Journal: J Cereb Blood Flow Metab

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Abstract

Sonic hedgehog is expressed in human brain arteriovenous malformations and induces arteriovenous malformations in vivo.

Giarretta I, Sturiale CL, Gatto I, Pacioni S, ... Pallini R, Pola R

Abnormalities in arterial versus venous endothelial cell identity and dysregulation of angiogenesis are deemed important in the pathophysiology of brain arteriovenous malformations (AVMs). The Sonic hedgehog (Shh) pathway is crucial for both angiogenesis and arterial versus venous differentiation of endothelial cells, through its dual role on the vascular endothelial growth factor/Notch signaling and the nuclear orphan receptor COUP-TFII. In this study, we show that Shh, Gli1 (the main transcription factor of the Shh pathway), and COUP-TFII (a target of the non-canonical Shh pathway) are aberrantly expressed in human brain AVMs. We also show that implantation of pellets containing Shh in the cornea of Efnb2/LacZ mice induces growth of distinct arteries and veins, interconnected by complex sets of arteriovenous shunts, without an interposed capillary bed, as seen in AVMs. We also demonstrate that injection in the rat brain of a plasmid containing the human Shh gene induces the growth of tangles of tortuous and dilated vessels, in part positive and in part negative for the arterial marker αSMA, with direct connections between αSMA-positive and -negative vessels. In summary, we show that the Shh pathway is active in human brain AVMs and that Shh-induced angiogenesis has characteristics reminiscent of those seen in AVMs in humans.



J Cereb Blood Flow Metab: 30 Jan 2021; 41:324-335
Giarretta I, Sturiale CL, Gatto I, Pacioni S, ... Pallini R, Pola R
J Cereb Blood Flow Metab: 30 Jan 2021; 41:324-335 | PMID: 32169015
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Abstract

Brain temperature regulation in poor-grade subarachnoid hemorrhage patients - A multimodal neuromonitoring study.

Addis A, Gaasch M, Schiefecker AJ, Kofler M, ... Schmutzhard E, Helbok R

Elevated body temperature (T) is associated with poor outcome after subarachnoid hemorrhage (SAH). Brain temperature (T) is usually higher than T. However, the implication of this difference (T) remains unclear. We aimed to study factors associated with higher T and its association with outcome. We included 46 SAH patients undergoing multimodal neuromonitoring, for a total of 7879 h of averaged data of T, T, cerebral blood flow, cerebral perfusion pressure, intracranial pressure and cerebral metabolism (CMD). Three-months good functional outcome was defined as modified Rankin Scale ≤2. T was tightly correlated with T (r = 0.948,  < 0.01), and was higher in 73.7% of neuromonitoring time (T +0.18°C, IQR -0.01 - 0.37°C). A higher T was associated with better metabolic state, indicated by lower CMD-glutamate ( = 0.003) and CMD-lactate ( < 0.001), and lower risk of mitochondrial dysfunction (MD) (OR = 0.2,  < 0.001). During MD, T was significantly lower (0°C, IQR -0.2 - 0.1;  < 0.001). A higher T was associated with improved outcome (OR = 7.7,  = 0.002). Our study suggests that T is associated with brain metabolic activity and exceeds T when mitochondrial function is preserved. Further studies are needed to understand how T may serve as a surrogate marker for brain function and predict clinical course and outcome after SAH.



J Cereb Blood Flow Metab: 30 Jan 2021; 41:359-368
Addis A, Gaasch M, Schiefecker AJ, Kofler M, ... Schmutzhard E, Helbok R
J Cereb Blood Flow Metab: 30 Jan 2021; 41:359-368 | PMID: 32151225
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Abstract

Excitatory/inhibitory neuronal metabolic balance in mouse hippocampus upon infusion of [U-C]glucose.

