Journal: J Cereb Blood Flow Metab

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Abstract

The INfoMATAS project: Methods for assessing cerebral autoregulation in stroke.

Simpson DM, Payne SJ, Panerai RB
Cerebral autoregulation refers to the physiological mechanism that aims to maintain blood flow to the brain approximately constant when blood pressure changes. Impairment of this protective mechanism has been linked to a number of serious clinical conditions, including carotid stenosis, head trauma, subarachnoid haemorrhage and stroke. While the concept and experimental evidence is well established, methods for the assessment of autoregulation in individual patients remains an open challenge, with no gold-standard having emerged. In the current review paper, we will outline some of the basic concepts of autoregulation, as a foundation for experimental protocols and signal analysis methods used to extract indexes of cerebral autoregulation. Measurement methods for blood flow and pressure are discussed, followed by an outline of signal pre-processing steps. An outline of the data analysis methods is then provided, linking the different approaches through their underlying principles and rationale. The methods cover correlation based approaches (e.g. Mx) through Transfer Function Analysis to non-linear, multivariate and time-variant approaches. Challenges in choosing which method may be \'best\' and some directions for ongoing and future research conclude this work.



J Cereb Blood Flow Metab: 18 Jul 2021:271678X211029049; epub ahead of print
Simpson DM, Payne SJ, Panerai RB
J Cereb Blood Flow Metab: 18 Jul 2021:271678X211029049; epub ahead of print | PMID: 34279146
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Abstract

A CBF decrease in the left supplementary motor areas: New insight into postoperative pediatric cerebellar mutism syndrome using arterial spin labeling perfusion MRI.

Boisgontier J, Fillon L, Rutten C, Saitovitch A, ... Boddaert N, Puget S
Postoperative pediatric cerebellar mutism syndrome (pCMS), characterized mainly by delayed onset transient mutism is a poorly understood complication that may occur after pediatric medulloblastoma (MB) resection. Our aim was to investigate postoperative changes in whole-brain cerebral blood flow (CBF) at rest in pCMS patients using arterial spin labeling (ASL) perfusion imaging. This study compared preoperative and postoperative T2-weighted signal abnormalities and CBF using a voxel-wise, whole-brain analysis in 27 children undergoing MB resection, including 11 patients who developed mutism and 16 who did not. Comparison of postoperative T2 signal abnormalities between patients who developed pCMS (mean age 7.0 years) and those who did not showed that pCMS (mean age 8.9 years) patients were significantly more likely to present with T2-weighted hyperintensities in the right dentate nucleus (DN) (p = 0.02). Comparison of preoperative and postoperative CBF in patients with pCMS showed a significant postoperative CBF decrease in the left pre-supplementary motor area (pre-SMA) (p = 0.007) and SMA (p = 0.009). In patients who did not develop pCMS, no significant differences were observed. Findings provide evidence of an association between pCMS, injury to the right DN, and left pre-SMA/SMA hypoperfusion, areas responsible for speech. This supports the relevance of CBF investigations in pCMS.



J Cereb Blood Flow Metab: 13 Jul 2021:271678X211031321; epub ahead of print
Boisgontier J, Fillon L, Rutten C, Saitovitch A, ... Boddaert N, Puget S
J Cereb Blood Flow Metab: 13 Jul 2021:271678X211031321; epub ahead of print | PMID: 34259072
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Abstract

Evaluation of [F]-JNJ-64326067-AAA tau PET tracer in humans.

Baker SL, Provost K, Thomas W, Whitman AJ, ... Rabinovici GD, Jagust WJ
The [18F]-JNJ-64326067-AAA ([18F]-JNJ-067) tau tracer was evaluated in healthy older controls (HCs), mild cognitive impairment (MCI), Alzheimer\'s disease (AD), and progressive supranuclear palsy (PSP) participants. Seventeen subjects (4 HCs, 5 MCIs, 5 ADs, and 3 PSPs) received a [11C]-PIB amyloid PET scan, and a tau [18F]-JNJ-067 PET scan 0-90 minutes post-injection. Only MCIs and ADs were amyloid positive. The simplified reference tissue model, Logan graphical analysis distribution volume ratio, and SUVR were evaluated for quantification. The [18F]-JNJ-067 tau signal relative to the reference region continued to increase to 90 min, indicating the tracer had not reached steady state. There was no significant difference in any bilateral ROIs for MCIs or PSPs relative to HCs; AD participants showed elevated tracer relative to controls in most cortical ROIs (P < 0.05). Only AD participants showed elevated retention in the entorhinal cortex. There was off-target signal in the putamen, pallidum, thalamus, midbrain, superior cerebellar gray, and white matter. [18F]-JNJ-067 significantly correlated (p < 0.05) with Mini-Mental State Exam in entorhinal cortex and temporal meta regions. There is clear binding of [18F]-JNJ-067 in AD participants. Lack of binding in HCs, MCIs and PSPs suggests [18F]-JNJ-067 may not bind to low levels of AD-related tau or 4 R tau.



J Cereb Blood Flow Metab: 13 Jul 2021:271678X211031035; epub ahead of print
Baker SL, Provost K, Thomas W, Whitman AJ, ... Rabinovici GD, Jagust WJ
J Cereb Blood Flow Metab: 13 Jul 2021:271678X211031035; epub ahead of print | PMID: 34259071
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Abstract

Integrative cerebral blood flow regulation in ischemic stroke.

Fan JL, Brassard P, Rickards CA, Nogueira RC, ... Fisher JP, Tzeng YC
Optimizing cerebral perfusion is key to rescuing salvageable ischemic brain tissue. Despite being an important determinant of cerebral perfusion, there are no effective guidelines for blood pressure (BP) management in acute stroke. The control of cerebral blood flow (CBF) involves a myriad of complex pathways which are largely unaccounted for in stroke management. Due to its unique anatomy and physiology, the cerebrovascular circulation is often treated as a stand-alone system rather than an integral component of the cardiovascular system. In order to optimize the strategies for BP management in acute ischemic stroke, a critical reappraisal of the mechanisms involved in CBF control is needed. In this review, we highlight the important role of collateral circulation and re-examine the pathophysiology of CBF control, namely the determinants of cerebral perfusion pressure gradient and resistance, in the context of stroke. Finally, we summarize the state of our knowledge regarding cardiovascular and cerebrovascular interaction and explore some potential avenues for future research in ischemic stroke.



J Cereb Blood Flow Metab: 13 Jul 2021:271678X211032029; epub ahead of print
Fan JL, Brassard P, Rickards CA, Nogueira RC, ... Fisher JP, Tzeng YC
J Cereb Blood Flow Metab: 13 Jul 2021:271678X211032029; epub ahead of print | PMID: 34259070
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Abstract

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

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



J Cereb Blood Flow Metab: 13 Jul 2021:271678X211028680; epub ahead of print
Pu H, Ma C, Zhao Y, Wang Y, ... Bennett MV, Chen J
J Cereb Blood Flow Metab: 13 Jul 2021:271678X211028680; epub ahead of print | PMID: 34259069
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Abstract

Deep-learning-based attenuation correction in dynamic [O]HO studies using PET/MRI in healthy volunteers.

Puig O, Henriksen OM, Andersen FL, Lindberg U, ... Law I, Ladefoged CN
Quantitative [15O]H2O positron emission tomography (PET) is the accepted reference method for regional cerebral blood flow (rCBF) quantification. To perform reliable quantitative [15O]H2O-PET studies in PET/MRI scanners, MRI-based attenuation-correction (MRAC) is required. Our aim was to compare two MRAC methods (RESOLUTE and DeepUTE) based on ultrashort echo-time with computed tomography-based reference standard AC (CTAC) in dynamic and static [15O]H2O-PET. We compared rCBF from quantitative perfusion maps and activity concentration distribution from static images between AC methods in 25 resting [15O]H2O-PET scans from 14 healthy men at whole-brain, regions of interest and voxel-wise levels. Average whole-brain CBF was 39.9 ± 6.0, 39.0 ± 5.8 and 40.0 ± 5.6 ml/100 g/min for CTAC, RESOLUTE and DeepUTE corrected studies respectively. RESOLUTE underestimated whole-brain CBF by 2.1 ± 1.50% and rCBF in all regions of interest (range -2.4%- -1%) compared to CTAC. DeepUTE showed significant rCBF overestimation only in the occipital lobe (0.6 ± 1.1%). Both MRAC methods showed excellent correlation on rCBF and activity concentration with CTAC, with slopes of linear regression lines between 0.97 and 1.01 and R2 over 0.99. In conclusion, RESOLUTE and DeepUTE provide AC information comparable to CTAC in dynamic [15O]H2O-PET but RESOLUTE is associated with a small but systematic underestimation.



J Cereb Blood Flow Metab: 10 Jul 2021:271678X211029178; epub ahead of print
Puig O, Henriksen OM, Andersen FL, Lindberg U, ... Law I, Ladefoged CN
J Cereb Blood Flow Metab: 10 Jul 2021:271678X211029178; epub ahead of print | PMID: 34250821
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Abstract

Isolation and identification of leukocyte populations in intracranial blood collected during mechanical thrombectomy.

Shaw BC, Maglinger GB, Ujas T, Rupareliya C, ... Turchan-Cholewo J, Stowe AM
Using standard techniques during mechanical thrombectomy, the Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) protocol (NCT03153683) isolates intracranial arterial blood distal to the thrombus and proximal systemic blood in the carotid artery. We augmented the current protocol to study leukocyte subpopulations both distal and proximal to the thrombus during human stroke (n = 16 patients), and from patients with cerebrovascular disease (CVD) undergoing angiography for unrelated conditions (e.g. carotid artery stenosis; n = 12 patients). We isolated leukocytes for flow cytometry from small volume (<1 mL) intracranial blood and systemic blood (5-10 mL) to identify adaptive and innate leukocyte populations, in addition to platelets and endothelial cells (ECs). Intracranial blood exhibited significant increases in T cell representation and decreases in myeloid/macrophage representation compared to within-patient carotid artery samples. CD4+ T cells and classical dendritic cells were significantly lower than CVD controls and correlated to within-patient edema volume and last known normal. This novel protocol successfully isolates leukocytes from small volume intracranial blood samples of stroke patients at time of mechanical thrombectomy and can be used to confirm preclinical results, as well as identify novel targets for immunotherapies.



J Cereb Blood Flow Metab: 10 Jul 2021:271678X211028496; epub ahead of print
Shaw BC, Maglinger GB, Ujas T, Rupareliya C, ... Turchan-Cholewo J, Stowe AM
J Cereb Blood Flow Metab: 10 Jul 2021:271678X211028496; epub ahead of print | PMID: 34250820
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Abstract

Nrf2-BDNF-TrkB pathway contributes to cortical hemorrhage-induced depression, but not sex differences.

Ren H, Han R, Liu X, Wang L, Koehler RC, Wang J
Post-stroke depression, observed in 30-50% of stroke patients, negatively affects quality of life and mortality. The pathogenesis of post-stroke depression is complex, but heightened reactive oxygen species production and inflammation might be two key factors. We have reported that intracerebral hemorrhage (ICH) in cerebral cortex produces depression-like behavior in young male mice. Here, we found that mice lacking nuclear factor erythroid-derived 2-related factor 2 (Nrf2), a transcription factor that upregulates antioxidant proteins and trophic factors such as brain-derived neurotrophic factor (BDNF), had more severe depression-like behavior than wild-type mice at days 21 to 28 after cortical ICH (c-ICH). Moreover, the expression of Nrf2, heme oxygenase-1, BDNF, and TrkB were significantly decreased in wild-type mice after c-ICH. Interestingly, TP-500 (2 mg/kg), a potent Nrf2 inducer, decreased the inflammatory response and reactive oxygen species production on day 28 after c-ICH and improved depression-like behaviors. TrkB receptor antagonist ANA-12 abolished this anti-depression effect. Depression was more severe in female than in male wild-type mice after ICH, but TP-500 improved depression-like behavior in females. These results suggest that downregulation of Nrf2-BDNF-TrkB signaling contributes to development of post-stroke depression, and that Nrf2 inducer TP-500 might improve depression after c-ICH.



J Cereb Blood Flow Metab: 07 Jul 2021:271678X211029060; epub ahead of print
Ren H, Han R, Liu X, Wang L, Koehler RC, Wang J
J Cereb Blood Flow Metab: 07 Jul 2021:271678X211029060; epub ahead of print | PMID: 34238051
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Abstract

MRI investigation of vascular remodeling for heterogeneous edema lesions in subacute ischemic stroke rat models: Correspondence between cerebral vessel structure and function.

Kang M, Jin S, Cho H
The spatial heterogeneity in the temporal occurrence of pseudo-normalization of MR apparent diffusion coefficient values for ischemic lesions may be related to morphological and functional vascular remodeling. As the area of accelerated pseudo-normalization tends to expand faster and more extensively into the chronic stage, detailed vascular characterization of such areas is necessary. During the subacute stage of transient middle cerebral artery occlusion rat models, the morphological size of the macrovasculature, microvascular vessel size index (VSI), and microvessel density (MVD) were quantified along with functional perfusion measurements of the relative cerebral blood flow (rCBF) and mean transit time (rMTT) of the corresponding areas (33 cases for each parameter). When compared with typical pseudo-normalization lesions, early pseudo-normalization lesions exhibited larger VSI and rCBF (p < 0.001) at reperfusion days 4 and 7, along with reduced MVD and elongated rMTT (p < 0.001) at reperfusion days 1, 4, and 7. The group median VSI and rCBF exhibited a strong positive correlation (r = 0.92), and the corresponding MVD and rMTT showed a negative correlation (r = -0.48). Light sheet fluorescence microscopy images were used to quantitatively validate the corresponding MRI-derived microvascular size, density, and cerebral blood volume.



J Cereb Blood Flow Metab: 06 Jul 2021:271678X211029197; epub ahead of print
Kang M, Jin S, Cho H
J Cereb Blood Flow Metab: 06 Jul 2021:271678X211029197; epub ahead of print | PMID: 34233533
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Abstract

Endovascular administration of magnetized nanocarriers targeting brain delivery after stroke.

Grayston A, Zhang Y, Garcia-Gabilondo M, Arrúe M, ... Roig A, Rosell A
The increasing use of mechanical thrombectomy in stroke management has opened the window to local intraarterial brain delivery of therapeutic agents. In this context, the use of nanomedicine could further improve the delivery of new treatments for specific brain targeting, tracking and guidance. In this study we take advantage of this new endovascular approach to deliver biocompatible poly(D-L-lactic-co-glycolic acid) (PLGA) nanocapsules functionalized with superparamagnetic iron oxide nanoparticles and Cy7.5 for magnetic targeting, magnetic resonance and fluorescent molecular imaging. A complete biodistribution study in naïve (n = 59) and ischemic (n = 51) mice receiving intravenous or intraarterial nanocapsules, with two different magnet devices and imaged from 30 min to 48 h, showed an extraordinary advantage of the intraarterial route for brain delivery with a specific improvement in cortical targeting when using a magnetic device in both control and ischemic conditions. Safety was evaluated in ischemic mice (n = 69) showing no signs of systemic toxicity nor increasing mortality, infarct lesions or hemorrhages. In conclusion, the challenging brain delivery of therapeutic nanomaterials could be efficiently and safely overcome with a controlled endovascular administration and magnetic targeting, which could be considered in the context of endovascular interventions for the delivery of multiple treatments for stroke.



