Subjects -> MEDICAL SCIENCES (Total: 8196 journals)
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    - UROLOGY, NEPHROLOGY AND ANDROLOGY (151 journals)

HEMATOLOGY (160 journals)                     

Showing 1 - 151 of 151 Journals sorted alphabetically
Acta Angiologica     Open Access   (Followers: 2)
Acta Haematologica     Full-text available via subscription   (Followers: 23)
Acta Haematologica Polonica     Open Access  
Adipocyte     Open Access  
Advances in Hematology     Open Access   (Followers: 13)
Africa Sanguine     Full-text available via subscription  
American Journal of Hematology     Hybrid Journal   (Followers: 52)
Anemia     Open Access   (Followers: 6)
Annals of Hematology     Hybrid Journal   (Followers: 14)
Archives of Hematology Case Reports and Reviews     Open Access  
Arteriosclerosis, Thrombosis and Vascular Biology     Full-text available via subscription   (Followers: 29)
Artery Research     Hybrid Journal   (Followers: 4)
Artificial Cells, Nanomedicine and Biotechnology     Hybrid Journal   (Followers: 3)
ASAIO Journal     Hybrid Journal   (Followers: 2)
Best Practice & Research Clinical Haematology     Hybrid Journal   (Followers: 5)
Blood     Hybrid Journal   (Followers: 284)
Blood Advances     Open Access   (Followers: 6)
Blood and Lymphatic Cancer : Targets and Therapy     Open Access   (Followers: 7)
Blood Cancer Journal     Open Access   (Followers: 18)
Blood Cells, Molecules, and Diseases     Hybrid Journal   (Followers: 8)
Blood Coagulation & Fibrinolysis     Hybrid Journal   (Followers: 61)
Blood Pressure     Hybrid Journal  
Blood Pressure Monitoring     Hybrid Journal   (Followers: 1)
Blood Purification     Full-text available via subscription   (Followers: 6)
Blood Reviews     Hybrid Journal   (Followers: 26)
BMC Hematology     Open Access   (Followers: 7)
BMJ Open Diabetes Research & Care     Open Access   (Followers: 29)
Bone Marrow Transplantation     Hybrid Journal   (Followers: 17)
British Journal of Diabetes & Vascular Disease     Open Access   (Followers: 21)
British Journal of Haematology     Hybrid Journal   (Followers: 60)
British Journal of Primary Care Nursing - Cardiovascular Disease, Diabetes and Kidney Care     Full-text available via subscription   (Followers: 10)
Canadian Journal of Diabetes     Hybrid Journal   (Followers: 28)
Case Reports in Hematology     Open Access   (Followers: 10)
Clinical and Applied Thrombosis/Hemostasis     Open Access   (Followers: 32)
Clinical Diabetes     Full-text available via subscription   (Followers: 40)
Clinical Diabetes and Endocrinology     Open Access   (Followers: 20)
Clinical Lymphoma & Myeloma     Full-text available via subscription   (Followers: 2)
Clinical Lymphoma Myeloma and Leukemia     Hybrid Journal   (Followers: 5)
Clinical Medicine Insights : Blood Disorders     Open Access   (Followers: 1)
Conquest : The Official Journal of Diabetes Australia     Full-text available via subscription   (Followers: 4)
Current Angiogenesis     Hybrid Journal  
Current Diabetes Reports     Hybrid Journal   (Followers: 24)
Current Diabetes Reviews     Hybrid Journal   (Followers: 27)
Current Hematologic Malignancy Reports     Hybrid Journal   (Followers: 2)
Current Opinion in Hematology     Hybrid Journal   (Followers: 19)
Cytotherapy     Full-text available via subscription   (Followers: 2)
Der Diabetologe     Hybrid Journal   (Followers: 2)
Diabetes     Full-text available via subscription   (Followers: 391)
Diabetes aktuell     Hybrid Journal   (Followers: 3)
Diabetes and Vascular Disease Research     Hybrid Journal   (Followers: 20)
Diabetes Care     Full-text available via subscription   (Followers: 450)
Diabetes Case Reports     Open Access   (Followers: 1)
Diabetes Educator     Hybrid Journal   (Followers: 27)
Diabetes Management     Full-text available via subscription   (Followers: 16)
Diabetes Research and Clinical Practice     Hybrid Journal   (Followers: 72)
Diabetes Spectrum     Full-text available via subscription   (Followers: 17)
Diabetes Technology & Therapeutics     Hybrid Journal   (Followers: 50)
Diabetes Therapy     Open Access   (Followers: 23)
Diabetic Foot & Ankle     Open Access   (Followers: 10)
Diabetic Medicine     Hybrid Journal   (Followers: 127)
Diabetologia     Hybrid Journal   (Followers: 190)
Diabetologia Kliniczna     Hybrid Journal  
Diabetologie und Stoffwechsel     Hybrid Journal   (Followers: 2)
Egyptian Journal of Haematology     Open Access  
eJHaem     Open Access  
European Journal of Haematology     Hybrid Journal   (Followers: 16)
Experimental Hematology     Hybrid Journal   (Followers: 6)
Experimental Hematology & Oncology     Open Access   (Followers: 6)
Expert Review of Hematology     Hybrid Journal   (Followers: 5)
Fluids and Barriers of the CNS     Open Access   (Followers: 1)
Global Journal of Transfusion Medicine     Open Access   (Followers: 1)
Haematologica - the Hematology journal     Open Access   (Followers: 33)
Haemophilia     Hybrid Journal   (Followers: 66)
Hematologia     Full-text available via subscription   (Followers: 3)
Hematología     Open Access  
Hematology     Open Access   (Followers: 15)
Hematology Reports     Open Access   (Followers: 4)
Hematology, Transfusion and Cell Therapy     Open Access   (Followers: 2)
Hematology/Oncology and Stem Cell Therapy     Open Access   (Followers: 6)
Hemodialysis International     Hybrid Journal   (Followers: 3)
Hepatitis Monthly     Open Access   (Followers: 3)
Immunohematology : Journal of Blood Group Serology and Molecular Genetics     Hybrid Journal   (Followers: 1)
Indian Journal of Hematology and Blood Transfusion     Hybrid Journal   (Followers: 2)
Info Diabetologie     Full-text available via subscription   (Followers: 1)
InFo Hämatologie + Onkologie : Interdisziplinäre Fortbildung von Ärzten für Ärzte     Full-text available via subscription  
Integrated Blood Pressure Control     Open Access  
International Blood Research & Reviews     Open Access  
International Journal of Clinical Transfusion Medicine     Open Access   (Followers: 3)
International Journal of Diabetes in Developing Countries     Hybrid Journal   (Followers: 6)
International Journal of Diabetes Research     Open Access   (Followers: 8)
International Journal of Hematologic Oncology     Open Access   (Followers: 2)
International Journal of Hematology     Hybrid Journal   (Followers: 4)
International Journal of Hematology Research     Open Access   (Followers: 2)
International Journal of Hematology-Oncology and Stem Cell Research     Open Access   (Followers: 2)
International Journal of Laboratory Hematology     Hybrid Journal   (Followers: 25)
Iraqi Journal of Hematology     Open Access  
JMIR Diabetes     Open Access  
Journal of Blood Disorders & Transfusion     Open Access   (Followers: 3)
Journal of Applied Hematology     Open Access   (Followers: 2)
Journal of Blood Medicine     Open Access   (Followers: 1)
Journal of Cerebral Blood Flow & Metabolism     Hybrid Journal   (Followers: 3)
Journal of Diabetes     Hybrid Journal   (Followers: 20)
Journal of Diabetes and its Complications     Hybrid Journal   (Followers: 26)
Journal of Diabetes and Metabolic Disorders     Open Access   (Followers: 8)
Journal of Diabetes Investigation     Open Access   (Followers: 12)
Journal of Diabetes Mellitus     Open Access   (Followers: 6)
Journal of Diabetes Research     Open Access   (Followers: 13)
Journal of Diabetes Research     Open Access   (Followers: 9)
Journal of Hematological Malignancies     Open Access  
Journal of Hematology     Open Access   (Followers: 2)
Journal of Hematology and Transfusion Medicine     Open Access   (Followers: 1)
Journal of Hematopathology     Hybrid Journal   (Followers: 3)
Journal of Hypo & Hyperglycemia     Partially Free  
Journal of Pediatric Hematology/Oncology     Hybrid Journal   (Followers: 8)
Journal of Social Health and Diabetes     Open Access   (Followers: 1)
Journal of Thrombosis and Haemostasis     Hybrid Journal   (Followers: 81)
Journal of Thrombosis and Thrombolysis     Hybrid Journal   (Followers: 35)
Journal of Transfusion Medicine     Full-text available via subscription  
Kidney and Blood Pressure Research     Open Access   (Followers: 4)
Leukemia     Hybrid Journal   (Followers: 22)
Leukemia and Lymphoma     Hybrid Journal   (Followers: 12)
Leukemia Research     Hybrid Journal   (Followers: 8)
Leukemia Research Reports     Open Access   (Followers: 1)
Leukemia Supplements     Full-text available via subscription  
Mediterranean Journal of Hematology and Infectious Diseases     Open Access  
Nederlands Tijdschrift voor Diabetologie     Hybrid Journal  
Nutrition & Diabetes     Open Access   (Followers: 20)
Oncohematology     Open Access   (Followers: 1)
Open Diabetes Journal     Open Access  
Open Hematology Journal     Open Access   (Followers: 1)
Open Hypertension Journal     Open Access  
Open Journal of Blood Diseases     Open Access  
Pediatric Blood & Cancer     Hybrid Journal   (Followers: 8)
Pediatric Hematology Oncology Journal     Open Access   (Followers: 3)
Peritoneal Dialysis International     Hybrid Journal  
Platelets     Hybrid Journal   (Followers: 3)
Practical Diabetes     Hybrid Journal   (Followers: 7)
Primary Care Diabetes     Hybrid Journal   (Followers: 27)
Research & Reviews : Journal of Oncology and Hematology     Full-text available via subscription   (Followers: 1)
Research and Practice in Thrombosis and Haemostasis     Open Access   (Followers: 1)
Revista Cubana de Hematología, Inmunología y Hemoterapia     Open Access  
Seminars in Hematology     Hybrid Journal   (Followers: 12)
Seminars in Thrombosis and Hemostasis     Hybrid Journal   (Followers: 47)
Thalassemia Reports     Open Access   (Followers: 1)
The Lancet Haematology     Full-text available via subscription   (Followers: 38)
Therapeutic Advances in Hematology     Hybrid Journal  
Thrombosis & Haemostasis     Hybrid Journal   (Followers: 124)
Thrombosis Research     Hybrid Journal   (Followers: 49)
Transfusionsmedizin - Immunhämatologie, Hämotherapie, Immungenetik, Zelltherapie     Hybrid Journal  
Transplantation and Cellular Therapy     Hybrid Journal   (Followers: 13)
Veins and Lymphatics     Open Access   (Followers: 1)

           

Similar Journals
Journal Cover
Journal of Cerebral Blood Flow & Metabolism
Journal Prestige (SJR): 2.558
Citation Impact (citeScore): 5
Number of Followers: 3  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0271-678X - ISSN (Online) 1559-7016
Published by Sage Publications Homepage  [1174 journals]
  • RNF213 loss of function reshapes vascular transcriptome and spliceosome
           leading to disrupted angiogenesis and aggravated vascular inflammatory
           responses

    • Free pre-print version: Loading...

      Authors: Liyin Zhang, Sherif Rashad, Yuan Zhou, Kuniyasu Niizuma, Teiji Tominaga
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      RNF213 gene mutations are the cause behind Moyamoya disease, a rare cerebrovascular occlusive disease. However, the function of RNF213 in the vascular system and the impact of its loss of function are not yet comprehended. To understand RNF23 function, we performed gene knockdown (KD) in vascular cells and performed various phenotypical analysis as well as extensive transcriptome and epitranscriptome profiling. Our data revealed that RNF213 KD led to disrupted angiogenesis in HUVEC, in part due to downregulation of DNA replication and proliferation pathways. Furthermore, HUVEC cells became sensitive to LPS induced inflammation after RNF213 KD, leading to retarded cell migration and enhanced macrophage transmigration. This was evident at the level of transcriptome as well. Interestingly, RNF213 led to extensive changes in mRNA splicing that were not previously reported. In vascular smooth muscle cells (vSMCs), RNF213 KD led to alteration in cytoskeletal organization, contractility, and vSMCs function related pathways. Finally, RNF213 KD disrupted endothelial-to-vSMCs communication in co-culture models. Overall, our results indicate that RNF213 KD sensitizes endothelial cells to inflammation, leading to altered angiogenesis. Our results shed the light on the important links between RNF213 mutations and inflammatory/immune inducers of MMD and on the unexplored role of epitranscriptome in MMD.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-06-25T07:08:18Z
      DOI: 10.1177/0271678X221110679
       
  • Diffusion-derived parameters in lesions, peri-lesion, and normal-appearing
           white matter in multiple sclerosis using tensor, kurtosis, and fixel-based
           analysis

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      Authors: Chris WJ van der Weijden, Anouk van der Hoorn, Jan Hendrik Potze, Remco J Renken, Ronald JH Borra, Rudi AJO Dierckx, Ingomar W Gutmann, Hakim Ouaalam, Davood Karimi, Ali Gholipour, Simon K Warfield, Erik FJ de Vries, Jan F Meilof
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      AbstractNeuronal damage is the primary cause of long-term disability of multiple sclerosis (MS) patients. Assessment of axonal integrity from diffusion MRI parameters might enable better disease characterisation. 16 diffusion derived measurements from diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and fixel-based analysis (FBA) in lesions, peri-lesion and normal appearing white matter were investigated. Diffusion MRI scans of 11 MS patients were processed to generate DTI, DKI, and FBA images. Fractional anisotropy (FA) and fibre density (FD) were used to assess axonal integrity across brain regions. Subsequently, 359 lesions were identified, and lesion and peri-lesion segmentation was performed using structural T1w, T2w, T2w-FLAIR, and T1w post-contrast MRI. The segmentations were then used to extract 16 diffusion MRI parameters from lesion, peri-lesion, and contralateral normal appearing white matter (NAWM). The measurements for axonal integrity, DTI-FA, DKI-FA, FBA-FD, produced similar results. All diffusion MRI parameters were affected in lesions as compared to NAWM (p 
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-06-25T07:04:57Z
      DOI: 10.1177/0271678X221107953
       