Cherix A, Donati G, Lizarbe B, Lanz B, ... Lei H, Gruetter R

Hippocampus plays a critical role in linking brain energetics and behavior typically associated to stress exposure. In this study, we aimed to simultaneously assess excitatory and inhibitory neuronal metabolism in mouse hippocampus in vivo by applying FDG-PET and indirect C magnetic resonance spectroscopy (H-[C]-MRS) at 14.1 T upon infusion of uniformly C-labeled glucose ([U-C]Glc). Improving the spectral fitting by taking into account variable decoupling efficiencies of [U-C]Glc and refining the compartmentalized model by including two γ-aminobutyric acid (GABA) pools permit us to evaluate the relative contributions of glutamatergic and GABAergic metabolism to total hippocampal neuroenergetics. We report that GABAergic activity accounts for ∼13% of total neurotransmission (V) and ∼27% of total neuronal TCA cycle (V) in mouse hippocampus suggesting a higher V/V ratio for inhibitory neurons compared to excitatory neurons. Finally, our results provide new strategies and tools for bringing forward the developments and applications of C-MRS in specific brain regions of small animals.



J Cereb Blood Flow Metab: 30 Jan 2021; 41:282-297
Cherix A, Donati G, Lizarbe B, Lanz B, ... Lei H, Gruetter R
J Cereb Blood Flow Metab: 30 Jan 2021; 41:282-297 | PMID: 32151224
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Abstract

Cerebral angiogenesis ameliorates pathological disorders in -deficient mice with small-vessel disease.

Jiang Y, Müller K, Khan MA, Assmann JC, ... Wenzel J, Schwaninger M

Cerebral small-vessel diseases (SVDs) often follow a progressive course. Little is known about the function of angiogenesis, which potentially induces regression of SVDs. Here, we investigated angiogenesis in a mouse model of incontinentia pigmenti (IP), a genetic disease comprising features of SVD. IP is caused by inactivating mutations of , the essential component of NF-κB signaling. When deletingin the majority of brain endothelial cells ( mice), the transcriptional profile of vessels indicated cell proliferation. Brain endothelial cells expressed Ki67 and showed signs of DNA synthesis. In addition to cell proliferation, we observed sprouting and intussusceptive angiogenesis inmice. Angiogenesis occurred in all segments of the vasculature and in proximity to vessel rarefaction and tissue hypoxia. Apparently, NEMO was required for productive angiogenesis because endothelial cells that had escapedinactivation showed a higher proliferation rate than -deficient cells. Therefore, newborn endothelial cells were particularly vulnerable to ongoing recombination. When we interfered with productive angiogenesis by inducing ongoing ablation of , mice did not recover from IP manifestations but rather showed severe functional deficits. In summary, the data demonstrate that angiogenesis is present in this model of SVD and suggest that it may counterbalance the loss of vessels.



J Cereb Blood Flow Metab: 30 Jan 2021; 41:219-235
Jiang Y, Müller K, Khan MA, Assmann JC, ... Wenzel J, Schwaninger M
J Cereb Blood Flow Metab: 30 Jan 2021; 41:219-235 | PMID: 32151223
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Abstract

Sodium butyrate attenuated neuronal apoptosis via GPR41/Gβγ/PI3K/Akt pathway after MCAO in rats.

Zhou Z, Xu N, Matei N, McBride DW, ... Tang J, Zhang JH

Sodium butyrate, a short-chain fatty acid, is predominantly produced by gut microbiota fermentation of dietary fiber and serves as an important neuromodulator in the central nervous system. Recent experimental evidence has suggested that sodium butyrate may be an endogenous ligand for two orphan G protein-coupled receptors, GPR41 and GP43, which regulate apoptosis and inflammation in ischemia-related pathologies, including stroke. In the present study, we evaluated the potential efficacy and mechanism of action of short-chain fatty acids in a rat model of middle cerebral artery occlusion (MCAO). Fatty acids were intranasally administered 1 h post MCAO. Short-chain fatty acids, especially sodium butyrate, reduced infarct volume and improved neurological function at 24 and 72 h after MCAO. At 24 h, the effects of MCAO, increased apoptosis, were ameliorated after treatment with sodium butyrate, which increased the expressions of GPR41, PI3K and phosphorylated Akt. To confirm these mechanistic links and characterize the GPR active subunit, PC12 cells were subjected to oxygen-glucose deprivation and reoxygenation, and pharmacological and siRNA interventions were used to reverse efficacy. Taken together, intranasal administration of sodium butyrate activated PI3K/Akt via GPR41/Gβγ and attenuated neuronal apoptosis after MCAO.