J Cereb Blood Flow Metab: 05 Jul 2021:271678X211028816; epub ahead of print
Grayston A, Zhang Y, Garcia-Gabilondo M, Arrúe M, ... Roig A, Rosell A
J Cereb Blood Flow Metab: 05 Jul 2021:271678X211028816; epub ahead of print | PMID: 34229512
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Abstract

Persistent CO reactivity deficits are associated with neurological dysfunction up to one year after repetitive mild closed head injury in adolescent mice.

Wu L, Chan ST, Edmiston WJ, Jin G, ... Whalen MJ, Chen YI
Cerebrovascular reactivity (CVR) deficits in adolescents with concussion may persist after resolution of neurological symptoms. Whether or not CVR deficits predict long term neurological function is unknown. We used adolescent mice closed head injury (CHI) models (54 g, 107 cm or 117 cm drop height), followed by blood oxygenation level dependent (BOLD)-functional MRI with CO2 challenge to assess CVR and brain connectivity. At one week, 3HD 107 cm mice showed delayed BOLD responses (p = 0.0074), normal striatal connectivity, and an impaired respiratory rate response to CO2 challenge (p = 0.0061 in ΔRmax). The 107 cm group developed rotarod deficits at 6 months (p = 0.02) and altered post-CO2 brain connectivity (3-fold increase in striatum to motor cortex correlation coefficient) by one year, but resolved their CVR and respiratory rate impairments, and did not develop cognitive or circadian activity deficits. In contrast, the 117 cm group had persistent CVR (delay time: p = 0.016; washout time: p = 0.039) and circadian activity deficits (free-running period: 23.7 hr in sham vs 23.9 hr in 3HD; amplitude: 0.15 in sham vs 0.2 in 3HD; peak activity: 18 in sham vs 21 in 3HD) at one year. Persistent CVR deficits after concussion may portend long-term neurological dysfunction. Further studies are warranted to determine the utility of CVR to predict chronic neurological outcome after mild traumatic brain injury.



J Cereb Blood Flow Metab: 05 Jul 2021:271678X211021771; epub ahead of print
Wu L, Chan ST, Edmiston WJ, Jin G, ... Whalen MJ, Chen YI
J Cereb Blood Flow Metab: 05 Jul 2021:271678X211021771; epub ahead of print | PMID: 34229511
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Abstract

A glucose-stimulated BOLD fMRI study of hypothalamic dysfunction in mice fed a high-fat and high-sucrose diet.

Mohr AA, Garcia-Serrano AM, Vieira JP, Skoug C, Davidsson H, Duarte JM
The hypothalamus is the central regulator of energy homeostasis. Hypothalamic neuronal circuits are disrupted upon overfeeding, and play a role in the development of metabolic disorders. While mouse models have been extensively employed for understanding the mechanisms of hypothalamic dysfunction, functional magnetic resonance imaging (fMRI) on hypothalamic nuclei has been challenging. We implemented a robust glucose-induced fMRI paradigm that allows to repeatedly investigate hypothalamic responses to glucose. This approach was used to test the hypothesis that hypothalamic nuclei functioning is impaired in mice exposed to a high-fat and high-sucrose diet (HFHSD) for seven days. The blood oxygen level-dependent (BOLD) fMRI signal was measured from brains of mice under light isoflurane anaesthesia, during which a 2.6 g/kg glucose load was administered. The mouse hypothalamus responded to glucose but not saline administration with a biphasic BOLD fMRI signal reduction. Relative to controls, HFHSD-fed mice showed attenuated or blunted responses in arcuate nucleus, lateral hypothalamus, ventromedial nucleus and dorsomedial nucleus, but not in paraventricular nucleus. In sum, we have developed an fMRI paradigm that is able to determine dysfunction of glucose-sensing neuronal circuits within the mouse hypothalamus in a non-invasive manner.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1734-1743
Mohr AA, Garcia-Serrano AM, Vieira JP, Skoug C, Davidsson H, Duarte JM
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1734-1743 | PMID: 32757742
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Abstract

Large-scale characterization of the microvascular geometry in development and disease by tissue clearing and quantitative ultramicroscopy.

Hahn A, Bode J, Alexander A, Karimian-Jazi K, ... Kurz FT, Breckwoldt MO
Three-dimensional assessment of optically cleared, entire organs and organisms has recently become possible by tissue clearing and selective plane illumination microscopy (\"ultramicroscopy\"). Resulting datasets can be highly complex, encompass over a thousand images with millions of objects and data of several gigabytes per acquisition. This constitutes a major challenge for quantitative analysis. We have developed post-processing tools to quantify millions of microvessels and their distribution in three-dimensional datasets from ultramicroscopy and demonstrate the capabilities of our pipeline within entire mouse brains and embryos. Using our developed acquisition, segmentation, and analysis platform, we quantify physiological vascular networks in development and the healthy brain. We compare various geometric vessel parameters (e.g. vessel density, radius, tortuosity) in the embryonic spinal cord and brain as well as in different brain regions (basal ganglia, corpus callosum, cortex). White matter tract structures (corpus callosum, spinal cord) showed lower microvascular branch densities and longer vessel branch length compared to grey matter (cortex, basal ganglia). Furthermore, we assess tumor neoangiogenesis in a mouse glioma model to compare tumor core and tumor border. The developed methodology allows rapid quantification of three-dimensional datasets by semi-automated segmentation of fluorescently labeled objects with conventional computer hardware. Our approach can aid preclinical investigations and paves the way towards \"quantitative ultramicroscopy\".



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1536-1546
Hahn A, Bode J, Alexander A, Karimian-Jazi K, ... Kurz FT, Breckwoldt MO
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1536-1546 | PMID: 33043767
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Abstract

Intravenously delivered multilineage-differentiating stress enduring cells dampen excessive glutamate metabolism and microglial activation in experimental perinatal hypoxic ischemic encephalopathy.

Suzuki T, Sato Y, Kushida Y, Tsuji M, ... Borlongan CV, Hayakawa M
Perinatal hypoxic ischemic encephalopathy (HIE) results in serious neurological dysfunction and mortality. Clinical trials of multilineage-differentiating stress enduring cells (Muse cells) have commenced in stroke using intravenous delivery of donor-derived Muse cells. Here, we investigated the therapeutic effects of human Muse cells in an HIE model. Seven-day-old rats underwent ligation of the left carotid artery then were exposed to 8% oxygen for 60 min, and 72 hours later intravenously transplanted with 1 × 104 of human-Muse and -non-Muse cells, collected from bone marrow-mesenchymal stem cells as stage-specific embryonic antigen-3 (SSEA-3)+ and -, respectively, or saline (vehicle) without immunosuppression. Human-specific probe revealed Muse cells distributed mainly to the injured brain at 2 and 4 weeks, and expressed neuronal and glial markers until 6 months. In contrast, non-Muse cells lodged in the lung at 2 weeks, but undetectable by 4 weeks. Magnetic resonance spectroscopy and positron emission tomography demonstrated that Muse cells dampened excitotoxic brain glutamatergic metabolites and suppressed microglial activation. Muse cell-treated group exhibited significant improvements in motor and cognitive functions at 4 weeks and 5 months. Intravenously transplanted Muse cells afforded functional benefits in experimental HIE possibly via regulation of glutamate metabolism and reduction of microglial activation.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1707-1720
Suzuki T, Sato Y, Kushida Y, Tsuji M, ... Borlongan CV, Hayakawa M
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1707-1720 | PMID: 33222596
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Abstract

Complete inhibition of ABCB1 and ABCG2 at the blood-brain barrier by co-infusion of erlotinib and tariquidar to improve brain delivery of the model ABCB1/ABCG2 substrate [C]erlotinib.

Tournier N, Goutal S, Mairinger S, Hernández-Lozano I, ... Wanek T, Langer O
P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) restrict at the blood-brain barrier (BBB) the brain distribution of the majority of currently known molecularly targeted anticancer drugs. To improve brain delivery of dual ABCB1/ABCG2 substrates, both ABCB1 and ABCG2 need to be inhibited simultaneously at the BBB. We examined the feasibility of simultaneous ABCB1/ABCG2 inhibition with i.v. co-infusion of erlotinib and tariquidar by studying brain distribution of the model ABCB1/ABCG2 substrate [11C]erlotinib in mice and rhesus macaques with PET. Tolerability of the erlotinib/tariquidar combination was assessed in human embryonic stem cell-derived cerebral organoids. In mice and macaques, baseline brain distribution of [11C]erlotinib was low (brain distribution volume, VT,brain < 0.3 mL/cm3). Co-infusion of erlotinib and tariquidar increased VT,brain in mice by 3.0-fold and in macaques by 3.4- to 5.0-fold, while infusion of erlotinib alone or tariquidar alone led to less pronounced VT,brain increases in both species. Treatment of cerebral organoids with erlotinib/tariquidar led to an induction of Caspase-3-dependent apoptosis. Co-infusion of erlotinib/tariquidar may potentially allow for complete ABCB1/ABCG2 inhibition at the BBB, while simultaneously achieving brain-targeted EGFR inhibition. Our protocol may be applicable to enhance brain delivery of molecularly targeted anticancer drugs for a more effective treatment of brain tumors.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1634-1646
Tournier N, Goutal S, Mairinger S, Hernández-Lozano I, ... Wanek T, Langer O
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1634-1646 | PMID: 33081568
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Abstract

Evaluation of the potassium channel tracer [F]3F4AP in rhesus macaques.

Guehl NJ, Ramos-Torres KM, Linnman C, Moon SH, ... Normandin MD, Brugarolas P
Demyelination causes slowed or failed neuronal conduction and is a driver of disability in multiple sclerosis and other neurological diseases. Currently, the gold standard for imaging demyelination is MRI, but despite its high spatial resolution and sensitivity to demyelinated lesions, it remains challenging to obtain specific and quantitative measures of molecular changes involved in demyelination. To understand the contribution of demyelination in different diseases and to assess the efficacy of myelin-repair therapies, it is critical to develop new in vivo imaging tools sensitive to changes induced by demyelination. Upon demyelination, axonal K+ channels, normally located underneath the myelin sheath, become exposed and increase in expression, causing impaired conduction. Here, we investigate the properties of the K+ channel PET tracer [18F]3F4AP in primates and its sensitivity to a focal brain injury that occurred three years prior to imaging. [18F]3F4AP exhibited favorable properties for brain imaging including high brain penetration, high metabolic stability, high plasma availability, high reproducibility, high specificity, and fast kinetics. [18F]3F4AP showed preferential binding in areas of low myelin content as well as in the previously injured area. Sensitivity of [18F]3F4AP for the focal brain injury was higher than [18F]FDG, [11C]PiB, and [11C]PBR28, and compared favorably to currently used MRI methods.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1721-1733
Guehl NJ, Ramos-Torres KM, Linnman C, Moon SH, ... Normandin MD, Brugarolas P
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1721-1733 | PMID: 33090071
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Abstract

Cholinergic upregulation by optogenetic stimulation of nucleus basalis after photothrombotic stroke in forelimb somatosensory cortex improves endpoint and motor but not sensory control of skilled reaching in mice.

Mirza Agha B, Akbary R, Ghasroddashti A, Nazari-Ahangarkolaee M, Whishaw IQ, Mohajerani MH
A network of cholinergic neurons in the basal forebrain innerve the forebrain and are proposed to contribute to a variety of functions including cortical plasticity, attention, and sensorimotor behavior. This study examined the contribution of the nucleus basalis cholinergic projection to the sensorimotor cortex on recovery on a skilled reach-to-eat task following photothrombotic stroke in the forelimb region of the somatosensory cortex. Mice were trained to perform a single pellet skilled reaching task and their pre and poststroke performance, from Day 4 to Day 28 poststroke, was assessed frame-by-frame by video analysis with endpoint, movement and sensorimotor integration measures. Somatosensory forelimb lesions produced impairments in endpoint and movement component measures of reaching and increased the incidence of fictive eating, a sensory impairment in mistaking a missed reach for a successful reach. Upregulated acetylcholine (ACh) release, as measured by local field potential recording, elicited via optogenetic stimulation of the nucleus basalis improved recovery of reaching and improved movement scores but did not affect sensorimotor integration impairment poststroke. The results show that the mouse cortical forelimb somatosensory region contributes to forelimb motor behavior and suggest that ACh upregulation could serve as an adjunct to behavioral therapy for acute treatment of stroke.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1608-1622
Mirza Agha B, Akbary R, Ghasroddashti A, Nazari-Ahangarkolaee M, Whishaw IQ, Mohajerani MH
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1608-1622 | PMID: 33103935
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Abstract

A novel molecular magnetic resonance imaging agent targeting activated leukocyte cell adhesion molecule as demonstrated in mouse brain metastasis models.

Zarghami N, Soto MS, Perez-Balderas F, Khrapitchev AA, ... Larkin JR, Sibson NR
Molecular magnetic resonance imaging (MRI) allows visualization of biological processes at the molecular level. Upregulation of endothelial ALCAM (activated leukocyte cell adhesion molecule) is a key element for leukocyte recruitment in neurological disease. The aim of this study, therefore, was to develop a novel molecular MRI contrast agent, by conjugating anti-ALCAM antibodies to microparticles of iron oxide (MPIO), for detection of endothelial ALCAM expression in vivo. Binding specificity of ALCAM-MPIO was demonstrated in vitro under static and flow conditions. Subsequently, in a proof-of-concept study, mouse models of brain metastasis were induced by intracardial injection of brain-tropic human breast carcinoma, lung adenocarcinoma or melanoma cells to upregulate endothelial ALCAM. At selected time-points, mice were injected intravenously with ALCAM-MPIO, and ALCAM-MPIO induced hypointensities were observed on T2*-weighted images in all three models. Post-gadolinium MRI confirmed an intact blood-brain barrier, indicating endoluminal binding. Correlation between endothelial ALCAM expression and ALCAM-MPIO binding was confirmed histologically. Statistical analysis indicated high sensitivity (80-90%) and specificity (79-83%) for detection of endothelial ALCAM in vivo with ALCAM-MPIO. Given reports of endothelial ALCAM upregulation in numerous neurological diseases, this advance in our ability to image ALCAM in vivo may yield substantial improvements for both diagnosis and targeted therapy.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1592-1607
Zarghami N, Soto MS, Perez-Balderas F, Khrapitchev AA, ... Larkin JR, Sibson NR
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1592-1607 | PMID: 33153376
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Abstract

Effects of O-GlcNAcylation on functional mitochondrial transfer from astrocytes.

Park JH, Nakamura Y, Li W, Hamanaka G, ... Lo EH, Hayakawa K
Mitochondria may be transferred from cell to cell in the central nervous system and this process may help defend neurons against injury and disease. But how mitochondria maintain their functionality during the process of release into extracellular space remains unknown. Here, we report that mitochondrial protein O-GlcNAcylation is a critical process to support extracellular mitochondrial functionality. Activation of CD38-cADPR signaling in astrocytes robustly induced protein O-GlcNAcylation in mitochondria, while oxygen-glucose deprivation and reoxygenation showed transient and mild protein modification. Blocking the endoplasmic reticulum - Golgi trafficking with Brefeldin A or slc35B4 siRNA reduced O-GlcNAcylation, and resulted in the secretion of mitochondria with decreased membrane potential and mtDNA. Finally, loss-of-function studies verified that O-GlcNAc-modified mitochondria demonstrated higher levels of neuroprotection after astrocyte-to-neuron mitochondrial transfer. Collectively, these findings suggest that post-translational modification by O-GlcNAc may be required for supporting the functionality and neuroprotective properties of mitochondria released from astrocytes.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1523-1535
Park JH, Nakamura Y, Li W, Hamanaka G, ... Lo EH, Hayakawa K
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1523-1535 | PMID: 33153373
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Abstract

Body mass index, time of day and genetics affect perivascular spaces in the white matter.