  • Pathological changes of brain oscillations following ischemic stroke

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      Authors: Yoshimichi Sato, Oliver Schmitt, Zachary Ip, Gratianne Rabiller, Shunsuke Omodaka, Teiji Tominaga, Azadeh Yazdan-Shahmorad, Jialing Liu
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Brain oscillations recorded in the extracellular space are among the most important aspects of neurophysiology data reflecting the activity and function of neurons in a population or a network. The signal strength and patterns of brain oscillations can be powerful biomarkers used for disease detection and prediction of the recovery of function. Electrophysiological signals can also serve as an index for many cutting-edge technologies aiming to interface between the nervous system and neuroprosthetic devices and to monitor the efficacy of boosting neural activity. In this review, we provided an overview of the basic knowledge regarding local field potential, electro- or magneto- encephalography signals, and their biological relevance, followed by a summary of the findings reported in various clinical and experimental stroke studies. We reviewed evidence of stroke-induced changes in hippocampal oscillations and disruption of communication between brain networks as potential mechanisms underlying post-stroke cognitive dysfunction. We also discussed the promise of brain stimulation in promoting post stroke functional recovery via restoring neural activity and enhancing brain plasticity.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-06-25T07:01:35Z
      DOI: 10.1177/0271678X221105677
       
  • Heterogeneity and developmental dynamics of LYVE-1 perivascular
           macrophages distribution in the mouse brain

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      Authors: Marie Karam, Hadrien Janbon, Guy Malkinson, Isabelle Brunet
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Brain perivascular macrophages (PVMs) are border-associated macrophages situated along blood vessels in the Virchow-Robin space and are thus found at a unique anatomical position between the endothelium and the parenchyma. Owing to their location and phagocytic capabilities, PVMs are regarded as important components that regulate various aspects of brain physiology in health and pathophysiological states. Here, we used LYVE-1 to identify PVMs in the mouse brain using brain-tissue sections and cleared whole-brains to learn about how they are distributed within the brain and across different developmental postnatal stages. We find that LYVE-1+ PVMs associate with the vasculature in different patterns and proportions depending on vessel diameter or arterio-venous differentiation. LYVE-1+ PVMs relate to blood vessels in a brain-region-dependent manner. We show that their postnatal distribution is developmentally dynamic and peaks at P10-P20 depending on the brain region. We further demonstrate that their density is reduced in the APP/PS1 mouse model of Alzheimer’s Disease proportionally to beta-amyloid deposits. In conclusion, our results reveal unexpected heterogeneity and dynamics of LYVE-1+ PVMs, with selective coverage of brain vasculature, compatible with potential unexplored roles for this population of PVMs in postnatal development, and in regulating brain functions in steady-state and disease conditions.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-06-25T05:17:08Z
      DOI: 10.1177/0271678X221101643
       
  • Redefining the Koizumi model of mouse cerebral ischemia: A comparative
           longitudinal study of cerebral and retinal ischemia in the Koizumi and
           Longa middle cerebral artery occlusion models

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      Authors: Helena Justić, Anja Barić, Iva Šimunić, Marin Radmilović, Rok Ister, Siniša Škokić, Marina Dobrivojević Radmilović
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Cerebral and retinal ischemia share similar pathogenesis and epidemiology, each carrying both acute and prolonged risk of the other and often co-occurring. The most used preclinical stroke models, the Koizumi and Longa middle cerebral artery occlusion (MCAO) methods, have reported retinal damage with great variability, leaving the disruption of retinal blood supply via MCAO poorly investigated, even providing conflicting assumptions on the origin of the ophthalmic artery in rodents. The aim of our study was to use longitudinal in vivo magnetic resonance assessment of cerebral and retinal vascular perfusion after the ischemic injury to clarify whether and how the Koizumi and Longa methods induce retinal ischemia and how they differ in terms of cerebral and retinal lesion evolution. We provided anatomical evidence of the origin of the ophthalmic artery in mice from the pterygopalatine artery. Following the Koizumi surgery, retinal responses to ischemia overlapped with those in the brain, resulting in permanent damage. In contrast, the Longa method produced only extensive cerebral lesions, with greater tissue loss than in the Koizumi method. Additionally, our data suggests the Koizumi method should be redefined as a model of ischemia with chronic hypoperfusion rather than of ischemia and reperfusion.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-06-24T07:01:38Z
      DOI: 10.1177/0271678X221109873
       
  • Quantitative kinetic modelling and mapping of cerebral glucose transport
           and metabolism using glucoCESL MRI

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      Authors: Ben R Dickie, Tao Jin, Ping Wang, Rainer Hinz, William Harris, Hervé Boutin, Geoff JM Parker, Laura M Parkes, Julian C Matthews
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Chemical-exchange spin-lock (CESL) MRI can map regional uptake and utilisation of glucose in the brain at high spatial resolution (i.e sub 0.2 mm3 voxels). We propose two quantitative kinetic models to describe glucose-induced changes in tissue R1ρ and apply them to glucoCESL MRI data acquired in tumour-bearing and healthy rats. When assuming glucose transport is saturable, the maximal transport capacity (Tmax) measured in normal tissue was 3.2 ± 0.6 µmol/min/mL, the half saturation constant (Kt) was 8.8 ± 2.2 mM, the metabolic rate of glucose consumption (MRglc) was 0.21 ± 0.13 µmol/min/mL, and the cerebral blood volume (vb) was 0.006 ± 0.005 mL/mL. Values in tumour were: Tmax = 7.1 ± 2.7 µmol/min/mL, Kt = 14 ± 1.7 mM, MRglc = 0.22 ± 0.09 µmol/min/mL, vb = 0.030 ± 0.035 mL/mL. Tmax and Kt were significantly higher in tumour tissue than normal tissue (p = 0.006 and p = 0.011, respectively). When assuming glucose uptake also occurs via free diffusion, the free diffusion rate (kd) was 0.061 ± 0.017 mL/min/mL in normal tissue and 0.12 ± 0.042 mL/min/mL in tumour. These parameter estimates agree well with literature values obtained using other approaches (e.g. NMR spectroscopy).
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-06-24T06:59:25Z
      DOI: 10.1177/0271678X221108841
       
  • Mitochondria transplantation/transfer between single cells

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      Authors: Qin Hu, Jianfei Lu, Xiaohua Zhang, Ran Liu, Shao-Hua Yang
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Mitochondrial transplantation/transfer has been increasingly recognized as a potential way for cell and tissue revitalization. In a recent study, Gabelein et al. reported a novel method for single cells mitochondria transplantation using “nanosyringe”. This technique combines atomic force microscopy, optical microscopy, and nanofluidics that enable intra- and intercellular organelle micromanipulation and cell-to-cell mitochondria transplantation with up to 95% success rate. The transferred mitochondria fuse to the host mitochondrial network and donor mtDNA incorporate into the recipient mitochondrial genome. The nanosyringe technique provides a novel tool for future mitochondrial research to offer insight into mitochondrial replacement therapy for stroke and fundamental mitochondrial biology.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-06-21T08:40:24Z
      DOI: 10.1177/0271678X221109685
       
  • Active conductive head cooling of normal and infarcted brain: A magnetic
           resonance spectroscopy imaging study

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      Authors: William K Diprose, Catherine A Morgan, Michael TM Wang, James P Diprose, Joanne C Lin, Sulaiman Sheriff, Doug Campbell, P Alan Barber
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Active conductive head cooling is a simple and non-invasive intervention that may slow infarct growth in ischemic stroke. We investigated the effect of active conductive head cooling on brain temperature using whole brain echo-planar spectroscopic imaging. A cooling cap (WElkins Temperature Regulation System, 2nd Gen) was used to administer cooling for 80 minutes to healthy volunteers and chronic stroke patients. Whole brain echo-planar spectroscopic imaging scans were obtained before and after cooling. Brain temperature was estimated using the Metabolite Imaging and Data Analysis System software package, which allows voxel-level temperature calculations using the chemical shift difference between metabolite (N-acetylaspartate, creatine, choline) and water resonances. Eleven participants (six healthy volunteers, five post-stroke) underwent 80 ± 5 minutes of cooling. The average temperature of the coolant was 1.3 ± 0.5°C below zero. Significant reductions in brain temperature (ΔT = –0.9 ± 0.7°C, P = 0.002), and to a lesser extent, rectal temperature (ΔT = –0.3 ± 0.1°C, P = 0.03) were observed. Exploratory analysis showed that the occipital lobes had the greatest reduction in temperature (ΔT = –1.5 ± 1.2°C, P = 0.002). Regions of infarction had similar temperature reductions to the contralateral normal brain. Future research could investigate the feasibility of head cooling as a potential neuroprotective strategy in patients being considered for acute stroke therapies.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-06-16T07:04:44Z
      DOI: 10.1177/0271678X221107988
       
  • Female-specific neuroprotection after ischemic stroke by vitronectin-focal
           adhesion kinase inhibition

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      Authors: Cuihong Jia, Chiharu Lovins, Hannah M Malone, Matthew P Keasey, Theo Hagg
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      We found that blood vitronectin (VTN) leaks into the brain and exacerbates tissue loss after stroke by increasing pro-inflammatory IL-6 expression in female, but not male, mice. VTN signals through integrins and downstream focal adhesion kinase (FAK). Here, a two day systemic treatment with a small molecule FAK inhibitor starting 6 h after middle cerebral artery occlusion reduced ipsilateral brain injury size by ∼40–45% at 7 and 14 d, as well as inflammation and motor dysfunction in wild-type female, but not male, mice. FAK inhibition also reduced IL-6 expression in the injured female striatum at 24 h by 62%. Inducible selective gene deletion of FAK in astrocytes also reduced acute IL-6 expression by 72% only in females, and mitigated infarct size by ∼80% and inflammation at 14 d after stroke. Lastly, VTN−/− females had better outcomes, but FAK inhibitor treatment had no additional protective or anti-inflammatory effects. Altogether, this suggests that VTN is detrimental in females primarily through FAK and that FAK inhibition provides neuroprotection (cerebroprotection) by reducing VTN-induced IL-6 expression in astrocytes. Thus, VTN signaling can be targeted to mitigate harmful inflammation with relevance to treatments for women with ischemic stroke, who often have worse outcomes than men.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-06-15T05:42:06Z
      DOI: 10.1177/0271678X221107871
       
  • Gut virome dysbiosis following focal cerebral ischemia in mice

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      Authors: Bharath Chelluboina, Kristopher Kieft, Adam Breister, Karthik Anantharaman, Raghu Vemuganti
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Stroke leads to gut bacterial dysbiosis that impacts the post-stroke outcome. The gut microbiome also contains a high abundance of viruses which might play a crucial role in disease progression and recovery by modulating the metabolism of both host and host’s gut bacteria. We presently analyzed the virome composition (viruses and phages) by shotgun metagenomics in the fecal samples obtained at 1 day of reperfusion following transient focal ischemia in adult mice. Viral genomes, viral auxiliary metabolic genes, and viral protein networks were compared between stroke and sham conditions (stroke vs sham, exclusive to sham and exclusive to stroke). Following focal ischemia, abundances of 2 viral taxa decreased, and 5 viral taxa increased compared with the sham. Furthermore, the abundance of Clostridia-like phages and Erysipelatoclostridiaceae-like phages were altered in the stroke compared with the sham cohorts. This is the first report to show that the gut virome responds acutely to stroke.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-06-15T05:39:26Z
      DOI: 10.1177/0271678X221107702
       
  • Depth-profile of impairments in endothelin-1 – induced focal
           cortical ischemia

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      Authors: Daria Vinokurova, Andrey Zakharov, Kseniya Chernova, Gulshat Burkhanova-Zakirova, Viktor Horst, Coline L Lemale, Jens P Dreier, Roustem Khazipov
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      The development of ischemic lesions has primarily been studied in horizontal cortical space. However, how ischemic lesions develop through the cortical depth remains largely unknown. We explored this question using direct current coupled recordings at different cortical depths using linear arrays of iridium electrodes in the focal epipial endothelin-1 (ET1) ischemia model in the rat barrel cortex. ET1-induced impairments were characterized by a vertical gradient with (i) rapid suppression of the spontaneous activity in the superficial cortical layers at the onset of ischemia, (ii) compartmentalization of spreading depolarizations (SDs) to the deep layers during progression of ischemia, and (iii) deeper suppression of activity and larger histological lesion size in superficial cortical layers. The level of impairments correlated strongly with the rate of spontaneous activity suppression, the rate of SD onset after ET1 application, and the amplitude of giant negative ultraslow potentials (∼−70 mV), which developed during ET1 application and were similar to the tent-shaped ultraslow potentials observed during focal ischemia in the human cortex. Thus, in the epipial ET1 ischemia model, ischemic lesions develop progressively from the surface to the cortical depth, and early changes in electrical activity at the onset of ET1-induced ischemia reliably predict the severity of ischemic damage.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-06-15T05:38:01Z
      DOI: 10.1177/0271678X221107422
       
  • Cerebral cavernous malformation development in chronic mouse models driven
           by dual recombinases induced gene deletion in brain endothelial cells

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      Authors: Xi Yang, Zifeng Dai, Caixia Gao, Yongqiang Yin, Changbin Shi, Renjing Liu, Qichuan Zhuge, Yue Huang, Bin Zhou, Zhiming Han, Xiangjian Zheng
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Cerebral cavernous malformation (CCM) is a brain vascular disease which can cause stroke, cerebral hemorrhage and neurological deficits in affected individuals. Loss-of-function mutations in three genes (CCM1, CCM2 and CCM3) cause CCM disease. Multiple mouse models for CCM disease have been developed although each of them are associated with various limitations. Here, we employed the Dre-Cre dual recombinase system to specifically delete Ccm genes in brain endothelial cells. In this new series of CCM mouse models, robust CCM lesions now develop in the cerebrum. The survival curve and lesion burden analysis revealed that Ccm2 deletion causes modest CCM lesions with a median life expectance of ∼10 months and Ccm3 gene deletion leads to the most severe CCM lesions with median life expectance of ∼2 months. The extended lifespan of these mutant mice enables their utility in behavioral analyses of neurologic deficits in adult mice, and allow the development of methods to quantify lesion burden in mice over time and also permit longitudinal drug testing in live animals.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-06-10T11:27:11Z
      DOI: 10.1177/0271678X221105995
       