J Cereb Blood Flow Metab: 30 Jan 2021; 41:267-281
Zhou Z, Xu N, Matei N, McBride DW, ... Tang J, Zhang JH
J Cereb Blood Flow Metab: 30 Jan 2021; 41:267-281 | PMID: 32151222
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Abstract

Serum 24S-hydroxycholesterol predicts long-term brain structural and functional outcomes after hypoxia-ischemia in neonatal mice.

Lu F, Fan S, Romo AR, Xu D, Ferriero DM, Jiang X

The major pathway of brain cholesterol turnover relies on its hydroxylation into 24S-hydroxycholesterol (24S-HC) using brain-specific cytochrome P450 46A1 (CYP46A1). 24S-HC produced exclusively in the brain normally traverses the blood-brain barrier to enter the circulation to the liver for excretion; therefore, the serum 24S-HC level is an indication of cholesterol metabolism in the brain. We recently reported an upregulation of CYP46A1 following hypoxia-ischemia (HI) in the neonatal mouse brain and a correlation between serum 24S-HC levels and acute brain damage. Here, we performed a longitudinal study to investigate whether the serum 24S-HC concentrations predict long-term brain structural and functional outcomes. In postnatal day 9 mice subjected to HI, the serum 24S-HC levels increased at 6 h and 24 h after HI and correlated with the infarct volumes measured histologically or by T2-weighted MRI. The 24 h levels were associated with white matter volume loss quantified by MBP immunostaining and luxol fast blue staining. The animals with higher serum 24S-HC at 6 h and 24 h corresponded to those with more severe motor and cognitive deficits at 35-40 days after HI. These data suggest that 24S-HC could be a novel and early blood biomarker for severity of neonatal HI brain damage and associated functional impairments.



J Cereb Blood Flow Metab: 30 Jan 2021; 41:312-323
Lu F, Fan S, Romo AR, Xu D, Ferriero DM, Jiang X
J Cereb Blood Flow Metab: 30 Jan 2021; 41:312-323 | PMID: 32169014
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Abstract

Astrocyte metabolism in multiple sclerosis investigated by 1-C-11 acetate PET.

Kato H, Okuno T, Isohashi K, Koda T, ... Nakatsuji Y, Hatazawa J

This study was aimed at evaluating the metabolism of reactive astrocytes in the brains of patients with multiple sclerosis by quantitative 1-C-11 acetate positron emission tomography (PET). Magnetic resonance imaging and 1-C-11 quantitative PET were performed in eight patients with multiple sclerosis and 10 normal control subjects. The efflux rate (k2) of 1-C-11 acetate, which reportedly reflects the metabolic rate of 1-C-11 acetate, was calculated based on the one-tissue compartmental model. Fractional anisotropy was also determined to evaluate the integrity of the neuronal tracts. The values of k2 in the patients with multiple sclerosis were significantly higher than those in the normal control subjects, in both the white matter ( = 0.003) and the gray matter ( = 0.02). In addition, the white matter/gray matter ratio of k2 was significantly higher in the multiple sclerosis patients than in the normal control subjects ( = 0.02). Voxel-based statistical analysis revealed most prominent increase in k2 in the neuronal fiber tracts, as well as decrease in fractional anisotropy in them in the multiple sclerosis patients. The present study clarified that the pathological changes associated with astrocytic reactivation in multiple sclerosis patients could be visualized by quantitative 1-C-11 acetate PET.



J Cereb Blood Flow Metab: 30 Jan 2021; 41:369-379
Kato H, Okuno T, Isohashi K, Koda T, ... Nakatsuji Y, Hatazawa J
J Cereb Blood Flow Metab: 30 Jan 2021; 41:369-379 | PMID: 32169013
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Abstract

Assessment of vascular stiffness in the internal carotid artery proximal to the carotid canal in Alzheimer\'s disease using pulse wave velocity from low rank reconstructed 4D flow MRI.