Barisano G, Sheikh-Bahaei N, Law M, Toga AW, Sepehrband F
The analysis of cerebral perivascular spaces (PVS) using magnetic resonance imaging (MRI) allows to explore in vivo their contributions to neurological disorders. To date the normal amount and distribution of PVS in healthy human brains are not known, thus hampering our ability to define with confidence pathogenic alterations. Furthermore, it is unclear which biological factors can influence the presence and size of PVS on MRI. We performed exploratory data analysis of PVS volume and distribution in a large population of healthy individuals (n = 897, age = 28.8 ± 3.7). Here we describe the global and regional amount of PVS in the white matter, which can be used as a reference for clinicians and researchers investigating PVS and may help the interpretation of the structural changes affecting PVS in pathological states. We found a relatively high inter-subject variability in the PVS amount in this population of healthy adults (range: 1.31-14.49 cm3). The PVS volume was higher in older and male individuals. Moreover, we identified body mass index, time of day, and genetics as new elements significantly affecting PVS in vivo under physiological conditions, offering a valuable foundation to future studies aimed at understanding the physiology of perivascular flow.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1563-1578
Barisano G, Sheikh-Bahaei N, Law M, Toga AW, Sepehrband F
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1563-1578 | PMID: 33183133
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Abstract

Cell-specific activation of RIPK1 and MLKL after intracerebral hemorrhage in mice.

Lule S, Wu L, Sarro-Schwartz A, Edmiston WJ, ... Degterev A, Whalen MJ
Receptor-interacting protein kinase-1 (RIPK1) is a master regulator of cell death and inflammation, and mediates programmed necrosis (necroptosis) via mixed-lineage kinase like (MLKL) protein. Prior studies in experimental intracerebral hemorrhage (ICH) implicated RIPK1 in the pathogenesis of neuronal death and cognitive outcome, but the relevant cell types involved and potential role of necroptosis remain unexplored. In mice subjected to autologous blood ICH, early RIPK1 activation was observed in neurons, endothelium and pericytes, but not in astrocytes. MLKL activation was detected in astrocytes and neurons but not endothelium or pericytes. Compared with WT controls, RIPK1 kinase-dead (RIPK1D138N/D138N) mice had reduced brain edema (24 h) and blood-brain barrier (BBB) permeability (24 h, 30 d), and improved postinjury rotarod performance. Mice deficient in MLKL (Mlkl-/-) had reduced neuronal death (24 h) and BBB permeability at 24 h but not 30d, and improved post-injury rotarod performance vs. WT. The data support a central role for RIPK1 in the pathogenesis of ICH, including cell death, edema, BBB permeability, and motor deficits. These effects may be mediated in part through the activation of MLKL-dependent necroptosis in neurons. The data support development of RIPK1 kinase inhibitors as therapeutic agents for human ICH.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1623-1633
Lule S, Wu L, Sarro-Schwartz A, Edmiston WJ, ... Degterev A, Whalen MJ
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1623-1633 | PMID: 33210566
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Abstract

Age-related impairment of cerebral blood flow response to K channel opener in Alzheimer\'s disease mice with presenilin-1 mutation.

Liu D, Ahmet I, Griess B, Tweedie D, Greig NH, Mattson MP
Local cerebral blood flow (CBF) responses to neuronal activity are essential for cognition and impaired CBF responses occur in Alzheimer\'s disease (AD). In this study, regional CBF (rCBF) responses to the KATP channel opener diazoxide were investigated in 3xTgAD, WT and mutant Presenilin 1(PS1M146V) mice from three age groups using Laser-Doppler flowmetry. The rCBF response was reduced early in young 3xTgAD mice and almost absent in old 3xTgAD mice, up to 30%-40% reduction with altered CBF velocity and mean arterial pressure versus WT mice. The impaired rCBF response in 3xTgAD mice was associated with progression of AD pathology, characterized by deposition of intracellular and vascular amyloid-β (Aβ) oligomers, senile plaques and tau pathology. The nitric oxide synthase (NOS) inhibitor Nω-nitro-L-arginine abolished rCBF response to diazoxide suggesting NO was involved in the mediation of vasorelaxation. Levels of phosphor-eNOS (Ser1177) diminished in 3xTgAD brains with age, while the rCBF response to the NO donor sodium nitroprusside remained. In PS1M146V mice, the rCBF response to dizoxide reduced and high molecular weight Abeta oligomers were increased indicating PS1M146V contributed to the dysregulation of rCBF response in AD mice. Our study revealed an Aβ oligomer-associated compromise of cerebrovascular function in rCBF response to diazoxide in AD mice with PS1M146V mutation.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1579-1591
Liu D, Ahmet I, Griess B, Tweedie D, Greig NH, Mattson MP
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1579-1591 | PMID: 33203296
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Abstract

False positive rates in positron emission tomography (PET) voxelwise analyses.

Ganz M, Nørgaard M, Beliveau V, Svarer C, Knudsen GM, Greve DN
Issues with inflated false positive rates (FPRs) in brain imaging have recently received significant attention. However, to what extent FPRs present a problem for voxelwise analyses of Positron Emission Tomography (PET) data remains unknown. In this work, we evaluate the FPR using real PET data under group assignments that should yield no significant results after correcting for multiple comparisons. We used data from 159 healthy participants, imaged with the serotonin transporter ([11C]DASB; N = 100) or the 5-HT4 receptor ([11C]SB207145; N = 59). Using this null data, we estimated the FPR by performing 1,000 group analyses with randomly assigned groups of either 10 or 20, for each tracer, and corrected for multiple comparisons using parametric Monte Carlo simulations (MCZ) or non-parametric permutation testing. Our analyses show that for group sizes of 10 or 20, the FPR for both tracers was 5-99% using MCZ, much higher than the expected 5%. This was caused by a heavier-than-Gaussian spatial autocorrelation, violating the parametric assumptions. Permutation correctly controlled the FPR in all cases. In conclusion, either a conservative cluster forming threshold and high smoothing levels, or a non-parametric correction for multiple comparisons should be performed in voxelwise analyses of brain PET data.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1647-1657
Ganz M, Nørgaard M, Beliveau V, Svarer C, Knudsen GM, Greve DN
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1647-1657 | PMID: 33241770
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Abstract

Cerebral oxygen extraction fraction (OEF): Comparison of challenge-free gradient echo QSM+qBOLD (QQ) with O PET in healthy adults.

Cho J, Lee J, An H, Goyal MS, Su Y, Wang Y
We aimed to validate oxygen extraction fraction (OEF) estimations by quantitative susceptibility mapping plus quantitative blood oxygen-level dependence (QSM+qBOLD, or QQ) using 15O-PET. In ten healthy adult brains, PET and MRI were acquired simultaneously on a PET/MR scanner. PET was acquired using C[15O], O[15O], and H2[15O]. Image-derived arterial input functions and standard models of oxygen metabolism provided quantification of PET. MRI included T1-weighted imaging, time-of-flight angiography, and multi-echo gradient-echo imaging that was processed for QQ. Region of interest (ROI) analyses compared PET OEF and QQ OEF. In ROI analyses, the averaged OEF differences between PET and QQ were generally small and statistically insignificant. For whole brains, the average and standard deviation of OEF was 32.8 ± 6.7% for PET; OEF was 34.2 ± 2.6% for QQ. Bland-Altman plots quantified agreement between PET OEF and QQ OEF. The interval between the 95% limits of agreement was 16.9 ± 4.0% for whole brains. Our validation study suggests that respiratory challenge-free QQ-OEF mapping may be useful for non-invasive clinical assessment of regional OEF impairment.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1658-1668
Cho J, Lee J, An H, Goyal MS, Su Y, Wang Y
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1658-1668 | PMID: 33243071
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Abstract

Longitudinal relation between blood pressure, antihypertensive use and cerebral blood flow, using arterial spin labelling MRI.

van Dalen JW, Mutsaerts HJ, Petr J, Caan MW, ... Nederveen AJ, Richard E
Consistent cerebral blood flow (CBF) is fundamental to brain function. Cerebral autoregulation ensures CBF stability. Chronic hypertension can lead to disrupted cerebral autoregulation in older people, potentially leading to blood pressure levels interfering with CBF. This study tested whether low BP and AHD use are associated with contemporaneous low CBF, and whether longitudinal change in BP is associated with change in CBF, using arterial spin labelling (ASL) MRI, in a prospective longitudinal cohort of 186 community-dwelling older individuals with hypertension (77 ± 3 years, 53% female), 125 (67%) of whom with 3-year follow-up. Diastolic blood pressure, systolic blood pressure, mean arterial pressure, and pulse pressure were assessed as blood pressure parameters. As additional cerebrovascular marker, we evaluated the ASL signal spatial coefficient of variation (ASL SCoV), a measure of ASL signal heterogeneity that may reflect cerebrovascular health. We found no associations between any of the blood pressure measures and concurrent CBF nor between changes in blood pressure measures and CBF over three-year follow-up. Antihypertensive use was associated with lower grey matter CBF (-5.49 ml/100 g/min, 95%CI = -10.7|-0.27, p = 0.04) and higher ASL SCoV (0.32 SD, 95%CI = 0.12|0.52, p = 0.002). These results warrant future research on the potential relations between antihypertensive use and cerebral perfusion.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1756-1766
van Dalen JW, Mutsaerts HJ, Petr J, Caan MW, ... Nederveen AJ, Richard E
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1756-1766 | PMID: 33325767
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Abstract

Linking cortical atrophy to white matter hyperintensities of presumed vascular origin.

Mayer C, Frey BM, Schlemm E, Petersen M, ... Thomalla G, Cheng B
We examined the relationship between white matter hyperintensities (WMH) and cortical neurodegeneration in cerebral small vessel disease (CSVD) by investigating whether cortical thickness is a remote effect of WMH through structural fiber tract connectivity in a population at increased risk of CSVD. We measured cortical thickness on T1-weighted images and segmented WMH on FLAIR images in 930 participants of a population-based cohort study at baseline. DWI-derived whole-brain probabilistic tractography was used to define WMH connectivity to cortical regions. Linear mixed-effects models were applied to analyze the relationship between cortical thickness and connectivity to WMH. Factors associated with cortical thickness (age, sex, hemisphere, region, individual differences in cortical thickness) were added as covariates. Median age was 64 [IQR 46-76] years. Visual inspection of surface maps revealed distinct connectivity patterns of cortical regions to WMH. WMH connectivity to the cortex was associated with reduced cortical thickness (p = 0.009) after controlling for covariates. This association was found for periventricular WMH (p = 0.001) only. Our results indicate an association between WMH and cortical thickness via connecting fiber tracts. The results imply a mechanism of secondary neurodegeneration in cortical regions distant, yet connected to subcortical vascular lesions, which appears to be driven by periventricular WMH.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1682-1691
Mayer C, Frey BM, Schlemm E, Petersen M, ... Thomalla G, Cheng B
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1682-1691 | PMID: 33259747
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Abstract

Role of endothelial nitric oxide synthase for early brain injury after subarachnoid hemorrhage in mice.

Lenz IJ, Plesnila N, Terpolilli NA
The first few hours and days after subarachnoid hemorrhage (SAH) are characterized by cerebral ischemia, spasms of pial arterioles, and a significant reduction of cerebral microperfusion, however, the mechanisms of this early microcirculatory dysfunction are still unknown. Endothelial nitric oxide production is reduced after SAH and exogenous application of NO reduces post-hemorrhagic microvasospasm. Therefore, we hypothesize that the endothelial NO-synthase (eNOS) may be involved in the formation of microvasospasms, microcirculatory dysfunction, and unfavorable outcome after SAH. SAH was induced in male eNOS deficient (eNOS-/-) mice by endovascular MCA perforation. Three hours later, the cerebral microcirculation was visualized using in vivo 2-photon-microscopy. eNOS-/- mice had more severe SAHs, more severe ischemia, three time more rebleedings, and a massively increased mortality (50 vs. 0%) as compared to wild type (WT) littermate controls. Three hours after SAH eNOS-/- mice had fewer perfused microvessels and 40% more microvasospasms than WT mice. The current study indicates that a proper function of eNOS plays a key role for a favorable outcome after SAH and helps to explain why patients suffering from hypertension or other conditions associated with impaired eNOS function, have a higher risk of unfavorable outcome after SAH.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1669-1681
Lenz IJ, Plesnila N, Terpolilli NA
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1669-1681 | PMID: 33256507
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Abstract

EphrinB2-EphB2 signaling for dendrite protection after neuronal ischemia and oxygen-glucose deprivation .

Yu Z, Li W, Lan J, Hayakawa K, ... Lo EH, Wang X
In order to rescue neuronal function, neuroprotection should be required not only for the neuron soma but also the dendrites. Here, we propose the hypothesis that ephrin-B2-EphB2 signaling may be involved in dendritic degeneration after ischemic injury. A mouse model of focal cerebral ischemia with middle cerebral artery occlusion (MCAO) method was used for EphB2 signaling test in vivo. Primary cortical neuron culture and oxygen-glucose deprivation were used to assess EphB2 signaling in vitro. siRNA and soluble ephrin-B2 ectodomain were used to block ephrin-B2-Ephb2 signaling. In the mouse model of focal cerebral ischemia and in neurons subjected to oxygen-glucose deprivation, clustering of ephrin-B2 with its receptor EphB2 was detected. Phosphorylation of EphB2 suggested activation of this signaling pathway. RNA silencing of EphB2 prevented neuronal death and preserved dendritic length. To assess therapeutic potential, we compared the soluble EphB2 ectodomain with the NMDA antagonist MK801 in neurons after oxygen-glucose deprivation. Both agents equally reduced lactate dehydrogenase release as a general marker of neurotoxicity. However, only soluble EphB2 ectodomain protected the dendrites. These findings provide a proof of concept that ephrin-B2-EphB2 signaling may represent a novel therapeutic target to protect both the neuron soma as well as dendrites against ischemic injury.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1744-1755
Yu Z, Li W, Lan J, Hayakawa K, ... Lo EH, Wang X
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1744-1755 | PMID: 33325764
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Abstract

T relaxation time of the normal-appearing white matter is related to the cognitive status in cerebral small vessel disease.

Brandhofe A, Stratmann C, Schüre JR, Pilatus U, ... Gracien RM, Seiler A
Previous diffusion tensor imaging (DTI) studies indicate that impaired microstructural integrity of the normal-appearing white matter (NAWM) is related to cognitive impairment in cerebral small vessel disease (SVD). This study aimed to investigate whether quantitative T2 relaxometry is a suitable imaging biomarker for the assessment of tissue changes related to cognitive abnormalities in patients with SVD. 39 patients and 18 age-matched healthy control subjects underwent 3 T magnetic resonance imaging (MRI) with T2-weighted multiple spin echo sequences for T2 relaxometry and DTI sequences, as well as comprehensive cognitive assessment. Averaged quantitative T2, fractional anisotropy (FA) and mean diffusivity (MD) were determined in the NAWM and related to cognitive parameters controlling for age, normalized brain volume, white matter hyperintensity volume and other conventional SVD markers. In SVD patients, quantitative T2 values were significantly increased compared to controls (p = 0.002) and significantly negatively correlated with the global cognitive performance (r= -0.410, p = 0.014) and executive function (r= -0.399, p = 0.016). DTI parameters did not correlate with cognitive function. T2 relaxometry of the NAWM seems to be sensitive to microstructural tissue damage associated with cognitive impairment in SVD and might be a promising imaging biomarker for evaluation of disease progression and possible effects of therapeutic interventions.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1767-1777
Brandhofe A, Stratmann C, Schüre JR, Pilatus U, ... Gracien RM, Seiler A
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1767-1777 | PMID: 33327818
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Abstract

Causes and consequences of baseline cerebral blood flow reductions in Alzheimer\'s disease.