  • An intravascular perspective on hyper-acute neutrophil, T-cell and
           platelet responses: Similarities between human and experimental stroke

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      Authors: Guido Stoll, Michael K Schuhmann, Bernhard Nieswandt, Alexander M Kollikowski, Mirko Pham
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      In stroke patients, local sampling of pial blood within the occluded vasculature before recanalization by mechanical thrombectomy emerged as powerful tool enabling insights into ultra-early stroke pathophysiology. Thereby, a strong intravascular inflammatory response hallmarked by hyper-acute neutrophil recruitment, altered lymphocyte composition and platelet activation could be observed. These human findings mirror experimental stroke. Here, neutrophil and T-cell activation are driven by platelets involving engagement of platelet glycoprotein receptor (GP)Ib, GPVI and CD84 as well as α-granule release orchestrating infarct progression. Thus, targeting of early intravascular inflammation may evolve as a new therapeutic strategy to augment the effects of recanalization.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-06-09T05:09:19Z
      DOI: 10.1177/0271678X221105764
       
  • Cohort study on the differential expression of inflammatory and angiogenic
           factors in thrombi, cerebral and peripheral plasma following acute large
           vessel occlusion stroke

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      Authors: Xavier O Scott, Stephanie H Chen, Roey Hadad, Dileep Yavagal, Eric C Peterson, Robert M Starke, W Dalton Dietrich, Robert W Keane, Juan Pablo de Rivero Vaccari
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Inflammation plays an important role in the pathogenesis of stroke. The differential expression of inflammatory and angiogenic factors in thrombi and plasma remain undefined. In this observational cohort study, we evaluated angiogenic factors and inflammatory cytokines, in cerebral thrombi, local cerebral plasma (CP), and peripheral plasma (PP) in patients with acute ischemic stroke. Protein analysis of thrombi, CP and PP were used to measure angiogenic and inflammatory proteins using electrochemiluminescence. Our data indicate that VEGF-A, VEGF-C, bFGF, IL-4, IL-13, IL-1β, IL-2, IL-8, IL-16, IL-6 and IL-12p70 were higher in the thrombi of acute ischemic stroke patients than in the CP and PP of stroke patients. Moreover, the protein levels of GM-CSF were lower in the PP than in the CP and the clot. Moreover, VEGF-D, Flt-1, PIGF, TIE-2, IL-5, TNF-β, IL-15, IL-12/IL-23p40, IFN-γ and IL-17A were higher in PP and CP than in thrombi. Our results show that cytokines mediating the inflammatory response and proteins involved in angiogenesis are differentially expressed in thrombi within the cerebral and peripheral circulations. These data highlight the importance of identifying new biomarkers in different compartments of the circulatory system and in thrombi that may be used for the diagnosis and treatment of stroke patients.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-06-08T08:27:47Z
      DOI: 10.1177/0271678X221106956
       
  • Oxygen extraction efficiency and white matter lesion burden in older
           adults exhibiting radiological evidence of capillary shunting

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      Authors: Meher R Juttukonda, Kimberly A Stephens, Yi-Fen Yen, Casey M Howard, Jonathan R Polimeni, Bruce R Rosen, David H Salat
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      White matter lesions (WML) have been linked to cognitive decline in aging as well as in Alzheimer’s disease. While hypoperfusion is frequently considered a cause of WMLs due to the resulting reduction in oxygen availability to brain tissue, such reductions could also be caused by impaired oxygen exchange. Here, we tested the hypothesis that venous hyperintense signal (VHS) in arterial spin labeling (ASL) magnetic resonance imaging (MRI) may represent a marker of impaired oxygen extraction in aging older adults. In participants aged 60–80 years (n = 30), we measured cerebral blood flow and VHS with arterial spin labeling, maximum oxygen extraction fraction (OEFmax) with dynamic susceptibility contrast, and WML volume with T1-weighted MRI. We found a significant interaction between OEFmax and VHS presence on WML volume (p = 0.02), where lower OEFmax was associated with higher WML volume in participants with VHS, and higher OEFmax was associated with higher WML volume in participants without VHS. These results indicate that VHS in perfusion-weighted ASL data may represent a distinct cerebrovascular aging pattern involving oxygen extraction inefficiency as well as hypoperfusion.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-06-08T08:16:27Z
      DOI: 10.1177/0271678X221105986
       
  • Inactivation of BACE1 increases expression of endothelial nitric oxide
           synthase in cerebrovascular endothelium

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      Authors: Tongrong He, Livius V d’Uscio, Ruohan Sun, Anantha Vijay R Santhanam, Zvonimir S Katusic
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Cerebrovascular effects of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) inactivation have not been systematically studied. In the present study we employed cultured human brain microvascular endothelial cells (BMECs), BACE1-knockout (BACE1−/−) mice and conditional (tamoxifen-induced) endothelium-specific BACE1-knockout (eBACE1−/−) mice to determine effect of BACE1 inhibition on expression and function of endothelial nitric oxide synthase (eNOS). Deletion of BACE1 caused upregulation of eNOS and glypican-1 (GPC1) in human BMECs treated with BACE1-siRNA, and cerebral microvessels of male BACE1−/− mice and male eBACE1−/− mice. In addition, BACE1siRNA treatment increased NO production in human BMECs. These effects appeared to be independent of amyloid β-peptide production. Furthermore, adenoviral-mediated overexpression of BACE1 in human BMECs down-regulated GPC1 and eNOS. Treatment of human BMECs with GPC1siRNA suppressed mRNA and protein levels of eNOS. In basilar arteries of male eBACE1−/− mice, endothelium-dependent relaxations to acetylcholine and endothelium-independent relaxations to NO donor, DEA-NONOate, were not affected, consistent with unchanged expression of eNOS and phosphorylation of eNOS at Ser1177 in large cerebral arteries. In aggregate, our findings suggest that under physiological conditions, inactivation of endothelial BACE1 increases expression of eNOS in cerebral microvessels but not in large brain arteries. This effect appears to be mediated by increased GPC1 expression.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-06-08T08:13:47Z
      DOI: 10.1177/0271678X221105683
       
  • Characterization of perivascular space pathology in a rat model of
           cerebral small vessel disease by in vivo magnetic resonance imaging

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      Authors: Brittany Monte, Stefan Constantinou, Sunil Koundal, Hedok Lee, Feng Dai, Zachary Gursky, William E Van Nostrand, Armine Darbinyan, Berislav V Zlokovic, Joanna Wardlaw, Helene Benveniste
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      One of the most common causes of dementia is cerebral small vessel disease (SVD), which is associated with enlarged perivascular spaces (PVS). Clinically, PVS are visible as hyperintensities on T2-weighted (T2w) magnetic resonance images (MRI). While rodent SVD models exhibit arteriolosclerosis, PVS have not been robustly documented by MRI casting doubts on their clinical relevance. Here we established that the severity of SVD in spontaneously hypertensive stroke prone (SHRSP) rats correlated to ‘moderate’ SVD in human post-mortem tissue. We then developed two approaches for detecting PVS in SHRSP rats: 1) T2w imaging and 2) T1-weighted imaging with administration of gadoteric acid into cerebrospinal fluid. We applied the two protocols to six Wistar-Kyoto (WKY) control rats and thirteen SHRSP rats at ∼12 month of age. The primary endpoint was the number of hyperintense lesions. We found more hyperintensities on T2w MRI in the SHRSP compared to WKY rats (p-value = 0.023). CSF enhancement with gadoteric acid increased the visibility of PVS-like lesions in SHRSP rats. In some of the SHRSP rats, the MRI hyperintensities corresponded to enlarged PVS on histopathology. The finding of PVS-like hyperintensities on T2w MRI support the SHRSP rat’s clinical relevance for studying the underlying pathophysiology of SVD.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-06-08T08:11:09Z
      DOI: 10.1177/0271678X221105668
       
  • Static and dynamic BOLD fMRI components along white matter fibre tracts
           and their dependence on the orientation of the local diffusion tensor axis
           relative to the B0-field

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      Authors: Olivia Viessmann, Qiyuan Tian, Michaël Bernier, Jonathan R Polimeni
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Recent studies have reported functional MRI (fMRI) activation within cerebral white matter (WM) using blood-oxygenation-level-dependent (BOLD) contrast. Many blood vessels in WM run parallel to the fibre bundles, and other studies observed dependence of susceptibility contrast-based measures of blood volume on the local orientation of the fibre bundles relative to the magnetic field or B0 axis. Motivated by this, we characterized the dependence of gradient-echo BOLD fMRI on fibre orientation (estimated by the local diffusion tensor) relative to the B0 axis to test whether the alignment between bundles and vessels imparts an orientation dependence on resting-state BOLD fluctuations in the WM. We found that the baseline signal level of the T2*-weighted data is 11% higher in voxels containing fibres parallel to B0 than those containing perpendicular fibres, consistent with a static influence of either fibre or vessel orientation on local T2* values. We also found that BOLD fluctuations in most bundles exhibit orientation effects expected from oxygenation changes, with larger amplitudes from voxels containing perpendicular fibres. Different magnitudes of this orientation effect were observed across the major WM bundles, with inferior fasciculus, corpus callosum and optic radiation exhibiting 14–19% higher fluctuations in voxels containing perpendicular compared to parallel fibres.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-06-02T04:32:33Z
      DOI: 10.1177/0271678X221106277
       
  • Measurement of glucose metabolism in the occipital lobe and frontal cortex
           after oral administration of [1-13C]glucose at 9.4 T

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      Authors: Theresia Ziegs, Johanna Dorst, Loreen Ruhm, Nikolai Avdievitch, Anke Henning
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      For the first time, labeling effects after oral intake of [1-13C]glucose are observed in the human brain with pure 1H detection at 9.4 T. Spectral time series were acquired using a short-TE 1H MRS MC-semiLASER (Metabolite Cycling semi Localization by Adiabatic SElective Refocusing) sequence in two voxels of 5.4 mL in the frontal cortex and the occipital lobe. High-quality time-courses of [4-13C]glutamate, [4-13C]glutamine, [3-13C]glutamate + glutamine, [2-13C] glutamate+glutamine and [3-13C]aspartate for individual volunteers and additionally, group-averaged time-courses of labeled and non-labeled brain glucose could be obtained. Using a one-compartment model, mean metabolic rates were calculated for each voxel position: The mean rate of the TCA-cycle (Vtca) value was determined to be 1.36 and 0.93 μmol min−1 g−1, the mean rate of glutamine synthesis (Vgln) was calculated to be 0.23 and 0.45 μmol min−1 g−1, the mean exchange rate between cytosolic amino acids and mitochondrial Krebs cycle intermediates (Vx) rate was found to be 0.57 and 1.21 μmol min−1 g−1 for the occipital lobe and the frontal cortex, respectively. These values were in agreement with previously reported data. Altogether, it can be shown that this most simple technique combining oral administration of [1-13C]Glc with pure 1H MRS acquisition is suitable to measure metabolic rates.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-05-28T05:11:00Z
      DOI: 10.1177/0271678X221104540
       
  • Point/counterpoint: We should take the direction of blood pressure change
           into consideration for dynamic cerebral autoregulation quantification

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      Authors: Lawrence Labrecque, Jonathan D Smirl, Yu-Chieh Tzeng, Patrice Brassard
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Accumulating evidence suggests asymmetrical responses of cerebral blood flow during large transient changes in mean arterial pressure. Specifically, the augmentation in cerebral blood flow is attenuated when mean arterial pressure acutely increases, compared with declines in cerebral blood flow when mean arterial pressure acutely decreases. However, common analytical tools to quantify dynamic cerebral autoregulation assume autoregulatory responses to be symmetric, which does not seem to be the case. Herein, we provide the rationale supporting the notion we need to consider the directional sensitivity of large and transient mean arterial pressure changes when characterizing dynamic cerebral autoregulation.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-05-27T04:28:12Z
      DOI: 10.1177/0271678X221104868
       
  • Cerebrovascular reactivity and deep white matter hyperintensities in
           migraine: A prospective CO2 targeting study

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      Authors: Mi Ji Lee, Bo-yong Park, Soohyun Cho, Seonwoo Kim, Hyunjin Park, Sung Tae Kim, Chin-Sang Chung
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Several studies suggested the association of migraine with deep white matter hyperintensities (WMHs). We aimed to explore the cerebrovascular reactivity (CVR), deep WMH burden, and their association in patients with migraine using a state-of-the-art methodology. A total of 31 patients with migraine without aura and 31 age/sex-matched controls underwent 3T MRI with prospective end-tidal carbon dioxide (CO2) targeting. We quantified deep WMH clusters using an automated segmentation tool and measured voxel-wise CVR by changes in blood oxygen level-dependent signal fitted to subjects’ end-tidal CO2. The association of migraine and CVR with the presence of WMH in each voxel and interaction of migraine and CVR on WMH were analysed. Patients had a higher number of deep WMHs than controls (p = 0.015). Migraine and reduced CVR were associated with increased probability of having WMHs in each voxel (adjusted OR 30.78 [95% CI 1.89–500.53], p = 0.016 and adjusted OR 0.30 [0.29–0.32], p 
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-05-24T08:57:40Z
      DOI: 10.1177/0271678X221103006
       
  • Global changes in diffusion tensor imaging during acute ischemic stroke
           and post-stroke cognitive performance

