of chronic demyelination and remyelination in a rat ischemic stroke model using macromolecular proton fraction mapping.

Khodanovich MY, Gubskiy IL, Kudabaeva MS, Namestnikova DD, ... Mustafina LR, Yarnykh VL
Remyelination is a key process enabling post-stroke brain tissue recovery and plasticity. This study aimed to explore the feasibility of demyelination and remyelination monitoring in experimental stroke from the acute to chronic stage using an emerging myelin imaging biomarker, macromolecular proton fraction (MPF). After stroke induction by transient middle cerebral artery occlusion, rats underwent repeated MRI examinations during 85 days after surgery with histological endpoints for the animal subgroups on the 7th, 21st, 56th, and 85th days. MPF maps revealed two sub-regions within the infarct characterized by distinct temporal profiles exhibiting either a persistent decrease by 30%-40% or a transient decrease followed by return to nearly normal values after one month of observation. Myelin histology confirmed that these sub-regions had nearly similar extent of demyelination in the sub-acute phase and then demonstrated either chronic demyelination or remyelination. The remyelination zones also exhibited active axonal regrowth, reconstitution of compact fiber bundles, and proliferation of neuronal and oligodendroglial precursors. The demyelination zones showed more extensive astrogliosis from the 21st day endpoint. Both sub-regions had substantially depleted neuronal population over all endpoints. These results histologically validate MPF mapping as a novel approach for quantitative assessment of myelin damage and repair in ischemic stroke.



J Cereb Blood Flow Metab: 30 Oct 2021; 41:2856-2869
Khodanovich MY, Gubskiy IL, Kudabaeva MS, Namestnikova DD, ... Mustafina LR, Yarnykh VL
J Cereb Blood Flow Metab: 30 Oct 2021; 41:2856-2869 | PMID: 34107787
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Abstract

Role of platelets in the pathogenesis of delayed injury after subarachnoid hemorrhage.

Dienel A, Kumar T P, Blackburn SL, McBride DW
Aneurysmal subarachnoid hemorrhage (aSAH) patients develop delayed cerebral ischemia and delayed deficits (DCI) within 2 weeks of aneurysm rupture at a rate of approximately 30%. DCI is a major contributor to morbidity and mortality after SAH. The cause of DCI is multi-factorial with contributions from microthrombi, blood vessel constriction, inflammation, and cortical spreading depolarizations. Platelets play central roles in hemostasis, inflammation, and vascular function. Within this review, we examine the potential roles of platelets in microthrombi formation, large artery vasospasm, microvessel constriction, inflammation, and cortical spreading depolarization. Evidence from experimental and clinical studies is provided to support the role(s) of platelets in each pathophysiology which contributes to DCI. The review concludes with a suggestion for future therapeutic targets to prevent DCI after aSAH.



J Cereb Blood Flow Metab: 30 Oct 2021; 41:2820-2830
Dienel A, Kumar T P, Blackburn SL, McBride DW
J Cereb Blood Flow Metab: 30 Oct 2021; 41:2820-2830 | PMID: 34112003
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Abstract

Leptomeningeal collateral activation indicates severely impaired cerebrovascular reserve capacity in patients with symptomatic unilateral carotid artery occlusion.

Sebök M, Niftrik CHBV, Lohaus N, Esposito G, ... Regli L, Fierstra J
For patients with symptomatic unilateral internal carotid artery (ICA) occlusion, impaired cerebrovascular reactivity (CVR) indicates increased stroke risk. Here, the role of collateral activation remains a matter of debate, whereas angio-anatomical collateral abundancy does not necessarily imply sufficient compensatory flow provided. We aimed to further elucidate the role of collateral activation in the presence of impaired CVR. From a prospective database, 62 patients with symptomatic unilateral ICA occlusion underwent blood oxygenation-level dependent (BOLD) fMRI CVR imaging and a transcranial Doppler (TCD) investigation for primary and secondary collateral activation. Descriptive statistic and multivariate analysis were used to evaluate the relationship between BOLD-CVR values and collateral activation. Patients with activated secondary collaterals exhibited more impaired BOLD-CVR values of the ipsilateral hemisphere (p = 0.02). Specifically, activation of leptomeningeal collaterals showed severely impaired ipsilateral hemisphere BOLD-CVR values when compared to activation of ophthalmic collaterals (0.05 ± 0.09 vs. 0.12 ± 0.04, p = 0.005). Moreover, the prediction analysis showed leptomeningeal collateral activation as a strong independent predictor for ipsilateral hemispheric BOLD-CVR. In our study, ipsilateral leptomeningeal collateral activation is the sole collateral pathway associated with severely impaired BOLD-CVR in patients with symptomatic unilateral ICA occlusion.



J Cereb Blood Flow Metab: 30 Oct 2021; 41:3039-3051
Sebök M, Niftrik CHBV, Lohaus N, Esposito G, ... Regli L, Fierstra J
J Cereb Blood Flow Metab: 30 Oct 2021; 41:3039-3051 | PMID: 34112002
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Abstract

Cortical cerebral microinfarcts on 7T MRI: Risk factors, neuroimaging correlates and cognitive functioning - The Medea-7T study.

Zwartbol MH, Rissanen I, Ghaznawi R, de Bresser J, ... Hendrikse J, Geerlings MI
We determined the occurrence and association of cortical cerebral microinfarcts (CMIs) at 7 T MRI with risk factors, neuroimaging markers of small and large vessel disease, and cognitive functioning. Within the Medea-7T study, a diverse cohort of older persons with normal cognition, patients with vascular disease, and memory clinic patients, we included 386 participants (68 ± 9 years) with available 7 T and 1.5 T/3T brain MRI, and risk factor and neuropsychological data. CMIs were found in 10% of participants and were associated with older age (RR = 1.79 per +10 years, 95%CI 1.28-2.50), history of stroke or TIA (RR = 4.03, 95%CI 2.18-7.43), cortical infarcts (RR = 5.28, 95%CI 2.91-9.55), lacunes (RR = 5.66, 95%CI 2.85-11.27), cerebellar infarcts (RR = 2.73, 95%CI 1.27-5.84) and decreased cerebral blood flow (RR = 1.35 per -100 ml/min, 95%CI 1.00-1.83), after adjustment for age and sex. Furthermore, participants with >2 CMIs had 0.5 SD (95%CI 0.05-0.91) lower global cognitive performance, compared to participants without CMIs. Our results indicate that CMIs on 7 T MRI are observed in vascular and memory clinic patients with similar frequency, and are associated with older age, history of stroke or TIA, other brain infarcts, and poorer global cognitive functioning.



J Cereb Blood Flow Metab: 30 Oct 2021; 41:3127-3138
Zwartbol MH, Rissanen I, Ghaznawi R, de Bresser J, ... Hendrikse J, Geerlings MI
J Cereb Blood Flow Metab: 30 Oct 2021; 41:3127-3138 | PMID: 34187229
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Abstract

Intranasal delivery of interleukin-4 attenuates chronic cognitive deficits via beneficial microglial responses in experimental traumatic brain injury.

Pu H, Ma C, Zhao Y, Wang Y, ... Bennett MV, Chen J
Traumatic brain injury (TBI) is commonly followed by long-term cognitive deficits that severely impact the quality of life in survivors. Recent studies suggest that microglial/macrophage (Mi/MΦ) polarization could have multidimensional impacts on post-TBI neurological outcomes. Here, we report that repetitive intranasal delivery of interleukin-4 (IL-4) nanoparticles for 4 weeks after controlled cortical impact improved hippocampus-dependent spatial and non-spatial cognitive functions in adult C57BL6 mice, as assessed by a battery of neurobehavioral tests for up to 5 weeks after TBI. IL-4-elicited enhancement of cognitive functions was associated with improvements in the integrity of the hippocampus at the functional (e.g., long-term potentiation) and structural levels (CA3 neuronal loss, diffusion tensor imaging of white matter tracts, etc.). Mechanistically, IL-4 increased the expression of PPARγ and arginase-1 within Mi/MΦ, thereby driving microglia toward a global inflammation-resolving phenotype. Notably, IL-4 failed to shift microglial phenotype after TBI in Mi/MΦ-specific PPARγ knockout (mKO) mice, indicating an obligatory role for PPARγ in IL-4-induced Mi/MΦ polarization. Accordingly, post-TBI treatment with IL-4 failed to improve hippocampal integrity or cognitive functions in PPARγ mKO mice. These results demonstrate that administration of exogenous IL-4 nanoparticles stimulates PPARγ-dependent beneficial Mi/MΦ responses, and improves hippocampal function after TBI.



J Cereb Blood Flow Metab: 30 Oct 2021; 41:2870-2886
Pu H, Ma C, Zhao Y, Wang Y, ... Bennett MV, Chen J
J Cereb Blood Flow Metab: 30 Oct 2021; 41:2870-2886 | PMID: 34259069
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Abstract

Tenascin-C induction exacerbates post-stroke brain damage.

Chelluboina B, Chokkalla AK, Mehta SL, Morris-Blanco KC, ... Park JS, Vemuganti R
The role of tenascin-C (TNC) in ischemic stroke pathology is not known despite its prognostic association with cerebrovascular diseases. Here, we investigated the effect of TNC knockdown on post-stroke brain damage and its putative mechanism of action in adult mice of both sexes. Male and female C57BL/6 mice were subjected to transient middle cerebral artery occlusion and injected (i.v.) with either TNC siRNA or a negative (non-targeting) siRNA at 5 min after reperfusion. Motor function (beam walk and rotarod tests) was assessed between days 1 and 14 of reperfusion. Infarct volume (T2-MRI), BBB damage (T1-MRI with contrast), and inflammatory markers were measured at 3 days of reperfusion. The TNC siRNA treated cohort showed significantly curtailed post-stroke TNC protein expression, motor dysfunction, infarction, BBB damage, and inflammation compared to the sex-matched negative siRNA treated cohort. These results demonstrate that the induction of TNC during the acute period after stroke might be a mediator of post-ischemic inflammation and secondary brain damage independent of sex.



J Cereb Blood Flow Metab: 24 Oct 2021:271678X211056392; epub ahead of print
Chelluboina B, Chokkalla AK, Mehta SL, Morris-Blanco KC, ... Park JS, Vemuganti R
J Cereb Blood Flow Metab: 24 Oct 2021:271678X211056392; epub ahead of print | PMID: 34689646
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Impact:
Abstract

Adult-induced genetic ablation distinguishes PDGFB roles in blood-brain barrier maintenance and development.

Vazquez-Liebanas E, Nahar K, Bertuzzi G, Keller A, Betsholtz C, Mäe MA
Platelet-derived growth factor B (PDGFB) released from endothelial cells is indispensable for pericyte recruitment during angiogenesis in embryonic and postnatal organ growth. Constitutive genetic loss-of-function of PDGFB leads to pericyte hypoplasia and the formation of a sparse, dilated and venous-shifted brain microvasculature with dysfunctional blood-brain barrier (BBB) in mice, as well as the formation of microvascular calcification in both mice and humans. Endothelial PDGFB is also expressed in the adult quiescent microvasculature, but here its importance is unknown. We show that deletion of Pdgfb in endothelial cells in 2-months-old mice causes a slowly progressing pericyte loss leading, at 12-18 months of age, to ≈50% decrease in endothelial:pericyte cell ratio, ≈60% decrease in pericyte longitudinal capillary coverage and >70% decrease in pericyte marker expression. Similar to constitutive loss of Pdgfb, this correlates with increased BBB permeability. However, in contrast to the constitutive loss of Pdgfb, adult-induced loss does not lead to vessel dilation, impaired arterio-venous zonation or the formation of microvascular calcifications. We conclude that PDFGB expression in quiescent adult microvascular brain endothelium is critical for the maintenance of pericyte coverage and normal BBB function, but that microvessel dilation, rarefaction, arterio-venous skewing and calcification reflect developmental roles of PDGFB.



J Cereb Blood Flow Metab: 24 Oct 2021:271678X211056395; epub ahead of print
Vazquez-Liebanas E, Nahar K, Bertuzzi G, Keller A, Betsholtz C, Mäe MA
J Cereb Blood Flow Metab: 24 Oct 2021:271678X211056395; epub ahead of print | PMID: 34689641
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Abstract

Selective therapeutic cooling: To maximize benefits and minimize side effects related to hypothermia.

Wu D, Chen J, Zhang X, Ilagan R, Ding Y, Ji X
Selective therapeutic cooling is a promising technique for reducing final infarct volume and improving outcomes in ischemic stroke, especially as research regarding brain reperfusion continues to be explored. A recent study provided promising results on the safety and feasibility of selective therapeutic hypothermia via a closed-loop cooling catheter system for intra-carotid blood cooling in an ovine stroke model, but they failed to find efficacy of this method in this model. It is a major step forward from bench to bed side, but enhancing benefits of selective therapeutic cooling may need to take into account a more targeted induction of brain hypothermia and should mitigate potential side effects related to inducing hypothermia.



J Cereb Blood Flow Metab: 19 Oct 2021:271678X211055959; epub ahead of print
Wu D, Chen J, Zhang X, Ilagan R, Ding Y, Ji X
J Cereb Blood Flow Metab: 19 Oct 2021:271678X211055959; epub ahead of print | PMID: 34670442
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Impact:
Abstract

Targeting maintains adult blood-brain barrier and central nervous system homeostasis.

Gueniot F, Rubin S, Bougaran P, Abelanet A, ... Couffinhal T, Duplàa C
Blood brain barrier (BBB) disruption is a critical component of the pathophysiology of cognitive impairment of vascular etiology (VCI) and associated with Alzheimer\'s disease (AD). The Wnt pathway plays a crucial role in BBB maintenance, but there is limited data on its role in cognitive pathologies. The E3 ubiquitin ligase PDZRN3 is a regulator of the Wnt pathway. In a murine model of VCI, overexpressing Pdzrn3 in endothelial cell (EC) exacerbated BBB hyperpermeability and accelerated cognitive decline. We extended these observations, in both VCI and AD models, showing that EC-specific depletion of Pdzrn3, reinforced the BBB, with a decrease in vascular permeability and a subsequent spare in cognitive decline. We found that in cerebral vessels, Pdzrn3 depletion protects against AD-induced Wnt target gene alterations and enhances endothelial tight junctional proteins. Our results provide evidence that Wnt signaling could be a molecular link regulating BBB integrity and cognitive decline under VCI and AD pathologies.



J Cereb Blood Flow Metab: 12 Oct 2021:271678X211048981; epub ahead of print
Gueniot F, Rubin S, Bougaran P, Abelanet A, ... Couffinhal T, Duplàa C
J Cereb Blood Flow Metab: 12 Oct 2021:271678X211048981; epub ahead of print | PMID: 34644209
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Abstract

Serotonin 1B receptor density mapping of the human brainstem using positron emission tomography and autoradiography.