Bracko O, Cruz Hernández JC, Park L, Nishimura N, Schaffer CB
Reductions of baseline cerebral blood flow (CBF) of ∼10-20% are a common symptom of Alzheimer\'s disease (AD) that appear early in disease progression and correlate with the severity of cognitive impairment. These CBF deficits are replicated in mouse models of AD and recent work shows that increasing baseline CBF can rapidly improve the performance of AD mice on short term memory tasks. Despite the potential role these data suggest for CBF reductions in causing cognitive symptoms and contributing to brain pathology in AD, there remains a poor understanding of the molecular and cellular mechanisms causing them. This review compiles data on CBF reductions and on the correlation of AD-related CBF deficits with disease comorbidities (e.g. cardiovascular and genetic risk factors) and outcomes (e.g. cognitive performance and brain pathology) from studies in both patients and mouse models, and discusses several potential mechanisms proposed to contribute to CBF reductions, based primarily on work in AD mouse models. Future research aimed at improving our understanding of the importance of and interplay between different mechanisms for CBF reduction, as well as at determining the role these mechanisms play in AD patients could guide the development of future therapies that target CBF reductions in AD.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1501-1516
Bracko O, Cruz Hernández JC, Park L, Nishimura N, Schaffer CB
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1501-1516 | PMID: 33444096
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Abstract

Cerebral arterial pulsatility is linked to hippocampal microvascular function and episodic memory in healthy older adults.

Vikner T, Eklund A, Karalija N, Malm J, ... Nyberg L, Wåhlin A
Microvascular damage in the hippocampus is emerging as a central cause of cognitive decline and dementia in aging. This could be a consequence of age-related decreases in vascular elasticity, exposing hippocampal capillaries to excessive cardiac-related pulsatile flow that disrupts the blood-brain barrier and the neurovascular unit. Previous studies have found altered intracranial hemodynamics in cognitive impairment and dementia, as well as negative associations between pulsatility and hippocampal volume. However, evidence linking features of the cerebral arterial flow waveform to hippocampal function is lacking. We used a high-resolution 4D flow MRI approach to estimate global representations of the time-resolved flow waveform in distal cortical arteries and in proximal arteries feeding the brain in healthy older adults. Waveform-based clustering revealed a group of individuals featuring steep systolic onset and high amplitude that had poorer hippocampus-sensitive episodic memory (p = 0.003), lower whole-brain perfusion (p = 0.001), and weaker microvascular low-frequency oscillations in the hippocampus (p = 0.035) and parahippocampal gyrus (p = 0.005), potentially indicating compromised neurovascular unit integrity. Our findings suggest that aberrant hemodynamic forces contribute to cerebral microvascular and hippocampal dysfunction in aging.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1778-1790
Vikner T, Eklund A, Karalija N, Malm J, ... Nyberg L, Wåhlin A
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1778-1790 | PMID: 33444091
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Abstract

Potential therapeutic effects of Nrf2 activators on intracranial hemorrhage.

Imai T, Matsubara H, Hara H
Intracranial hemorrhage (ICH) is a devastating disease which induces high mortality and poor outcomes including severe neurological dysfunctions. ICH pathology is divided into two types: primary brain injury (PBI) and secondary brain injury (SBI). Although there are numerous preclinical studies documenting neuroprotective agents in experimental ICH models, no effective drugs have been developed for clinical use due to complicated ICH pathology. Oxidative and inflammatory stresses play central roles in the onset and progression of brain injury after ICH, especially SBI. Nrf2 is a crucial transcription factor in the anti-oxidative stress defense system. Under normal conditions, Nrf2 is tightly regulated by the Keap1. Under ICH pathological conditions, such as overproduction of reactive oxygen species (ROS), Nrf2 is translocated into the nucleus where it up-regulates the expression of several anti-oxidative phase II enzymes such as heme oxygenase-1 (HO-1). Recently, many reports have suggested the therapeutic potential of Nrf2 activators (including natural or synthesized compounds) for treating neurodegenerative diseases. Moreover, several Nrf2 activators attenuate ischemic stroke-induced brain injury in several animal models. This review summarizes the efficacy of several Nrf2 activators in ICH animal models. In the future, Nrf2 activators might be approved for the treatment of ICH patients.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1483-1500
Imai T, Matsubara H, Hara H
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1483-1500 | PMID: 33444090
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Abstract

Three-dimensional remodeling of functional cerebrovascular architecture and gliovascular unit in leptin receptor-deficient mice.

Liu Y, Chen D, Smith A, Ye Q, Gao Y, Zhang W
The cerebrovascular sequelae of diabetes render victims more susceptible to ischemic stroke, vascular cognitive impairment, and Alzheimer\'s disease. However, limited knowledge exists on the progressive changes in cerebrovascular structure and functional remodeling in type 2 diabetes. To ascertain the impact of diabetes on whole-brain cerebrovascular perfusion, leptin-receptor-deficient mice were transcardially injected with tomato-lectin before sacrifice. The whole brain was clarified by the Fast free-of-acrylamide clearing tissue technique. Functional vascular anatomy of the cerebrum was visualized by light-sheet microscopy, followed by analysis in Imaris software. We observed enhanced neovascularization in adult db/db mice, characterized by increased branch level and loop structures. Microvascular hypoperfusion was initially detected in juvenile db/db mice, suggesting early onset of insufficient microcirculation. Furthermore, gliovascular unit remodeling was verified by loss of pericytes and overactivation of microglia and astrocytes in adult diabetic mice. However, the integrity of the blood-brain barrier (BBB) was fundamentally preserved, as shown by a lack of extravasation of IgG into the brain parenchyma. In summary, we, for the first time, reveal that functional cerebrovascular remodeling occurs as early as four weeks in db/db mice and the deficit in gliovascular coupling may play a role in cerebral hypoperfusion before BBB breakdown in 16-week-old db/db mice.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1547-1562
Liu Y, Chen D, Smith A, Ye Q, Gao Y, Zhang W
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1547-1562 | PMID: 33818188
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Abstract

Much ado about eating: Intermittent fasting and post-stroke neuroprotection.

Vemuganti R, Arumugam TV
A proper diet is important for health and longevity. Controlling the amount of food consumed is immensely beneficial as it promotes multiple cellular and molecular protective mechanisms and simultaneously prevents toxic mechanisms. Intermittent fasting (IF) is a flexible and easy-to-adopt dietary modification that helps to mitigate metabolic disorders like diabetes and hypertension, and thus the devastating age-related diseases like heart attack, stroke and dementia. The benefits of IF seem to be mediated by altered epigenetic and transcriptional programming leading to reduced oxidative stress, inflammation, mitochondrial damage and cell death.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1791-1793
Vemuganti R, Arumugam TV
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1791-1793 | PMID: 33853407
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Abstract

Influence of metabolic syndrome on post-stroke outcome, angiogenesis and vascular function in old rats determined by dynamic contrast enhanced MRI.

Pradillo JM, Hernández-Jiménez M, Fernández-Valle ME, Medina V, ... Moro MA, Lizasoain I
Stroke affects primarily aged and co-morbid people, aspects not properly considered to date. Since angiogenesis/vasculogenesis are key processes for stroke recovery, we purposed to determine how different co-morbidities affect the outcome and angiogenesis/vasculogenesis, using a rodent model of metabolic syndrome, and by dynamic enhanced-contrast imaging (DCE-MRI) to assess its non-invasive potential to determine these processes. Twenty/twenty-two month-old corpulent (JCR:LA-Cp/Cp), a model of metabolic syndrome and lean rats were used. After inducing the experimental ischemia by transient MCAO, angiogenesis was analyzed by histology, vasculogenesis by determination of endothelial progenitor cells in peripheral blood by flow cytometry and evaluating their pro-angiogenic properties in culture and the vascular function by DCE-MRI at 3, 7 and 28 days after tMCAO. Our results show an increased infarct volume, BBB damage and an impaired outcome in corpulent rats compared with their lean counterparts. Corpulent rats also displayed worse post-stroke angiogenesis/vasculogenesis, outcome that translated in an impaired vascular function determined by DCE-MRI. These data confirm that outcome and angiogenesis/vasculogenesis induced by stroke in old rats are negatively affected by the co-morbidities present in the corpulent genotype and also that DCE-MRI might be a technique useful for the non-invasive evaluation of vascular function and angiogenesis processes.



J Cereb Blood Flow Metab: 29 Jun 2021; 41:1692-1706
Pradillo JM, Hernández-Jiménez M, Fernández-Valle ME, Medina V, ... Moro MA, Lizasoain I
J Cereb Blood Flow Metab: 29 Jun 2021; 41:1692-1706 | PMID: 34152893
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Abstract

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

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



J Cereb Blood Flow Metab: 29 Jun 2021:271678X211025447; epub ahead of print
Zwartbol MH, Rissanen I, Ghaznawi R, de Bresser J, ... Hendrikse J, Geerlings MI
J Cereb Blood Flow Metab: 29 Jun 2021:271678X211025447; epub ahead of print | PMID: 34187229
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Impact:
Abstract

Endogenous zinc protoporphyrin formation critically contributes to hemorrhagic stroke-induced brain damage.

Pan R, Yu S, Zhang H, Timmins GS, ... Zhou X, Liu KJ
Hemorrhagic stroke is a leading cause of death. The causes of intracerebral hemorrhage (ICH)-induced brain damage are thought to include lysis of red blood cells, hemin release and iron overload. These mechanisms, however, have not proven very amenable to therapeutic intervention, and so other mechanistic targets are being sought. Here we report that accumulation of endogenously formed zinc protoporphyrin (ZnPP) also critically contributes to ICH-induced brain damage. ICH caused a significant accumulation of ZnPP in brain tissue surrounding hematoma, as evidenced by fluorescence microscopy of ZnPP, and further confirmed by fluorescence spectroscopy and supercritical fluid chromatography-mass spectrometry. ZnPP formation was dependent upon both ICH-induced hypoxia and an increase in free zinc accumulation. Notably, inhibiting ferrochelatase, which catalyzes insertion of zinc into protoporphyrin, greatly decreased ICH-induced endogenous ZnPP generation. Moreover, a significant decrease in brain damage was observed upon ferrochelatase inhibition, suggesting that endogenous ZnPP contributes to the damage in ICH. Our findings reveal a novel mechanism of ICH-induced brain damage through ferrochelatase-mediated formation of ZnPP in ICH tissue. Since ferrochelatase can be readily inhibited by small molecules, such as protein kinase inhibitors, this may provide a promising new and druggable target for ICH therapy.



J Cereb Blood Flow Metab: 28 Jun 2021:271678X211028475; epub ahead of print
Pan R, Yu S, Zhang H, Timmins GS, ... Zhou X, Liu KJ
J Cereb Blood Flow Metab: 28 Jun 2021:271678X211028475; epub ahead of print | PMID: 34187233
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Impact:
Abstract

Wdfy3 regulates glycophagy, mitophagy, and synaptic plasticity.

Napoli E, Panoutsopoulos AA, Kysar P, Satriya N, ... Zarbalis KS, Giulivi C
Autophagy is essential to cell function, as it enables the recycling of intracellular constituents during starvation and in addition functions as a quality control mechanism by eliminating spent organelles and proteins that could cause cellular damage if not properly removed. Recently, we reported on Wdfy3\'s role in mitophagy, a clinically relevant macroautophagic scaffold protein that is linked to intellectual disability, neurodevelopmental delay, and autism spectrum disorder. In this study, we confirm our previous report that Wdfy3 haploinsufficiency in mice results in decreased mitophagy with accumulation of mitochondria with altered morphology, but expanding on that observation, we also note decreased mitochondrial localization at synaptic terminals and decreased synaptic density, which may contribute to altered synaptic plasticity. These changes are accompanied by defective elimination of glycogen particles and a shift to increased glycogen synthesis over glycogenolysis and glycophagy. This imbalance leads to an age-dependent higher incidence of brain glycogen deposits with cerebellar hypoplasia. Our results support and further extend Wdfy3\'s role in modulating both brain bioenergetics and synaptic plasticity by including glycogen as a target of macroautophagic degradation.



J Cereb Blood Flow Metab: 28 Jun 2021:271678X211027384; epub ahead of print
Napoli E, Panoutsopoulos AA, Kysar P, Satriya N, ... Zarbalis KS, Giulivi C
J Cereb Blood Flow Metab: 28 Jun 2021:271678X211027384; epub ahead of print | PMID: 34187232
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Impact:
Abstract

Recent advances in cell therapy for stroke.

Park YJ, Borlongan CV
The last 50 years have witnessed the translation of stem cell therapy from the laboratory to the clinic for treating brain disorders, in particular stroke. From the focal stereotaxic transplantation to the minimally invasive intravenous and intraarterial delivery, stem cells display the ability to replenish injured cells and to secrete therapeutic molecules, altogether promoting brain repair. The increased stroke incidence in COVID-19 survivors poses as a new disease indication for cell therapy, owing in part to the cells\' robust anti-inflammatory properties. Optimization of the cell transplant regimen will ensure the safe and effective clinical application of cell therapy in stroke and relevant neurological disorders.



J Cereb Blood Flow Metab: 28 Jun 2021:271678X211026507; epub ahead of print
Park YJ, Borlongan CV
J Cereb Blood Flow Metab: 28 Jun 2021:271678X211026507; epub ahead of print | PMID: 34187231
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Impact:
Abstract

Repeated hypoxia exposure induces cognitive dysfunction, brain inflammation, and amyloidβ/-Tau accumulation through reduced brain -GlcNAcylation in zebrafish.

Park J, Jung S, Kim SM, Park IY, ... Hwang GS, Han IO
Repetitive hypoxia (RH) exposure affects the initiation and progression of cognitive dysfunction, but little is known about the mechanisms of hypoxic brain damage. In this study, we show that sublethal RH increased anxiety, impaired learning and memory (L/M), and triggered downregulation of brain levels of glucose and several glucose metabolites in zebrafish, and that supplementation of glucose or glucosamine (GlcN) restored RH-induced L/M impairment. Fear conditioning (FC)-induced brain activation of and PKA/CREB signaling was abrogated by RH, and this effect was reversed by GlcN supplementation. RH was associated with decreased brain O-GlcNAcylation and an increased O-GlcNAcase (OGA) level. RH increased brain inflammation and p-Tau and amyloid β accumulation, and these effects were suppressed by GlcN. Our observations collectively suggest that changes in O-GlcNAc flux during hypoxic exposure could be an important causal factor for neurodegeneration, and that supplementation of the HBP/O-GlcNAc flux may be a potential novel therapeutic or preventive target for addressing hypoxic brain damage.



J Cereb Blood Flow Metab: 25 Jun 2021:271678X211027381; epub ahead of print
Park J, Jung S, Kim SM, Park IY, ... Hwang GS, Han IO
J Cereb Blood Flow Metab: 25 Jun 2021:271678X211027381; epub ahead of print | PMID: 34176340
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Impact:
Abstract

Selective intra-carotid blood cooling in acute ischemic stroke: A safety and feasibility study in an ovine stroke model.