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      Authors: Kyle C Kern, Clinton B Wright, Richard Leigh
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Post-stroke cognitive impairment is related to the effects of the acute stroke and pre-stroke brain health. We tested whether diffusion tensor imaging (DTI) can detect acute, global effects of stroke and predict post-stroke cognitive performance. Patients with stroke or TIA enrolled in a prospective cohort study were included if they had 1) at least one DTI acquisition at acute presentation, 24 hours, 5 days, or 30 days, and 2) follow-up testing with the telephone Montreal Cognitive Assessment (T-MoCA) at 30 and/or 90 days. A whole brain, white-matter skeleton excluding the infarct was used to derive mean global DTI measures for mean diffusivity (MD), fractional anisotropy (FA), free water (FW), FW-corrected MD (MDtissue), and FW-corrected FA (FAtissue). In 74 patients with ischemic stroke or TIA, there was a transient 4.2% increase in mean global FW between acute presentation and 24 hours (p = 0.024) that returned to initial values by 30 days (p = 0.03). Each acute global DTI measure was associated with 30-day T-MoCA score (n = 61, p = 0.0011–0.0076). Acute global FW, MD, FA and FAtissue were also associated with 90-day T-MoCA (n = 56, p = 0.0034–0.049). Transient global FW elevation likely reflects stroke-related interstitial edema, whereas other global DTI measures are more representative of pre-stroke brain health.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-05-17T10:39:53Z
      DOI: 10.1177/0271678X221101644
       
  • Validation, kinetic modeling, and test-retest reproducibility of
           [18F]SynVesT-1 for PET imaging of synaptic vesicle glycoprotein 2A in mice
           

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      Authors: Daniele Bertoglio, Franziska Zajicek, Stef De Lombaerde, Alan Miranda, Sigrid Stroobants, Yuchuan Wang, Celia Dominguez, Ignacio Munoz-Sanjuan, Jonathan Bard, Longbin Liu, Jeroen Verhaeghe, Steven Staelens
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Alterations in synaptic vesicle glycoprotein 2 A (SV2A) have been associated with several neuropsychiatric and neurodegenerative disorders. Therefore, SV2A positron emission tomography (PET) imaging may provide a unique tool to investigate synaptic density dynamics during disease progression and after therapeutic intervention. This study aims to extensively characterize the novel radioligand [18F]SynVesT-1 for preclinical applications. In C57Bl/6J mice (n = 39), we assessed the plasma profile of [18F]SynVesT-1, validated the use of a noninvasive image-derived input function (IDIF) compared to an arterial input function (AIF), performed a blocking study with levetiracetam (50 and 200 mg/kg, i.p.) to verify the specificity towards SV2A, examined kinetic models for volume of distribution (VT) quantification, and explored test-retest reproducibility of [18F]SynVesT-1 in the central nervous system (CNS). Plasma availability of [18F]SynVesT-1 decreased rapidly (13.4 ± 1.5% at 30 min post-injection). VT based on AIF and IDIF showed excellent agreement (r2 = 0.95, p 
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-05-14T11:31:13Z
      DOI: 10.1177/0271678X221101648
       
  • Increased interictal synchronicity of respiratory related brain pulsations
           in epilepsy

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      Authors: Janne Kananen, Matti Järvelä, Vesa Korhonen, Timo Tuovinen, Niko Huotari, Lauri Raitamaa, Heta Helakari, Tommi Väyrynen, Ville Raatikainen, Maiken Nedergaard, Hanna Ansakorpi, Julia Jacobs, Pierre LeVan, Vesa Kiviniemi
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Respiratory brain pulsations have recently been shown to drive electrophysiological brain activity in patients with epilepsy. Furthermore, functional neuroimaging indicates that respiratory brain pulsations have increased variability and amplitude in patients with epilepsy compared to healthy individuals. To determine whether the respiratory drive is altered in epilepsy, we compared respiratory brain pulsation synchronicity between healthy controls and patients. Whole brain fast functional magnetic resonance imaging was performed on 40 medicated patients with focal epilepsy, 20 drug-naïve patients and 102 healthy controls. Cerebrospinal fluid associated respiratory pulsations were used to generate individual whole brain respiratory synchronization maps, which were compared between groups. Finally, we analyzed the seizure frequency effect and diagnostic accuracy of the respiratory synchronization defect in epilepsy. Respiratory brain pulsations related to the verified fourth ventricle pulsations were significantly more synchronous in patients in frontal, periventricular and mid-temporal regions, while the seizure frequency correlated positively with synchronicity. The respiratory brain synchronicity had a good diagnostic accuracy (ROCAUC = 0.75) in discriminating controls from medicated patients. The elevated respiratory brain synchronicity in focal epilepsy suggests altered physiological effect of cerebrospinal fluid pulsations possibly linked to regional brain water dynamics involved with interictal brain physiology.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-05-14T11:27:45Z
      DOI: 10.1177/0271678X221099703
       
  • Intracerebral hemorrhage and thrombin-induced alterations in cerebral
           microvessel matrix

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      Authors: Yu-Huan Gu, Brian T Hawkins, Yoshikane Izawa, Yoji Yoshikawa, James A Koziol, Gregory J del Zoppo
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Four phase III clinical trials of oral direct factor Xa or thrombin inhibitors demonstrated significantly lower intracranial hemorrhage compared to warfarin in patients with nonvalvular-atrial fibrillation. This is counter-intuitive to the principle that inhibiting thrombosis should increase hemorrhagic risk. We tested the novel hypothesis that anti-thrombin activity decreases the risk of intracerebral hemorrhage by directly inhibiting thrombin-mediated degradation of cerebral microvessel basal lamina matrix, responsible for preventing hemorrhage. Collagen IV, laminin, and perlecan each contain one or more copies of the unique α-thrombin cleavage site consensus sequence. In blinded controlled experiments, α-thrombin significantly degraded each matrix protein in vitro and in vivo in a concentration-dependent fashion. In vivo stereotaxic injection of α-thrombin significantly increased permeability, local IgG extravasation, and hemoglobin (Hgb) deposition together with microvessel matrix degradation in a mouse model. In all formats the direct anti-thrombin dabigatran completely inhibited matrix degradation by α-thrombin. Fourteen-day oral exposure to dabigatran etexilate-containing chow completely inhibited matrix degradation, the permeability to large molecules, and cerebral hemorrhage associated with α-thrombin. These experiments demonstrate that thrombin can degrade microvessel matrix, leading to hemorrhage, and that inhibition of microvessel matrix degradation by α-thrombin decreases cerebral hemorrhage. Implications for focal ischemia and other conditions are discussed.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-05-05T10:28:03Z
      DOI: 10.1177/0271678X221099092
       
  • Point-Counterpoint: Transfer function analysis of dynamic cerebral
           autoregulation: To band or not to band'

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      Authors: Jia Liu, David M Simpson, Ronney B Panerai
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Transfer function analysis (TFA) is the most frequently adopted method for assessing dynamic cerebral autoregulation (CA) with continuously recorded arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV). Conventionally, values of autoregulatory metrics (e.g., gain and phase) derived from TFA are averaged within three frequency bands separated by cut-off frequencies at 0.07 Hz and 0.20 Hz, respectively, to represent the efficiency of dynamic CA. However, this is of increasing concerns, as there remains no solid evidence for choosing these specific cut-off frequencies, and the rigid adoption of these bands can stifle further developments in TFA of dynamic CA. In this ‘Point-Counterpoint’ mini-review, we provide evidence against the fixed banding, indicate possible alternatives, and call for awareness of the risk of the ‘one-size-fits-all’ banding becoming dogmatic. We conclude that we need to remain open to the multiple possibilities offered by TFA to realize its full potential in studies of human dynamic CA.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-05-05T10:25:10Z
      DOI: 10.1177/0271678X221098448
       
  • Microglial phagocytosis and regulatory mechanisms after stroke

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      Authors: Weijie Chen, Yueman Zhang, Xiaozhu Zhai, Lv Xie, Yunlu Guo, Chen Chen, Yan Li, Fajun Wang, Ziyu Zhu, Li Zheng, Jieqing Wan, Peiying Li
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Stroke, including ischemic stroke and hemorrhagic stroke can cause massive neuronal death and disruption of brain structure, which is followed by secondary inflammatory injury initiated by pro-inflammatory molecules and cellular debris. Phagocytic clearance of cellular debris by microglia, the brain’s scavenger cells, is pivotal for neuroinflammation resolution and neurorestoration. However, microglia can also exacerbate neuronal loss by phagocytosing stressed-but-viable neurons in the penumbra, thereby expanding the injury area and hindering neurofunctional recovery. Microglia constantly patrol the central nervous system using their processes to scour the cellular environment and start or cease the phagocytosis progress depending on the “eat me” or “don’t eat me’’ signals on cellular surface. An optimal immune response requires a delicate balance between different phenotypic states to regulate neuro-inflammation and facilitate reconstruction after stroke. Here, we examine the literature and discuss the molecular mechanisms and cellular pathways regulating microglial phagocytosis, their resulting effects in brain injury and neural regeneration, as well as the potential therapeutic targets that might modulate microglial phagocytic activity to improve neurological function after stroke.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-05-02T04:21:36Z
      DOI: 10.1177/0271678X221098841
       
  • Temporal brain transcriptome analysis reveals key pathological events
           after germinal matrix hemorrhage in neonatal rats

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      Authors: Juan Song, Gisela Nilsson, Yiran Xu, Aura Zelco, Eridan Rocha-Ferreira, Yafeng Wang, Xiaoli Zhang, Shan Zhang, Joakim Ek, Henrik Hagberg, Changlian Zhu, Xiaoyang Wang
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Germinal matrix hemorrhage (GMH) is a common complication in preterm infants and is associated with high risk of adverse neurodevelopmental outcomes. We used a rat GMH model and performed RNA sequencing to investigate the signaling pathways and biological processes following hemorrhage. GMH induced brain injury characterized by early hematoma and subsequent tissue loss. At 6 hours after GMH, gene expression indicated an increase in mitochondrial activity such as ATP metabolism and oxidative phosphorylation along with upregulation of cytoprotective pathways and heme metabolism. At 24 hours after GMH, the expression pattern suggested an increase in cell cycle progression and downregulation of neurodevelopmental-related pathways. At 72 hours after GMH, there was an increase in genes related to inflammation and an upregulation of ferroptosis. Hemoglobin components and genes related to heme metabolism and ferroptosis such as Hmox1, Alox15, and Alas2 were among the most upregulated genes. We observed dysregulation of processes involved in development, mitochondrial function, cholesterol biosynthesis, and inflammation, all of which contribute to neurodevelopmental deterioration following GMH. This study is the first temporal transcriptome profile providing a comprehensive overview of the molecular mechanisms underlying brain injury following GMH, and it provides useful guidance in the search for therapeutic interventions.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-05-02T04:12:08Z
      DOI: 10.1177/0271678X221098811
       
  • The meningeal lymphatic vessels and the glymphatic system: Potential
           therapeutic targets in neurological disorders

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      Authors: Gaowei Li, Yi Cao, Xin Tang, Jianhan Huang, Linjun Cai, Liangxue Zhou
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      The recent discovery of the meningeal lymphatic vessels (mLVs) and glymphatic pathways has challenged the long-lasting dogma that the central nervous system (CNS) lacks a lymphatic system and therefore does not interact with peripheral immunity. This discovery has reshaped our understanding of mechanisms underlying CNS drainage. Under normal conditions, a close connection between mLVs and the glymphatic system enables metabolic waste removal, immune cell trafficking, and CNS immune surveillance. Dysfunction of the glymphatic-mLV system can lead to toxic protein accumulation in the brain, and it contributes to the development of a series of neurodegenerative disorders, such as Alzheimer’s and Parkinson's diseases. The identification of precise cerebral transport routes is based mainly on indirect, invasive imaging of animals, and the results cannot always be applied to humans. Here we review the functions of the glymphatic-mLV system and evidence for its involvement in some CNS diseases. We focus on emerging noninvasive imaging techniques to evaluate the human glymphatic-mLV system and their potential for preclinical diagnosis and prevention of neurodegenerative diseases. Potential strategies that target the glymphatic-mLV system in order to treat and prevent neurological disorders are also discussed.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-04-29T06:13:29Z
      DOI: 10.1177/0271678X221098145
       
  • Early disturbance of dynamic synchronization and neurovascular coupling in
           cognitively normal Parkinson’s disease

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      Authors: Song’an Shang, Jing Ye, Jingtao Wu, Hongying Zhang, Weiqiang Dou, Vijaya Prakash Krishnan Muthaiah, Youyong Tian, Yingdong Zhang, Yu-Chen Chen, Xindao Yin
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Pathological process in Parkinson’s disease (PD) is accompanied with functional and metabolic alterations. The time-varying properties of functional coherence and their coupling to regional perfusion are still rarely elucidated. To investigate early disruption of dynamic regional homogeneity (dReho) and neurovascular coupling in cognitively normal PD patients, dynamic neuronal synchronization and regional perfusion were measured using dReho and cerebral blood flow (CBF), respectively. Neurovascular coupling was assessed by CBF-ReHo correlation coefficient and CBF/ReHo ratio. Multivariate pattern analysis was conducted for the differentiating ability of each feature. Relative to healthy controls (HC) subjects, PD patients demonstrated increased dReho in middle temporal gyrus (MTG), rectus gyrus, middle occipital gyrus, and precuneus, whereas reduced dReho in putamen and supplementary motor area (SMA); while higher CBF/dReho ratio was located in putamen, SMA, paracentral lobule, and postcentral gyrus, whereas lower CBF/dReho ratio in superior temporal gyrus, MTG, precuneus, and angular gyrus (AG). Global and regional CBF-Reho decoupling were both observed in PD groups. The CBF/Reho ratio features achieved more powerful classification performance than other features. From the view of dynamic neural synchronization and neurovascular coupling, this study reinforced the insights into neural basis underlying PD and the potential role in the disease diagnosis and differentiation.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-04-27T06:52:27Z
      DOI: 10.1177/0271678X221098503
       
  • The lateral entorhinal cortex is a hub for local and global dysfunction in
           early Alzheimer’s disease states