Veldman ER, Varrone A, Varnäs K, Svedberg MM, ... Halldin C, Lundberg J
The serotonin 1B (5-HT1B) receptor has lately received considerable interest in relation to psychiatric and neurological diseases, partly due to findings based on quantification using Positron Emission Tomography (PET). Although the brainstem is an important structure in this regard, PET radioligand binding quantification in brainstem areas often shows poor reliability. This study aims to improve PET quantification of 5-HT1B receptor binding in the brainstem.Volumes of interest (VOIs) were selected based on a 3D [3H]AZ10419369 Autoradiography brainstem model, which visualized 5-HT1B receptor distribution in high resolution. Two previously developed VOI delineation methods were tested and compared to a conventional manual method. For a method based on template data, a [11C]AZ10419369 PET template was created by averaging parametric binding potential (BPND) images of 52 healthy subjects. VOIs were generated based on a predefined volume and BPND thresholding and subsequently applied to test-retest [11C]AZ10419369 parametric BPND images of 8 healthy subjects. For a method based on individual subject data, VOIs were generated directly on each individual parametric image.Both methods showed improved reliability compared to a conventional manual VOI. The VOIs created with [11C]AZ10419369 template data can be automatically applied to future PET studies measuring 5-HT1B receptor binding in the brainstem.



J Cereb Blood Flow Metab: 12 Oct 2021:271678X211049185; epub ahead of print
Veldman ER, Varrone A, Varnäs K, Svedberg MM, ... Halldin C, Lundberg J
J Cereb Blood Flow Metab: 12 Oct 2021:271678X211049185; epub ahead of print | PMID: 34644198
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Abstract

Reliability and validity of the mean flow index (Mx) for assessing cerebral autoregulation in humans: A systematic review of the methodology.

Olsen MH, Riberholt CG, Mehlsen J, Berg RM, Møller K
Cerebral autoregulation is a complex mechanism that serves to keep cerebral blood flow relatively constant within a wide range of cerebral perfusion pressures. The mean flow index (Mx) is one of several methods to assess dynamic cerebral autoregulation, but its reliability and validity have never been assessed systematically. The purpose of the present systematic review was to evaluate the methodology, reliability and validity of Mx.Based on 128 studies, we found inconsistency in the pre-processing of the recordings and the methods for calculation of Mx. The reliability in terms of repeatability and reproducibility ranged from poor to excellent, with optimal repeatability when comparing overlapping recordings. The discriminatory ability varied depending on the patient populations; in general, those with acute brain injury exhibited a higher Mx than healthy volunteers. The prognostic ability in terms of functional outcome and mortality ranged from chance result to moderate accuracy.Since the methodology was inconsistent between studies, resulting in varying reliability and validity estimates, the results were difficult to compare. The optimal method for deriving Mx is currently unknown.



J Cereb Blood Flow Metab: 06 Oct 2021:271678X211052588; epub ahead of print
Olsen MH, Riberholt CG, Mehlsen J, Berg RM, Møller K
J Cereb Blood Flow Metab: 06 Oct 2021:271678X211052588; epub ahead of print | PMID: 34617816
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Abstract

Association of cerebral small vessel disease burden with brain structure and cognitive and vascular risk trajectories in mid-to-late life.

Jansen MG, Griffanti L, Mackay CE, Anatürk M, ... Ebmeier KP, Suri S
We characterize the associations of total cerebral small vessel disease (SVD) burden with brain structure, trajectories of vascular risk factors, and cognitive functions in mid-to-late life. Participants were 623 community-dwelling adults from the Whitehall II Imaging Sub-study with multi-modal MRI (mean age 69.96, SD = 5.18, 79% men). We used linear mixed-effects models to investigate associations of SVD burden with up to 25-year retrospective trajectories of vascular risk and cognitive performance. General linear modelling was used to investigate concurrent associations with grey matter (GM) density and white matter (WM) microstructure, and whether these associations were modified by cognitive status (Montreal Cognitive Asessment [MoCA] scores of < 26 vs. ≥ 26). Severe SVD burden in older age was associated with higher mean arterial pressure throughout midlife (β = 3.36, 95% CI [0.42-6.30]), and faster cognitive decline in letter fluency (β = -0.07, 95% CI [-0.13--0.01]), and verbal reasoning (β = -0.05, 95% CI [-0.11--0.001]). Moreover, SVD burden was related to lower GM volumes in 9.7% of total GM, and widespread WM microstructural decline (FWE-corrected p < 0.05). The latter association was most pronounced in individuals who demonstrated cognitive impairments on MoCA (MoCA < 26; F3,608 = 2.14, p = 0.007). These findings highlight the importance of managing midlife vascular health to preserve brain structure and cognitive function in old age.



J Cereb Blood Flow Metab: 04 Oct 2021:271678X211048411; epub ahead of print
Jansen MG, Griffanti L, Mackay CE, Anatürk M, ... Ebmeier KP, Suri S
J Cereb Blood Flow Metab: 04 Oct 2021:271678X211048411; epub ahead of print | PMID: 34610763
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Abstract

Genetic deletion of endothelial microRNA-15a/16-1 promotes cerebral angiogenesis and neurological recovery in ischemic stroke through Src signaling pathway.

Sun P, Ma F, Xu Y, Zhou C, Stetler RA, Yin KJ
Cerebral angiogenesis is tightly controlled by specific microRNAs (miRs), including the miR-15a/16-1 cluster. Recently, we reported that endothelium-specific conditional knockout of the miR-15a/16-1 cluster (EC-miR-15a/16-1 cKO) promotes post-stroke angiogenesis and improves long-term neurological recovery by increasing protein levels of VEGFA, FGF2, and their respective receptors VEGFR2 and FGFR1. Herein, we further investigated the underlying signaling mechanism of these pro-angiogenic factors after ischemic stroke using a selective Src family inhibitor AZD0530. EC-miR-15a/16-1 cKO and age- and sex-matched wild-type littermate (WT) mice were subjected to 1 h middle cerebral artery occlusion (MCAO) and 28d reperfusion. AZD0530 was administered daily by oral gavage to both genotypes of mice 3-21d after MCAO. Compared to WT, AZD0530 administration exacerbated spatial cognitive impairments and brain atrophy in EC-miR-15a/16-1 cKO mice following MCAO. AZD0530 also attenuated long-term recovery of blood flow and inhibited the formation of new microvessels, including functional vessels with blood circulation, in the penumbra of stroked cKO mice. Moreover, AZD0530 blocked the Src signaling pathway by downregulating phospho-Src and its downstream mediators (p-Stat3, p-Akt, p-FAK, p-p44/42 MAPK, p-p38 MAPK) in post-ischemic brains. Collectively, our data demonstrated that endothelium-targeted deletion of the miR-15a/16-1 cluster promotes post-stroke angiogenesis and improves long-term neurological recovery via activating Src signaling pathway.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2725-2742
Sun P, Ma F, Xu Y, Zhou C, Stetler RA, Yin KJ
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2725-2742 | PMID: 33910400
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Abstract

Preclinical and clinical evidence of IGF-1 as a prognostic marker and acute intervention with ischemic stroke.

Hayes CA, Valcarcel-Ares MN, Ashpole NM
Ischemic strokes are highly prevalent in the elderly population and are a leading cause of mortality and morbidity worldwide. The risk of ischemic stroke increases in advanced age, corresponding with a noted decrease in circulating insulin growth factor-1 (IGF-1). IGF-1 is a known neuroprotectant involved in embryonic development, neurogenesis, neurotransmission, cognition, and lifespan. Clinically, several studies have shown that reduced levels of IGF-1 correlate with increased mortality rate, poorer functional outcomes, and increased morbidities following an ischemic stroke. In animal models of ischemia, administering exogenous IGF-1 using various routes of administration (intranasal, intravenous, subcutaneous, or topical) at various time points prior to and following insult attenuates neurological damage and accompanying behavioral changes caused by ischemia. However, there are some contrasting findings in select clinical and preclinical studies. This review discusses the role of IGF-1 as a determinant factor of ischemic stroke outcomes, both within the clinical settings and preclinical animal models. Furthermore, the review provides insight on the role of IGF-1 in mechanisms and cellular processes that contribute to stroke damage.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2475-2491
Hayes CA, Valcarcel-Ares MN, Ashpole NM
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2475-2491 | PMID: 33757314
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Abstract

Dilated perivascular space is related to reduced free-water in surrounding white matter among healthy adults and elderlies but not in patients with severe cerebral small vessel disease.

Jiaerken Y, Lian C, Huang P, Yu X, ... Shen D, Zhang M
Perivascular space facilitates cerebral interstitial water clearance. However, it is unclear how dilated perivascular space (dPVS) affects the interstitial water of surrounding white matter. We aimed to determine the presence and extent of changes in normal-appearing white matter water components around dPVS in different populations. Twenty healthy elderly subjects and 15 elderly subjects with severe cerebral small vessel disease (CSVD, with lacunar infarction 6 months before the scan) were included in our study. And other 28 healthy adult subjects were enrolled under a different scanning parameter to see if the results are comparable. The normal-appearing white matter around dPVS was categorized into 10 layers (1 mm thickness each) based on their distance to dPVS. We evaluated the mean isotropic-diffusing water volume fraction in each layer. We discovered a significantly reduced free-water content in the layers closely adjacent to the dPVS in the healthy elderlies. however, this reduction around dPVS was weaker in the CSVD subjects. We also discovered an elevated free-water content within dPVS. DPVS played different roles in healthy subjects or CSVD subjects. The reduced water content around dPVS in healthy subjects suggests these MR-visible PVSs are not always related to the stagnation of fluid.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2561-2570
Jiaerken Y, Lian C, Huang P, Yu X, ... Shen D, Zhang M
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2561-2570 | PMID: 33818186
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Impact:
Abstract

A large portion of the astrocyte proteome is dedicated to perivascular endfeet, including critical components of the electron transport chain.

Stokum JA, Shim B, Huang W, Kane M, ... Gerzanich V, Simard JM
The perivascular astrocyte endfoot is a specialized and diffusion-limited subcellular compartment that fully ensheathes the cerebral vasculature. Despite their ubiquitous presence, a detailed understanding of endfoot physiology remains elusive, in part due to a limited understanding of the proteins that distinguish the endfoot from the greater astrocyte body. Here, we developed a technique to isolate astrocyte endfeet from brain tissue, which was used to study the endfoot proteome in comparison to the astrocyte somata. In our approach, brain microvessels, which retain their endfoot processes, were isolated from mouse brain and dissociated, whereupon endfeet were recovered using an antibody-based column astrocyte isolation kit. Our findings expand the known set of proteins enriched at the endfoot from 10 to 516, which comprised more than 1/5th of the entire detected astrocyte proteome. Numerous critical electron transport chain proteins were expressed only at the endfeet, while enzymes involved in glycogen storage were distributed to the somata, indicating subcellular metabolic compartmentalization. The endfoot proteome also included numerous proteins that, while known to have important contributions to blood-brain barrier function, were not previously known to localize to the endfoot. Our findings highlight the importance of the endfoot and suggest new routes of investigation into endfoot function.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2546-2560
Stokum JA, Shim B, Huang W, Kane M, ... Gerzanich V, Simard JM
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2546-2560 | PMID: 33818185
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Impact:
Abstract

Nicotinamide phosphoribosyltransferase inhibitor ameliorates mouse aging-induced cognitive impairment.

Zeng M, Wei TF, Chen C, Shen C, ... Lu YB, Zhang WP
Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme for the synthesis of nicotinamide adenine dinucleotide (NAD) in the salvaging pathway. Though NAMPT inhibitors such as FK866 were originally developed as anti-cancer drugs, they also display neuroprotective effects. Here we show that the administration of FK866 at 0.5 mg/kg (ip, qod) for four weeks, i.e., ∼1% of the dose used for the treatment of cancer, significantly alleviates the aging-induced impairment of cognition and locomotor activity. Mechanistically, FK866 enhanced autophagy, reduced protein aggregation, and inhibited neuroinflammation indicated by decreasing TNFα, IL-6, GFAP, and Iba1 levels in the aged mouse brain. Though FK866 did not affect the total NAD and nicotinamide mononucleotide (NMN) levels in the mouse brain at the dose we used, FK866 increased nicotinamide (NAM) level in the young mouse brain and decreased NAM level in the aged mouse brain. On the other hand, FK866 did not affect the serum glucose, cholesterol, and triglyceride of young and aged mice and exhibited no effects on the various indices of young mice. Thus, the NAMPT inhibitor can be repurpose to counteract the cognitive impairment upon aging. We also envision that NAMPT inhibitor can be used for the treatment of age-related neurodegenerative diseases.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2510-2523
Zeng M, Wei TF, Chen C, Shen C, ... Lu YB, Zhang WP
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2510-2523 | PMID: 33818184
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Impact:
Abstract

Neurovascular coupling dysfunction in end-stage renal disease patients related to cognitive impairment.

Li P, Mu J, Ma X, Ding D, ... Liu J, Zhang M
We aimed to investigate the neurovascular coupling (NVC) dysfunction in end-stage renal disease (ESRD) patients related with cognitive impairment. Twenty-five ESRD patients and 22 healthy controls were enrolled. To assess the NVC dysfunctional pattern, resting-state functional MRI and arterial spin labeling were explored to estimate the coupling of spontaneous neuronal activity and cerebral blood perfusion based on amplitude of low-frequency fluctuation (ALFF)-cerebral blood flow (CBF), fractional ALFF (fALFF)-CBF, regional homogeneity (ReHo)-CBF, and degree centrality (DC)-CBF correlation coefficients. Multivariate partial least-squares correlation and mediation analyses were used to evaluate the relationship among NVC dysfunctional pattern, cognitive impairment and clinical characteristics. The NVC dysfunctional patterns in ESRD patients were significantly decreased in 34 brain regions compared with healthy controls. The decreased fALFF-CBF coefficients in the cingulate gyrus (CG) were associated positively with lower kinetic transfer/volume urea (Kt/V) and lower short-term memory scores, and were negatively associated with higher serum urea. The relationship between Kt/V and memory deficits of ESRD patients was partially mediated by the fALFF-CBF alteration of the CG. These findings reveal the NVC dysfunction may be a potential neural mechanism for cognitive impairment in ESRD. The regional NVC dysfunction may mediate the impact of dialysis adequacy on memory function.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2593-2606
Li P, Mu J, Ma X, Ding D, ... Liu J, Zhang M
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2593-2606 | PMID: 33853410
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Abstract

Assessing cerebral arterial pulse wave velocity using 4D flow MRI.

Björnfot C, Garpebring A, Qvarlander S, Malm J, Eklund A, Wåhlin A
Intracranial arterial stiffening is a potential early marker of emerging cerebrovascular dysfunction and could be mechanistically involved in disease processes detrimental to brain function via several pathways. A prominent consequence of arterial wall stiffening is the increased velocity at which the systolic pressure pulse wave propagates through the vasculature. Previous non-invasive measurements of the pulse wave propagation have been performed on the aorta or extracranial arteries with results linking increased pulse wave velocity to brain pathology. However, there is a lack of intracranial \"target-organ\" measurements. Here we present a 4D flow MRI method to estimate pulse wave velocity in the intracranial vascular tree. The method utilizes the full detectable branching structure of the cerebral vascular tree in an optimization framework that exploits small temporal shifts that exists between waveforms sampled at varying depths in the vasculature. The method is shown to be stable in an internal consistency test, and of sufficient sensitivity to robustly detect age-related increases in intracranial pulse wave velocity.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2769-2777
Björnfot C, Garpebring A, Qvarlander S, Malm J, Eklund A, Wåhlin A
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2769-2777 | PMID: 33853409
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Abstract

Plasminogen deficiency causes reduced angiogenesis and behavioral recovery after stroke in mice.