Cattaneo GF, Herrmann AM, Eiden SA, Wieser M, ... Boltze J, Meckel S
Selective therapeutic hypothermia (TH) showed promising preclinical results as a neuroprotective strategy in acute ischemic stroke. We aimed to assess safety and feasibility of an intracarotid cooling catheter conceived for fast and selective brain cooling during endovascular thrombectomy in an ovine stroke model.Transient middle cerebral artery occlusion (MCAO, 3 h) was performed in 20 sheep. In the hypothermia group (n = 10), selective TH was initiated 20 minutes before recanalization, and was maintained for another 3 h. In the normothermia control group (n = 10), a standard 8 French catheter was used instead. Primary endpoints were intranasal cooling performance (feasibility) plus vessel patency assessed by digital subtraction angiography and carotid artery wall integrity (histopathology, both safety). Secondary endpoints were neurological outcome and infarct volumes.Computed tomography perfusion demonstrated MCA territory hypoperfusion during MCAO in both groups. Intranasal temperature decreased by 1.1 °C/3.1 °C after 10/60 minutes in the TH group and 0.3 °C/0.4 °C in the normothermia group (p < 0.001). Carotid artery and branching vessel patency as well as carotid wall integrity was indifferent between groups. Infarct volumes (p = 0.74) and neurological outcome (p = 0.82) were similar in both groups.Selective TH was feasible and safe. However, a larger number of subjects might be required to demonstrate efficacy.



J Cereb Blood Flow Metab: 22 Jun 2021:271678X211024952; epub ahead of print
Cattaneo GF, Herrmann AM, Eiden SA, Wieser M, ... Boltze J, Meckel S
J Cereb Blood Flow Metab: 22 Jun 2021:271678X211024952; epub ahead of print | PMID: 34159825
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Impact:
Abstract

Tissue outcome prediction in hyperacute ischemic stroke: Comparison of machine learning models.

Benzakoun J, Charron S, Turc G, Hassen WB, ... Thirion B, Oppenheim C
Machine Learning (ML) has been proposed for tissue fate prediction after acute ischemic stroke (AIS), with the aim to help treatment decision and patient management. We compared three different ML models to the clinical method based on diffusion-perfusion thresholding for the voxel-based prediction of final infarct, using a large MRI dataset obtained in a cohort of AIS patients prior to recanalization treatment. Baseline MRI (MRI0), including diffusion-weighted sequence (DWI) and Tmax maps from perfusion-weighted sequence, and 24-hr follow-up MRI (MRI24h) were retrospectively collected in consecutive 394 patients AIS patients (median age = 70 years; final infarct volume = 28mL). Manually segmented DWI24h lesion was considered the final infarct. Gradient Boosting, Random Forests and U-Net were trained using DWI, apparent diffusion coefficient (ADC) and Tmax maps on MRI0 as inputs to predict final infarct. Tissue outcome predictions were compared to final infarct using Dice score. Gradient Boosting had significantly better predictive performance (median [IQR] Dice Score as for median age, maybe you can replace the comma with an equal sign for consistency 0.53 [0.29-0.68]) than U-Net (0.48 [0.18-0.68]), Random Forests (0.51 [0.27-0.66]), and clinical thresholding method (0.45 [0.25-0.62]) (P < 0.001). In this benchmark of ML models for tissue outcome prediction in AIS, Gradient Boosting outperformed other ML models and clinical thresholding method and is thus promising for future decision-making.



J Cereb Blood Flow Metab: 22 Jun 2021:271678X211024371; epub ahead of print
Benzakoun J, Charron S, Turc G, Hassen WB, ... Thirion B, Oppenheim C
J Cereb Blood Flow Metab: 22 Jun 2021:271678X211024371; epub ahead of print | PMID: 34159824
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Impact:
Abstract

[C]PBR28 radiotracer kinetics are not driven by alterations in cerebral blood flow.

Sander CY, Bovo S, Torrado-Carvajal A, Albrecht D, ... Hooker JM, Loggia ML
The positron emission tomography (PET) radiotracer [11C]PBR28 has been increasingly used to image the translocator protein (TSPO) as a marker of neuroinflammation in a variety of brain disorders. Interrelatedly, similar clinical populations can also exhibit altered brain perfusion, as has been shown using arterial spin labelling in magnetic resonance imaging (MRI) studies. Hence, an unsolved debate has revolved around whether changes in perfusion could alter delivery, uptake, or washout of the radiotracer [11C]PBR28, and thereby influence outcome measures that affect interpretation of TSPO upregulation. In this simultaneous PET/MRI study, we demonstrate that [11C]PBR28 signal elevations in chronic low back pain patients are not accompanied, in the same regions, by increases in cerebral blood flow (CBF) compared to healthy controls, and that areas of marginal hypoperfusion are not accompanied by decreases in [11C]PBR28 signal. In non-human primates, we show that hypercapnia-induced increases in CBF during radiotracer delivery or washout do not alter [11C]PBR28 outcome measures. The combined results from two methodologically distinct experiments provide support from human data and direct experimental evidence from non-human primates that changes in CBF do not influence outcome measures reported by [11C]PBR28 PET imaging studies and corresponding interpretations of the biological meaning of TSPO upregulation.



J Cereb Blood Flow Metab: 22 Jun 2021:271678X211023387; epub ahead of print
Sander CY, Bovo S, Torrado-Carvajal A, Albrecht D, ... Hooker JM, Loggia ML
J Cereb Blood Flow Metab: 22 Jun 2021:271678X211023387; epub ahead of print | PMID: 34159823
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Impact:
Abstract

Review of treatment and therapeutic targets in brain arteriovenous malformation.

Pan P, Weinsheimer S, Cooke D, Winkler E, ... Kim H, Su H
Brain arteriovenous malformations (bAVM) are an important cause of intracranial hemorrhage (ICH), especially in younger patients. The pathogenesis of bAVM are largely unknown. Current understanding of bAVM etiology is based on studying genetic syndromes, animal models, and surgically resected specimens from patients. The identification of activating somatic mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene and other mitogen-activated protein kinase (MAPK) pathway genes has opened up new avenues for bAVM study, leading to a paradigm shift to search for somatic, de novo mutations in sporadic bAVMs instead of focusing on inherited genetic mutations. Through the development of new models and understanding of pathways involved in maintaining normal vascular structure and functions, promising therapeutic targets have been identified and safety and efficacy studies are underway in animal models and in patients. The goal of this paper is to provide a thorough review or current diagnostic and treatment tools, known genes and key pathways involved in bAVM pathogenesis to summarize current treatment options and potential therapeutic targets uncovered by recent discoveries.



J Cereb Blood Flow Metab: 22 Jun 2021:271678X211026771; epub ahead of print
Pan P, Weinsheimer S, Cooke D, Winkler E, ... Kim H, Su H
J Cereb Blood Flow Metab: 22 Jun 2021:271678X211026771; epub ahead of print | PMID: 34162280
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Impact:
Abstract

Clinical characteristics of fast and slow progressors of infarct growth in anterior circulation large vessel occlusion stroke.

Rocha M, Desai S, Son J, Tonetti DA, Jovin T, Jadhav AP
Fast and slow progressor phenotypes of infarct growth due to anterior circulation large vessel occlusion (ACLVO) remain poorly understood. We aimed to define clinical predictors of fast and slow progressors in a retrospective study of patients with ACLVO who underwent baseline advanced imaging within 24 hours of stroke onset. Fast progressors (ischemic core > 70 ml, < 6 hours after onset) and slow progressors (ischemic core ≤ 30 ml, 6 to 24 hours after onset) were identified amongst 185 patients. Clinical and laboratory variables were tested for association with fast or slow progressor status. In the early epoch, no significant differences were found between fast progressors and controls. In the delayed epoch, slow progressors had a median NIHSS of 14 versus 20 (p < 0.01) and MCA occlusion in 80% versus 63% (p < 0.05) relative to controls. In multivariate analyses, NIHSS (OR 0.83, 95% CI 0.73-0.95), hyperlipidemia (OR 4.24, 95% CI 1.01 - 19.3) and hemoglobin concentration (OR 0.75, 95% CI 0.57 - 0.99) were independently associated with slow progressor status. This study indicates that lower initial stroke symptom severity, a history of hyperlipidemia and mild anemia are associated with individual tolerance to ACLVO stroke.



J Cereb Blood Flow Metab: 16 Jun 2021:271678X211015068; epub ahead of print
Rocha M, Desai S, Son J, Tonetti DA, Jovin T, Jadhav AP
J Cereb Blood Flow Metab: 16 Jun 2021:271678X211015068; epub ahead of print | PMID: 34139885
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Impact:
Abstract

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

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



J Cereb Blood Flow Metab: 09 Jun 2021:271678X211020865; epub ahead of print
Dienel A, Kumar T P, Blackburn SL, McBride DW
J Cereb Blood Flow Metab: 09 Jun 2021:271678X211020865; epub ahead of print | PMID: 34112003
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Impact:
Abstract

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

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



J Cereb Blood Flow Metab: 09 Jun 2021:271678X211024373; epub ahead of print
Sebök M, Niftrik CHBV, Lohaus N, Esposito G, ... Regli L, Fierstra J
J Cereb Blood Flow Metab: 09 Jun 2021:271678X211024373; epub ahead of print | PMID: 34112002
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Impact:
Abstract

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

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



J Cereb Blood Flow Metab: 08 Jun 2021:271678X211020860; epub ahead of print
Khodanovich MY, Gubskiy IL, Kudabaeva MS, Namestnikova DD, ... Mustafina LR, Yarnykh VL
J Cereb Blood Flow Metab: 08 Jun 2021:271678X211020860; epub ahead of print | PMID: 34107787
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Impact:
Abstract

Cerebrospinal fluid hemoglobin drives subarachnoid hemorrhage-related secondary brain injury.

Akeret K, Buzzi RM, Schaer CA, Thomson BR, ... Hugelshofer M, Schaer DJ
Secondary brain injury after aneurysmal subarachnoid hemorrhage (SAH-SBI) contributes to poor outcomes in patients after rupture of an intracranial aneurysm. The lack of diagnostic biomarkers and novel drug targets represent an unmet need. The aim of this study was to investigate the clinical and pathophysiological association between cerebrospinal fluid hemoglobin (CSF-Hb) and SAH-SBI. In a cohort of 47 patients, we collected daily CSF-samples within 14 days after aneurysm rupture. There was very strong evidence for a positive association between spectrophotometrically determined CSF-Hb and SAH-SBI. The accuracy of CSF-Hb to monitor for SAH-SBI markedly exceeded that of established methods (AUC: 0.89 [0.85-0.92]). Temporal proteome analysis revealed erythrolysis accompanied by an adaptive macrophage response as the two dominant biological processes in the CSF-space after aneurysm rupture. Ex-vivo experiments on the vasoconstrictive and oxidative potential of Hb revealed critical inflection points overlapping CSF-Hb thresholds in patients with SAH-SBI. Selective depletion and in-solution neutralization by haptoglobin or hemopexin efficiently attenuated the vasoconstrictive and lipid peroxidation activities of CSF-Hb. Collectively, the clinical association between high CSF-Hb levels and SAH-SBI, the underlying pathophysiological rationale, and the favorable effects of haptoglobin and hemopexin in ex-vivo experiments position CSF-Hb as a highly attractive biomarker and potential drug target.



J Cereb Blood Flow Metab: 07 Jun 2021:271678X211020629; epub ahead of print
Akeret K, Buzzi RM, Schaer CA, Thomson BR, ... Hugelshofer M, Schaer DJ
J Cereb Blood Flow Metab: 07 Jun 2021:271678X211020629; epub ahead of print | PMID: 34102922
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Impact:
Abstract

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

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



J Cereb Blood Flow Metab: 07 Jun 2021:271678X211021313; epub ahead of print
Wang R, Oh JM, Motovylyak A, Ma Y, ... Eisenmenger L, Okonkwo OC
J Cereb Blood Flow Metab: 07 Jun 2021:271678X211021313; epub ahead of print | PMID: 34102919
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Impact:
Abstract

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

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



J Cereb Blood Flow Metab: 07 Jun 2021:271678X211023660; epub ahead of print
Wang C, Shi Z, Yang M, Huang L, ... Ding J, Wang H
J Cereb Blood Flow Metab: 07 Jun 2021:271678X211023660; epub ahead of print | PMID: 34102912
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Impact:
Abstract

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

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



J Cereb Blood Flow Metab: 01 Jun 2021:271678X211020863; epub ahead of print
Dounavi ME, Low A, McKiernan EF, Mak E, ... Su L, O'Brien JT
J Cereb Blood Flow Metab: 01 Jun 2021:271678X211020863; epub ahead of print | PMID: 34078163
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Impact:
Abstract

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

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



J Cereb Blood Flow Metab: 01 Jun 2021:271678X211020589; epub ahead of print
Rischka L, Godbersen GM, Pichler V, Michenthaler P, ... Lanzenberger R, Hahn A
J Cereb Blood Flow Metab: 01 Jun 2021:271678X211020589; epub ahead of print | PMID: 34078145
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Impact:
Abstract

Mutations of are responsible for sporadic cerebral cavernous malformation and lead to a mulberry-like cluster in zebrafish.

Lin J, Liang J, Wen J, Luo M, ... Yang S, Sheng W
Although familial forms of cerebral cavernous malformation are mainly attributed to three CCM genes (KRIT1, CCM2 and PDCD10), no mutation is identified in sporadic cerebral cavernous malformation cases with a unique lesion, indicating additional genes for sporadic cerebral cavernous malformation. To screen the candidate genes, we conducted whole exome sequencing in 31 sporadic cerebral cavernous malformation patients and 32 healthy controls, and identified 5 affected individuals carrying 6 heterozygous deleterious mutations in RNF213 but no RNF213 mutation in healthy individuals. To further confirm RNF213 was associated with cerebral cavernous malformation, we generated rnf213a homozygous knockout zebrafish and found mutation of rnf213a in zebrafish led to a mulberry-like cluster of disordered-flow vascular channels which was reminiscent of human cerebral cavernous malformation. In addition, we revealed kbtbd7 and anxa6 were significantly downregulated due to rnf213a mutation through transcriptomic sequencing and RT-qPCR analysis. Based on the mulberry-like phenotype partly rescued by mRNA of kbtbd7 as well as anxa6, we suggested that rnf213a promoted mulberry-like cluster via downregulation of kbtbd7 and anxa6. Altogether, we firstly demonstrate RNF213is a novel candidate gene for sporadic cerebral cavernous malformation and the mutation of rnf213a is responsible for the mulberry-like cluster in zebrafish.



J Cereb Blood Flow Metab: 30 May 2021; 41:1251-1263
Lin J, Liang J, Wen J, Luo M, ... Yang S, Sheng W
J Cereb Blood Flow Metab: 30 May 2021; 41:1251-1263 | PMID: 32248732
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Impact:
Abstract

Reduced parenchymal cerebral blood flow is associated with greater progression of brain atrophy: The SMART-MR study.

Ghaznawi R, Zwartbol MH, Zuithoff NP, Bresser J, ... Geerlings MI, UCC-SMART Study Group
Global cerebral hypoperfusion may be involved in the aetiology of brain atrophy; however, long-term longitudinal studies on this relationship are lacking. We examined whether reduced cerebral blood flow was associated with greater progression of brain atrophy. Data of 1165 patients (61 ± 10 years) from the SMART-MR study, a prospective cohort study of patients with arterial disease, were used of whom 689 participated after 4 years and 297 again after 12 years. Attrition was substantial. Total brain volume and total cerebral blood flow were obtained from magnetic resonance imaging scans and expressed as brain parenchymal fraction (BPF) and parenchymal cerebral blood flow (pCBF). Mean decrease in BPF per year was 0.22% total intracranial volume (95% CI: -0.23 to -0.21). Mean decrease in pCBF per year was 0.24 ml/min per 100 ml brain volume (95% CI: -0.29 to -0.20). Using linear mixed models, lower pCBF at baseline was associated with a greater decrease in BPF over time (p =0.01). Lower baseline BPF, however, was not associated with a greater decrease in pCBF (p =0.43). These findings indicate that reduced cerebral blood flow is associated with greater progression of brain atrophy and provide further support for a role of cerebral blood flow in the process of neurodegeneration.