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      Authors: Francesca Mandino, Ling Yun Yeow, Renzhe Bi, Lee Sejin, Han Gyu Bae, Seung Hyun Baek, Chun-Yao Lee, Hasan Mohammad, Corey Horien, Chai Lean Teoh, Jasinda H Lee, Mitchell KP Lai, Sangyong Jung, Yu Fu, Malini Olivo, John Gigg, Joanes Grandjean
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Functional network activity alterations are one of the earliest hallmarks of Alzheimer’s disease (AD), detected prior to amyloidosis and tauopathy. Better understanding the neuronal underpinnings of such network alterations could offer mechanistic insight into AD progression. Here, we examined a mouse model (3xTgAD mice) recapitulating this early AD stage. We found resting functional connectivity loss within ventral networks, including the entorhinal cortex, aligning with the spatial distribution of tauopathy reported in humans. Unexpectedly, in contrast to decreased connectivity at rest, 3xTgAD mice show enhanced fMRI signal within several projection areas following optogenetic activation of the entorhinal cortex. We corroborate this finding by demonstrating neuronal facilitation within ventral networks and synaptic hyperexcitability in projection targets. 3xTgAD mice, thus, reveal a dichotomic hypo-connected:resting versus hyper-responsive:active phenotype. This strong homotopy between the areas affected supports the translatability of this pathophysiological model to tau-related, early-AD deficits in humans.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-04-25T10:28:50Z
      DOI: 10.1177/0271678X221082016
       
  • Free-water diffusion MRI detects structural alterations surrounding white
           matter hyperintensities in the early stage of cerebral small vessel
           disease

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      Authors: Carola Mayer, Felix L Nägele, Marvin Petersen, Benedikt M Frey, Uta Hanning, Ofer Pasternak, Elina Petersen, Christian Gerloff, Götz Thomalla, Bastian Cheng
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      In cerebral small vessel disease (CSVD), both white matter hyperintensities (WMH) of presumed vascular origin and the normal-appearing white matter (NAWM) contain microstructural brain alterations on diffusion-weighted MRI (DWI). Contamination of DWI-derived metrics by extracellular free-water can be corrected with free-water (FW) imaging. We investigated the alterations in FW and FW-corrected fractional anisotropy (FA-t) in WMH and surrounding tissue and their association with cerebrovascular risk factors. We analysed 1,000 MRI datasets from the Hamburg City Health Study. DWI was used to generate FW and FA-t maps. WMH masks were segmented on FLAIR and T1-weighted MRI and dilated repeatedly to create 8 NAWM masks representing increasing distance from WMH. Linear models were applied to compare FW and FA-t across WMH and NAWM masks and in association with cerebrovascular risk. Median age was 64 ± 14 years. FW and FA-t were altered 8 mm and 12 mm beyond WMH, respectively. Smoking was significantly associated with FW in NAWM (p = 0.008) and FA-t in WMH (p = 0.008) and in NAWM (p = 0.003) while diabetes and hypertension were not. Further research is necessary to examine whether FW and FA-t alterations in NAWM are predictors for developing WMH.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-04-12T05:03:48Z
      DOI: 10.1177/0271678X221093579
       
  • Genetic ablation of smooth muscle KIR2.1 is inconsequential to the
           function of mouse cerebral arteries

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      Authors: Paulina M Kowalewska, Jacob Fletcher, William F Jackson, Suzanne E Brett, Michelle SM Kim, Galina Yu Mironova, Nadia Haghbin, David M Richter, Nathan R Tykocki, Mark T Nelson, Donald G Welsh
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Cerebral blood flow is a finely tuned process dependent on coordinated changes in arterial tone. These changes are strongly tied to smooth muscle membrane potential and inwardly rectifying K+ (KIR) channels are thought to be a key determinant. To elucidate the role of KIR2.1 in cerebral arterial tone development, this study examined the electrical and functional properties of cells, vessels and living tissue from tamoxifen-induced smooth muscle cell (SMC)-specific KIR2.1 knockout mice. Patch-clamp electrophysiology revealed a robust Ba2+-sensitive inwardly rectifying K+ current in cerebral arterial myocytes irrespective of KIR2.1 knockout. Immunolabeling clarified that KIR2.1 expression was low in SMCs while KIR2.2 labeling was remarkably abundant at the membrane. In alignment with these observations, pressure myography revealed that the myogenic response and K+-induced dilation were intact in cerebral arteries post knockout. At the whole organ level, this translated to a maintenance of brain perfusion in SMC KIR2.1−/− mice, as assessed with arterial spin-labeling MRI. We confirmed these findings in superior epigastric arteries and implicated KIR2.2 as more functionally relevant in SMCs. Together, these results suggest that subunits other than KIR2.1 play a significant role in setting native current in SMCs and driving arterial tone.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-04-12T04:58:40Z
      DOI: 10.1177/0271678X221093432
       
  • Altered resting-state cerebral blood flow and functional connectivity
           mediate suicidal ideation in major depressive disorder

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      Authors: Dandan Fan, Cancan He, Xinyi Liu, Feifei Zang, Yao Zhu, Haisan Zhang, Hongxing Zhang, Zhijun Zhang, Chunming Xie
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      The relationships among cerebral blood flow (CBF), functional connectivity (FC) and suicidal ideation (SI) in major depressive disorder (MDD) patients have remained elusive. In this study, we characterized the changes in CBF and FC among 175 individuals including 47 MDD without SI (MDDNSI), 59 MDD with SI (MDDSI), and 69 healthy control (HC) who underwent arterial spin labeling and resting-state functional MRI scans. Then the voxel-wise CBF, seed-based FC and partial correlation analyses were measured. Mediation analysis was carried out to reveal the effects of FC on the association between CBF and behavioral performances in both subgroups. Results showed that CBF was higher in MDDSI patients in the bilateral precuneus compared to HC and MDDNSI participants. MDDSI patients exhibited enhanced FC in the prefrontal-limbic system and decreased FC in the sensorimotor cortex (SMC) relative to MDDNSI patients. CBF and FC were significantly correlated with clinical variables. More importantly, exploratory mediation analyses identified that abnormal FC can mediate the association between regional CBF and behavioral performances. These results highlight the potential role of precuneus gyrus, prefrontal-limbic system as well as SMC in the process of suicide and provide new insights into the neural mechanism underlying suicide in MDD patients.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-03-30T04:57:15Z
      DOI: 10.1177/0271678X221090998
       
  • Decreased rates of cerebral protein synthesis in conscious young adults
           with fragile X syndrome demonstrated by L-[1-11C]leucine PET

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      Authors: Kathleen C Schmidt, Inna Loutaev, Thomas V Burlin, Audrey Thurm, Carrie Sheeler, Carolyn Beebe Smith
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Fragile X mental retardation protein, a putative translation suppressor, is significantly reduced in FXS. The prevailing hypothesis is that rates of cerebral protein synthesis (rCPS) are increased by the absence of this regulatory protein. We have previously reported increased rCPS in the Fmr1 knockout mouse model of FXS. To address the hypothesis in human subjects, we measured rCPS in young men with FXS with L-[1-11C]leucine PET. In previous studies we had used sedation during imaging, and we did not find increases in rCPS as had been seen in the mouse model. Since mouse measurements were conducted in awake animals, we considered the possibility that sedation may have confounded our results. In the present study we used a modified and validated PET protocol that made it easier for participants with FXS to undergo the study awake. We compared rCPS in 10 fragile X participants and 16 healthy controls all studied while awake. Contrary to the prevailing hypothesis and findings in Fmr1 knockout mice, results indicate that rCPS in awake participants with FXS are decreased in whole brain and most brain regions by 13–21% compared to healthy controls.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-03-30T04:53:13Z
      DOI: 10.1177/0271678X221090997
       
  • Altered glymphatic enhancement of cerebrospinal fluid tracer in
           individuals with chronic poor sleep quality

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      Authors: Per Kristian Eide, Are Hugo Pripp, Benedikte Berge, Harald Hrubos-Strøm, Geir Ringstad, Lars Magnus Valnes
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Chronic sleep disturbance is a risk factor for dementia disease, possibly due to impaired sleep-dependent clearance of toxic metabolic by-products. We compared enrichment of a cerebrospinal fluid (CSF) tracer within brain of patients reporting good or poor sleep quality, assessed by the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Tracer enrichment in a selection of brain regions was assessed using multiphase magnetic resonance imaging up to 48 hours after intrathecal administration of the contrast agent gadobutrol (0.5 ml of 1 mmol/ml) serving as tracer. Tracer enrichment differed between patients with good (PSQI ≤5) and poor (PSQI>5) sleep quality in a cohort of non-dementia individuals (n = 44; age 42.3 ± 14.5 years), and in patients with the dementia subtype idiopathic normal pressure hydrocephalus (n = 24; age 71.0 ± 4.9 years). Sleep impairment was associated with increased CSF tracer enrichment in several brain regions. Cortical brain volume as well as entorhinal cortex thickness was reduced in the oldest cohort and was correlated with the severity of sleep disturbance and the degree of cortical tracer enrichment. We suggest chronic sleep disturbance is accompanied by altered glymphatic function along enlarged perivascular spaces.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-03-30T04:50:15Z
      DOI: 10.1177/0271678X221090747
       
  • pH and proton-sensitive receptors in brain ischemia

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      Authors: Xiang-ming Zha, Zhi-Gang Xiong, Roger P Simon
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Extracellular proton concentration is at 40 nM when pH is 7.4. In disease conditions such as brain ischemia, proton concentration can reach µM range. To respond to this increase in extracellular proton concentration, the mammalian brain expresses at least three classes of proton receptors. Acid-sensing ion channels (ASICs) are the main neuronal cationic proton receptor. The proton-activated chloride channel (PAC), which is also known as (aka) acid-sensitive outwardly rectifying anion channel (ASOR; TMEM206), mediates acid-induced chloride currents. Besides proton-activated channels, GPR4, GPR65 (aka TDAG8, T-cell death-associated gene 8), and GPR68 (aka OGR1, ovarian cancer G protein-coupled receptor 1) function as proton-sensitive G protein-coupled receptors (GPCRs). Though earlier studies on these GPCRs mainly focus on peripheral cells, we and others have recently provided evidence for their functional importance in brain injury. Specifically, GPR4 shows strong expression in brain endothelium, GPR65 is present in a fraction of microglia, while GPR68 exhibits predominant expression in brain neurons. Here, to get a better view of brain acid signaling and its contribution to ischemic injury, we will review the recent findings regarding the differential contribution of proton-sensitive GPCRs to cerebrovascular function, neuroinflammation, and neuronal injury following acidosis and brain ischemia.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-03-18T10:47:57Z
      DOI: 10.1177/0271678X221089074
       
  • Astrocyte regulation of cerebral blood flow during hypoglycemia

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      Authors: Amy R Nippert, Pei-Pei Chiang, Armani P Del Franco, Eric A Newman
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Hypoglycemia triggers increases in cerebral blood flow (CBF), augmenting glucose supply to the brain. We have tested whether astrocytes, which can regulate vessel tone, contribute to this CBF increase. We hypothesized that hypoglycemia-induced adenosine signaling acts to increase astrocyte Ca2+ activity, which then causes the release of prostaglandins (PGs) and epoxyeicosatrienoic acids (EETs), leading to the dilation of brain arterioles and blood flow increases. We used an awake mouse model to investigate the effects of insulin-induced hypoglycemia on arterioles and astrocytes in the somatosensory cortex. During insulin-induced hypoglycemia, penetrating arterioles dilated and astrocyte Ca2+ signaling increased when blood glucose dropped below a threshold of ∼50 mg/dL. Application of the A2A adenosine receptor antagonist ZM-241385 eliminated hypoglycemia-evoked astrocyte Ca2+ increases and reduced arteriole dilations by 44% (p 
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-03-17T07:13:46Z
      DOI: 10.1177/0271678X221089091
       
  • Aging related impairment of brain microvascular bioenergetics involves
           oxidative phosphorylation and glycolytic pathways

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      Authors: Siva SVP Sakamuri, Venkata N Sure, Lahari Kolli, Wesley R Evans, Jared A Sperling, Gregory J Bix, Xiaoying Wang, Dmitriy N Atochin, Walter L Murfee, Ricardo Mostany, Prasad VG Katakam
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Mitochondrial and glycolytic energy pathways regulate the vascular functions. Aging impairs the cerebrovascular function and increases the risk of stroke and cognitive dysfunction. The goal of our study is to characterize the impact of aging on brain microvascular energetics. We measured the oxygen consumption and extracellular acidification rates of freshly isolated brain microvessels (BMVs) from young (2–4 months) and aged (20–22 months) C57Bl/6 male mice. Cellular ATP production in BMVs was predominantly dependent on oxidative phosphorylation (OXPHOS) with glucose as the preferred energy substrate. Aged BMVs exhibit lower ATP production rate with diminished OXPHOS and glycolytic rate accompanied by increased utilization of glutamine. Impairments of glycolysis displayed by aged BMVs included reduced compensatory glycolysis whereas impairments of mitochondrial respiration involved reduction of spare respiratory capacity and proton leak. Aged BMVs showed reduced levels of key glycolysis proteins including glucose transporter 1 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 but normal lactate dehydrogenase activity. Mitochondrial protein levels were mostly unchanged whereas citrate synthase activity was reduced, and glutamate dehydrogenase was increased in aged BMVs. Thus, for the first time, we identified the dominant role of mitochondria in bioenergetics of BMVs and the alterations of the energy pathways that make the aged BMVs vulnerable to injury.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-03-17T06:46:03Z
      DOI: 10.1177/0271678X211069266
       
  • Cerebrovascular responses to somatomotor stimulation in Parkinson’s
           disease: A multivariate analysis

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      Authors: Sam C Barnes, Ronney B Panerai, Lucy Beishon, Martha Hanby, Thompson G Robinson, Victoria J Haunton
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Parkinson’s disease (PD) is a common neurodegenerative disorder, yet little is known about cerebral haemodynamics in this patient population. Previous studies assessing dynamic cerebral autoregulation (dCA), neurovascular coupling (NVC) and vasomotor reactivity (VMR) have yielded conflicting findings. By using multi-variate modelling, we aimed to determine whether cerebral blood flow (CBF) regulation is impaired in PD patients.55 healthy controls (HC) and 49 PD patients were recruited. PD subjects underwent a second recording following a period of abstinence from their anti-Parkinsonian medication. Continuous bilateral transcranial Doppler in the middle cerebral arteries, beat-to-beat mean arterial blood pressure (MAP; Finapres), heart rate (HR; electrocardiogram), and end-tidal CO2 (EtCO2; capnography) were measured. After a 5-min baseline period, a passive motor paradigm comprising 60 s of elbow flexion was performed. Multi-variate modelling quantified the contributions of MAP, ETCO2 and neural stimulation to changes in CBF velocity (CBFV). dCA, VMR and NVC were quantified to assess the integrity of CBF regulation.Neural stimulation was the dominant input. dCA, NVC and VMR were all found to be impaired in the PD population relative to HC (p 
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-03-15T07:19:09Z
      DOI: 10.1177/0271678X211065204
       