Fang J, Chopp M, Xin H, Zhang L, ... He L, Liu Z
Plasminogen is involved in the process of angiogenesis; however, the underlying mechanism is unclear. Here, we investigated the potential contribution of plasmin/plasminogen in mediating angiogenesis and thereby contributing to functional recovery post-stroke. Wild-type plasminogen naive (Plg+/+) mice and plasminogen knockout (Plg-/-) mice were subjected to unilateral permanent middle cerebral artery occlusion (MCAo). Blood vessels were labeled with FITC-dextran. Functional outcomes, and cerebral vessel density were compared between Plg+/+ and Plg-/- mice at different time points after stroke. We found that Plg-/- mice exhibited significantly reduced functional recovery, associated with significantly decreased vessel density in the peri-infarct area in the ipsilesional cortex compared with Plg+/+ mice. In vitro, cerebral endothelial cells harvested from Plg-/- mice exhibited significantly reduced angiogenesis assessed using tube formation assay, and migration, as evaluated using Scratch assays, compared to endothelial cells harvested from Plg+/+ mice. In addition, using Western blots, expression of thrombospondin (TSP)-1 and TSP-2 were increased after MCAo in the Plg-/- group compared to Plg+/+ mice, especially in the ipsilesional side of brain. Taken together, our data suggest that plasmin/plasminogen down-regulates the expression level of TSP-1 and TSP-2, and thereby promotes angiogenesis in the peri-ischemic brain tissue, which contributes to functional recovery after ischemic stroke.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2583-2592
Fang J, Chopp M, Xin H, Zhang L, ... He L, Liu Z
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2583-2592 | PMID: 33853408
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Abstract

[C]deschloroclozapine is an improved PET radioligand for quantifying a human muscarinic DREADD expressed in monkey brain.

Yan X, Telu S, Dick RM, Liow JS, ... Richmond BJ, Eldridge MA
Previous work found that [11C]deschloroclozapine ([11C]DCZ) is superior to [11C]clozapine ([11C]CLZ) for imaging Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). This study used PET to quantitatively and separately measure the signal from transfected receptors, endogenous receptors/targets, and non-displaceable binding in other brain regions to better understand this superiority. A genetically-modified muscarinic type-4 human receptor (hM4Di) was injected into the right amygdala of a male rhesus macaque. [11C]DCZ and [11C]CLZ PET scans were conducted 2-24 months later. Uptake was quantified relative to the concentration of parent radioligand in arterial plasma at baseline (n = 3 scans/radioligand) and after receptor blockade (n = 3 scans/radioligand). Both radioligands had greater uptake in the transfected region and displaceable uptake in other brain regions. Displaceable uptake was not uniformly distributed, perhaps representing off-target binding to endogenous receptor(s). After correction, [11C]DCZ signal was 19% of that for [11C]CLZ, and background uptake was 10% of that for [11C]CLZ. Despite stronger [11C]CLZ binding, the signal-to-background ratio for [11C]DCZ was almost two-fold greater than for [11C]CLZ. Both radioligands had comparable DREADD selectivity. All reference tissue models underestimated signal-to-background ratio in the transfected region by 40%-50% for both radioligands. Thus, the greater signal-to-background ratio of [11C]DCZ was due to its lower background uptake.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2571-2582
Yan X, Telu S, Dick RM, Liow JS, ... Richmond BJ, Eldridge MA
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2571-2582 | PMID: 33853405
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Abstract

Microvascular changes associated with epilepsy: A narrative review.

van Lanen RH, Melchers S, Hoogland G, Schijns OE, ... Haeren RH, Rijkers K
The blood-brain barrier (BBB) is dysfunctional in temporal lobe epilepsy (TLE). In this regard, microvascular changes are likely present. The aim of this review is to provide an overview of the current knowledge on microvascular changes in epilepsy, and includes clinical and preclinical evidence of seizure induced angiogenesis, barriergenesis and microcirculatory alterations. Anatomical studies show increased microvascular density in the hippocampus, amygdala, and neocortex accompanied by BBB leakage in various rodent epilepsy models. In human TLE, a decrease in afferent vessels, morphologically abnormal vessels, and an increase in endothelial basement membranes have been observed. Both clinical and experimental evidence suggests that basement membrane changes, such as string vessels and protrusions, indicate and visualize a misbalance between endothelial cell proliferation and barriergenesis. Vascular endothelial growth factor (VEGF) appears to play a crucial role. Following an altered vascular anatomy, its physiological functioning is affected as expressed by neurovascular decoupling that subsequently leads to hypoperfusion, disrupted parenchymal homeostasis and potentially to seizures\". Thus, epilepsy might be a condition characterized by disturbed cerebral microvasculature in which VEGF plays a pivotal role. Additional physiological data from patients is however required to validate findings from models and histological studies on patient biopsies.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2492-2509
van Lanen RH, Melchers S, Hoogland G, Schijns OE, ... Haeren RH, Rijkers K
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2492-2509 | PMID: 33866850
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Abstract

Magnetic resonance imaging-based changes in vascular morphology and cerebral perfusion in subacute ischemic stroke.

Kufner A, Khalil AA, Galinovic I, Kellner E, ... Endres M, Nave AH
MRI-based vessel size imaging (VSI) allows for in-vivo assessment of cerebral microvasculature and perfusion. This exploratory analysis of vessel size (VS) and density (Q; both assessed via VSI) in the subacute phase of ischemic stroke involved sixty-two patients from the BAPTISe cohort (\'Biomarkers And Perfusion--Training-Induced changes after Stroke\') nested within a randomized controlled trial (intervention: 4-week training vs. relaxation). Relative VS, Q, cerebral blood volume (rCBV) and -flow (rCBF) were calculated for: ischemic lesion, perilesional tissue, and region corresponding to ischemic lesion on the contralateral side (mirrored lesion). Linear mixed-models detected significantly increased rVS and decreased rQ within the ischemic lesion compared to the mirrored lesion (coefficient[standard error]: 0.2[0.08] p = 0.03 and -1.0[0.3] p = 0.02, respectively); lesion rCBF and rCBV were also significantly reduced. Mixed-models did not identify time-to-MRI, nor training as modifying factors in terms of rVS or rQ up to two months post-stroke. Larger lesion VS was associated with larger lesion volumes (β 34, 95%CI 6.2-62; p = 0.02) and higher baseline NIHSS (β 3.0, 95%CI 0.49-5.3;p = 0.02), but was not predictive of six-month outcome. In summary, VSI can assess the cerebral microvasculature and tissue perfusion in the subacute phases of ischemic stroke, and may carry relevant prognostic value in terms of lesion volume and stroke severity.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2617-2627
Kufner A, Khalil AA, Galinovic I, Kellner E, ... Endres M, Nave AH
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2617-2627 | PMID: 33866849
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Abstract

Hemodynamic and structural brain measures in high and low sedentary older adults.

Maasakkers CM, Thijssen DH, Knight SP, Newman L, ... Claassen JA, Looze C
Due to its cardiovascular effects sedentary behaviour might impact cerebrovascular function in the long term, affecting cerebrovascular regulatory mechanisms and perfusion levels. Consequently this could underly potential structural brain abnormalities associated with cognitive decline. We therefore assessed the association between sedentary behaviour and brain measures of cerebrovascular perfusion and structural abnormalities in community-dwelling older adults. Using accelerometery (GENEActiv) data from The Irish Longitudinal Study on Ageing (TILDA) we categorised individuals by low- and high-sedentary behaviour (≤8 vs >8 hours/day). We examined prefrontal haemoglobin oxygenation levels using Near-Infrared Spectroscopy during rest and after an orthostatic challenge in 718 individuals (66 ± 8 years, 52% female). Global grey matter cerebral blood flow, total grey and white matter volume, total and subfield hippocampal volumes, cortical thickness, and white matter hyperintensities were measured using arterial spin labelling, T1, and FLAIR MRI in 86 individuals (72 ± 6 years, 55% female). While no differences in prefrontal or global cerebral hemodynamics were found between groups, high-sedentary individuals showed lower hippocampal volumes and increased white matter hyperintensities compared to their low-sedentary counterparts. Since these structural cerebral abnormalities are associated with cognitive decline and Alzheimer\'s disease, future work exploring the causal pathways underlying these differences is needed.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2607-2616
Maasakkers CM, Thijssen DH, Knight SP, Newman L, ... Claassen JA, Looze C
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2607-2616 | PMID: 33866848
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Abstract

Cerebral cortical microinfarcts in patients with internal carotid artery occlusion.

van den Brink H, Ferro DA, Bresser J, Bron EE, ... Biessels GJ, Heart-Brain Connection Consortium
Cerebral cortical microinfarcts (CMI) are small ischemic lesions that are associated with cognitive impairment and probably have multiple etiologies. Cerebral hypoperfusion has been proposed as a causal factor. We studied CMI in patients with internal carotid artery (ICA) occlusion, as a model for cerebral hemodynamic compromise. We included 95 patients with a complete ICA occlusion (age 66.2 ± 8.3, 22% female) and 125 reference participants (age 65.5 ± 7.4, 47% female). Participants underwent clinical, neuropsychological, and 3 T brain MRI assessment. CMI were more common in patients with an ICA occlusion (54%, median 2, range 1-33) than in the reference group (6%, median 0; range 1-7; OR 14.3; 95% CI 6.2-33.1; p<.001). CMI were more common ipsilateral to the occlusion than in the contralateral hemisphere (median 2 and 0 respectively; p<.001). In patients with CMI compared to patients without CMI, the number of additional occluded or stenosed cervical arteries was higher (p=.038), and cerebral blood flow was lower (B -6.2 ml/min/100 ml; 95% CI -12.0:-0.41; p=.036). In conclusion, CMI are common in patients with an ICA occlusion, particularly in the hemisphere of the occluded ICA. CMI burden was related to the severity of cervical arterial compromise, supporting a role of hemodynamics in CMI etiology.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2690-2698
van den Brink H, Ferro DA, Bresser J, Bron EE, ... Biessels GJ, Heart-Brain Connection Consortium
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2690-2698 | PMID: 33899560
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Abstract

Connexin43 promotes angiogenesis through activating the HIF-1α/VEGF signaling pathway under chronic cerebral hypoperfusion.

Yu W, Jin H, Sun W, Nan D, ... Yu Z, Huang Y
Chronic cerebral hypoperfusion, a major vascular contributor to vascular cognitive impairment and dementia, can exacerbate small vessel pathology. Connexin43, the most abundant gap junction protein in brain tissue, has been found to be critically involved in the pathological changes of vascular cognitive impairment and dementia caused by chronic cerebral hypoperfusion. However, the precise mechanisms underpinning its role are unclear. We established a mouse model via bilateral common carotid arteries stenosis on connexin43 heterozygous male mice and demonstrated that connexin43 improves brain blood flow recovery by mediating reparative angiogenesis under chronic cerebral hypoperfusion, which subsequently reduces the characteristic pathologies of vascular cognitive impairment and dementia including white matter lesions and irreversible neuronal injury. We additionally found that connexin43 mediates hypoxia inducible factor-1α expression and then activates the PKA signaling pathway to regulate vascular endothelial growth factor-induced angiogenesis. All the above findings were replicated in bEnd.3 cells treated with 375 µM CoCl2 in vitro. These results suggest that connexin 43 could be instrumental in developing potential therapies for vascular cognitive impairment and dementia caused by chronic cerebral hypoperfusion.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2656-2675
Yu W, Jin H, Sun W, Nan D, ... Yu Z, Huang Y
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2656-2675 | PMID: 33899559
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Abstract

Differential pial and penetrating arterial responses examined by optogenetic activation of astrocytes and neurons.

Hatakeyama N, Unekawa M, Murata J, Tomita Y, ... Tanaka KF, Masamoto K
A variety of brain cells participates in neurovascular coupling by transmitting and modulating vasoactive signals. The present study aimed to probe cell type-dependent cerebrovascular (i.e., pial and penetrating arterial) responses with optogenetics in the cortex of anesthetized mice. Two lines of the transgenic mice expressing a step function type of light-gated cation channel (channelrhodopsine-2; ChR2) in either cortical neurons (muscarinic acetylcholine receptors) or astrocytes (Mlc1-positive) were used in the experiments. Photo-activation of ChR2-expressing astrocytes resulted in a widespread increase in cerebral blood flow (CBF), extending to the nonstimulated periphery. In contrast, photo-activation of ChR2-expressing neurons led to a relatively localized increase in CBF. The differences in the spatial extent of the CBF responses are potentially explained by differences in the involvement of the vascular compartments. In vivo imaging of the cerebrovascular responses revealed that ChR2-expressing astrocyte activation led to the dilation of both pial and penetrating arteries, whereas ChR2-expressing neuron activation predominantly caused dilation of the penetrating arterioles. Pharmacological studies showed that cell type-specific signaling mechanisms participate in the optogenetically induced cerebrovascular responses. In conclusion, pial and penetrating arterial vasodilation were differentially evoked by ChR2-expressing astrocytes and neurons.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2676-2689
Hatakeyama N, Unekawa M, Murata J, Tomita Y, ... Tanaka KF, Masamoto K
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2676-2689 | PMID: 33899558
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Abstract

Hemodynamic and oxygen-metabolic responses of the awake mouse brain to hypercapnia revealed by multi-parametric photoacoustic microscopy.

Cao R, Tran A, Li J, Xu Z, ... Zuo Z, Hu S
A widely used cerebrovascular stimulus and common pathophysiologic condition, hypercapnia is of great interest in brain research. However, it remains controversial how hypercapnia affects brain hemodynamics and energy metabolism. By using multi-parametric photoacoustic microscopy, the multifaceted responses of the awake mouse brain to different levels of hypercapnia are investigated. Our results show significant and vessel type-dependent increases of the vessel diameter and blood flow in response to the hypercapnic challenges, along with a decrease in oxygen extraction fraction due to elevated venous blood oxygenation. Interestingly, the increased blood flow and decreased oxygen extraction are not commensurate with each other, which leads to reduced cerebral oxygen metabolism. Further, time-lapse imaging over 2-hour chronic hypercapnic challenges reveals that the structural, functional, and metabolic changes induced by severe hypercapnia (10% CO2) are not only more pronounced but more enduring than those induced by mild hypercapnia (5% CO2), indicating that the extent of brain\'s compensatory response to chronic hypercapnia is inversely related to the severity of the challenge. Offering quantitative, dynamic, and CO2 level-dependent insights into the hemodynamic and metabolic responses of the brain to hypercapnia, these findings might provide useful guidance to the application of hypercapnia in brain research.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2628-2639
Cao R, Tran A, Li J, Xu Z, ... Zuo Z, Hu S
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2628-2639 | PMID: 33899557
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Abstract

Low neuronal metabolism during isoflurane-induced burst suppression is related to synaptic inhibition while neurovascular coupling and mitochondrial function remain intact.