J Cereb Blood Flow Metab: 30 May 2021; 41:1229-1239
Ghaznawi R, Zwartbol MH, Zuithoff NP, Bresser J, ... Geerlings MI, UCC-SMART Study Group
J Cereb Blood Flow Metab: 30 May 2021; 41:1229-1239 | PMID: 32807000
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Abstract

Feasibility of oscillating and pulsed gradient diffusion MRI to assess neonatal hypoxia-ischemia on clinical systems.

Gao F, Shen X, Zhang H, Ba R, ... Zhang Y, Wu D
Diffusion-time- (td) dependent diffusion MRI (dMRI) extends our ability to characterize brain microstructure by measuring dMRI signals at varying td. The use of oscillating gradient (OG) is essential for accessing short td but is technically challenging on clinical MRI systems. This study aims to investigate the clinical feasibility and value of td-dependent dMRI in neonatal hypoxic-ischemic encephalopathy (HIE). Eighteen HIE neonates and six normal term-born neonates were scanned on a 3 T scanner, with OG-dMRI at an oscillating frequency of 33 Hz (equivalent td ≈ 7.5 ms) and pulsed gradient (PG)-dMRI at a td of 82.8 ms and b-value of 700 s/mm2. The td-dependence, as quantified by the difference in apparent diffusivity coefficients between OG- and PG-dMRI (ΔADC), was observed in the normal neonatal brains, and the ΔADC was higher in the subcortical white matter than the deep grey matter. In HIE neonates with severe and moderate injury, ΔADC significantly increased in the basal ganglia (BG) compared to the controls (23.7% and 10.6%, respectively). In contrast, the conventional PG-ADC showed a 12.6% reduction only in the severe HIE group. White matter edema regions also demonstrated increased ΔADC, where PG-ADC did not show apparent changes. Our result demonstrated that td-dependent dMRI provided high sensitivity in detecting moderate-to-severe HIE.



J Cereb Blood Flow Metab: 30 May 2021; 41:1240-1250
Gao F, Shen X, Zhang H, Ba R, ... Zhang Y, Wu D
J Cereb Blood Flow Metab: 30 May 2021; 41:1240-1250 | PMID: 32811261
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Abstract

Rapid hematoma growth triggers spreading depolarizations in experimental intracortical hemorrhage.

Fischer P, Sugimoto K, Chung DY, Tamim I, ... Sakadzic S, Ayata C
Recurrent waves of spreading depolarization (SD) occur in brain injury and are thought to affect outcomes. What triggers SD in intracerebral hemorrhage is poorly understood. We employed intrinsic optical signaling, laser speckle flowmetry, and electrocorticography to elucidate the mechanisms triggering SD in a collagenase model of intracortical hemorrhage in mice. Hematoma growth, SD occurrence, and cortical blood flow changes were tracked. During early hemorrhage (0-4 h), 17 out of 38 mice developed SDs, which always originated from the hematoma. No SD was detected at late time points (8-52 h). Neither hematoma size, nor peri-hematoma perfusion were associated with SD occurrence. Further, arguing against ischemia as a trigger factor, normobaric hyperoxia did not inhibit SD occurrence. Instead, SDs always occurred during periods of rapid hematoma growth, which was two-fold faster immediately preceding an SD compared with the peak growth rates in animals that did not develop any SDs. Induced hypertension accelerated hematoma growth and resulted in a four-fold increase in SD occurrence compared with normotensive animals. Altogether, our data suggest that spontaneous SDs in this intracortical hemorrhage model are triggered by the mechanical distortion of tissue by rapidly growing hematomas.



J Cereb Blood Flow Metab: 30 May 2021; 41:1264-1276
Fischer P, Sugimoto K, Chung DY, Tamim I, ... Sakadzic S, Ayata C
J Cereb Blood Flow Metab: 30 May 2021; 41:1264-1276 | PMID: 32936730
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Abstract

Hippocampal blood-brain barrier permeability is related to the APOE4 mutation status of elderly individuals without dementia.

Moon WJ, Lim C, Ha IH, Kim Y, ... Kim HJ, Han SH
Blood-brain barrier (BBB) disruption, modulated by APOE4 mutation, is implicated in the pathogenesis of cognitive decline. We determined whether BBB permeability differed according to cognitive functioning and APOE4 status in elderly subjects without dementia. In this prospective study, 33 subjects with mild cognitive impairment (MCI) and 33 age-matched controls (normal cognition [NC]) underwent 3 T brain magnetic resonance imaging. The Patlak model was used to calculate tissue permeability (Ktrans). A region-of interest analysis of Ktrans was performed to compare relevant brain regions. Effects of Ktrans on cognitive functioning were evaluated with linear regression analysis adjusted for confounding factors. NC and MCI groups did not differ in terms of vascular risk factors or hippocampal Ktrans, except for hippocampal volume. Hippocampal Ktrans was significantly higher in APOE4 carriers than in non-carriers (p = 0.007). Factors which predicted cognitive functioning included hippocampal volume (beta=-0.445, standard error [SE]=0.137, p = 0.003) and hippocampal BBB permeability (beta = 0.142, SE = 0.050, p = 0.008) after correcting for age, education, and APOE4 status. This suggests that hippocampal BBB permeability is associated with APOE4 mutation, and may predict cognitive functioning. BBB permeability imaging represents a distinct imaging biomarker for APOE4 mutations in NC and MCI subjects and for determining the degree of APOE4-related pathology.



J Cereb Blood Flow Metab: 30 May 2021; 41:1351-1361
Moon WJ, Lim C, Ha IH, Kim Y, ... Kim HJ, Han SH
J Cereb Blood Flow Metab: 30 May 2021; 41:1351-1361 | PMID: 32936729
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Abstract

Remote ischemic conditioning enhances oxygen supply to ischemic brain tissue in a mouse model of stroke: Role of elevated 2,3-biphosphoglycerate in erythrocytes.

Wang L, Ren C, Li Y, Gao C, ... Xia C, Ji X
Oxygen supply for ischemic brain tissue during stroke is critical to neuroprotection. Remote ischemic conditioning (RIC) treatment is effective for stroke. However, it is not known whether RIC can improve brain tissue oxygen supply. In current study, we employed a mouse model of stroke created by middle cerebral artery occlusion (MCAO) to investigate the effect of RIC on oxygen supply to the ischemic brain tissue using a hypoxyprobe system. Erythrocyte oxygen-carrying capacity and tissue oxygen exchange were assessed by measuring oxygenated hemoglobin and oxygen dissociation curve. We found that RIC significantly mitigated hypoxic signals and decreased neural cell death, thereby preserving neurological functions. The tissue oxygen exchange was markedly enhanced, along with the elevated hemoglobin P50 and right-shifted oxygen dissociation curve. Intriguingly, RIC markedly elevated 2,3-biphosphoglycerate (2,3-BPG) levels in erythrocyte, and the erythrocyte 2,3-BPG levels were highly negatively correlated with the hypoxia in the ischemic brain tissue. Further, adoptive transfusion of 2,3-BPG-rich erythrocytes prepared from RIC-treated mice significantly enhanced the oxygen supply to the ischemic tissue in MCAO mouse model. Collectively, RIC protects against ischemic stroke through improving oxygen supply to the ischemic brain tissue where the enhanced tissue oxygen delivery and exchange by RIC-induced 2,3-BPG-rich erythrocytes may play a role.



J Cereb Blood Flow Metab: 30 May 2021; 41:1277-1290
Wang L, Ren C, Li Y, Gao C, ... Xia C, Ji X
J Cereb Blood Flow Metab: 30 May 2021; 41:1277-1290 | PMID: 32933360
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Abstract

Long-term outcome of endovascular therapy for acute basilar artery occlusion.

Wu L, Zhang D, Chen J, Sun C, ... Wu D, Ji X
The long-term functional outcome of acute basilar artery occlusion (BAO) patients who received modern endovascular therapy (EVT) is unclear. We sought to assess the long-term functional outcome of BAO patients treated with EVT and determine the prognostic factors associated with favorable outcome. We enrolled consecutive BAO patients who received EVT between December 2012 and December 2018 in this observational study. Baseline characteristics and outcomes were presented. Multivariable logistic regression analysis was performed to identify the prognostic factors associated with long-term outcome. Among the 177 BAO patients included in this study, 80 patients (45.2%) obtained favorable outcome and 97 patients (54.8%) had unfavorable outcome at long-term follow-up with a median observation time of 12 months (interquartile range, 3-19). A total of 67 patients (37.9%) died. National Institutes of Health Stroke Scale (NIHSS), posterior circulation Alberta Stroke Program Early Computed Tomography Score (pc-ASPECTS), time from stroke onset to recanalization, and recanalization condition were identified as independent predictors for long-term outcome. Over 40% of BAO patients who were treated with modern EVT achieved favorable outcome at long-term follow-up. NIHSS, pc-ASPECTS, time from stroke onset to recanalization, and recanalization condition were identified as independent prognostic factors of long-term outcome.



J Cereb Blood Flow Metab: 30 May 2021; 41:1210-1218
Wu L, Zhang D, Chen J, Sun C, ... Wu D, Ji X
J Cereb Blood Flow Metab: 30 May 2021; 41:1210-1218 | PMID: 32955959
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Abstract

Simplified quantification of [F]FE-PE2I PET in Parkinson\'s disease: Discriminative power, test-retest reliability and longitudinal validity during early peak and late pseudo-equilibrium.

Brumberg J, Kerstens V, Cselényi Z, Svenningsson P, ... Fazio P, Varrone A
Quantification of dopamine transporter (DAT) availability with [18F]FE-PE2I PET enables the detection of presynaptic dopamine deficiency and provides a potential progression marker for Parkinson`s disease (PD). Simplified quantification is feasible, but the time window of short acquisition protocols may have a substantial impact on the reliability of striatal binding estimates. Dynamic [18F]FE-PE2I PET data of cross-sectional (33 PD patients, 24 controls), test-retest (9 patients), and longitudinal (12 patients) cohorts were used to assess the variability and reliability of specific binding ratios (SBR) measured during early peak and late pseudo-equilibrium. Receiver operating characteristics area under the curve (PD vs. controls) was high for early (0.996) and late (0.991) SBR. Early SBR provided more favourable effect size, absolute variability, and standard error of measurement than late SBR (caudate: 1.29 vs. 1.23; 6.9% vs. 9.8%; 0.09 vs. 0.20; putamen: 1.75 vs. 1.67; 7.7% vs. 14.0%; 0.08 vs. 0.17). The annual percentage change was comparable for both time windows (-7.2%-8.5%), but decline was significant only for early SBR. Whereas early and late [18F]FE-PE2I PET acquisitions have similar discriminative power to separate PD patients and controls, the early peak equilibrium acquisition can be recommended if [18F]FE-PE2I is used to measure longitudinal changes of DAT availability.



J Cereb Blood Flow Metab: 30 May 2021; 41:1291-1300
Brumberg J, Kerstens V, Cselényi Z, Svenningsson P, ... Fazio P, Varrone A
J Cereb Blood Flow Metab: 30 May 2021; 41:1291-1300 | PMID: 32955955
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Abstract

Distinct peripheral blood monocyte and neutrophil transcriptional programs following intracerebral hemorrhage and different etiologies of ischemic stroke.

Carmona-Mora P, Ander BP, Jickling GC, Dykstra-Aiello C, ... Sharp FR, Stamova B
Understanding cell-specific transcriptome responses following intracerebral hemorrhage (ICH) and ischemic stroke (IS) will improve knowledge of the immune response to brain injury. Transcriptomic profiles of 141 samples from 48 subjects with ICH, different IS etiologies, and vascular risk factor controls were characterized using RNA-seq in isolated neutrophils, monocytes and whole blood. In both IS and ICH, monocyte genes were down-regulated, whereas neutrophil gene expression changes were generally up-regulated. The monocyte down-regulated response to ICH included innate, adaptive immune, dendritic, NK cell and atherosclerosis signaling. Neutrophil responses to ICH included tRNA charging, mitochondrial dysfunction, and ER stress pathways. Common monocyte and neutrophil responses to ICH included interferon signaling, neuroinflammation, death receptor signaling, and NFAT pathways. Suppressed monocyte responses to IS included interferon and dendritic cell maturation signaling, phagosome formation, and IL-15 signaling. Activated neutrophil responses to IS included oxidative phosphorylation, mTOR, BMP, growth factor signaling, and calpain proteases-mediated blood-brain barrier (BBB) dysfunction. Common monocyte and neutrophil responses to IS included JAK1, JAK3, STAT3, and thrombopoietin signaling. Cell-type and cause-specific approaches will assist the search for future IS and ICH biomarkers and treatments.



J Cereb Blood Flow Metab: 30 May 2021; 41:1398-1416
Carmona-Mora P, Ander BP, Jickling GC, Dykstra-Aiello C, ... Sharp FR, Stamova B
J Cereb Blood Flow Metab: 30 May 2021; 41:1398-1416 | PMID: 32960689
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Abstract

NMDA receptor ion channel activation detected in vivo with [F]GE-179 PET after electrical stimulation of rat hippocampus.

Vibholm AK, Landau AM, Møller A, Jacobsen J, ... Sørensen JC, Brooks DJ
The positron emission tomography (PET) tracer [18F]GE-179 binds to the phencyclidine (PCP) site in the open N-methyl-D-aspartate receptor ion channel (NMDAR-IC). To demonstrate that PET can visualise increased [18F]GE-179 uptake by active NMDAR-ICs and that this can be blocked by the PCP antagonist S-ketamine, 15 rats had an electrode unilaterally implanted in their ventral hippocampus. Seven rats had no stimulation, five received pulsed 400 µA supra-threshold 60 Hz stimulation alone, and three received intravenous S-ketamine injection prior to stimulation. Six other rats were not implanted. Each rat had a 90 min [18F]GE-179 PET scan. Stimulated rats had simultaneous depth-EEG recordings of induced seizure activity. [18F]GE-179 uptake (volume of distribution, VT) was compared between hemispheres and between groups. Electrical stimulation induced a significant increase in [18F]GE-179 uptake at the electrode site compared to the contralateral hippocampus (mean 22% increase in VT, p =0.0014) and to non-stimulated comparator groups. Rats injected with S-ketamine prior to stimulation maintained non-stimulated levels of [18F]GE-179 uptake during stimulation. In conclusion, PET visualisation of focal [18F]GE-179 uptake during electrically activated NMDAR-ICs and the demonstration of specificity for PCP sites by blockade with S-ketamine support the in vivo utility of [18F]GE-179 PET as a use-dependent marker of NMDAR-IC activation.



J Cereb Blood Flow Metab: 30 May 2021; 41:1301-1312
Vibholm AK, Landau AM, Møller A, Jacobsen J, ... Sørensen JC, Brooks DJ
J Cereb Blood Flow Metab: 30 May 2021; 41:1301-1312 | PMID: 32960687
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Abstract

Intracranial vessel wall lesions on 7T MRI and MRI features of cerebral small vessel disease: The SMART-MR study.