  • Prediction of the trans-stenotic pressure gradient with
           arteriography-derived hemodynamic features in patients with idiopathic
           intracranial hypertension

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      Authors: Yupeng Zhang, Chao Ma, Changxuan Li, Xiaoqing Li, Raynald Liu, Minke Liu, Haoyu Zhu, Fei Liang, Yilong Wang, Kehui Dong, Chuhan Jiang, Zhongrong Miao, Dapeng Mo
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      The pathogenesis of idiopathic intracranial hypertension (IIH) is attributed to segmental stenosis of the venous sinus. The current treatment paradigm requires a trans-stenotic pressure gradient of ≥8 mmHg or ≥6 mmHg threshold. This study aimed to develop a machine learning screening method to identify patients with IIH using hemodynamic features. A total of 204 venous manometry instances (n = 142, training and validation; n = 62, test) from 135 patients were included. Radiomic features extracted from five arteriography perfusion parameter maps were selected using least absolute shrinkage and selection operator and then entered into support vector machine (SVM) classifiers. The Thr8-23-SVM classifier was created with 23 radiomic features to predict if the pressure gradient was ≥8 mmHg. On an independent test dataset, prediction sensitivity, specificity, accuracy, and AUC were 0.972, 0.846, 0.919, and 0.980, respectively (95% confidence interval: 0.980–1.000). For the 6 mmHg threshold, thr6-28-SVM incorporated 28 features, and its sensitivity, specificity, accuracy, and AUC were 0.923, 0.956, 0.935, and 0.969, respectively (95% confidence interval: 0.927–1.000). The trans-stenotic pressure gradient result was associated with perfusion pattern changes, and SVM classifiers trained with arteriography perfusion map-derived radiomic features could predict the 8 mmHg and 6 mmHg dichotomized trans-stenotic pressure gradients with favorable accuracy.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-03-08T08:45:08Z
      DOI: 10.1177/0271678X221086408
       
  • Activation of lactate receptor HCAR1 down-modulates neuronal activity in
           rodent and human brain tissue

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      Authors: Marc Briquet, Anne-Bérengère Rocher, Maxime Alessandri, Nadia Rosenberg, Haissa de Castro Abrantes, Joel Wellbourne-Wood, Céline Schmuziger, Vanessa Ginet, Julien Puyal, Etienne Pralong, Roy Thomas Daniel, Stefan Offermanns, Jean-Yves Chatton
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Lactate can be used by neurons as an energy substrate to support their activity. Evidence suggests that lactate also acts on a metabotropic receptor called HCAR1, first described in the adipose tissue. Whether HCAR1 also modulates neuronal circuits remains unclear. In this study, using qRT-PCR, we show that HCAR1 is present in the human brain of epileptic patients who underwent resective surgery. In brain slices from these patients, pharmacological HCAR1 activation using a non-metabolized agonist decreased the frequency of both spontaneous neuronal Ca2+ spiking and excitatory post-synaptic currents (sEPSCs). In mouse brains, we found HCAR1 expression in different regions using a fluorescent reporter mouse line and in situ hybridization. In the dentate gyrus, HCAR1 is mainly present in mossy cells, key players in the hippocampal excitatory circuitry and known to be involved in temporal lobe epilepsy. By using whole-cell patch clamp recordings in mouse and rat slices, we found that HCAR1 activation causes a decrease in excitability, sEPSCs, and miniature EPSCs frequency of granule cells, the main output of mossy cells. Overall, we propose that lactate can be considered a neuromodulator decreasing synaptic activity in human and rodent brains, which makes HCAR1 an attractive target for the treatment of epilepsy.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-03-04T04:42:48Z
      DOI: 10.1177/0271678X221080324
       
  • Using arterial spin labeling to measure cerebrovascular reactivity in
           Moyamoya disease: Insights from simultaneous PET/MRI

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      Authors: Moss Y Zhao, Audrey P Fan, David Yen-Ting Chen, Yosuke Ishii, Mohammad Mehdi Khalighi, Michael Moseley, Gary K Steinberg, Greg Zaharchuk
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Cerebrovascular reactivity (CVR) reflects the CBF change to meet different physiological demands. The reference CVR technique is PET imaging with vasodilators but is inaccessible to most patients. DSC can measure transit time to evaluate patients suspected of stroke, but the use of gadolinium may cause side-effects. Arterial spin labeling (ASL) is a non-invasive MRI technique for CBF measurements. Here, we investigate the effectiveness of ASL with single and multiple post labeling delays (PLD) to replace PET and DSC for CVR and transit time mapping in 26 Moyamoya patients. Images were collected using simultaneous PET/MRI with acetazolamide. CVR, CBF, arterial transit time (ATT), and time-to-maximum (Tmax) were measured in different flow territories. Results showed that CVR was lower in occluded regions than normal regions (by 68 ± 12%, 52 ± 5%, and 56 ± 9%, for PET, single- and multi-PLD PCASL, respectively, all p 
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-03-03T05:25:17Z
      DOI: 10.1177/0271678X221083471
       
  • Comparison of three novel radiotracers for GluN2B-containing NMDA
           receptors in non-human primates: (R)-[11C]NR2B-Me, (R)-[18F]of-Me-NB1, and
           (S)-[18F]of-NB1

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      Authors: Kelly Smart, Ming-Qiang Zheng, Hazem Ahmed, Hanyi Fang, Yuping Xu, Lisheng Cai, Daniel Holden, Michael Kapinos, Ahmed Haider, Zachary Felchner, Jim R Ropchan, Gilles Tamagnan, Robert B Innis, Victor W Pike, Simon M Ametamey, Yiyun Huang, Richard E Carson
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      The NMDA receptor GluN2B subunit is a target of interest in neuropsychiatric disorders but to date there is no selective radiotracer available to quantify its availability in vivo. Here we report direct comparisons in non-human primates of three GluN2B-targeting radioligands: (R)-[11C]NR2B-Me, (R)-[18F]OF-Me-NB1, and (S)-[18F]OF-NB1. Plasma free fraction, metabolism, tissue distribution and kinetics, and quantitative kinetic modeling methods and parameters were evaluated in two adult rhesus macaques. Free fraction in plasma was 68%) blockade across the brain by the GluN2B-targeting drug Co-101,244 (0.25 mg/kg), including in the cerebellum. Time-activity curves were well-fitted by the one-tissue compartment model, with volume of distribution values of 20–40 mL/cm3 for (R)-[11C]NR2B-Me, 8–16 mL/cm3 for (R)-[18F]OF-Me-NB1, and 15–35 mL/cm3 for (S)-[18F]OF-NB1. Estimates of regional non-displaceable binding potential were in the range of 2–3 for (R)-[11C]NR2B-Me and (S)-[18F]-OF-NB1, and 0.5-1 for (R)-[18F]OF-Me-NB1. Altogether, each radiotracer showed an acceptable profile for quantitative imaging of GluN2B. (S)-[18F]OF-NB1 has particularly promising imaging characteristics for potential translation into humans. However, the source of unexpected displaceable binding in the cerebellum for each of these compounds requires further investigation.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-02-25T09:11:55Z
      DOI: 10.1177/0271678X221084416
       
  • Neurovascular coupling on trial: How the number of trials completed
           impacts the accuracy and precision of temporally derived neurovascular
           coupling estimates

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      Authors: Joel S Burma, Rowan K Van Roessel, Ibukunoluwa K Oni, Jeff F Dunn, Jonathan D Smirl
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Standard practices for quantifying neurovascular coupling (NVC) with transcranial Doppler ultrasound (TCD) require participants to complete one-to-ten repetitive trials. However, limited empirical evidence exists regarding how the number of trials completed influences the validity and reliability of temporally derived NVC metrics. Secondary analyses was performed on 60 young healthy participants (30 females/30 males) who completed eight cyclical eyes-closed (20-seconds), eyes-open (40-seconds) NVC trials, using the “Where’s Waldo'” visual paradigm. TCD data was obtained in posterior and middle cerebral arteries (PCA and MCA, respectively). The within-day (n = 11) and between-day (n = 17) reliability were assessed at seven- and three-time points, respectively. Repeat testing from the reliability aims were also used for the concurrent validity analysis (n = 160). PCA metrics (i.e., baseline, peak, percent increase, and area-under-the-curve) demonstrated five trials produced excellent intraclass correlation coefficient (ICC) 95% confidence intervals for validity and within-day reliability (>0.900), whereas between-day reliability was good-to-excellent (>0.750). Likewise, 95% confidence intervals for coefficient of variation (CoV) measures ranged from acceptable (
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-02-25T08:59:23Z
      DOI: 10.1177/0271678X221084400
       
  • Machine learning based analysis of stroke lesions on mouse tissue sections

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      Authors: Gerasimos Damigos, Evangelia I Zacharaki, Nefeli Zerva, Angelos Pavlopoulos, Konstantina Chatzikyrkou, Argyro Koumenti, Konstantinos Moustakas, Constantinos Pantos, Iordanis Mourouzis, Athanasios Lourbopoulos
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      An unbiased, automated and reliable method for analysis of brain lesions in tissue after ischemic stroke is missing. Manual infarct volumetry or by threshold-based semi-automated approaches is laborious, and biased to human error or biased by many false -positive and -negative data, respectively. Thereby, we developed a novel machine learning, atlas-based method for fully automated stroke analysis in mouse brain slices stained with 2% Triphenyltetrazolium-chloride (2% TTC), named “StrokeAnalyst”, which runs on a user-friendly graphical interface. StrokeAnalyst registers subject images on a common spatial domain (a novel mouse TTC- brain atlas of 80 average mathematical images), calculates pixel-based, tissue-intensity statistics (z-scores), applies outlier-detection and machine learning (Random-Forest) models to increase accuracy of lesion detection, and produces volumetry data and detailed neuroanatomical information per lesion. We validated StrokeAnalyst in two separate experimental sets using the filament stroke model. StrokeAnalyst detects stroke lesions in a rater-independent and reproducible way, correctly detects hemispheric volumes even in presence of post-stroke edema and significantly minimizes false-positive errors compared to threshold-based approaches (false-positive rate 1.2–2.3%, p 
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-02-25T08:53:40Z
      DOI: 10.1177/0271678X221083387
       
  • Altered functional connectivity during hypoglycaemia in type 1 diabetes

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      Authors: Peter Jacob, Munachiso Nwokolo, Sally M Cordon, Ian A Macdonald, Fernando O Zelaya, Stephanie A Amiel, Owen O’Daly, Pratik Choudhary
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Behavioural responses to hypoglycaemia require coordinated recruitment of broadly distributed networks of interacting brain regions. We investigated hypoglycaemia-related changes in brain connectivity in people without diabetes (ND) and with type 1 diabetes with normal (NAH) or impaired (IAH) hypoglycaemia awareness. Two-step hyperinsulinaemic hypoglycaemic clamps were performed in 14 ND, 15 NAH and 22 IAH participants. BOLD timeseries were acquired at euglycaemia (5.0 mmol/L) and hypoglycaemia (2.6 mmol/L), with symptom and counter-regulatory hormone measurements. We investigated hypoglycaemia-related connectivity changes using established seed regions for the default mode (DMN), salience (SN) and central executive (CEN) networks and regions whose activity is modulated by hypoglycaemia: the thalamus and right inferior frontal gyrus (RIFG). Hypoglycaemia-induced changes in the DMN, SN and CEN were evident in NAH (all p 
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-02-25T08:47:03Z
      DOI: 10.1177/0271678X221082911
       
  • Genome-wide association study of brain arteriolosclerosis

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      Authors: Lincoln MP Shade, Yuriko Katsumata, Timothy J Hohman, Kwangsik Nho, Andrew J Saykin, Shubhabrata Mukherjee, Kevin L Boehme, John SK Kauwe, Lindsay A Farrer, Gerard D Schellenberg, Jonathan L Haines, Richard P Mayeux, Julie A Schneider, Peter T Nelson, David W Fardo
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Brain arteriolosclerosis (B-ASC) is characterized by pathologically altered brain parenchymal arterioles. B-ASC is associated with cognitive impairment and increased likelihood of clinical dementia. To date, no study has been conducted on genome-wide genetic risk of autopsy-proven B-ASC. We performed a genome-wide association study (GWAS) of the B-ASC phenotype using multiple independent aged neuropathologic cohorts. Included in the study were participants with B-ASC autopsy and genotype data available from the NACC, ROSMAP, ADNI, and ACT data sets. Initial Stage 1 GWAS (n = 3382) and Stage 2 mega-analysis (n = 4569) were performed using data from the two largest cohorts (NACC and ROSMAP). Replication of top variants and additional Stage 3 mega-analysis were performed incorporating two smaller cohorts (ADNI and ACT). Lead variants in the top two loci in the Stage 2 mega-analysis (rs7902929, p = [math]; rs2603462, p = [math]) were significant in the ADNI cohort (rs7902929, p = [math]; rs2603462, p = [math]). The rs2603462 lead variant colocalized with ELOVL4 expression in the cerebellum (posterior probability = 90.1%). Suggestive associations were also found near SORCS1 and SORCS3. We thus identified putative loci associated with B-ASC risk, but additional replication is needed.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-02-14T12:53:39Z
      DOI: 10.1177/0271678X211066299
       
  • Increased capillary stalling is associated with endothelial glycocalyx
           loss in subcortical vascular dementia