Berndt N, Kovács R, Schoknecht K, Rösner J, ... Spies C, Liotta A
Deep anaesthesia may impair neuronal, vascular and mitochondrial function facilitating neurological complications, such as delirium and stroke. On the other hand, deep anaesthesia is performed for neuroprotection in critical brain diseases such as status epilepticus or traumatic brain injury. Since the commonly used anaesthetic propofol causes mitochondrial dysfunction, we investigated the impact of the alternative anaesthetic isoflurane on neuro-metabolism. In deeply anaesthetised Wistar rats (burst suppression pattern), we measured increased cortical tissue oxygen pressure (ptiO2), a ∼35% drop in regional cerebral blood flow (rCBF) and burst-associated neurovascular responses. In vitro, 3% isoflurane blocked synaptic transmission and impaired network oscillations, thereby decreasing the cerebral metabolic rate of oxygen (CMRO2). Concerning mitochondrial function, isoflurane induced a reductive shift in flavin adenine dinucleotide (FAD) and decreased stimulus-induced FAD transients as Ca2+ influx was reduced by ∼50%. Computer simulations based on experimental results predicted no direct effects of isoflurane on mitochondrial complexes or ATP-synthesis. We found that isoflurane-induced burst suppression is related to decreased ATP consumption due to inhibition of synaptic activity while neurovascular coupling and mitochondrial function remain intact. The neurometabolic profile of isoflurane thus appears to be superior to that of propofol which has been shown to impair the mitochondrial respiratory chain.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2640-2655
Berndt N, Kovács R, Schoknecht K, Rösner J, ... Spies C, Liotta A
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2640-2655 | PMID: 33899556
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Abstract

Choroid plexus perfusion in sickle cell disease and moyamoya vasculopathy: Implications for glymphatic flow.

Johnson SE, McKnight CD, Jordan LC, Claassen DO, ... Fusco M, Donahue MJ
Cerebrospinal fluid (CSF) and interstitial fluid exchange have been shown to increase following pharmacologically-manipulated increases in cerebral arterial pulsatility, consistent with arterial pulsatility improving CSF circulation along perivascular glymphatic pathways. The choroid plexus (CP) complexes produce CSF, and CP activity may provide a centralized indicator of perivascular flow. We tested the primary hypothesis that elevated cortical cerebral blood volume and flow, present in sickle cell disease (SCD), is associated with fractionally-reduced CP perfusion relative to healthy adults, and the supplementary hypothesis that reduced arterial patency, present in moyamoya vasculopathy, is associated with elevated fractional CP perfusion relative to healthy adults. Participants (n = 75) provided informed consent and were scanned using a 3-Tesla arterial-spin-labeling MRI sequence for CP and cerebral gray matter (GM) perfusion quantification. ANOVA was used to calculate differences in CP-to-GM perfusion ratios between groups, and regression analyses applied to evaluate the dependence of the CP-to-GM perfusion ratio on group after co-varying for age and sex. ANOVA yielded significant (p < 0.001) group differences, with CP-to-GM perfusion ratios increasing between SCD (ratio = 0.93 ± 0.28), healthy (ratio = 1.04 ± 0.32), and moyamoya (ratio = 1.29 ± 0.32) participants, which was also consistent with regression analyses. Findings are consistent with CP perfusion being inversely associated with cortical perfusion.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2699-2711
Johnson SE, McKnight CD, Jordan LC, Claassen DO, ... Fusco M, Donahue MJ
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2699-2711 | PMID: 33906512
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Abstract

Altered regional cerebral blood flow in obstructive sleep apnea is associated with sleep fragmentation and oxygen desaturation.

Yan L, Park HR, Kezirian EJ, Yook S, ... Joo EY, Kim H
Altered cerebral perfusion has been reported in obstructive sleep apnea (OSA). Using dynamic susceptibility contrast MRI, we compared cerebral perfusion between male OSA patients and male healthy reference subjects and assessed correlations of perfusion abnormalities of OSA patients with sleep parameters and neuropsychological deficits at 3 T MRI, polysomnography and neuropsychological tests in 68 patients with OSA and 21 reference subjects. We found lower global and regional cerebral blood flow and cerebral blood volume, localized mainly in bilateral parietal and prefrontal cortices, as well as multiple focal cortical and deep structures related to the default mode network and attention network. In the correlation analysis between regional hypoperfusion and parameters of polysomnography, different patterns of regional hypoperfusion were distinctively associated with parameters of intermittent hypoxia and sleep fragmentation, which involved mainly parietal and orbitofrontal cortices, respectively. There was no association between brain perfusion and cognition in OSA patients in areas where significant association was observed in reference subjects, largely overlapping with nodes of the default mode network and attention network. Our results suggest that impaired cerebral perfusion in important areas of functional networks could be an important pathomechanism of neurocognitive deficits in OSA.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2712-2724
Yan L, Park HR, Kezirian EJ, Yook S, ... Joo EY, Kim H
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2712-2724 | PMID: 33906511
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Abstract

CSF lipocalin-2 increases early in subarachnoid hemorrhage are associated with neuroinflammation and unfavorable outcome.

Yu F, Saand A, Xing C, Lee JW, ... Lo EH, Chou SH
Lipocalin-2 mediates neuro-inflammation and iron homeostasis in vascular injuries of the central nervous system (CNS) and is upregulated in extra-CNS systemic inflammation. We postulate that cerebrospinal fluid (CSF) and blood lipocalin-2 levels are associated with markers of inflammation and functional outcome in subarachnoid hemorrhage (SAH). We prospectively enrolled 67 SAH subjects, serially measured CSF and plasma lipocalin-2, matrix metallopeptidase 9 (MMP-9), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) on post-SAH days 1-5 and assessed outcome by modified Rankin Scale (mRS) every 3 months. Unfavorable outcome is defined as mRS > 2. Twenty non-SAH patients undergoing lumbar drain trial were enrolled as controls. Lipocalin-2 was detectable in the CSF and significantly higher in SAH compared to controls (p < 0.0001). Higher CSF LCN2 throughout post-SAH days 1-5 was associated with unfavorable outcome at 3 (p = 0.0031) and 6 months (p = 0.014). Specifically, higher CSF lipocalin-2 on post-SAH days 3 (p = 0.036) and 5 (p = 0.016) were associated with unfavorable 3-month outcome. CSF lipocalin-2 levels positively correlated with CSF IL-6, TNF-α and MMP-9 levels. Higher plasma lipocalin-2 levels over time were associated with worse 6-month outcome. Additional studies are required to understand the role of lipocalin-2 in SAH and to validate CSF lipocalin-2 as a potential biomarker for SAH outcome.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2524-2533
Yu F, Saand A, Xing C, Lee JW, ... Lo EH, Chou SH
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2524-2533 | PMID: 33951946
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Abstract

Impaired cerebral vascular and metabolic responses to parametric N-back tasks in subjective cognitive decline.

Zhang Y, Du W, Yin Y, Li H, ... Han Y, Gao JH
Previous studies reported abnormally increased and/or decreased blood oxygen level-dependent (BOLD) activations during functional tasks in subjective cognitive decline (SCD). The neurophysiological basis underlying these functional aberrations remains debated. This study aims to investigate vascular and metabolic responses and their dependence on cognitive processing loads during functional tasks in SCD. Twenty-one SCD and 18 control subjects performed parametric N-back working-memory tasks during MRI scans. Task-evoked percentage changes (denoted as δ) in cerebral blood volume (δCBV), cerebral blood flow (δCBF), BOLD signal (δBOLD) and cerebral metabolic rate of oxygen (δCMRO2) were evaluated. In the frontal lobe, trends of decreased δCBV, δCBF and δCMRO2 and increased δBOLD were observed in SCD compared with control subjects under lower loads, and these trends increased to significant differences under the 3-back load. δCBF was significantly correlated with δCMRO2 in controls, but not in SCD subjects. As N-back loads increased, the differences between SCD and control subjects in δCBF and δCMRO2 tended to enlarge. In the parietal lobe, no significant between-group difference was observed. Our findings suggested that impaired vascular and metabolic responses to functional tasks occurred in the frontal lobe of SCD, which contributed to unusual BOLD hyperactivation and was modulated by cognitive processing loads.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2743-2755
Zhang Y, Du W, Yin Y, Li H, ... Han Y, Gao JH
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2743-2755 | PMID: 33951945
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Abstract

Frequency selective neuronal modulation triggers spreading depolarizations in the rat endothelin-1 model of stroke.

Bazzigaluppi P, Mester J, Joo IL, Weisspapir I, ... Carlen P, Stefanovic B
Ischemia is one of the most common causes of acquired brain injury. Central to its noxious sequelae are spreading depolarizations (SDs), waves of persistent depolarizations which start at the location of the flow obstruction and expand outwards leading to excitotoxic damage. The majority of acute stage of stroke studies to date have focused on the phenomenology of SDs and their association with brain damage. In the current work, we investigated the role of peri-injection zone pyramidal neurons in triggering SDs by optogenetic stimulation in an endothelin-1 rat model of focal ischemia. Our concurrent two photon fluorescence microscopy data and local field potential recordings indicated that a ≥ 60% drop in cortical arteriolar red blood cell velocity was associated with SDs at the ET-1 injection site. SDs were also observed in the peri-injection zone, which subsequently exhibited elevated neuronal activity in the low-frequency bands. Critically, SDs were triggered by low- but not high-frequency optogenetic stimulation of peri-injection zone pyramidal neurons. Our findings depict a complex etiology of SDs post focal ischemia and reveal that effects of neuronal modulation exhibit spectral and spatial selectivity.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2756-2768
Bazzigaluppi P, Mester J, Joo IL, Weisspapir I, ... Carlen P, Stefanovic B
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2756-2768 | PMID: 33969731
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Abstract

Reproducibility of findings in modern PET neuroimaging: insight from the NRM2018 grand challenge.

Veronese M, Rizzo G, Belzunce M, Schubert J, ... Gunn RN, and the Grand Challenge Participants#
The reproducibility of findings is a compelling methodological problem that the neuroimaging community is facing these days. The lack of standardized pipelines for image processing, quantification and statistics plays a major role in the variability and interpretation of results, even when the same data are analysed. This problem is well-known in MRI studies, where the indisputable value of the method has been complicated by a number of studies that produce discrepant results. However, any research domain with complex data and flexible analytical procedures can experience a similar lack of reproducibility. In this paper we investigate this issue for brain PET imaging. During the 2018 NeuroReceptor Mapping conference, the brain PET community was challenged with a computational contest involving a simulated neurotransmitter release experiment. Fourteen international teams analysed the same imaging dataset, for which the ground-truth was known. Despite a plurality of methods, the solutions were consistent across participants, although not identical. These results should create awareness that the increased sharing of PET data alone will only be one component of enhancing confidence in neuroimaging results and that it will be important to complement this with full details of the analysis pipelines and procedures that have been used to quantify data.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2778-2796
Veronese M, Rizzo G, Belzunce M, Schubert J, ... Gunn RN, and the Grand Challenge Participants#
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2778-2796 | PMID: 33993794
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Abstract

Hemispheric cerebral blood flow predicts outcome in acute small subcortical infarcts.

Hong L, Ling Y, Su Y, Yang L, ... Cheng X, Dong Q
The association between baseline perfusion measures and clinical outcomes in patients with acute small subcortical infarcts (SSIs) has not been studied in detail. Post-processed acute perfusion CT and follow-up diffusion-weighted imaging of 71 patients with SSIs were accurately co-registered. Relative perfusion values were calculated from the perfusion values of the infarct lesion divided by those of the mirrored contralateral area. The association between perfusion measures with clinical outcomes and the interaction with intravenous thrombolysis were studied. Additionally, the perfusion measures for patients having perfusion CT before and after thrombolysis were compared. Higher contralateral hemispheric cerebral blood flow (CBF) was the only independent predictor of an excellent clinical outcome (modified Rankin Scale of 0-1) at 3 months (OR = 1.3, 95% CI 1.1-1.4, P = 0.001) amongst all the perfusion parameters, and had a significant interaction with thrombolysis (P = 0.04). Patients who had perfusion CT after thrombolysis demonstrated a better perfusion profile (relative CBF ≥1) than those who had perfusion CT before thrombolysis (After:45.5%, Before:21.1%, P = 0.03). This study implies that for patients with SSIs, hemispheric CBF is a predictor of clinical outcome and has an influence on the effect of intravenous thrombolysis.



J Cereb Blood Flow Metab: 29 Sep 2021; 41:2534-2545
Hong L, Ling Y, Su Y, Yang L, ... Cheng X, Dong Q
J Cereb Blood Flow Metab: 29 Sep 2021; 41:2534-2545 | PMID: 34435912
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Abstract

Imaging effective oxygen diffusivity in the human brain with multiparametric magnetic resonance imaging.

Kufer J, Preibisch C, Epp S, Göttler J, ... Hyder F, Kaczmarz S
Cerebrovascular diseases can impair blood circulation and oxygen extraction from the blood. The effective oxygen diffusivity (EOD) of the capillary bed is a potential biomarker of microvascular function that has gained increasing interest, both for clinical diagnosis and for elucidating oxygen transport mechanisms. Models of capillary oxygen transport link EOD to measurable oxygen extraction fraction (OEF) and cerebral blood flow (CBF). In this work, we confirm that two well established mathematical models of oxygen transport yield nearly equivalent EOD maps. Furthermore, we propose an easy-to-implement and clinically applicable multiparametric magnetic resonance imaging (MRI) protocol for quantitative EOD mapping. Our approach is based on imaging OEF and CBF with multiparametric quantitative blood oxygenation level dependent (mq-BOLD) MRI and pseudo-continuous arterial spin labeling (pCASL), respectively. We evaluated the imaging protocol by comparing MRI-EOD maps of 12 young healthy volunteers to PET data from a published study in different individuals. Our results show comparably good correlation between MRI- and PET-derived cortical EOD, OEF and CBF. Importantly, absolute values of MRI and PET showed high accordance for all three parameters. In conclusion, our data indicates feasibility of the proposed MRI protocol for EOD mapping, rendering the method promising for future clinical evaluation of patients with cerebrovascular diseases.



J Cereb Blood Flow Metab: 29 Sep 2021:271678X211048412; epub ahead of print
Kufer J, Preibisch C, Epp S, Göttler J, ... Hyder F, Kaczmarz S
J Cereb Blood Flow Metab: 29 Sep 2021:271678X211048412; epub ahead of print | PMID: 34590895
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Abstract

The cholinergic system modulates negative BOLD responses in the prefrontal cortex once electrical perforant pathway stimulation triggers neuronal afterdischarges in the hippocampus.

Arboit A, Krautwald K, Angenstein F
Repeated high-frequency pulse-burst stimulations of the rat perforant pathway elicited positive BOLD responses in the right hippocampus, septum and prefrontal cortex. However, when the first stimulation period also triggered neuronal afterdischarges in the hippocampus, then a delayed negative BOLD response in the prefrontal cortex was generated. While neuronal activity and cerebral blood volume (CBV) increased in the hippocampus during the period of hippocampal neuronal afterdischarges (h-nAD), CBV decreased in the prefrontal cortex, although neuronal activity did not decrease. Only after termination of h-nAD did CBV in the prefrontal cortex increase again. Thus, h-nAD triggered neuronal activity in the prefrontal cortex that counteracted the usual neuronal activity-related functional hyperemia. This process was significantly enhanced by pilocarpine, a mACh receptor agonist, and completely blocked when pilocarpine was co-administered with scopolamine, a mACh receptor antagonist. Scopolamine did not prevent the formation of the negative BOLD response, thus mACh receptors modulate the strength of the negative BOLD response.



J Cereb Blood Flow Metab: 29 Sep 2021:271678X211049820; epub ahead of print
Arboit A, Krautwald K, Angenstein F
J Cereb Blood Flow Metab: 29 Sep 2021:271678X211049820; epub ahead of print | PMID: 34590894
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Abstract

Perfusion profile evaluated by severity-weighted multiple Tmax strata predicts early neurological deterioration in minor stroke with large vessel occlusion.