Rivera-Rivera LA, Cody KA, Eisenmenger L, Cary P, ... Johnson SC, Johnson KM

Clinical evidence shows vascular factors may co-occur and complicate the expression of Alzheimer\'s disease (AD); yet, the pathologic mechanisms and involvement of different compartments of the vascular network are not well understood. Diseases such as arteriosclerosis diminish vascular compliance and will lead to arterial stiffness, a well-established risk factor for cardiovascular morbidity. Arterial stiffness can be assessed using pulse wave velocity (PWV); however, this is usually done from carotid-to-femoral artery ratios. To probe the brain vasculature, intracranial PWV measures would be ideal. In this study, high temporal resolution 4D flow MRI was used to assess transcranial PWV in 160 subjects including AD, mild cognitive impairment (MCI), healthy controls, and healthy subjects with apolipoprotein ɛ4 positivity (APOE4+) and parental history of AD dementia (FH+). High temporal resolution imaging was achieved by high temporal binning of retrospectively gated data using a local-low rank approach. Significantly higher transcranial PWV in AD dementia and MCI subjects was found when compared to old-age-matched controls (AD vs. old-age-matched controls:  <0.001, AD vs. MCI:  = 0.029, MCI vs. old-age-matched controls  = 0.013). Furthermore, vascular changes were found in clinically healthy middle-age adults with APOE4+ and FH+ indicating significantly higher transcranial PWV compared to controls ( <0.001).



J Cereb Blood Flow Metab: 30 Jan 2021; 41:298-311
Rivera-Rivera LA, Cody KA, Eisenmenger L, Cary P, ... Johnson SC, Johnson KM
J Cereb Blood Flow Metab: 30 Jan 2021; 41:298-311 | PMID: 32169012
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Abstract

Comparison of Tmax values between full- and half-dose gadolinium perfusion studies.

Christensen S, Amukotuwa S, Lansberg MG, Kemp S, ... Albers GW, Bammer R

AHA guidelines recommend use of perfusion imaging for patient selection in the 6-24 h window. Recently, the safety of gadolinium-based contrast agents for MR perfusion imaging has been questioned based on findings that gadolinium accumulates in brain tissue. Regulatory bodies have recommended to limit the use of gadolinium-based contrast agents where possible. Focusing specifically on the time to maximum of the tissue residue function (Tmax) parameter, used in DAWN and DEFUSE 3, we hypothesized that half-dose scans would yield a similar Tmax delay pattern to full-dose scans. We prospectively recruited 10 acute ischemic stroke patients imaged with two perfusion scans at their follow-up visit, one with a standard dose gadolinium followed by a half-dose injection a median of 7 min apart. The brain was parcellated into a grid of 3 × 3 regions and the mean of the difference in Tmax between the 3 × 3 regions on the half- and full-dose Tmax maps was 0.1 s (iqr 0.38 s). The fraction of brain tissue that differed by no more than ±1 s was 93.7%. In patients with normal or modest Tmax delays, half-dose gadolinium appears to provide comparable Tmax measurements to those of full-dose scans.



J Cereb Blood Flow Metab: 30 Jan 2021; 41:336-341
Christensen S, Amukotuwa S, Lansberg MG, Kemp S, ... Albers GW, Bammer R
J Cereb Blood Flow Metab: 30 Jan 2021; 41:336-341 | PMID: 32208802
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Abstract

Neuroprotective role of lactate in rat neonatal hypoxia-ischemia.