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      Authors: Jin-Hui Yoon, Paul Shin, Jongyoon Joo, Gaon S Kim, Wang-Yuhl Oh, Yong Jeong
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Proper regulation and patency of cerebral microcirculation are crucial for maintaining a healthy brain. Capillary stalling, i.e., the brief interruption of microcirculation has been observed in the normal brain and several diseases related to microcirculation. We hypothesized that endothelial glycocalyx, which is located on the luminal side of the vascular endothelium and involved in cell-to-cell interaction regulation in peripheral organs, is also related to cerebral capillary stalling. We measured capillary stalling and the cerebral endothelial glycocalyx (cEG) in male mice using in vivo optical coherence tomography angiography (OCT-A) and two-photon microscopy. Our findings revealed that some capillary segments were prone to capillary stalling and had less cEG. In addition, we demonstrated that the enzymatic degradation of the cEG increased the capillary stalling, mainly by leukocyte plugging. Further, we noted decreased cEG along with increased capillary stalling in a mouse model of subcortical vascular dementia (SVaD) with impaired cortical microcirculation. Moreover, gene expression related to cEG production or degradation changed in the SVaD model. These results indicate that cEG mediates capillary stalling and impacts cerebral blood flow and is involved in the pathogenesis of SVaD.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-02-10T07:12:48Z
      DOI: 10.1177/0271678X221076568
       
  • Treatment with apocynin selectively restores hippocampal arteriole
           function and seizure-induced hyperemia in a model of preeclampsia

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      Authors: Marilyn J Cipolla, Sarah Tremble, Nicole DeLance, Dana Allison, Abbie C Johnson
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with neurovascular dysfunction, cognitive impairment and increased seizure susceptibility. Here, we sought to determine if treatment of experimental PE (ePE) rats with apocynin could prevent hippocampal arteriolar (HA) dysfunction and impaired seizure-induced hyperemia within the hippocampus, a brain region central to cognition and seizure generation. Isolated and pressurized HAs from Sprague Dawley rats that were normal pregnant (Preg; n = 8), ePE (n = 8) or ePE treated with apocynin for 2 weeks of gestation (ePE + apo; n = 8) were compared. Hippocampal blood flow (n = 6/group) was measured using hydrogen clearance before and during seizure. Aorta elastin was quantified using histochemistry. ePE was associated with HA dysfunction including reduced contraction to endothelin-1 and diminished dilation to the endothelium-dependent vasodilator NS309 that was prevented by apocynin. However, apocynin had no effect on ePE-induced impairment of dilation to the nitric oxide donor sodium nitroprusside, but increased myogenic tone and substantially increased HA distensibility. Seizure-induced hyperemia was impaired in ePE rats that was restored by apocynin. Aorta from ePE rats had reduced elastin content, suggesting large artery stiffness, that was unaffected by apocynin. Thus, while apocynin partially prevented HA dysfunction, its restoration of functional hyperemia may be protective of seizure-induced injury during eclampsia.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-02-09T10:10:50Z
      DOI: 10.1177/0271678X221080092
       
  • Rates of pyruvate carboxylase, glutamate and GABA neurotransmitter
           cycling, and glucose oxidation in multiple brain regions of the awake rat
           using a combination of [2-13C]/[1-13C]glucose infusion and 1H-[13C]NMR ex
           vivo

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      Authors: Laura M McNair, Graeme F Mason, Golam MI Chowdhury, Lihong Jiang, Xiaoxian Ma, Douglas L Rothman, Helle S Waagepetersen, Kevin L Behar
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Anaplerosis occurs predominately in astroglia through the action of pyruvate carboxylase (PC). The rate of PC (Vpc) has been reported for cerebral cortex (or whole brain) of awake humans and anesthetized rodents, but regional brain rates remain largely unknown and, hence, were subjected to investigation in the current study. Awake male rats were infused with either [2-13C]glucose or [1-13C]glucose (n = 27/30) for 8, 15, 30, 60 or 120 min, followed by rapid euthanasia with focused-beam microwave irradiation to the brain. Blood plasma and extracts of cerebellum, hippocampus, striatum, and cerebral cortex were analyzed by 1H-[13C]-NMR to establish 13C-enrichment time courses for glutamate-C4,C3,C2, glutamine-C4,C3, GABA-C2,C3,C4 and aspartate-C2,C3. Metabolic rates were determined by fitting a three-compartment metabolic model (glutamatergic and GABAergic neurons and astroglia) to the eighteen time courses. Vpc varied by 44% across brain regions, being lowest in the cerebellum (0.087 ± 0.004 µmol/g/min) and highest in striatum (0.125 ± 0.009) with intermediate values in cerebral cortex (0.106 ± 0.005) and hippocampus (0.114 ± 0.005). Vpc constituted 13–19% of the oxidative glucose consumption rate. Combination of cerebral cortical data with literature values revealed a positive correlation between Vpc and the rates of glutamate/glutamine-cycling and oxidative glucose consumption, respectively, consistent with earlier observations.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-01-20T12:44:33Z
      DOI: 10.1177/0271678X221074211
       
  • Mapping oxidative metabolism in the human brain with calibrated fMRI in
           health and disease

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      Authors: J Jean Chen, Biranavan Uthayakumar, Fahmeed Hyder
      First page: 1139
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Conventional functional MRI (fMRI) with blood-oxygenation level dependent (BOLD) contrast is an important tool for mapping human brain activity non-invasively. Recent interest in quantitative fMRI has renewed the importance of oxidative neuroenergetics as reflected by cerebral metabolic rate of oxygen consumption (CMRO2) to support brain function. Dynamic CMRO2 mapping by calibrated fMRI require multi-modal measurements of BOLD signal along with cerebral blood flow (CBF) and/or volume (CBV). In human subjects this “calibration” is typically performed using a gas mixture containing small amounts of carbon dioxide and/or oxygen-enriched medical air, which are thought to produce changes in CBF (and CBV) and BOLD signal with minimal or no CMRO2 changes. However non-human studies have demonstrated that the “calibration” can also be achieved without gases, revealing good agreement between CMRO2 changes and underlying neuronal activity (e.g., multi-unit activity and local field potential). Given the simpler set-up of gas-free calibrated fMRI, there is evidence of recent clinical applications for this less intrusive direction. This up-to-date review emphasizes technological advances for such translational gas-free calibrated fMRI experiments, also covering historical progression of the calibrated fMRI field that is impacting neurological and neurodegenerative investigations of the human brain.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-03-17T06:50:58Z
      DOI: 10.1177/0271678X221077338
       
  • Choroid plexus function in neurological homeostasis and disorders: The
           awakening of the circadian clocks and orexins

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      Authors: Jennaya Christensen, Crystal Li, Richelle Mychasiuk
      First page: 1163
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      As research regarding the role of circadian rhythms, sleep, and the orexinergic system in neurodegenerative diseases is growing, it is surprising that the choroid plexus (CP) remains underappreciated in this realm. Despite its extensive role in the regulation of circadian rhythms and orexinergic signalling, as well as acting as the primary conduit between cerebrospinal fluid (CSF) and the circulatory system, providing a mechanism by which toxic waste molecules can be removed from the brain, the CP has been largely unexplored in neurodegeneration. In this review, we explore the role of the CP in maintaining brain homeostasis and circadian rhythms, regulating CSF dynamics, and how these functions change across the lifespan, from development to senescence. In addition, we examine the relationship between the CP, orexinergic signalling, and the glymphatic system, highlighting gaps in the literature and areas that require immediate exploration. Finally, we assess current knowledge, including possible therapeutic strategies, regarding the role of the CP in neurological disorders, such as traumatic brain injury, migraine, Alzheimer’s disease, and multiple sclerosis.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-03-17T07:01:58Z
      DOI: 10.1177/0271678X221082786
       
  • Nox2 underpins microvascular inflammation and vascular contributions to
           cognitive decline

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      Authors: Alessio Alfieri, Juraj Koudelka, Mosi Li, Sanny Scheffer, Jessica Duncombe, Andrea Caporali, Rajesh N Kalaria, Colin Smith, Ajay M Shah, Karen Horsburgh
      First page: 1176
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Chronic microvascular inflammation and oxidative stress are inter-related mechanisms underpinning white matter disease and vascular cognitive impairment (VCI). A proposed mediator is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2), a major source of reactive oxygen species (ROS) in the brain. To assess the role of Nox2 in VCI, we studied a tractable model with white matter pathology and cognitive impairment induced by bilateral carotid artery stenosis (BCAS). Mice with genetic deletion of Nox2 (Nox2 KO) were compared to wild-type (WT) following BCAS. Sustained BCAS over 12 weeks in WT mice induced Nox2 expression, indices of microvascular inflammation and oxidative damage, along with white matter pathology culminating in a marked cognitive impairment, which were all protected by Nox2 genetic deletion. Neurovascular coupling was impaired in WT mice post-BCAS and restored in Nox2 KO mice. Increased vascular expression of chemoattractant mediators, cell-adhesion molecules and endothelial activation factors in WT mice post-BCAS were ameliorated by Nox2 deficiency. The clinical relevance was confirmed by increased vascular Nox2 and indices of microvascular inflammation in human post-mortem subjects with cerebral vascular disease. Our results support Nox2 activity as a critical determinant of VCI, whose targeting may be of therapeutic benefit in cerebral vascular disease.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-02-01T12:12:11Z
      DOI: 10.1177/0271678X221077766
       
  • A flow-diffusion model of oxygen transport for quantitative mapping of
           

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      Authors: Antonio M Chiarelli, Michael Germuska, Hannah Chandler, Rachael Stickland, Eleonora Patitucci, Emma Biondetti, Daniele Mascali, Neeraj Saxena, Sharmila Khot, Jessica Steventon, Catherine Foster, Ana E Rodríguez-Soto, Erin Englund, Kevin Murphy, Valentina Tomassini, Felix W Wehrli, Richard G Wise
      First page: 1192
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      One promising approach for mapping CMRO2 is dual-calibrated functional MRI (dc-fMRI). This method exploits the Fick Principle to combine estimates of CBF from ASL, and OEF derived from BOLD-ASL measurements during arterial O2 and CO2 modulations. Multiple gas modulations are required to decouple OEF and deoxyhemoglobin-sensitive blood volume. We propose an alternative single gas calibrated fMRI framework, integrating a model of oxygen transport, that links blood volume and CBF to OEF and creates a mapping between the maximum BOLD signal, CBF and OEF (and CMRO2). Simulations demonstrated the method’s viability within physiological ranges of mitochondrial oxygen pressure, PmO2, and mean capillary transit time. A dc-fMRI experiment, performed on 20 healthy subjects using O2 and CO2 challenges, was used to validate the approach. The validation conveyed expected estimates of model parameters (e.g., low PmO2), with spatially uniform OEF maps (grey matter, GM, OEF spatial standard deviation ≈ 0.13). GM OEF estimates obtained with hypercapnia calibrated fMRI correlated with dc-fMRI (r = 0.65, p = 2·10−3). For 12 subjects, OEF measured with dc-fMRI and the single gas calibration method were correlated with whole-brain OEF derived from phase measures in the superior sagittal sinus (r = 0.58, p = 0.048; r = 0.64, p = 0.025 respectively). Simplified calibrated fMRI using hypercapnia holds promise for clinical application.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-02-02T12:51:09Z
      DOI: 10.1177/0271678X221077332
       
  • SIRT1 mediates hypoxic postconditioning- and resveratrol-induced
           protection against functional connectivity deficits after subarachnoid
           hemorrhage

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      Authors: Julian V Clarke, Lindsey M Brier, Rachel M Rahn, Deepti Diwan, Jane Y Yuan, Annie R Bice, Shin-ichiro Imai, Ananth K Vellimana, Joseph P Culver, Gregory J Zipfel
      First page: 1210
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Functional connectivity (FC) is a sensitive metric that provides a readout of whole cortex coordinate neural activity in a mouse model. We examine the impact of experimental SAH modeled through endovascular perforation, and the effectiveness of subsequent treatment on FC, through three key questions: 1) Does the endovascular perforation model of SAH induce deficits in FC; 2) Does exposure to hypoxic conditioning provide protection against these FC deficits and, if so, is this neurovascular protection SIRT1-mediated; and 3) does treatment with the SIRT1 activator resveratrol alone provide protection against these FC deficits' Cranial windows were adhered on skull-intact mice that were then subjected to either sham or SAH surgery and either left untreated or treated with hypoxic post-conditioning (with or without EX527) or resveratrol for 3 days. Mice were imaged 3 days post-SAH/sham surgery, temporally aligned with the onset of major SAH sequela in mice. Here we show that the endovascular perforation model of SAH induces global and network-specific deficits in FC by day 3, corresponding with the time frame of DCI in mice. Hypoxic conditioning provides SIRT1-mediated protection against these network-specific FC deficits post-SAH, as does treatment with resveratrol. Conditioning-based strategies provide multifaceted neurovascular protection in experimental SAH.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-02-09T10:07:44Z
      DOI: 10.1177/0271678X221079902
       
  • Post-mortem correlates of Virchow-Robin spaces detected on in vivo MRI

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      Authors: Lukas Haider, Simon Hametner, Verena Endmayr, Stephanie Mangesius, Andrea Eppensteiner, Josa M Frischer, Juan Eugenio Iglesias, Frederik Barkhof, Gregor Kasprian
      First page: 1224
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      The purpose of our study is to quantify the extent to which Virchow-Robin spaces (VRS) detected on in vivo MRI are reproducible by post-mortem MRI.Double Echo Steady State 3T MRIs were acquired post-mortem in 49 double- and 32 single-hemispheric formalin-fixed brain sections from 12 patients, who underwent conventional diagnostic 1.5 or 3T MRI in median 22 days prior to death (25% to 75%: 12 to 134 days). The overlap of in vivo and post-mortem VRS segmentations was determined accounting for potential confounding factors.The reproducibility of VRS found on in vivo MRI by post-mortem MRI, in the supratentorial white matter was in median 80% (25% to 75%: 60 to 100). A lower reproducibility was present in the basal ganglia, with a median of 47% (25% to 75%: 30 to 50).VRS segmentations were histologically confirmed in one double hemispheric section.Overall, the majority of VRS found on in vivo MRI was stable throughout death and formalin fixation, emphasizing the translational potential of post-mortem VRS studies.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-05-18T03:54:28Z
      DOI: 10.1177/0271678X211067455
       
  • Impact of meningeal uptake and partial volume correction techniques on
           [18F]MK-6240 binding in aMCI patients and healthy controls