Gwak DS, Choi W, Kwon JA, Shim DH, Kim YW, Hwang YH
Minor stroke due to large vessel occlusion (LVO) is associated with poor outcomes. Hypoperfused tissue fate may be more accurately predicted by severity-weighted multiple perfusion strata than by a single perfusion threshold. We investigated whether poor perfusion profile evaluated by multiple Tmax strata is associated with early neurological deterioration (END) in patients with minor stroke with LVO. Ninety-four patients with a baseline National Institute of Health Stroke Scale score ≤5 and anterior circulation LVO admitted within 24 hours of onset were included. Tmax strata proportions (Tmax 2-4 s, 4-6 s, 6-8 s, 8-10 s, and >10 s) against the entire hypoperfusion volume (Tmax >2 s) were measured. The perfusion profile was defined as the shift of the distribution of the Tmax strata proportions towards worse hypoperfusion severity compared with that of the entire cohort using the Wilcoxon-Mann-Whitney generalised odds ratio (OR); its performance to predict END was tested. The area under the curve of perfusion profile was 0.785 (95% confidence interval [CI]: 0.691-0.878, p < 0.001). Poor perfusion profile (generalised OR >1.052) was independently associated with END (adjusted OR 13.42 [95% CI: 4.38-41.15], p < 0.001). Thus, perfusion profile with severity-weighted multiple Tmax strata may predict END in minor stroke and LVO.



J Cereb Blood Flow Metab: 23 Sep 2021:271678X211029165; epub ahead of print
Gwak DS, Choi W, Kwon JA, Shim DH, Kim YW, Hwang YH
J Cereb Blood Flow Metab: 23 Sep 2021:271678X211029165; epub ahead of print | PMID: 34559021
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Abstract

Brain oxygen extraction fraction mapping in patients with multiple sclerosis.

Cho J, Nguyen TD, Huang W, Sweeney EM, ... Gauthier SA, Wang Y
We aimed to demonstrate the feasibility of whole brain oxygen extraction fraction (OEF) mapping for measuring lesion specific and regional OEF abnormalities in multiple sclerosis (MS) patients. In 22 MS patients and 11 healthy controls (HC), OEF and neural tissue susceptibility (χn) maps were computed from MRI multi-echo gradient echo data. In MS patients, 80 chronic active lesions with hyperintense rim on quantitative susceptibility mapping were identified, and the mean OEF and χn within the rim and core were compared using linear mixed-effect model analysis. The rim showed higher OEF and χn than the core: relative to their adjacent normal appearing white matter, OEF contrast = -6.6 ± 7.0% vs. -9.8 ± 7.8% (p < 0.001) and χn contrast = 33.9 ± 20.3 ppb vs. 25.7 ± 20.5 ppb (p = 0.017). Between MS and HC, OEF and χn were compared using a linear regression model in subject-based regions of interest. In the whole brain, compared to HC, MS had lower OEF, 30.4 ± 3.3% vs. 21.4 ± 4.4% (p < 0.001), and higher χn, -23.7 ± 7.0 ppb vs. -11.3 ± 7.7 ppb (p = 0.018). Our feasibility study suggests that OEF may serve as a useful quantitative marker of tissue oxygen utilization in MS.



J Cereb Blood Flow Metab: 23 Sep 2021:271678X211048031; epub ahead of print
Cho J, Nguyen TD, Huang W, Sweeney EM, ... Gauthier SA, Wang Y
J Cereb Blood Flow Metab: 23 Sep 2021:271678X211048031; epub ahead of print | PMID: 34558996
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Abstract

Mitochondrial quality control in acute ischemic stroke.

An H, Zhou B, Ji X
Mitochondria play a central role in the pathophysiological processes of acute ischemic stroke. Disruption of the cerebral blood flow during acute ischemic stroke interrupts oxygen and glucose delivery, leading to the dysfunction of mitochondrial oxidative phosphorylation and cellular bioenergetic stress. Cells can respond to such stress by activating mitochondrial quality control mechanisms, including the mitochondrial unfolded protein response, mitochondrial fission and fusion, mitophagy, mitochondrial biogenesis, and intercellular mitochondrial transfer. Collectively, these adaptive response strategies contribute to retaining the integrity and function of the mitochondrial network, thereby helping to recover the homeostasis of the neurovascular unit. In this review, we focus on mitochondrial quality control mechanisms occurring in acute ischemic stroke. A better understanding of how these regulatory pathways work in maintaining mitochondrial homeostasis will provide a rationale for developing innovative neuroprotectants when these mechanisms fail in acute ischemic stroke.



J Cereb Blood Flow Metab: 21 Sep 2021:271678X211046992; epub ahead of print
An H, Zhou B, Ji X
J Cereb Blood Flow Metab: 21 Sep 2021:271678X211046992; epub ahead of print | PMID: 34551609
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Abstract

Changes in synaptic density in the subacute phase after ischemic stroke: A C-UCB-J PET/MR study.

Michiels L, Mertens N, Thijs L, Radwan A, ... Van Laere K, Lemmens R
Functional alterations after ischemic stroke have been described with Magnetic Resonance Imaging (MRI) and perfusion Positron Emission Tomography (PET), but no data on in vivo synaptic changes exist. Recently, imaging of synaptic density became available by targeting synaptic vesicle protein 2 A, a protein ubiquitously expressed in all presynaptic nerve terminals. We hypothesized that in subacute ischemic stroke loss of synaptic density can be evaluated with 11C-UCB-J PET in the ischemic tissue and that alterations in synaptic density can be present in brain regions beyond the ischemic core. We recruited ischemic stroke patients to undergo 11C-UCB-J PET/MR imaging 21 ± 8 days after stroke onset to investigate regional 11C-UCB-J SUVR (standardized uptake value ratio). There was a decrease (but residual signal) of 11C-UCB-J SUVR within the lesion of 16 stroke patients compared to 40 healthy controls (ratiolesion/controls = 0.67 ± 0.28, p = 0.00023). Moreover, 11C-UCB-J SUVR was lower in the non-lesioned tissue of the affected hemisphere compared to the unaffected hemisphere (ΔSUVR = -0.17, p = 0.0035). The contralesional cerebellar hemisphere showed a lower 11C-UCB-J SUVR compared to the ipsilesional cerebellar hemisphere (ΔSUVR = -0.14, p = 0.0048). In 8 out of 16 patients, the asymmetry index suggested crossed cerebellar diaschisis. Future research is required to longitudinally study these changes in synaptic density and their association with outcome.



J Cereb Blood Flow Metab: 21 Sep 2021:271678X211047759; epub ahead of print
Michiels L, Mertens N, Thijs L, Radwan A, ... Van Laere K, Lemmens R
J Cereb Blood Flow Metab: 21 Sep 2021:271678X211047759; epub ahead of print | PMID: 34550834
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Abstract

Occult blood flow patterns distal to an occluded artery in acute ischemic stroke.

Arrarte Terreros N, van Willigen BG, Niekolaas WS, Tolhuisen ML, ... van Bavel E, Marquering HA
Residual blood flow distal to an arterial occlusion in patients with acute ischemic stroke (AIS) is associated with favorable patient outcome. Both collateral flow and thrombus permeability may contribute to such residual flow. We propose a method for discriminating between these two mechanisms, based on determining the direction of flow in multiple branches distal to the occluding thrombus using dynamic Computed Tomography Angiography (dynamic CTA). We analyzed dynamic CTA data of 30 AIS patients and present patient-specific cases that identify typical blood flow patterns and velocities. We distinguished patterns with anterograde (N = 10), retrograde (N = 9), and both flow directions (N = 11), with a large variability in velocities for each flow pattern. The observed flow patterns reflect the interplay between permeability and collaterals. The presented method characterizes distal flow and provides a tool to study patient-specific distal tissue perfusion.



J Cereb Blood Flow Metab: 21 Sep 2021:271678X211044941; epub ahead of print
Arrarte Terreros N, van Willigen BG, Niekolaas WS, Tolhuisen ML, ... van Bavel E, Marquering HA
J Cereb Blood Flow Metab: 21 Sep 2021:271678X211044941; epub ahead of print | PMID: 34550818
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Abstract

A review of bioeffects induced by focused ultrasound combined with microbubbles on the neurovascular unit.

Chen S, Nazeri A, Baek H, Ye D, ... Rubin JB, Chen H
Focused ultrasound combined with circulating microbubbles (FUS+MB) can transiently enhance blood-brain barrier (BBB) permeability at targeted brain locations. Its great promise in improving drug delivery to the brain is reflected by a rapidly growing number of clinical trials using FUS+MB to treat various brain diseases. As the clinical applications of FUS+MB continue to expand, it is critical to have a better understanding of the molecular and cellular effects induced by FUS+MB to enhance the efficacy of current treatment and enable the discovery of new therapeutic strategies. Existing studies primarily focus on FUS+MB-induced effects on brain endothelial cells, the major cellular component of BBB. However, bioeffects induced by FUS+MB expand beyond the BBB to cells surrounding blood vessels, including astrocytes, microglia, and neurons. Together these cell types comprise the neurovascular unit (NVU). In this review, we examine cell-type-specific bioeffects of FUS+MB on different NVU components, including enhanced permeability in endothelial cells, activation of astrocytes and microglia, as well as increased intraneuron protein metabolism and neuronal activity. Finally, we discuss knowledge gaps that must be addressed to further advance clinical applications of FUS+MB.



J Cereb Blood Flow Metab: 21 Sep 2021:271678X211046129; epub ahead of print
Chen S, Nazeri A, Baek H, Ye D, ... Rubin JB, Chen H
J Cereb Blood Flow Metab: 21 Sep 2021:271678X211046129; epub ahead of print | PMID: 34551608
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Abstract

Cerebral haemodynamic response to somatosensory stimulation in preterm lambs and 7-10-day old lambs born at term: Direct synchrotron microangiography assessment.

Inocencio IM, Tran NT, Nakamura S, Khor SJ, ... Pearson JT, Wong FY
Neurovascular coupling has been well-defined in the adult brain, but variable and inconsistent responses have been observed in the neonatal brain. The mechanisms that underlie functional haemodynamic responses in the developing brain are unknown. Synchrotron radiation (SR) microangiography enables in vivo high-resolution imaging of the cerebral vasculature. We exploited SR microangiography to investigate the microvascular changes underlying the cerebral haemodynamic response in preterm (n = 7) and 7-10-day old term lambs (n = 4), following median nerve stimulation of 1.8, 4.8 and 7.8 sec durations.Increasing durations of somatosensory stimulation significantly increased the number of cortical microvessels of ≤200 µm diameter in 7-10-day old term lambs (p < 0.05) but not preterm lambs where, in contrast, stimulation increased the diameter of cerebral microvessels with a baseline diameter of ≤200 µm. Preterm lambs demonstrated positive functional responses with increased oxyhaemoglobin measured by near infrared spectroscopy, while 7-10-day old term lambs demonstrated both positive and negative responses. Our findings suggest the vascular mechanisms underlying the functional haemodynamic response differ between the preterm and 7-10-day old term brain. The preterm brain depends on vasodilatation of microvessels without recruitment of additional vessels, suggesting a limited capacity to mount higher cerebral haemodynamic responses when faced with prolonged or stronger neural stimulation.



J Cereb Blood Flow Metab: 21 Sep 2021:271678X211045848; epub ahead of print
Inocencio IM, Tran NT, Nakamura S, Khor SJ, ... Pearson JT, Wong FY
J Cereb Blood Flow Metab: 21 Sep 2021:271678X211045848; epub ahead of print | PMID: 34551607
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Abstract

A functional cerebral endothelium is necessary to protect against cognitive decline.

Trigiani LJ, Bourourou M, Lacalle-Aurioles M, Lecrux C, ... Schwaninger M, Hamel E
A vascular insult occurring early in disease onset may initiate cognitive decline leading to dementia, while pharmacological and lifestyle interventions can prevent this progression. Mice with a selective, tamoxifen-inducible deletion of NF-κB essential modulator (Nemo) in brain endothelial cells were studied as a model of vascular cognitive impairment. Groups included NemoFl controls and three NemobeKO groups: One untreated, and two treated with simvastatin or exercise. Social preference and nesting were impaired in NemobeKO mice and were not countered by treatments. Cerebrovascular function was compromised in NemobeKO groups regardless of treatment, with decreased changes in sensory-evoked cerebral blood flow and total hemoglobin levels, and impaired endothelium-dependent vasodilation. NemobeKO mice had increased string vessel pathology, blood-brain barrier disruption, neuroinflammation, and reduced cortical somatostatin-containing interneurons. These alterations were reversed when endothelial function was recovered. Findings strongly suggest that damage to the cerebral endothelium can trigger pathologies associated with dementia and its functional integrity should be an effective target in future therapeutic efforts.



J Cereb Blood Flow Metab: 12 Sep 2021:271678X211045438; epub ahead of print
Trigiani LJ, Bourourou M, Lacalle-Aurioles M, Lecrux C, ... Schwaninger M, Hamel E
J Cereb Blood Flow Metab: 12 Sep 2021:271678X211045438; epub ahead of print | PMID: 34515549
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Abstract

MRS-measured glutamate versus GABA reflects excitatory versus inhibitory neural activities in awake mice.

Takado Y, Takuwa H, Sampei K, Urushihata T, ... Shibata K, Higuchi M
To assess if magnetic resonance spectroscopy (MRS)-measured Glutamate (Glu) and GABA reflect excitatory and inhibitory neural activities, respectively, we conducted MRS measurements along with two-photon mesoscopic imaging of calcium signals in excitatory and inhibitory neurons of living, unanesthetized mice. For monitoring stimulus-driven activations of a brain region, MRS signals and mesoscopic neural activities were measured during two consecutive sessions of 15-min prolonged sensory stimulations. In the first session, putative excitatory neuronal activities were increased, while inhibitory neuronal activities remained at the baseline level. In the second half, while excitatory neuronal activities remained elevated, inhibitory neuronal activities were significantly enhanced. We assessed regional neurochemical statuses by measuring MRS signals, which were overall in accordance with the neural activities, and neuronal activities and neurochemical statuses in a mouse model of Dravet syndrome under resting condition. Mesoscopic assessments showed that activities of inhibitory neurons in the cortex were diminished relative to wild-type mice in contrast to spared activities of excitatory neurons. Consistent with these observations, the Dravet model exhibited lower concentrations of GABA than wild-type controls. Collectively, the current investigations demonstrate that MRS-measured Glu and GABA can reflect spontaneous and stimulated activities of neurons producing and releasing these neurotransmitters in an awake condition.



J Cereb Blood Flow Metab: 12 Sep 2021:271678X211045449; epub ahead of print
Takado Y, Takuwa H, Sampei K, Urushihata T, ... Shibata K, Higuchi M
J Cereb Blood Flow Metab: 12 Sep 2021:271678X211045449; epub ahead of print | PMID: 34515548
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Abstract

Review of studies on dynamic cerebral autoregulation in the acute phase of stroke and the relationship with clinical outcome.