Zwartbol MH, van der Kolk AG, Kuijf HJ, Witkamp TD, ... Geerlings MI, UCC-SMART Study Group*
The etiology of cerebral small vessel disease (CSVD) is the subject of ongoing research. Although intracranial atherosclerosis (ICAS) has been proposed as a possible cause, studies on their relationship remain sparse. We used 7 T vessel wall magnetic resonance imaging (MRI) to study the association between intracranial vessel wall lesions-a neuroimaging marker of ICAS-and MRI features of CSVD. Within the SMART-MR study, cross-sectional analyses were performed in 130 patients (68 ± 9 years; 88% male). ICAS burden-defined as the number of vessel wall lesions-was determined on 7 T vessel wall MRI. CSVD features were determined on 1.5 T and 7 T MRI. Associations between ICAS burden and CSVD features were estimated with linear or modified Poisson regression, adjusted for age, sex, vascular risk factors, and medication use. In 125 patients, ≥1 vessel wall lesions were found (mean 8.5 ± 5.7 lesions). ICAS burden (per + 1 SD) was associated with presence of large subcortical and/or cortical infarcts (RR = 1.65; 95%CI: 1.12-2.43), lacunes (RR = 1.45; 95% CI: 1.14-1.86), cortical microinfarcts (RR = 1.48; 95%CI: 1.13-1.94), and total white matter hyperintensity volume (b = 0.24; 95%CI: 0.02-0.46). Concluding, patients with a higher ICAS burden had more CSVD features, although no evidence of co-location was observed. Further longitudinal studies are required to determine if ICAS precedes development of CSVD.



J Cereb Blood Flow Metab: 30 May 2021; 41:1219-1228
Zwartbol MH, van der Kolk AG, Kuijf HJ, Witkamp TD, ... Geerlings MI, UCC-SMART Study Group*
J Cereb Blood Flow Metab: 30 May 2021; 41:1219-1228 | PMID: 33023386
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Abstract

Cerebrovascular effects of glibenclamide investigated using high-resolution magnetic resonance imaging in healthy volunteers.

Al-Karagholi MA, Ghanizada H, Nielsen CAW, Ansari A, ... Amin FM, Ashina M
Glibenclamide inhibits sulfonylurea receptor (SUR), which regulates several ion channels including SUR1-transient receptor potential melastatin 4 (SUR1-TRPM4) channel and ATP-sensitive potassium (KATP) channel. Stroke upregulates SURl-TRPM4 channel, which causes a rapid edema formation and brain swelling. Glibenclamide may antagonize the formation of cerebral edema during stroke. Preclinical studies showed that glibenclamide inhibits KATP channel-induced vasodilation without altering the basal vascular tone. The in vivo human cerebrovascular effects of glibenclamide have not previously been investigated.In a randomized, double-blind, placebo-controlled, three-way cross-over study, we used advanced 3 T MRI methods to investigate the effects of glibenclamide and KATP channel opener levcromakalim on mean global cerebral blood flow (CBF) and intra- and extracranial artery circumferences in 15 healthy volunteers. Glibenclamide administration did not alter the mean global CBF and the basal vascular tone. Following levcromakalim infusion, we observed a 14% increase of the mean global CBF and an 8% increase of middle cerebral artery (MCA) circumference, and glibenclamide did not attenuate levcromakalim-induced vascular changes. Collectively, the findings demonstrate the vital role of KATP channels in cerebrovascular hemodynamic and indicate that glibenclamide does not inhibit the protective effects of KATP channel activation during hypoxia and ischemia-induced brain injury.



J Cereb Blood Flow Metab: 30 May 2021; 41:1328-1337
Al-Karagholi MA, Ghanizada H, Nielsen CAW, Ansari A, ... Amin FM, Ashina M
J Cereb Blood Flow Metab: 30 May 2021; 41:1328-1337 | PMID: 33028147
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Abstract

A local-neighborhood Lassen plot filter for creating occupancy and non-displaceable binding images.

de Laat B, Morris ED
For radioligands without a reference region, the Lassen plot can be used to estimate receptor occupancy by an exogenous drug (ODrug). However, the Lassen plot is not well-suited for spatial variation in ODrug. To overcome this limitation, we introduce a Lassen plot filter, i.e. a Lassen plot applied to local neighborhoods in PET images. Image data were simulated with regional variation in VND, ODrug, both, or neither and analyzed using the change in binding potential (ΔBPND), the conventional Lassen plot, and the Lassen plot filter at the region of interest (ROI) and voxel level. All methods were also applied to a human [11C]flumazenil occupancy study using PF-06372865. This combination of a non-selective radioligand and selective drug should lead to varying ODrug provided the distribution of subtypes varies spatially. In contrast with ΔBPND and the conventional Lassen plot, ROI-level and voxel-level Lassen plot filter estimates remained unbiased in the presence of regional variation in VND or ODrug. In the [11C]flumazenil data-set, ODrug was shown to vary regionally in accordance with the distribution of binding sites for [11C]flumazenil and PF-06372865. We demonstrate that a local-neighborhood Lassen plot filter provides robust and unbiased estimates of ODrug and VND without the need for any user intervention.



J Cereb Blood Flow Metab: 30 May 2021; 41:1379-1389
de Laat B, Morris ED
J Cereb Blood Flow Metab: 30 May 2021; 41:1379-1389 | PMID: 33050827
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Abstract

Impaired capillary-to-arteriolar electrical signaling after traumatic brain injury.

Mughal A, Sackheim AM, Sancho M, Longden TA, ... Nelson MT, Freeman K
Traumatic brain injury (TBI) acutely impairs dynamic regulation of local cerebral blood flow, but long-term (>72 h) effects on functional hyperemia are unknown. Functional hyperemia depends on capillary endothelial cell inward rectifier potassium channels (Kir2.1) responding to potassium (K+) released during neuronal activity to produce a regenerative, hyperpolarizing electrical signal that propagates from capillaries to dilate upstream penetrating arterioles. We hypothesized that TBI causes widespread disruption of electrical signaling from capillaries-to-arterioles through impairment of Kir2.1 channel function. We randomized mice to TBI or control groups and allowed them to recover for 4 to 7 days post-injury. We measured in vivo cerebral hemodynamics and arteriolar responses to local stimulation of capillaries with 10 mM K+ using multiphoton laser scanning microscopy through a cranial window under urethane and α-chloralose anesthesia. Capillary angio-architecture was not significantly affected following injury. However, K+-induced hyperemia was significantly impaired. Electrophysiology recordings in freshly isolated capillary endothelial cells revealed diminished Ba2+-sensitive Kir2.1 currents, consistent with a reduction in channel function. In pressurized cerebral arteries isolated from TBI mice, K+ failed to elicit the vasodilation seen in controls. We conclude that disruption of endothelial Kir2.1 channel function impairs capillary-to-arteriole electrical signaling, contributing to altered cerebral hemodynamics after TBI.



J Cereb Blood Flow Metab: 30 May 2021; 41:1313-1327
Mughal A, Sackheim AM, Sancho M, Longden TA, ... Nelson MT, Freeman K
J Cereb Blood Flow Metab: 30 May 2021; 41:1313-1327 | PMID: 33050826
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Abstract

Impairment of cerebrovascular reactivity in response to hypercapnic challenge in a mouse model of repetitive mild traumatic brain injury.

Lynch CE, Eisenbaum M, Algamal M, Balbi M, ... Crawford F, Bachmeier C
Incidences of repetitive mild TBI (r-mTBI), like those sustained by contact sports athletes and military personnel, are thought to be a risk factor for development of neurodegenerative disorders. Those suffering from chronic TBI-related illness demonstrate deficits in cerebrovascular reactivity (CVR), the ability of the cerebral vasculature to respond to a vasoactive stimulus. CVR is thus an important measure of traumatic cerebral vascular injury (TCVI), and a possible in vivo endophenotype of TBI-related neuropathogenesis. We combined laser speckle imaging of CVR in response to hypercapnic challenge with neurobehavioral assessment of learning and memory, to investigate if decreased cerebrovascular responsiveness underlies impaired cognitive function in our mouse model of chronic r-mTBI. We demonstrate a profile of blunted hypercapnia-evoked CVR in the cortices of r-mTBI mice like that of human TBI, alongside sustained memory and learning impairment, without biochemical or immunohistopathological signs of cerebral vessel laminar or endothelium constituent loss. Transient decreased expression of alpha smooth muscle actin and platelet-derived growth factor receptor β, indicative of TCVI, is obvious only at the time of the most pronounced CVR deficit. These findings implicate CVR as a valid preclinical measure of TCVI, perhaps useful for developing therapies targeting TCVI after recurrent mild head trauma.



J Cereb Blood Flow Metab: 30 May 2021; 41:1362-1378
Lynch CE, Eisenbaum M, Algamal M, Balbi M, ... Crawford F, Bachmeier C
J Cereb Blood Flow Metab: 30 May 2021; 41:1362-1378 | PMID: 33050825
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Abstract

Arterial elasticity, endothelial function and intracranial vascular health: A multimodal MRI study.

Liu W, Chen Z, Ortega D, Liu X, ... Li H, Yang J
Vascular dysfunctions, including arterial stiffness and endothelial dysfunction, are prevalent in hypertensive subjects. We aimed to study their relations to subclinical intracranial vascular health in this study. A total of 200 older hypertensive males without overt cardiovascular or cerebrovascular diseases were recruited. Arterial elasticity was measured as carotid-femoral pulse wave velocity (cfPWV) and endothelial function was measured as digital reactive hyperemia index (RHI). Cerebrovascular health was evaluated using MRI in four aspects: intracranial atherosclerosis, brain perfusion as cerebral blood flow (CBF), vascular rarefaction analyzed as visible arterial branches on angiography using a custom-developed analysis technique and small vessel disease measured as white matter hyperintensity (WMH). There was a significant negative association between cfPWV and CBF, suggesting a link between arterial stiffness and CBF decline. Higher cfPWV was also associated with presence of intracranial stenotic plaque and greater WMH volume. RHI was positively related to CBF, indicating that endothelial dysfunction was associated with reduced CBF. All the associations remained significant after adjustment for confounding variables. Arterial stiffness and endothelial dysfunction are associated with reduced brain perfusion in older hypertensive males. Arterial stiffness is also associated with global cerebral vascular injury, affecting both small and medium-to-large arteries.



J Cereb Blood Flow Metab: 30 May 2021; 41:1390-1397
Liu W, Chen Z, Ortega D, Liu X, ... Li H, Yang J
J Cereb Blood Flow Metab: 30 May 2021; 41:1390-1397 | PMID: 33081567
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Abstract

Blood lipid markers are associated with hippocampal viscoelastic properties and memory in humans.

Sanjana F, Delgorio PL, Hiscox LV, DeConne TM, ... Johnson CL, Martens CR
Age-related memory loss shares similar risk factors as cardiometabolic diseases including elevated serum triglycerides (TGs) and low-density lipoprotein cholesterol (LDL-C) and reduced high-density lipoprotein cholesterol (HDL-C). The mechanisms linking these aberrant blood lipids to memory loss are not completely understood but may be partially mediated by reduced integrity of the hippocampus (HC), the primary brain structure for encoding and recalling memories. In this study, we tested the hypothesis that blood lipid markers are independently associated with memory performance and HC viscoelasticity-a noninvasive measure of brain tissue microstructural integrity assessed by high-resolution magnetic resonance elastography (MRE). Twenty-six individuals across the adult lifespan were recruited (14 M/12 F; mean age: 42 ± 15 y; age range: 22-78 y) and serum lipid profiles were related to episodic memory and HC viscoelasticity. All subjects were generally healthy without clinically abnormal blood lipids or memory loss. Episodic memory was negatively associated with the TG/HDL-C ratio. HC viscoelasticity was negatively associated with serum TGs and the TG/HDL-C ratio, independent of age and in the absence of associations with HC volume. These data, although cross-sectional, suggest that subtle differences in blood lipid profiles in healthy adults may contribute to a reduction in memory function and HC tissue integrity.



J Cereb Blood Flow Metab: 30 May 2021; 41:1417-1427
Sanjana F, Delgorio PL, Hiscox LV, DeConne TM, ... Johnson CL, Martens CR
J Cereb Blood Flow Metab: 30 May 2021; 41:1417-1427 | PMID: 33103936
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Abstract

Protective effects of edaravone on white matter pathology in a novel mouse model of Alzheimer\'s disease with chronic cerebral hypoperfusion.

Feng T, Yamashita T, Sasaki R, Tadokoro K, ... Hishikawa N, Abe K
White matter lesions (WMLs) caused by cerebral chronic hypoperfusion (CCH) may contribute to the pathophysiology of Alzheimer\'s disease (AD). However, the underlying mechanisms and therapeutic approaches have yet to be totally identified. In the present study, we investigated a potential therapeutic effect of the free radical scavenger edaravone (EDA) on WMLs in our previously reported novel mouse model of AD (APP23) plus CCH with motor and cognitive deficits. Relative to AD with CCH mice at 12 months (M) of age, EDA strongly improved CCH-induced WMLs in the corpus callosum of APP23 mice at 12 M by improving the disruption of white matter integrity, enhancing the proliferation of oligodendrocyte progenitor cells, attenuating endothelium/astrocyte unit dysfunction, and reducing neuroinflammation and oxidative stress. The present study demonstrates that the long-term administration of EDA may provide a promising therapeutic approach for WMLs in AD plus CCH disease with cognitive deficits.



J Cereb Blood Flow Metab: 30 May 2021; 41:1437-1448
Feng T, Yamashita T, Sasaki R, Tadokoro K, ... Hishikawa N, Abe K
J Cereb Blood Flow Metab: 30 May 2021; 41:1437-1448 | PMID: 33106078
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Abstract

Relative signal intensity on time-of-flight magnetic resonance angiography as a novel indicator of aggressive presentation of intracranial dural arteriovenous fistulas.

Ryu B, Sato S, Mochizuki T, Niimi Y
Asymptomatic dural arteriovenous fistulas (DAVFs) with cortical venous reflux (CVR) are now more commonly encountered. However, patients with an incidental onset may have a less aggressive clinical course. It is desirable to explore methods and indicators to predict the clinical outcomes. This study investigates whether the relative signal intensity (rSI) of the draining vessels on the time-of-flight magnetic resonance angiography is related to clinical behavior in patients with intracranial DAVFs. We retrospectively reviewed 36 intracranial DAVFs. The patients were categorized as those with either aggressive-presentation or non-aggressive-presentation (n = 16 and 20, respectively). The rSIs of the shunt points, affected sinuses, and veins with CVR were compared between the two groups. The two groups were not significantly different in terms of rSIs of the shunt points and affected sinuses (p = 0.37 and 0.41, respectively). However, a significant positive correlation was observed in the rSI of the veins with CVR between the aggressive and non-aggressive behavior groups (p < 0.0001). The rSI of the veins with CVR could serve as a reliable indicator of aggressive behavior in intracranial DAVFs, and its optimal cutoff value was 1.63 with high sensitivity and specificity for predicting aggressive behavior (area under the curve, 0.909).



J Cereb Blood Flow Metab: 30 May 2021; 41:1428-1436
Ryu B, Sato S, Mochizuki T, Niimi Y
J Cereb Blood Flow Metab: 30 May 2021; 41:1428-1436 | PMID: 33106077
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Abstract

Modulation of premotor cortex response to sequence motor learning during escitalopram intake.

Molloy EN, Mueller K, Beinhölzl N, Blöchl M, ... Villringer A, Sacher J
The contribution of selective serotonin reuptake inhibitors to motor learning by inducing motor cortical plasticity remains controversial given diverse findings from positive preclinical data to negative findings in recent clinical trials. To empirically address this translational disparity, we use functional magnetic resonance imaging in a double-blind, randomized controlled study to assess whether 20 mg escitalopram improves sequence-specific motor performance and modulates cortical motor response in 64 healthy female participants. We found decreased left premotor cortex responses during sequence-specific learning performance comparing single dose and steady escitalopram state. Escitalopram plasma levels negatively correlated with the premotor cortex response. We did not find evidence in support of improved motor performance after a week of escitalopram intake. These findings do not support the conclusion that one week escitalopram intake increases motor performance but could reflect early adaptive plasticity with improved neural processing underlying similar task performance when steady peripheral escitalopram levels are reached.