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      Authors: Nathalie Mertens, Laura Michiels, Greet Vanderlinden, Mathieu Vandenbulcke, Robin Lemmens, Koen Van Laere, Michel Koole
      First page: 1236
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      [18F]MK-6240 is a second-generation tau PET-tracer to quantify neurofibrillary tangles in-vivo. However, individually variable levels of meningeal uptake induce spill-in-effects into the cortex, complicating [18F]MK-6240 PET quantification. Group SUVR differences between age-matched HC subgroups with varying extracerebral uptake (EC-low/mixed/high), and between aMCI and each HC subgroup were assessed without and with partial volume correction (PVC). Both Müller-Gartner (MG-)PVC and region-based voxelwise (RBV-)PVC, with the latter also correcting for extracerebral spill-in-effects, were implemented. Between HC groups, where no differences are to be expected, HC EC-high showed spill-in differences compared to HC EC-low when no PVC was applied while for MG-PVC, differences were reduced and, for RBV-PVC, no statistically significant differences were observed. Between aMCI and HC, cortical SUVR differences were statistically significant, both without and with PVC, but modulated by the varying meningeal uptake in HC subgroups when no PVC was applied. After applying PVC, correlations to clinical parameters improved and effect sizes between HC and aMCI increased, independent of the HC-subgroup. Therefore, appropriate PVC with correction for extracerebral spill-in-effects is recommended to minimize the impact of varying meningeal uptake on cortical differences between HC and aMCI.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-01-22T07:45:33Z
      DOI: 10.1177/0271678X221076023
       
  • Changes in neurovascular coupling with cerebral perfusion pressure
           indicate a link to cerebral autoregulation

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      Authors: Deepshikha Acharya, Alexander Ruesch, Samantha Schmitt, Jason Yang, Matthew A Smith, Jana M Kainerstorfer
      First page: 1247
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Cerebral autoregulation ensures a stable average blood supply to brain tissue across steady state cerebral perfusion pressure (CPP) levels. Neurovascular coupling, in turn, relies on sufficient blood flow to meet neuronal demands during activation. These mechanisms break down in pathologies where extreme levels of CPP can cause dysregulation in cerebral blood flow. Here, we experimentally tested the influence of changes in CPP on neurovascular coupling in a hydrocephalus-type non-human primate model (n = 3). We recorded local neural and vascular evoked responses to a checkerboard visual stimulus, non-invasively, using electroencephalography and near-infrared spectroscopy respectively. The evoked signals showed changes in various waveform features in the visual evoked potentials and the hemodynamic responses, with CPP. We further used these signals to fit for a hemodynamic response function (HRF) to describe neurovascular coupling. We estimated n = 26 distinct HRFs at a subset of CPP values ranging from 40–120 mmHg across all subjects. The HRFs, when compared to a subject dependent healthy baseline (CPP 70–90 mmHg) HRF, showed significant changes in shape with increasing CPP (ρCPP = −0.55, p-valueCPP = 0.0049). Our study provides preliminary experimental evidence on the relationship between neurovascular coupling and CPP changes, especially when beyond the limits of static autoregulation.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-01-26T07:25:56Z
      DOI: 10.1177/0271678X221076566
       
  • Characterizing region-specific glucose metabolic profile of the rodent
           brain using Seahorse XFe96 analyzer

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      Authors: Linshu Wang, Kiran Chaudhari, Ali Winters, Yuanhong Sun, Ran Liu, Shao-Hua Yang
      First page: 1259
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      The brain is highly complex with diverse structural characteristics in accordance with specific functions. Accordingly, differences in regional function, cellular compositions, and active metabolic pathways may link to differences in glucose metabolism at different brain regions. In the current study, we optimized an acute biopsy punching method and characterized region-specific glucose metabolism of rat and mouse brain by a Seahorse XFe96 analyzer. We demonstrated that 0.5 mm diameter tissue punches from 180-µm thick brain sections allow metabolic measurements of anatomically defined brain structures using Seahorse XFe96 analyzer. Our result indicated that the cerebellum displays a more quiescent phenotype of glucose metabolism than cerebral cortex, basal ganglia, and hippocampus. In addition, the cerebellum has higher AMPK activation than other brain regions evidenced by the expression of pAMPK, upstream pLKB1, and downstream pACC. Furthermore, rodent brain has relatively low mitochondrial oxidative phosphorylation efficiency with up to 30% of respiration linked to proton leak. In summary, our study discovered region-specific glucose metabolic profile and relative high proton leak coupled respiration in the brain. Our study warrants future research on spatial mapping of the brain glucose metabolism in physiological and pathological conditions and exploring the mechanisms and significance of mitochondrial uncoupling in the brain.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-01-26T07:32:32Z
      DOI: 10.1177/0271678X221077341
       
  • Effect of vascular amyloid on white matter disease is mediated by vascular
           dysfunction in cerebral amyloid angiopathy

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      Authors: Elif Gokcal, Mitchell J Horn, J. Alex Becker, Alvin S Das, Kristin Schwab, Alessandro Biffi, Natalia Rost, Jonathan Rosand, Anand Viswanathan, Jonathan R Polimeni, Keith A Johnson, Steven M Greenberg, M Edip Gurol
      First page: 1272
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      We postulated that vascular dysfunction mediates the relationship between amyloid load and white matter hyperintensities (WMH) in cerebral amyloid angiopathy (CAA). Thirty-eight cognitively healthy patients with CAA (mean age 70 ± 7.1) were evaluated. WMH was quantified and expressed as percent of total intracranial volume (pWMH) using structural MRI. Mean global cortical Distribution Volume Ratio representing Pittsburgh Compound B (PiB) uptake (PiB-DVR) was calculated from PET scans. Time-to-peak [TTP] of blood oxygen level-dependent response to visual stimulation was used as an fMRI measure of vascular dysfunction. Higher PiB-DVR correlated with prolonged TTP (r = 0.373, p = 0.021) and higher pWMH (r = 0.337, p = 0.039). Prolonged TTP also correlated with higher pWMH (r = 0.485, p = 0.002). In a multivariate linear regression model, TTP remained independently associated with pWMH (p = 0.006) while PiB-DVR did not (p = 0.225). In a bootstrapping model, TTP had a significant indirect effect (ab = 0.97, 95% CI: 0.137–2.461), supporting that the association between PiB-DVR and pWMH is mediated by TTP response. There was no longer a direct effect independent of the hypothesized pathway. Our study suggests that the effect of vascular amyloid load on white matter disease is mediated by vascular dysfunction in CAA. Amyloid lowering strategies might prevent pathophysiological processes leading to vascular dysfunction, therefore limiting ischemic brain injury.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-01-28T09:02:45Z
      DOI: 10.1177/0271678X221076571
       
  • A cluster of blood-based protein biomarkers reflecting coagulation relates
           to the burden of cerebral small vessel disease

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      Authors: Sanne Kuipers, L Malin Overmars, Bram van Es, Jeroen de Bresser, Esther E Bron, Imo E Hoefer, L Jaap Kappelle, Charlotte E Teunissen, Geert Jan Biessels, Saskia Haitjema
      First page: 1282
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Biological processes underlying cerebral small vessel disease (cSVD) are largely unknown. We hypothesized that identification of clusters of inter-related bood-based biomarkers that are associated with the burden of cSVD provides leads on underlying biological processes. In 494 participants (mean age 67.6 ± 8.7 years; 36% female; 75% cardiovascular diseases; 25% reference participants) we assessed the relation between 92 blood-based biomarkers from the OLINK cardiovascular III panel and cSVD, using cluster-based analyses. We focused particularly on white matter hyperintensities (WMH). Nineteen biomarkers individually correlated with WMH ratio (r range: 0.16–0.27, Bonferroni corrected p-values
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-01-28T06:39:59Z
      DOI: 10.1177/0271678X221077339
       
  • Neuronal GPR81 regulates developmental brain angiogenesis and promotes
           brain recovery after a hypoxic ischemic insult

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      Authors: Prabhas Chaudhari, Ankush Madaan, José Carlos Rivera, Iness Charfi, Tiffany Habelrih, Xin Hou, Mohammad Nezhady, Gregory Lodygensky, Graciela Pineyro, Thierry Muanza, Sylvain Chemtob
      First page: 1294
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Perinatal hypoxic/ischemic (HI) brain injury is a major clinical problem with devastating neurodevelopmental outcomes in neonates. During HI brain injury, dysregulated factor production contributes to microvascular impairment. Glycolysis-derived lactate accumulated during ischemia has been proposed to protect against ischemic injury, but its mechanism of action is poorly understood. Herein, we hypothesize that lactate via its G-protein coupled receptor (GPR81) controls postnatal brain angiogenesis and plays a protective role after HI injury. We show that GPR81 is predominantly expressed in neurons of the cerebral cortex and hippocampus. GPR81-null mice displayed a delay in cerebral microvascular development linked to reduced levels of various major angiogenic factors and augmented expression of anti-angiogenic Thrombospondin-1 (TSP-1) in comparison to their WT littermates. Coherently, lactate stimulation induced an increase in growth factors (VEGF, Ang1 and 2, PDGF) and reduced TSP-1 expression in neurons, which contributed to accelerating angiogenesis. HI injury in GPR81-null animals curtailed vascular density and consequently increased infarct size compared to changes seen in WT mice; conversely intracerebroventricular lactate injection increased vascular density and diminished infarct size in WT but not in GPR81-null mice. Collectively, we show that lactate acting via GPR81 participates in developmental brain angiogenesis, and attenuates HI injury by restoring compromised microvasculature.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-02-02T12:57:43Z
      DOI: 10.1177/0271678X221077499
       
  • Assessment of motion and model bias on the detection of dopamine response
           to behavioral challenge

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      Authors: Michael A Levine, Joseph B Mandeville, Finnegan Calabro, David Izquierdo-Garcia, Daniel B Chonde, Kevin T Chen, Inki Hong, Julie C Price, Beatriz Luna, Ciprian Catana
      First page: 1309
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Compartmental modeling analysis of 11C-raclopride (RAC) PET data can be used to measure the dopaminergic response to intra-scan behavioral tasks. Bias in estimates of binding potential (BPND) and its dynamic changes (ΔBPND) can arise both when head motion is present and when the compartmental model used for parameter estimation deviates from the underlying biology. The purpose of this study was to characterize the effects of motion and model bias within the context of a behavioral task challenge, examining the impacts of different mitigation strategies. Seventy healthy adults were administered bolus plus constant infusion RAC during a simultaneous PET/magnetic resonance (MR) scan with a reward task experiment. BPND and ΔBPND were estimated using an extension of the Multilinear Reference Tissue Model (E-MRTM2) and a new method (DE-MRTM2) was proposed to selectively discount the contribution of the initial uptake period. Motion was effectively corrected with a standard frame-based approach, which performed equivalently to a more complex reconstruction-based approach. DE-MRTM2 produced estimates of ΔBPND in putamen and nucleus accumbens that were significantly different from those estimated from E-MRTM2, while also decoupling ΔBPND values from first-pass k2′ estimation and removing skew in the spatial bias distribution of parametric ΔBPND estimates within the striatum.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-02-04T01:01:36Z
      DOI: 10.1177/0271678X221078616
       
  • Efficacy and safety of spot heating and ultrasound irradiation on in vitro
           and in vivo thrombolysis models

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      Authors: Ryuta Morihara, Toru Yamashita, Yosuke Osakada, Tian Feng, Xinran Hu, Yusuke Fukui, Koh Tadokoro, Mami Takemoto, Koji Abe
      First page: 1322
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      The feasibility of transcranial sonothrombolysis has been demonstrated, although little is known about the relationships between thermal or mechanical mechanisms and thrombolytic outcomes. Therefore, the present study aims to reveal the effect and safety of temperature and ultrasound through in vitro and in vivo thrombolysis models. Artificial clots in microtubes were heated in a water bath or sonicated by ultrasound irradiation, and then clots weight decrease with rising temperature and sonication time was confirmed. In the in vitro thrombotic occlusion model, based on spot heating, clot volume was reduced and clots moved to the distal side, followed by recanalization of the occlusion. In the in vivo study, the common carotid artery of rats was exposed to a spot heater or to sonication. No brain infarct or brain blood barrier disruption was shown, but endothelial junctional dysintegrity and an inflammatory response in the carotid artery were detected. The present spot heating and ultrasound irradiation models seem to be effective for disintegrating clots in vitro, but the safety of the in vivo model was not fully supported by the data. However, the data indicates that a shorter time exposure could be less invasive than a longer exposure.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-02-08T08:25:00Z
      DOI: 10.1177/0271678X221079127
       
  • Chronic cerebral hypoperfusion and blood-brain barrier disruption in
           uninjured brain areas of rhesus monkeys subjected to transient ischemic
           stroke

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      Authors: Yingqian Zhang, Bangcheng Zhao, Qi Lai, Qinxi Li, Xun Tang, Yinbing Zhang, Zhixiang Pan, Qiang Gao, Zhihui Zhong
      First page: 1335
      Abstract: Journal of Cerebral Blood Flow & Metabolism, Ahead of Print.
      Blood-brain barrier (BBB) disruption is a pivotal pathophysiological process in ischemic stroke. Although temporal changes in BBB permeability during the acute phase have been widely studied, little is known about the chronic phase of cerebrovascular changes that may have a large impact on the long-term outcome. Therefore, this study was aimed to measure cerebral vascular abnormalities using CT perfusion in nine rhesus monkeys subjected to transient middle cerebral artery occlusion (tMCAO) for ≥1 year (MCAO-1Y+). The level of cerebral perfusion demonstrated by mean transit time was significantly higher in the ipsilateral caudate nucleus, white matter, thalamus, hippocampus, and contralateral thalamus in MCAO-1Y+ compared with the other nine age-matched control monkeys. The increase in BBB permeability measured through the permeability surface was found in the same ten regions of interest ipsilaterally and contralaterally. We also found decreased levels of Aβ 42/40 ratio in the cerebrospinal fluid (CSF), suggesting a potential link between post-MCAO cognitive decline and Aβ metabolism. Overall, we demonstrated significant cerebral hypoperfusion, BBB disruption, and CSF Aβ decrease during the rehabilitation stage of ischemic stroke in a non-human primate model. Future studies are needed to elucidate the cause-effect relationship between cerebrovascular disruptions and long-term neurological deficits.
      Citation: Journal of Cerebral Blood Flow & Metabolism
      PubDate: 2022-02-09T01:09:47Z
      DOI: 10.1177/0271678X221078065
       
 
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