Nogueira RC, Aries M, Minhas JS, H Petersen N, ... Kainerstorfer JM, Castro P
Acute stroke is associated with high morbidity and mortality. In the last decades, new therapies have been investigated with the aim of improving clinical outcomes in the acute phase post stroke onset. However, despite such advances, a large number of patients do not demonstrate improvement, furthermore, some unfortunately deteriorate. Thus, there is a need for additional treatments targeted to the individual patient. A potential therapeutic target is interventions to optimize cerebral perfusion guided by cerebral hemodynamic parameters such as dynamic cerebral autoregulation (dCA). This narrative led to the development of the INFOMATAS (Identifying New targets FOr Management And Therapy in Acute Stroke) project, designed to foster interventions directed towards understanding and improving hemodynamic aspects of the cerebral circulation in acute cerebrovascular disease states. This comprehensive review aims to summarize relevant studies on assessing dCA in patients suffering acute ischemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage. The review will provide to the reader the most consistent findings, the inconsistent findings which still need to be explored further and discuss the main limitations of these studies. This will allow for the creation of a research agenda for the use of bedside dCA information for prognostication and targeted perfusion interventions.



J Cereb Blood Flow Metab: 12 Sep 2021:271678X211045222; epub ahead of print
Nogueira RC, Aries M, Minhas JS, H Petersen N, ... Kainerstorfer JM, Castro P
J Cereb Blood Flow Metab: 12 Sep 2021:271678X211045222; epub ahead of print | PMID: 34515547
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Abstract

Role of microcirculatory impairment in delayed cerebral ischemia and outcome after aneurysmal subarachnoid hemorrhage.

Naraoka M, Matsuda N, Shimamura N, Ohkuma H
Early brain injury (EBI) is considered an important cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). As a factor in EBI, microcirculatory dysfunction has become a focus of interest, but whether microcirculatory dysfunction is more important than angiographic vasospasm (aVS) remains unclear. Using data from 128 cases, we measured the time to peak (TTP) in several regions of interest on digital subtraction angiography. The intracerebral circulation time (iCCT) was obtained between the TTP in the ultra-early phase (the baseline iCCT) and in the subacute phase and/or at delayed cerebral ischemia (DCI) onset (the follow-up iCCT). In addition, the difference in the iCCT was calculated by subtracting the baseline iCCT from the follow-up iCCT. Univariate analysis showed that DCI was significantly increased in those patients with a prolonged baseline iCCT, prolonged follow-up iCCT, increased differences in the iCCT, and with severe aVS. Poor outcome was significantly increased in patients with prolonged follow-up iCCT and increased differences in the iCCT. Multivariate analysis revealed that increased differences in the iCCT were a significant risk factor that increased DCI and poor outcome. The results suggest that the increasing microcirculatory dysfunction over time, not aVS, causes DCI and poor outcome after aneurysmal aSAH.



J Cereb Blood Flow Metab: 08 Sep 2021:271678X211045446; epub ahead of print
Naraoka M, Matsuda N, Shimamura N, Ohkuma H
J Cereb Blood Flow Metab: 08 Sep 2021:271678X211045446; epub ahead of print | PMID: 34496662
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Abstract

Comparative vulnerability of PET radioligands to partial inhibition of P-glycoprotein at the blood-brain barrier: A criterion of choice?

Breuil L, Marie S, Goutal S, Auvity S, ... Caillé F, Tournier N
Only partial deficiency/inhibition of P-glycoprotein (P-gp, ABCB1) function at the blood-brain barrier (BBB) is likely to occur in pathophysiological situations or drug-drug interactions. This raises questions regarding the sensitivity of available PET imaging probes to detect moderate changes in P-gp function at the living BBB. In vitro, the half-maximum inhibitory concentration (IC50) of the potent P-gp inhibitor tariquidar in P-gp-overexpressing cells was significantly different using either [11C]verapamil (44 nM), [11C]N-desmethyl-loperamide (19 nM) or [11C]metoclopramide (4 nM) as substrate probes. In vivo PET imaging in rats showed that the half-maximum inhibition of P-gp-mediated efflux of [11C]metoclopramide, achieved using 1 mg/kg tariquidar (in vivo IC50 = 82 nM in plasma), increased brain exposure by 2.1-fold for [11C]metoclopramide (p < 0.05, n = 4) and 2.4-fold for [11C]verapamil (p < 0.05, n = 4), whereby cerebral uptake of the \"avid\" substrate [11C]N-desmethyl-loperamide was unaffected (p > 0.05, n = 4). This comparative study points to differences in the \"vulnerability\" to P-gp inhibition among radiolabeled substrates, which were apparently unrelated to their \"avidity\" (maximal response to P-gp inhibition). Herein, we advocate that partial inhibition of transporter function, in addition to complete inhibition, should be a primary criterion of evaluation regarding the sensitivity of radiolabeled substrates to detect moderate but physiologically-relevant changes in transporter function in vivo.



J Cereb Blood Flow Metab: 08 Sep 2021:271678X211045444; epub ahead of print
Breuil L, Marie S, Goutal S, Auvity S, ... Caillé F, Tournier N
J Cereb Blood Flow Metab: 08 Sep 2021:271678X211045444; epub ahead of print | PMID: 34496661
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Abstract

Single-cell RNA-seq reveals the transcriptional landscape in ischemic stroke.

Zheng K, Lin L, Jiang W, Chen L, ... Ren Y, Hao J
Ischemic stroke (IS) is a detrimental neurological disease with limited treatments options. It has been challenging to define the roles of brain cell subsets in IS onset and progression due to cellular heterogeneity in the CNS. Here, we employed single-cell RNA sequencing (scRNA-seq) to comprehensively map the cell populations in the mouse model of MCAO (middle cerebral artery occlusion). We identified 17 principal brain clusters with cell-type specific gene expression patterns as well as specific cell subpopulations and their functions in various pathways. The CNS inflammation triggered upregulation of key cell type-specific genes unpublished before. Notably, microglia displayed a cell differentiation diversity after stroke among its five distinct subtypes. Importantly, we found the potential trajectory branches of the monocytes/macrophage\'s subsets. Finally, we also identified distinct subclusters among brain vasculature cells, ependymal cells and other glia cells. Overall, scRNA-seq revealed the precise transcriptional changes during neuroinflammation at the single-cell level, opening up a new field for exploration of the disease mechanisms and drug discovery in stroke based on the cell-subtype specific molecules.



J Cereb Blood Flow Metab: 08 Sep 2021:271678X211026770; epub ahead of print
Zheng K, Lin L, Jiang W, Chen L, ... Ren Y, Hao J
J Cereb Blood Flow Metab: 08 Sep 2021:271678X211026770; epub ahead of print | PMID: 34496660
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Abstract

Focally administered succinate improves cerebral metabolism in traumatic brain injury patients with mitochondrial dysfunction.

Khellaf A, Garcia NM, Tajsic T, Alam A, ... Thelin EP, Helmy A
Following traumatic brain injury (TBI), raised cerebral lactate/pyruvate ratio (LPR) reflects impaired energy metabolism. Raised LPR correlates with poor outcome and mortality following TBI. We prospectively recruited patients with TBI requiring neurocritical care and multimodal monitoring, and utilised a tiered management protocol targeting LPR. We identified patients with persistent raised LPR despite adequate cerebral glucose and oxygen provision, which we clinically classified as cerebral \'mitochondrial dysfunction\' (MD). In patients with TBI and MD, we administered disodium 2,3-13C2 succinate (12 mmol/L) by retrodialysis into the monitored region of the brain. We recovered 13C-labelled metabolites by microdialysis and utilised nuclear magnetic resonance spectroscopy (NMR) for identification and quantification.Of 33 patients with complete monitoring, 73% had MD at some point during monitoring. In 5 patients with multimodality-defined MD, succinate administration resulted in reduced LPR(-12%) and raised brain glucose(+17%). NMR of microdialysates demonstrated that the exogenous 13C-labelled succinate was metabolised intracellularly via the tricarboxylic acid cycle. By targeting LPR using a tiered clinical algorithm incorporating intracranial pressure, brain tissue oxygenation and microdialysis parameters, we identified MD in TBI patients requiring neurointensive care. In these, focal succinate administration improved energy metabolism, evidenced by reduction in LPR. Succinate merits further investigation for TBI therapy.



J Cereb Blood Flow Metab: 07 Sep 2021:271678X211042112; epub ahead of print
Khellaf A, Garcia NM, Tajsic T, Alam A, ... Thelin EP, Helmy A
J Cereb Blood Flow Metab: 07 Sep 2021:271678X211042112; epub ahead of print | PMID: 34494481
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Abstract

Arachnoid membrane as a source of sphingosine-1-phosphate that regulates mouse middle cerebral artery tone.

Jiménez-Altayó F, Marzi J, Galan M, Dantas AP, ... Jiménez-Xarrié E, Planas AM
Growing evidence indicates that perivascular tissue is critical to modulate vessel function. We hypothesized that the arachnoid membrane surrounding middle cerebral artery (MCA) regulates its function via sphingosine-1-phosphate (S1P)-induced vasoconstriction. The MCA from 3- to 9-month-old male and female wild-type (Oncine France 1 and C57BL/6) mice and sphingosine kinase 2 knockout (SphK2-/-) mice in the C57BL/6 background was mounted in pressure myographs with and without arachnoid membrane. Raman microspectroscopy and imaging were used for in situ detection of S1P. The presence of arachnoid tissue was associated with reduced external and lumen MCA diameters, and with an increase in basal tone regardless of sex and strain background. Strong S1P-positive signals were detected in the arachnoid surrounding the MCA wall in both mice models, as well as in a human post-mortem specimen. Selective S1P receptor 3 antagonist TY 52156 markedly reduced both MCA vasoconstriction induced by exogenous S1P and arachnoid-dependent basal tone increase. Compared to 3-month-old mice, the arachnoid-mediated contractile influence persisted in 9-month-old mice despite a decline in arachnoid S1P deposits. Genetic deletion of SphK2 decreased arachnoid S1P content and vasoconstriction. This is the first experimental evidence that arachnoid membrane regulates the MCA tone mediated by S1P.



J Cereb Blood Flow Metab: 01 Sep 2021:271678X211033362; epub ahead of print
Jiménez-Altayó F, Marzi J, Galan M, Dantas AP, ... Jiménez-Xarrié E, Planas AM
J Cereb Blood Flow Metab: 01 Sep 2021:271678X211033362; epub ahead of print | PMID: 34474613
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Abstract

Achieving brain clearance and preventing neurodegenerative diseases-A glymphatic perspective.

Kylkilahti TM, Berends E, Ramos M, Shanbhag NC, ... Markenroth Bloch K, Lundgaard I
Age-related neurodegenerative diseases are a growing burden to society, and many are sporadic, meaning that the environment, diet and lifestyle play significant roles. Cerebrospinal fluid (CSF)-mediated clearing of brain waste products via perivascular pathways, named the glymphatic system, is receiving increasing interest, as it offers unexplored perspectives on understanding neurodegenerative diseases. The glymphatic system is involved in clearance of metabolic by-products such as amyloid-β from the brain, and its function is believed to lower the risk of developing some of the most common neurodegenerative diseases. Here, we present magnetic resonance imaging (MRI) data on the heart cycle\'s control of CSF flow in humans which corroborates findings from animal studies. We also review the importance of sleep, diet, vascular health for glymphatic clearance and find that these factors are also known players in brain longevity.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2137-2149
Kylkilahti TM, Berends E, Ramos M, Shanbhag NC, ... Markenroth Bloch K, Lundgaard I
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2137-2149 | PMID: 33461408
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Abstract

Cerebral blood flow measurements with O-water PET using a non-invasive machine-learning-derived arterial input function.

Kuttner S, Wickstrøm KK, Lubberink M, Tolf A, ... Appel L, Axelsson J
Cerebral blood flow (CBF) can be measured with dynamic positron emission tomography (PET) of 15O-labeled water by using tracer kinetic modelling. However, for quantification of regional CBF, an arterial input function (AIF), obtained from arterial blood sampling, is required. In this work we evaluated a novel, non-invasive approach for input function prediction based on machine learning (MLIF), against AIF for CBF PET measurements in human subjects.Twenty-five subjects underwent two 10 min dynamic 15O-water brain PET scans with continuous arterial blood sampling, before (baseline) and following acetazolamide medication. Three different image-derived time-activity curves were automatically segmented from the carotid arteries and used as input into a Gaussian process-based AIF prediction model, considering both baseline and acetazolamide scans as training data. The MLIF approach was evaluated by comparing AIF and MLIF curves, as well as whole-brain grey matter CBF values estimated by kinetic modelling derived with either AIF or MLIF.The results showed that AIF and MLIF curves were similar and that corresponding CBF values were highly correlated and successfully differentiated before and after acetazolamide medication. In conclusion, our non-invasive MLIF method shows potential to replace the AIF obtained from blood sampling for CBF measurements using 15O-water PET and kinetic modelling.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2229-2241
Kuttner S, Wickstrøm KK, Lubberink M, Tolf A, ... Appel L, Axelsson J
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2229-2241 | PMID: 33557691
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Abstract

Effects of mild hypoxia on oxygen extraction fraction responses to brain stimulation.

Yin Y, Shu S, Qin L, Shan Y, Gao JH, Lu J
Characterizing the effect of limited oxygen availability on brain metabolism during brain activation is an essential step towards a better understanding of brain homeostasis and has obvious clinical implications. However, how the cerebral oxygen extraction fraction (OEF) depends on oxygen availability during brain activation remains unclear, which is mostly attributable to the scarcity and safety of measurement techniques. Recently, a magnetic resonance imaging (MRI) method that enables noninvasive and dynamic measurement of the OEF has been developed and confirmed to be applicable to functional MRI studies. Using this novel method, the present study investigated the motor-evoked OEF response in both normoxia (21% O2) and hypoxia (12% O2). Our results showed that OEF activation decreased in the brain areas involved in motor task execution. Decreases in the motor-evoked OEF response were greater under hypoxia (-21.7% ± 5.5%) than under normoxia (-11.8% ± 3.7%) and showed a substantial decrease as a function of arterial oxygen saturation. These findings suggest a different relationship between oxygen delivery and consumption during hypoxia compared to normoxia. This methodology may provide a new perspective on the effects of mild hypoxia on brain function.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2216-2228
Yin Y, Shu S, Qin L, Shan Y, Gao JH, Lu J
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2216-2228 | PMID: 33563081
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Abstract

Flow induces barrier and glycocalyx-related genes and negative surface charge in a lab-on-a-chip human blood-brain barrier model.

Santa-Maria AR, Walter FR, Figueiredo R, Kincses A, ... Dér A, Deli MA
Microfluidic lab-on-a-chip (LOC) devices allow the study of blood-brain barrier (BBB) properties in dynamic conditions. We studied a BBB model, consisting of human endothelial cells derived from hematopoietic stem cells in co-culture with brain pericytes, in an LOC device to study fluid flow in the regulation of endothelial, BBB and glycocalyx-related genes and surface charge. The highly negatively charged endothelial surface glycocalyx functions as mechano-sensor detecting shear forces generated by blood flow on the luminal side of brain endothelial cells and contributes to the physical barrier of the BBB. Despite the importance of glycocalyx in the regulation of BBB permeability in physiological conditions and in diseases, the underlying mechanisms remained unclear. The MACE-seq gene expression profiling analysis showed differentially expressed endothelial, BBB and glycocalyx core protein genes after fluid flow, as well as enriched pathways for the extracellular matrix molecules. We observed increased barrier properties, a higher intensity glycocalyx staining and a more negative surface charge of human brain-like endothelial cells (BLECs) in dynamic conditions. Our work is the first study to provide data on BBB properties and glycocalyx of BLECs in an LOC device under dynamic conditions and confirms the importance of fluid flow for BBB culture models.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2201-2215
Santa-Maria AR, Walter FR, Figueiredo R, Kincses A, ... Dér A, Deli MA
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2201-2215 | PMID: 33563079
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Abstract

ErbB3 is a critical regulator of cytoskeletal dynamics in brain microvascular endothelial cells: Implications for vascular remodeling and blood brain barrier modulation.