J Cereb Blood Flow Metab: 30 May 2021; 41:1449-1462
Molloy EN, Mueller K, Beinhölzl N, Blöchl M, ... Villringer A, Sacher J
J Cereb Blood Flow Metab: 30 May 2021; 41:1449-1462 | PMID: 33148103
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Abstract

Impact of blood pressure changes in cerebral blood perfusion of patients with ischemic Moyamoya disease evaluated by SPECT.

Liming Z, Weiliang S, Jia J, Hao L, ... Andrade-Barazarte H, Chaoyue L
Our aim was to determine the impact of targeted blood pressure modifications on cerebral blood flow in ischemic moyamoya disease patients assessed by single-photon emission computed tomography (SPECT). From March to September 2018, we prospectively collected data of 154 moyamoya disease patients and selected 40 patients with ischemic moyamoya disease. All patients underwent in-hospital blood pressure monitoring to determine the mean arterial pressure baseline values. The study cohort was subdivided into two subgroups: (1) Group A or relative high blood pressure (RHBP) with an induced mean arterial pressure 10-20% higher than baseline and (2) Group B or relative low blood pressure (RLBP) including patients with mean arterial pressure 10-20% lower than baseline. All patients underwent initial SPECT study on admission-day, and on the following day, every subgroup underwent a second SPECT study under their respective targeted blood pressure values. In general, RHBP patients showed an increment in perfusion of 10.13% (SD 2.94%), whereas RLBP patients showed a reduction of perfusion of 12.19% (SD 2.68%). Cerebral blood flow of moyamoya disease patients is susceptible to small blood pressure changes, and cerebral autoregulation might be affected due to short dynamic blood pressure modifications.



J Cereb Blood Flow Metab: 30 May 2021; 41:1472-1480
Liming Z, Weiliang S, Jia J, Hao L, ... Andrade-Barazarte H, Chaoyue L
J Cereb Blood Flow Metab: 30 May 2021; 41:1472-1480 | PMID: 33153375
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Abstract

Physiological determinants of residual cerebral arterial pulsatility on best medical treatment after TIA or minor stroke.

Webb AJ, Lawson A, Li L, Mazzucco S, Rothwell PM, Oxford Vascular Study Phenotyped Cohort
Cerebral arterial pulsatility is strongly associated with cerebral small vessel disease and lacunar stroke yet its dependence on central versus local haemodynamic processes is unclear. In a population-based study of patients on best medical managment, 4-6 weeks after a TIA or non-disabling stroke, arterial stiffness and aortic systolic, diastolic and pulse pressures were measured (Sphygmocor). Middle cerebral artery peak and trough flow velocities and Gosling\'s pulsatility index were measured by transcranial ultrasound. In 981 participants, aortic and cerebral pulsatility rose strongly with age in both sexes, but aortic diastolic pressure fell more with age in men whilst cerebral trough velocity fell more in women. There was no significant association between aortic systolic or diastolic blood pressure with cerebral peak or trough flow velocity but aortic pulse pressure explained 37% of the variance in cerebral arterial pulsatility, before adjustment, whilst 49% of the variance was explained by aortic pulse pressure, arterial stiffness, age, gender and cardiovascular risk factors. Furthermore, arterial stiffness partially mediated the relationship between aortic and cerebral pulsatility. Overall, absolute aortic pressures and cerebral blood flow velocity were poorly correlated but aortic and cerebral pulsatility were strongly related, suggesting a key role for transmission of aortic pulsatility to the brain.



J Cereb Blood Flow Metab: 30 May 2021; 41:1463-1471
Webb AJ, Lawson A, Li L, Mazzucco S, Rothwell PM, Oxford Vascular Study Phenotyped Cohort
J Cereb Blood Flow Metab: 30 May 2021; 41:1463-1471 | PMID: 33153374
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Abstract

Targeted temperature management and early neuro-prognostication after cardiac arrest.

Chen S, Lachance BB, Gao L, Jia X
Targeted temperature management (TTM) is a recommended neuroprotective intervention for coma after out-of-hospital cardiac arrest (OHCA). However, controversies exist concerning the proper implementation and overall efficacy of post-CA TTM, particularly related to optimal timing and depth of TTM and cooling methods. A review of the literature finds that optimizing and individualizing TTM remains an open question requiring further clinical investigation. This paper will summarize the preclinical and clinical trial data to-date, current recommendations, and future directions of this therapy, including new cooling methods under investigation. For now, early induction, maintenance for at least 24 hours, and slow rewarming utilizing endovascular methods may be preferred. Moreover, timely and accurate neuro-prognostication is valuable for guiding ethical and cost-effective management of post-CA coma. Current evidence for early neuro-prognostication after TTM suggests that a combination of initial prediction models, biomarkers, neuroimaging, and electrophysiological methods is the optimal strategy in predicting neurological functional outcomes.



J Cereb Blood Flow Metab: 30 May 2021; 41:1193-1209
Chen S, Lachance BB, Gao L, Jia X
J Cereb Blood Flow Metab: 30 May 2021; 41:1193-1209 | PMID: 33444088
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Abstract

Kinetics and 28-day test-retest repeatability and reproducibility of [C]UCB-J PET brain imaging.

Tuncel H, Boellaard R, Coomans EM, de Vries EF, ... van Berckel BN, Golla SS
[11C]UCB-J is a novel radioligand that binds to synaptic vesicle glycoprotein 2A (SV2A). The main objective of this study was to determine the 28-day test-retest repeatability (TRT) of quantitative [11C]UCB-J brain positron emission tomography (PET) imaging in Alzheimer\'s disease (AD) patients and healthy controls (HCs). Nine HCs and eight AD patients underwent two 60 min dynamic [11C]UCB-J PET scans with arterial sampling with an interval of 28 days. The optimal tracer kinetic model was assessed using the Akaike criteria (AIC). Micro-/macro-parameters such as tracer delivery (K1) and volume of distribution (VT) were estimated using the optimal model. Data were also analysed for simplified reference tissue model (SRTM) with centrum semi-ovale (white matter) as reference region. Based on AIC, both 1T2k_VB and 2T4k_VB described the [11C]UCB-J kinetics equally well. Analysis showed that whole-brain grey matter TRT for VT, DVR and SRTM BPND were -2.2% ± 8.5, 0.4% ± 12.0 and -8.0% ± 10.2, averaged over all subjects. [11C]UCB-J kinetics can be well described by a 1T2k_VB model, and a 60 min scan duration was sufficient to obtain reliable estimates for both plasma input and reference tissue models. TRT for VT, DVR and BPND was <15% (1SD) averaged over all subjects and indicates adequate quantitative repeatability of [11C]UCB-J PET.



J Cereb Blood Flow Metab: 30 May 2021; 41:1338-1350
Tuncel H, Boellaard R, Coomans EM, de Vries EF, ... van Berckel BN, Golla SS
J Cereb Blood Flow Metab: 30 May 2021; 41:1338-1350 | PMID: 34013797
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Abstract

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

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



J Cereb Blood Flow Metab: 29 May 2021:271678X211019827; epub ahead of print
Hahn A, Reed MB, Pichler V, Michenthaler P, ... Hacker M, Lanzenberger R
J Cereb Blood Flow Metab: 29 May 2021:271678X211019827; epub ahead of print | PMID: 34053336
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Abstract

Binding characteristics of [F]PI-2620 distinguish the clinically predicted tau isoform in different tauopathies by PET.

Song M, Beyer L, Kaiser L, Barthel H, ... Ziegler S, Brendel M
The novel tau-PET tracer [18F]PI-2620 detects the 3/4-repeat-(R)-tauopathy Alzheimer\'s disease (AD) and the 4R-tauopathies corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). We determined whether [18F]PI-2620 binding characteristics deriving from non-invasive reference tissue modelling differentiate 3/4R- and 4R-tauopathies. Ten patients with a 3/4R tauopathy (AD continuum) and 29 patients with a 4R tauopathy (CBS, PSP) were evaluated. [18F]PI-2620 PET scans were acquired 0-60 min p.i. and the distribution volume ratio (DVR) was calculated. [18F]PI-2620-positive clusters (DVR ≥ 2.5 SD vs. 11 healthy controls) were evaluated by non-invasive kinetic modelling. R1 (delivery), k2 & k2a (efflux), DVR, 30-60 min standardized-uptake-value-ratios (SUVR30-60) and the linear slope of post-perfusion phase SUVR (9-60 min p.i.) were compared between 3/4R- and 4R-tauopathies. Cortical clusters of 4R-tau cases indicated higher delivery (R1SRTM: 0.92 ± 0.21 vs. 0.83 ± 0.10, p = 0.0007), higher efflux (k2SRTM: 0.17/min ±0.21/min vs. 0.06/min ± 0.07/min, p < 0.0001), lower DVR (1.1 ± 0.1 vs. 1.4 ± 0.2, p < 0.0001), lower SUVR30-60 (1.3 ± 0.2 vs. 1.8 ± 0.3, p < 0.0001) and flatter slopes of the post-perfusion phase (slope9-60: 0.006/min ± 0.007/min vs. 0.016/min ± 0.008/min, p < 0.0001) when compared to 3/4R-tau cases. [18F]PI-2620 binding characteristics in cortical regions differentiate 3/4R- and 4R-tauopathies. Higher tracer clearance indicates less stable binding in 4R tauopathies when compared to 3/4R-tauopathies.



J Cereb Blood Flow Metab: 26 May 2021:271678X211018904; epub ahead of print
Song M, Beyer L, Kaiser L, Barthel H, ... Ziegler S, Brendel M
J Cereb Blood Flow Metab: 26 May 2021:271678X211018904; epub ahead of print | PMID: 34044665
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Abstract

Glyceryl trinitrate for the treatment of ischaemic stroke: Determining efficacy in rodent and ovine species for enhanced clinical translation.

Sorby-Adams AJ, Learoyd AE, Bath PM, Burrows F, ... Turner RJ, Trueman RC
Hypertension is a leading risk factor for death and dependency after ischaemic stroke. However, administering anti-hypertensive medications post-stroke remains contentious with concerns regarding deleterious effects on cerebral blood flow and infarct expansion. This study sought to determine the effect of glyceryl trinitrate (GTN) treatment in both lissencephalic and gyrencephalic pre-clinical stroke models. Merino sheep underwent middle cerebral artery occlusion (MCAO) followed by GTN or control patch administration (0.2 mg/h). Monitoring of numerous physiologically relevant measures over 24 h showed that GTN administration was associated with decreased intracranial pressure, infarct volume, cerebral oedema and midline shift compared to vehicle treatment (p < 0.05). No significant changes in blood pressure or cerebral perfusion pressure were observed. Using optical imaging spectroscopy and laser speckle imaging, the effect of varying doses of GTN (0.69-50 µg/h) on cerebral blood flow and tissue oxygenation was examined in mice. No consistent effect was found. Additional mice undergoing MCAO followed by GTN administration (doses varying from 0-60 µg/h) also showed no improvement in infarct volume or neurological score within 24 h post-stroke. GTN administration significantly improved numerous stroke-related physiological outcomes in sheep but was ineffective in mice. This suggests that, whilst GTN administration could potentially benefit patients, further research into mechanisms of action are required.



J Cereb Blood Flow Metab: 25 May 2021:271678X211018901; epub ahead of print
Sorby-Adams AJ, Learoyd AE, Bath PM, Burrows F, ... Turner RJ, Trueman RC
J Cereb Blood Flow Metab: 25 May 2021:271678X211018901; epub ahead of print | PMID: 34039053
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Abstract

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

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



J Cereb Blood Flow Metab: 25 May 2021:271678X211004150; epub ahead of print
Kubota M, Kimura Y, Shimojo M, Takado Y, ... Suhara T, Higuchi M
J Cereb Blood Flow Metab: 25 May 2021:271678X211004150; epub ahead of print | PMID: 34039039
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Abstract

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

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



J Cereb Blood Flow Metab: 25 May 2021:271678X211020587; epub ahead of print
Sone JY, Li Y, Hobson N, Romanos SG, ... Girard R, Awad IA
J Cereb Blood Flow Metab: 25 May 2021:271678X211020587; epub ahead of print | PMID: 34039038
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Abstract

Integrative analysis of the human brain mural cell transcriptome.

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



J Cereb Blood Flow Metab: 21 May 2021:271678X211013700; epub ahead of print
Gastfriend BD, Foreman KL, Katt ME, Palecek SP, Shusta EV
J Cereb Blood Flow Metab: 21 May 2021:271678X211013700; epub ahead of print | PMID: 34027687
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Abstract

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

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



J Cereb Blood Flow Metab: 20 May 2021:271678X211017796; epub ahead of print
Svensson JE, Schain M, Knudsen GM, Ogden RT, Plavén-Sigray P
J Cereb Blood Flow Metab: 20 May 2021:271678X211017796; epub ahead of print | PMID: 34018825
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Abstract

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

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



J Cereb Blood Flow Metab: 19 May 2021:271678X211018317; epub ahead of print
Bøgh N, Olin RB, Hansen ES, Gordon JW, ... Vigneron DB, Laustsen C
J Cereb Blood Flow Metab: 19 May 2021:271678X211018317; epub ahead of print | PMID: 34013807
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Abstract

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

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



J Cereb Blood Flow Metab: 19 May 2021:271678X211018035; epub ahead of print
Fedinec AL, Liu J, Zhang R, Harsono M, Pourcyrous M, Parfenova H
J Cereb Blood Flow Metab: 19 May 2021:271678X211018035; epub ahead of print | PMID: 34013806
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Abstract

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

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



J Cereb Blood Flow Metab: 19 May 2021:271678X211018210; epub ahead of print
Dhar R, Hamzehloo A, Kumar A, Chen Y, ... Strbian D, Lee JM
J Cereb Blood Flow Metab: 19 May 2021:271678X211018210; epub ahead of print | PMID: 34013805
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Abstract

Acute micro-thrombosis after subarachnoid hemorrhage: A new therapeutic target?

Ye F, Keep RF, Hua Y, Garton HJ, Xi G
Microthrombi formation in the brain following subarachnoid hemorrhage (SAH) has been recognized and suspected to contribute to cerebral ischemia. A recent study found that ultra-early cerebral micro-thrombosis occured four hours after experimental SAH. The number of thrombotic microvessels correlated with brain-blood barrier disruption and neuronal injury. If acute cerebral micro-thrombi also occur in humans, is it time to develop a therapy with systemic thrombolysis for SAH patients?



J Cereb Blood Flow Metab: 16 May 2021:271678X211013595; epub ahead of print
Ye F, Keep RF, Hua Y, Garton HJ, Xi G
J Cereb Blood Flow Metab: 16 May 2021:271678X211013595; epub ahead of print | PMID: 33993796
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Abstract

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

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



J Cereb Blood Flow Metab: 16 May 2021:271678X211017696; epub ahead of print
Ng FC, Churilov L, Yassi N, Kleinig TJ, ... Mitchell PJ, Campbell BC
J Cereb Blood Flow Metab: 16 May 2021:271678X211017696; epub ahead of print | PMID: 33993795
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Abstract

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

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



J Cereb Blood Flow Metab: 16 May 2021:271678X211015101; epub ahead of print
Veronese M, Rizzo G, Belzunce M, Schubert J, ... Gunn RN, and the Grand Challenge Participants#
J Cereb Blood Flow Metab: 16 May 2021:271678X211015101; epub ahead of print | PMID: 33993794
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