Wu L, Islam MR, Lee J, Takase H, ... Ramirez SH, Lok J
Neuregulin (NRG)1 - ErbB receptor signaling has been shown to play an important role in the biological function of peripheral microvascular endothelial cells. However, little is known about how NRG1/ErbB signaling impacts brain endothelial function and blood-brain barrier (BBB) properties. NRG1/ErbB pathways are affected by brain injury; when brain trauma was induced in mice in a controlled cortical impact model, endothelial ErbB3 gene expression was reduced to a greater extent than that of other NRG1 receptors. This finding suggests that ErbB3-mediated processes may be significantly compromised after injury, and that an understanding of ErbB3 function would be important in the of study of endothelial biology in the healthy and injured brain. Towards this goal, cultured brain microvascular endothelial cells were transfected with siRNA to ErbB3, resulting in alterations in F-actin organization and microtubule assembly, cell morphology, migration and angiogenic processes. Importantly, a significant increase in barrier permeability was observed when ErbB3 was downregulated, suggesting ErbB3 involvement in BBB regulation. Overall, these results indicate that neuregulin-1/ErbB3 signaling is intricately connected with the cytoskeletal processes of the brain endothelium and contributes to morphological and angiogenic changes as well as to BBB integrity.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2242-2255
Wu L, Islam MR, Lee J, Takase H, ... Ramirez SH, Lok J
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2242-2255 | PMID: 33583260
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Abstract

Optical coherence tomography of arteriolar diameter and capillary perfusion during spreading depolarizations.

Anzabi M, Li B, Wang H, Kura S, ... Østergaard L, Ayata C
Spreading depolarization (SD) is associated with profound oligemia and reduced oxygen availability in the mouse cortex during the depolarization phase. Coincident pial arteriolar constriction has been implicated as the primary mechanism for the oligemia. However, where in the vascular bed the hemodynamic response starts has been unclear. To resolve the origin of the hemodynamic response, we used optical coherence tomography (OCT) to simultaneously monitor changes in the vascular tree from capillary bed to pial arteries in mice during two consecutive SDs 15 minutes apart. We found that capillary flow dropped several seconds before pial arteriolar constriction. Moreover, penetrating arterioles constricted before pial arteries suggesting upstream propagation of constriction. Smaller caliber distal pial arteries constricted stronger than larger caliber proximal arterioles, suggesting that the farther the constriction propagates, the weaker it gets. Altogether, our data indicate that the hemodynamic response to cortical SD originates in the capillary bed.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2256-2263
Anzabi M, Li B, Wang H, Kura S, ... Østergaard L, Ayata C
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2256-2263 | PMID: 33593116
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Abstract

Change and predictive ability of circulating immunoregulatory lymphocytes in long-term outcomes of acute ischemic stroke.

Li S, Huang Y, Liu Y, Rocha M, ... Zhao J, Gao Y
Lymphocytes play an important role in the immune response after stroke. However, our knowledge of the circulating lymphocytes in ischemic stroke is limited. Herein, we collected the blood samples of clinical ischemic stroke patients to detect the change of lymphocytes from admission to 3 months after ischemic stroke by flow cytometry. A total of 87 healthy controls and 210 patients were enrolled, and the percentages of circulating T cells, CD4+ T cells, CD8+ T cells, double negative T cells (DNTs), CD4+ regulatory T cells (Tregs), CD8+ Tregs, B cells and regulatory B cells (Bregs) were measured. Among patients, B cells, Bregs and CD8+ Tregs increased significantly, while CD4+ Tregs dropped and soon reversed after ischemic stroke. CD4+ Tregs, CD8+ Tregs, and DNTs also showed high correlations with the infarct volume and neurological scores of patients. Moreover, these lymphocytes enhanced the predictive ability of long-term prognosis of neurological scores when added to basic clinical information. The percentage of CD4+ Tregs within lymphocytes showed high correlations with both acute and long-term neurological outcomes, which exhibited a great independent predictive ability. These findings suggest that CD4+ Tregs can be a biomarker to predict stroke outcomes and improve existing therapeutic strategies of immunoregulatory lymphocytes.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2280-2294
Li S, Huang Y, Liu Y, Rocha M, ... Zhao J, Gao Y
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2280-2294 | PMID: 33641517
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Abstract

Reduction of neuroinflammation alleviated mouse post bone fracture and stroke memory dysfunction.

Huo K, Wei M, Zhang M, Wang Z, ... Wong J, Su H
Tibia fracture (BF) enhances stroke injury and post-stroke memory dysfunction in mouse. Reduction of neuroinflammation by activation of α-7 nicotinic acetylcholine receptor (α-7 nAchR) reduced acute neuronal injury and sensorimotor dysfunction in mice with BF 1-day after stroke. We hypothesize that reduction of neuroinflammation by activation of α-7 nAchR improves long-term memory function of mice with BF 6-h before stroke. The mice were randomly assigned to saline, PHA-568487 (α-7 nAchR agonist) and methyllycaconitine (antagonist) treatment groups. The sensorimotor function was tested by adhesive removal and corner tests at 3 days, the memory function was tested by Y-maze test weekly for 8 weeks and novel objective recognition test at 8 weeks post-injuries. We found PHA-568487 treatment reduced, methyllycaconitine increased the number of CD68+ cells in the peri-infarct and hippocampal regions, neuronal injury in the infarct region, sensorimotor and long-term memory dysfunctions. PHA-568487 treatment also reduced, while methyllycaconitine treatment increased atrophy of hippocampal granule cell layer and white matter damage in the striatum. In addition, PHA-568487 treatment increased neuron proliferation in granule cell layer. Our data indicated that reduction of neuroinflammation through activation of α-7 nAchR decreased neuronal damage, sensorimotor and long-term memory dysfunction of mice with BF shortly before stroke.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2162-2173
Huo K, Wei M, Zhang M, Wang Z, ... Wong J, Su H
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2162-2173 | PMID: 33641516
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Abstract

Glymphatic pathways in the gyrencephalic brain.

Bèchet NB, Shanbhag NC, Lundgaard I
Identification of the perivascular compartment as the point of exchange between cerebrospinal fluid (CSF) and interstitial fluid mediating solute clearance in the brain, named the glymphatic system, has emerged as an important clearance pathway for neurotoxic peptides such as amyloid-beta. However, the foundational science of the glymphatic system is based on rodent studies. Here we investigated whether the glymphatic system exists in a large mammal with a highly gyrified brain. CSF penetration into the brain via perivascular pathways, a hallmark of glymphatic function, was seen throughout the gyrencephalic cortex and subcortical structures, validating the conservation of the glymphatic system in a large mammal. Macroscopic CSF tracer distribution followed the sulci and fissures showing that these folds enhance CSF dispersion. Three-dimensional renditions from light sheet microscopy showed a PVS influx density 4-fold larger in the pig brain than in mice. This demonstrates the existence of an advanced solute transport system in the gyrencephalic brain that could be utilised therapeutically for enhancing waste clearance.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2264-2279
Bèchet NB, Shanbhag NC, Lundgaard I
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2264-2279 | PMID: 33641515
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Abstract

Brain energy metabolism in intracerebroventricularly administered streptozotocin mouse model of Alzheimer\'s disease: A H-[C]-NMR study.

Soni ND, Ramesh A, Roy D, Patel AB
Alzheimer\'s disease (AD) is a very common neurodegenerative disorder. Although a majority of the AD cases are sporadic, most of the studies are conducted using transgenic models. Intracerebroventricular (ICV) administered streptozotocin (STZ) animals have been used to explore mechanisms in sporadic AD. In this study, we have investigated memory and neurometabolism of ICV-STZ-administered C57BL6/J mice. The neuronal and astroglial metabolic activity was measured in 1H-[13C]-NMR spectrum of cortical and hippocampal tissue extracts of mice infused with [1,6-13C2]glucose and [2-13C]acetate, respectively. STZ-administered mice exhibited reduced (p = 0.00002) recognition index for memory. The levels of creatine, GABA, glutamate and NAA were reduced (p ≤ 0.04), while that of myo-inositol was increased (p < 0.05) in STZ-treated mice. There was a significant (p ≤ 0.014) reduction in aspartate-C3, glutamate-C4/C3, GABA-C2 and glutamine-C4 labeling from [1,6-13C2]glucose. This resulted in decreased rate of glucose oxidation in the cerebral cortex (0.64 ± 0.05 vs. 0.77 ± 0.05 µmol/g/min, p = 0.0008) and hippocampus (0.60 ± 0.04 vs. 0.73 ± 0.07 µmol/g/min, p = 0.001) of STZ-treated mice, due to similar reductions of glucose oxidation in glutamatergic and GABAergic neurons. Additionally, reduced glutamine-C4 labeling points towards compromised synaptic neurotransmission in STZ-treated mice. These data suggest that the ICV-STZ model exhibits neurometabolic deficits typically observed in AD, and its utility in understanding the mechanism of sporadic AD.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2344-2355
Soni ND, Ramesh A, Roy D, Patel AB
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2344-2355 | PMID: 33657898
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Abstract

Activation of astroglial CB1R mediates cerebral ischemic tolerance induced by electroacupuncture.

Yang C, Liu J, Wang J, Yin A, ... Wang F, Xiong L
There are no effective treatments for stroke. The activation of endogenous protective mechanisms is a promising therapeutic approach, which evokes the intrinsic ability of the brain to protect itself. Accumulated evidence strongly suggests that electroacupuncture (EA) pretreatment induces rapid tolerance to cerebral ischemia. With regard to mechanisms underlying ischemic tolerance induced by EA, many molecules and signaling pathways are involved, such as the endocannabinoid system, although the exact mechanisms have not been fully elucidated. In the current study, we employed mutant mice, neuropharmacology, microdialysis, and virus transfection techniques in a middle cerebral artery occlusion (MCAO) model to explore the cell-specific and brain region-specific mechanisms of EA-induced neuroprotection. EA pretreatment resulted in increased ambient endocannabinoid (eCB) levels and subsequent activation of ischemic penumbral astroglial cannabinoid type 1 receptors (CB1R) which led to moderate upregulation of extracellular glutamate that protected neurons from cerebral ischemic injury. These findings provide a novel cellular mechanism of EA and a potential therapeutic target for ischemic stroke.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2295-2310
Yang C, Liu J, Wang J, Yin A, ... Wang F, Xiong L
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2295-2310 | PMID: 33663269
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Abstract

Targeting neutrophils as a novel therapeutic strategy after stroke.

Chen C, Huang T, Zhai X, Ma Y, ... Yin J, Li P
Stroke is followed by an intricate immune interaction involving the engagement of multiple immune cells, including neutrophils. As one of the first responders recruited to the brain, the crucial roles of neutrophils in the ischemic brain damage are receiving increasing attention in recent years. Notably, neutrophils are not homogenous, and yet there is still a lack of full knowledge about the extent and impact of neutrophil heterogeneity. The biological understanding of the neutrophil response to both innate and pathological conditions is rapidly evolving as single-cell-RNA sequencing uncovers overall neutrophil profiling across maturation and differentiation contexts. In this review, we scrutinize the latest research that points to the multifaceted role of neutrophils in different conditions and summarize the regulatory signals that may determine neutrophil diversity. In addition, we list several potential targets or therapeutic strategies targeting neutrophils to limit brain damage following ischemic stroke.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2150-2161
Chen C, Huang T, Zhai X, Ma Y, ... Yin J, Li P
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2150-2161 | PMID: 33691513
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Abstract

Crossed cerebellar diaschisis on F-FDG PET: Frequency across neurodegenerative syndromes and association with C-PIB and F-Flortaucipir.

Provost K, La Joie R, Strom A, Iaccarino L, ... Jagust WJ, Rabinovici GD
We used 18F-FDG-PET to investigate the frequency of crossed cerebellar diaschisis (CCD) in 197 patients with various syndromes associated with neurodegenerative diseases. In a subset of 117 patients, we studied relationships between CCD and cortical asymmetry of Alzheimer\'s pathology (β-amyloid (11C-PIB) and tau (18F-Flortaucipir)). PET images were processed using MRIs to derive parametric SUVR images and define regions of interest. Indices of asymmetry were calculated in the cerebral cortex, basal ganglia and cerebellar cortex. Across all patients, cerebellar 18F-FDG asymmetry was associated with reverse asymmetry of 18F-FDG in the cerebral cortex (especially frontal and parietal areas) and basal ganglia. Based on our operational definition (cerebellar asymmetry >3% with contralateral supratentorial hypometabolism), significant CCD was present in 47/197 (24%) patients and was most frequent in corticobasal syndrome and semantic and logopenic variants of primary progressive aphasia. In β-amyloid-positive patients, mediation analyses showed that 18F-Flortaucipir cortical asymmetry was associated with cerebellar 18F-FDG asymmetry, but that cortical 18F-FDG asymmetry mediated this relationship. Analysis of 18F-FDG-SUVR values suggested that CCD might also occur in the absence of frank cerebellar 18F-FDG asymmetry due to symmetrical supratentorial degeneration resulting in a bilateral diaschisis process.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2329-2343
Provost K, La Joie R, Strom A, Iaccarino L, ... Jagust WJ, Rabinovici GD
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2329-2343 | PMID: 33691512
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Abstract

Transcriptome analysis reveals sexual disparities in gene expression in rat brain microvessels.

Chandra PK, Cikic S, Baddoo MC, Rutkai I, ... Katakam PV, Busija DW
Sex is an important determinant of brain microvessels (MVs) function and susceptibility to cerebrovascular and neurological diseases, but underlying mechanisms are unclear. Using high throughput RNA sequencing analysis, we examined differentially expressed (DE) genes in brain MVs from young, male, and female rats. Bioinformatics analysis of the 23,786 identified genes indicates that 298 (1.2%) genes were DE using False Discovery Rate criteria (FDR; p < 0.05), of which 119 (40%) and 179 (60%) genes were abundantly expressed in male and female MVs, respectively. Nucleic acid binding, enzyme modulator, and transcription factor were the top three DE genes, which were more highly expressed in male than female MVs. Synthesis of glycosylphosphatidylinositol (GPI), biosynthesis of GPI-anchored proteins, steroid and cholesterol synthesis, were the top three significantly enriched canonical pathways in male MVs. In contrast, respiratory chain, ribosome, and 3 ́-UTR-mediated translational regulation were the top three enriched canonical pathways in female MVs. Different gene functions of MVs were validated by proteomic analysis and western blotting. Our novel findings reveal major sex disparities in gene expression and canonical pathways of MVs and these differences provide a foundation to study the underlying mechanisms and consequences of sex-dependent differences in cerebrovascular and other neurological diseases.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2311-2328
Chandra PK, Cikic S, Baddoo MC, Rutkai I, ... Katakam PV, Busija DW
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2311-2328 | PMID: 33715494
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Abstract

Telmisartan prevents high-fat diet-induced neurovascular impairments and reduces anxiety-like behavior.

Huber G, Ogrodnik M, Wenzel J, Stölting I, ... Jurk D, Raasch W
Angiotensin II receptor blockers (telmisartan) prevent rodents from diet-induced obesity and improve their metabolic status. Hyperglycemia and obesity are associated with reduced cerebral blood flow and neurovascular uncoupling which may lead to behavioral deficits. We wanted to know whether a treatment with telmisartan prevents these changes in obesity.We put young mice on high-fat diet and simultaneously treated them with telmisartan. At the end of treatment, we performed laser speckle imaging and magnetic resonance imaging to assess the effect on neurovascular coupling and cerebral blood flow. Different behavioral tests were used to investigate cognitive function.Mice developed diet-induced obesity and after 16, not 8 weeks of high-fat diet, however, the response to whisker pad stimulation was about 30% lower in obese compared to lean mice. Simultaneous telmisartan treatment increased the response again by 10% compared to obese mice. Moreover, telmisartan treatment normalized high-fat diet-induced reduction of cerebral blood flow and prevented a diet-induced anxiety-like behavior. In addition to that, telmisartan affects cellular senescence and string vessel formation in obesity.We conclude, that telmisartan protects against neurovascular unit impairments in a diet-induced obesity setting and may play a role in preventing obesity related cognitive deficits in Alzheimer\'s disease.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2356-2369
Huber G, Ogrodnik M, Wenzel J, Stölting I, ... Jurk D, Raasch W
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2356-2369 | PMID: 33730932
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Abstract

Global proteomic analysis of extracellular matrix in mouse and human brain highlights relevance to cerebrovascular disease.

Pokhilko A, Brezzo G, Handunnetthi L, Heilig R, ... Horsburgh K, Cader MZ
The extracellular matrix (ECM) is a key interface between the cerebrovasculature and adjacent brain tissues. Deregulation of the ECM contributes to a broad range of neurological disorders. However, despite this importance, our understanding of the ECM composition remains very limited mainly due to difficulties in its isolation. To address this, we developed an approach to extract the cerebrovascular ECM from mouse and human post-mortem normal brain tissues. We then used mass spectrometry with off-line high-pH reversed-phase fractionation to increase the protein detection. This identified more than 1000 proteins in the ECM-enriched fraction, with > 66% of the proteins being common between the species. We report 147 core ECM proteins of the human brain vascular matrisome, including collagens, laminins, fibronectin and nidogens. We next used network analysis to identify the connection between the brain ECM proteins and cerebrovascular diseases. We found that genes related to cerebrovascular diseases, such as COL4A1, COL4A2, VCAN and APOE were significantly enriched in the cerebrovascular ECM network. This provides unique mechanistic insight into cerebrovascular disease and potential drug targets. Overall, we provide a powerful resource to study the functions of brain ECM and highlight a specific role for brain vascular ECM in cerebral vascular disease.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2423-2438
Pokhilko A, Brezzo G, Handunnetthi L, Heilig R, ... Horsburgh K, Cader MZ
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2423-2438 | PMID: 33730931
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Abstract

PET imaging of colony-stimulating factor 1 receptor: A head-to-head comparison of a novel radioligand, C-GW2580, and C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey.

Zhou X, Ji B, Seki C, Nagai Y, ... Kimura Y, Higuchi M
Colony-stimulating factor 1 receptor (CSF1R) is a specific biomarker for microglia. In this study, we developed a novel PET radioligand for CSF1R, 11C-GW2580, and compared it to a reported CSF1R tracer, 11C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey. Dynamic 11C-GW2580- and 11C-CPPC-PET images were quantified by reference tissue-based models and standardized uptake value ratio. Both tracers exhibited increased uptake in the lesioned striata of lipopolysaccharide-injected mice and in the forebrains of AppNL-G-F/NL-G-F-knock-in mice, spatially in agreement with an increased 18-kDa translocator protein radioligand retention. Moreover, 11C-GW2580 captured changes in CSF1R availability more sensitively than 11C-CPPC, with a larger dynamic range and a smaller inter-individual variability, in these model animals. PET imaging of CSF1R in a rhesus monkey displayed moderate-to-high tracer retention in the brain at baseline. Homologous blocker (i. e. unlabeled tracer) treatment reduced the uptake of 11C-GW2580 by ∼30% in all examined brain regions except for centrum semi-ovale white matter, but did not affect the retention of 11C-CPPC. In summary, our results demonstrated that 11C-GW2580-PET captured inflammatory microgliosis in the mouse brain with higher sensitivity than a reported radioligand, and displayed saturable binding in the monkey brain, potentially providing an imaging-based quantitative biomarker for reactive microgliosis.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2410-2422
Zhou X, Ji B, Seki C, Nagai Y, ... Kimura Y, Higuchi M
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2410-2422 | PMID: 33757319
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Abstract

Comparison of [C]UCB-J and [F]FDG PET in Alzheimer\'s disease: A tracer kinetic modeling study.

Chen MK, Mecca AP, Naganawa M, Gallezot JD, ... van Dyck CH, Carson RE
[11C]UCB-J PET for synaptic vesicle glycoprotein 2 A (SV2A) has been proposed as a suitable marker for synaptic density in Alzheimer\'s disease (AD). We compared [11C]UCB-J binding for synaptic density and [18F]FDG uptake for metabolism (correlated with neuronal activity) in 14 AD and 11 cognitively normal (CN) participants. We assessed both absolute and relative outcome measures in brain regions of interest, i.e., K1 or R1 for [11C]UCB-J perfusion, VT (volume of distribution) or DVR to cerebellum for [11C]UCB-J binding to SV2A; and Ki or KiR to cerebellum for [18F]FDG metabolism. [11C]UCB-J binding and [18F]FDG metabolism showed a similar magnitude of reduction in the medial temporal lobe of AD -compared to CN participants. However, the magnitude of reduction of [11C]UCB-J binding in neocortical regions was less than that observed with [18F]FDG metabolism. Inter-tracer correlations were also higher in the medial temporal regions between synaptic density and metabolism, with lower correlations in neocortical regions. [11C]UCB-J perfusion showed a similar pattern to [18F]FDG metabolism, with high inter-tracer regional correlations. In summary, we conducted the first in vivo PET imaging of synaptic density and metabolism in the same AD participants and reported a concordant reduction in medial temporal regions but a discordant reduction in neocortical regions.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2395-2409
Chen MK, Mecca AP, Naganawa M, Gallezot JD, ... van Dyck CH, Carson RE
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2395-2409 | PMID: 33757318
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Abstract

Deep white matter hyperintensity is associated with the dilation of perivascular space.

Huang P, Zhang R, Jiaerken Y, Wang S, ... Wu X, Zhang M
Understanding the pathophysiology of white matter hyperintensity (WMH) is necessary to reduce its harmfulness. Dilated perivascular space (PVS) had been found related to WMH. In the present study, we aimed to examine the topological connections between WMH and PVS, and to investigate whether increased interstitial fluid mediates the correlation between PVS and WMH volumes. One hundred and thirty-six healthy elder subjects were retrospectively included from a prospectively collected community cohort. Sub-millimeter T2 weighted and FLAIR images were acquired for assessing the association between PVS and WMH. Diffusion tensor imaging and free-water (FW) analytical methods were used to quantify white matter free water content, and to explore whether it mediates the PVS-WMH association. We found that most (89%) of the deep WMH lesions were spatially connected with PVS, exhibiting several interesting topological types. PVS and WMH volumes were also significantly correlated (r = 0.222, p < 0.001). FW mediated this association in the whole sample (β = 0.069, p = 0.037) and in subjects with relatively high WMH load (β = 0.118, p = 0.006). These findings suggest a tight association between PVS dilation and WMH formation, which might be linked by the impaired glymphatic drainage function and accumulated local interstitial fluid.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2370-2380
Huang P, Zhang R, Jiaerken Y, Wang S, ... Wu X, Zhang M
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2370-2380 | PMID: 33757317
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Abstract

Urokinase-type plasminogen activator promotes N-cadherin-mediated synaptic recovery in the ischemic brain.

Diaz A, Merino P, McCann P, Yepes MA, ... Tong FC, Yepes M
Urokinase-type plasminogen activator (uPA) is a serine proteinase that catalyzes the generation of plasmin on the cell surface and activates cell signaling pathways that promote remodeling and repair. Neuronal cadherin (NCAD) is a transmembrane protein that in the mature brain mediates the formation of synaptic contacts in the II/III and V cortical layers. Our studies show that uPA is preferentially found in the II/III and V cortical laminae of the gyrencephalic cortex of the non-human primate. Furthermore, we found that in murine cerebral cortical neurons and induced pluripotent stem cell (iPSC)-derived neurons prepared from healthy human donors, most of this uPA is associated with pre-synaptic vesicles. Our in vivo experiments revealed that in both, the gyrencephalic cortex of the non-human primate and the lissecephalic murine brain, cerebral ischemia decreases the number of intact synaptic contacts and the expression of uPA and NCAD in a band of tissue surrounding the necrotic core. Additionally, our in vitro data show that uPA induces the synthesis of NCAD in cerebral cortical neurons, and in line with these observations, intravenous treatment with recombinant uPA three hours after the onset of cerebral ischemia induces NCAD-mediated repair of synaptic contacts in the area surrounding the necrotic core.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2381-2394
Diaz A, Merino P, McCann P, Yepes MA, ... Tong FC, Yepes M
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2381-2394 | PMID: 33757316
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Abstract

Periinfarct rewiring supports recovery after primary motor cortex stroke.

van Assche M, Dirren E, Bourgeois A, Kleinschmidt A, Richiardi J, Carrera E
After stroke restricted to the primary motor cortex (M1), it is uncertain whether network reorganization associated with recovery involves the periinfarct or more remote regions. We studied 16 patients with focal M1 stroke and hand paresis. Motor function and resting-state MRI functional connectivity (FC) were assessed at three time points: acute (<10 days), early subacute (3 weeks), and late subacute (3 months). FC correlates of recovery were investigated at three spatial scales, (i) ipsilesional non-infarcted M1, (ii) core motor network (M1, premotor cortex (PMC), supplementary motor area (SMA), and primary somatosensory cortex), and (iii) extended motor network including all regions structurally connected to the upper limb representation of M1. Hand dexterity was impaired only in the acute phase (P = 0.036). At a small spatial scale, clinical recovery was more frequently associated with connections involving ipsilesional non-infarcted M1 (Odds Ratio = 6.29; P = 0.036). At a larger scale, recovery correlated with increased FC strength in the core network compared to the extended motor network (rho = 0.71;P = 0.006). These results suggest that FC changes associated with motor improvement involve the perilesional M1 and do not extend beyond the core motor network. Core motor regions, and more specifically ipsilesional non-infarcted M1, could hence become primary targets for restorative therapies.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2174-2184
van Assche M, Dirren E, Bourgeois A, Kleinschmidt A, Richiardi J, Carrera E
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2174-2184 | PMID: 33757315
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Abstract

More than motor impairment: A spatiotemporal analysis of cognitive impairment and associated neuropathological changes following cortical photothrombotic stroke.

Sanchez-Bezanilla S, Hood RJ, Collins-Praino LE, Turner RJ, ... Nilsson M, Ong LK
There is emerging evidence suggesting that a cortical stroke can cause delayed and remote hippocampal dysregulation, leading to cognitive impairment. In this study, we aimed to investigate motor and cognitive outcomes after experimental stroke, and their association with secondary neurodegenerative processes. Specifically, we used a photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Motor function was assessed using the cylinder and grid walk tasks. Changes in cognition were assessed using a mouse touchscreen platform. Neuronal loss, gliosis and amyloid-β accumulation were investigated in the peri-infarct and ipsilateral hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed persistent impairment in cognitive function post-stroke, whilst there was a modest spontaneous motor recovery over the investigated period of 84 days. In the peri-infarct region, we detected a reduction in neuronal loss and decreased neuroinflammation over time post-stroke, which potentially explains the spontaneous motor recovery. Conversely, we observed persistent neuronal loss together with concomitant increased neuroinflammation and amyloid-β accumulation in the hippocampus, which likely accounts for the persistent cognitive dysfunction. Our findings indicate that cortical stroke induces secondary neurodegenerative processes in the hippocampus, a region remote from the primary infarct, potentially contributing to the progression of post-stroke cognitive impairment.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2439-2455
Sanchez-Bezanilla S, Hood RJ, Collins-Praino LE, Turner RJ, ... Nilsson M, Ong LK
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2439-2455 | PMID: 33779358
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Abstract

Cerebral critical closing pressure and resistance-area product: the influence of dynamic cerebral autoregulation, age and sex.

Panerai RB, Haunton VJ, Llwyd O, Minhas JS, ... Maggio P, Robinson TG
Instantaneous arterial pressure-flow (or velocity) relationships indicate the existence of a cerebral critical closing pressure (CrCP), with the slope of the relationship expressed by the resistance-area product (RAP). In 194 healthy subjects (20-82 years, 90 female), cerebral blood flow velocity (CBFV, transcranial Doppler), arterial blood pressure (BP, Finapres) and end-tidal CO2 (EtCO2, capnography) were measured continuously for five minutes during spontaneous fluctuations of BP at rest. The dynamic cerebral autoregulation (CA) index (ARI) was extracted with transfer function analysis from the CBFV step response to the BP input and step responses were also obtained for the BP-CrCP and BP-RAP relationships. ARI was shown to decrease with age at a rate of -0.025 units/year in men (p = 0.022), but not in women (p = 0.40). The temporal patterns of the BP-CBFV, BP-CrCP and BP-RAP step responses were strongly influenced by the ARI (p < 0.0001), but not by sex. Age was also a significant determinant of the peak of the CBFV step response and the tail of the RAP response. Whilst the RAP step response pattern is consistent with a myogenic mechanism controlling dynamic CA, further work is needed to explore the potential association of the CrCP step response with the flow-mediated component of autoregulation.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2456-2469
Panerai RB, Haunton VJ, Llwyd O, Minhas JS, ... Maggio P, Robinson TG
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2456-2469 | PMID: 33818187
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Abstract

Three-dimensional ultrastructure of the brain pericyte-endothelial interface.

Ornelas S, Berthiaume AA, Bonney SK, Coelho-Santos V, ... Lippens S, Shih AY
Pericytes and endothelial cells share membranous interdigitations called \"peg-and-socket\" interactions that facilitate their adhesion and biochemical crosstalk during vascular homeostasis. However, the morphology and distribution of these ultrastructures have remained elusive. Using a combination of 3D electron microscopy techniques, we examined peg-and-socket interactions in mouse brain capillaries. We found that pegs extending from pericytes to endothelial cells were morphologically diverse, exhibiting claw-like morphologies at the edge of the cell and bouton-shaped swellings away from the edge. Reciprocal endothelial pegs projecting into pericytes were less abundant and appeared as larger columnar protuberances. A large-scale 3D EM data set revealed enrichment of both pericyte and endothelial pegs around pericyte somata. The ratio of pericyte versus endothelial pegs was conserved among the pericytes examined, but total peg abundance was heterogeneous across cells. These data show considerable investment between pericytes and endothelial cells, and provide morphological evidence for pericyte somata as sites of enriched physical and biochemical interaction.



J Cereb Blood Flow Metab: 30 Aug 2021; 41:2185-2200
Ornelas S, Berthiaume AA, Bonney SK, Coelho-Santos V, ... Lippens S, Shih AY
J Cereb Blood Flow Metab: 30 Aug 2021; 41:2185-2200 | PMID: 33970018
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