Roumes H, Dumont U, Sanchez S, Mazuel L, ... Pellerin L, Bouzier-Sore AK

Hypoxic-ischemic (HI) encephalopathy remains a major cause of perinatal mortality and chronic disability in newborns worldwide (1-6 for 1000 births). The only current clinical treatment is hypothermia, which is efficient for less than 60% of babies. Mainly considered as a waste product in the past, lactate, in addition to glucose, is increasingly admitted as a supplementary fuel for neurons and, more recently, as a signaling molecule in the brain. Our aim was to investigate the neuroprotective effect of lactate in a neonatal (seven day old) rat model of hypoxia-ischemia. Pups received intra-peritoneal injection(s) of lactate (40 μmol). Size and apparent diffusion coefficients of brain lesions were assessed by magnetic resonance diffusion-weighted imaging. Oxiblot analyses and long-term behavioral studies were also conducted. A single lactate injection induced a 30% reduction in brain lesion volume, indicating a rapid and efficient neuroprotective effect. When oxamate, a lactate dehydrogenase inhibitor, was co-injected with lactate, the neuroprotection was completely abolished, highlighting the role of lactate metabolism in this protection. After three lactate injections (one per day), pups presented the smallest brain lesion volume and a complete recovery of neurological reflexes, sensorimotor capacities and long-term memory, demonstrating that lactate administration is a promising therapy for neonatal HI insult.



J Cereb Blood Flow Metab: 30 Jan 2021; 41:342-358
Roumes H, Dumont U, Sanchez S, Mazuel L, ... Pellerin L, Bouzier-Sore AK
J Cereb Blood Flow Metab: 30 Jan 2021; 41:342-358 | PMID: 32208801
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Abstract

Hemodynamic impairments within individual watershed areas in asymptomatic carotid artery stenosis by multimodal MRI.

Kaczmarz S, Göttler J, Petr J, Hansen MB, ... Hyder F, Preibisch C

Improved understanding of complex hemodynamic impairments in asymptomatic internal carotid artery stenosis (ICAS) is crucial to better assess stroke risks. Multimodal MRI is ideal for measuring brain hemodynamics and has the potential to improve diagnostics and treatment selections. We applied MRI-based perfusion and oxygenation-sensitive imaging in ICAS with the hypothesis that the sensitivity to hemodynamic impairments will improve within individual watershed areas (iWSA). We studied cerebral blood flow (CBF), cerebrovascular reactivity (CVR), relative cerebral blood volume (rCBV), relative oxygen extraction fraction (rOEF), oxygen extraction capacity (OEC) and capillary transit-time heterogeneity (CTH) in 29 patients with asymptomatic, unilateral ICAS (age 70.3 ± 7.0 y) and 30 age-matched healthy controls. In ICAS, we found significant impairments of CBF, CVR, rCBV, OEC, and CTH (strongest lateralization ΔCVR = -24%), but not of rOEF. Although the spatial overlap of compromised hemodynamic parameters within each patient varied in a complex manner, most pronounced changes of CBF, CVR and rCBV were detected within iWSAs (strongest effect ΔCVR = +117%). At the same time, CTH impairments were iWSA independent, indicating widespread dysfunction of capillary-level oxygen diffusivity. In summary, complementary MRI-based perfusion and oxygenation parameters offer deeper perspectives on complex microvascular impairments in individual patients. Furthermore, knowledge about iWSAs improves the sensitivity to hemodynamic impairments.



J Cereb Blood Flow Metab: 30 Jan 2021; 41:380-396
Kaczmarz S, Göttler J, Petr J, Hansen MB, ... Hyder F, Preibisch C
J Cereb Blood Flow Metab: 30 Jan 2021; 41:380-396 | PMID: 32237952
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Abstract

Dynamic capillary stalls in reperfused ischemic penumbra contribute to injury: A hyperacute role for neutrophils in persistent traffic jams.

Erdener ŞE, Tang J, Kılıç K, Postnov D, ... Schaffer CB, Boas DA

Ever since the introduction of thrombolysis and the subsequent expansion of endovascular treatments for acute ischemic stroke, it remains to be identified why the actual outcomes are less favorable despite recanalization. Here, by high spatio-temporal resolution imaging of capillary circulation in mice, we introduce the pathological phenomenon of dynamic flow stalls in cerebral capillaries, occurring persistently in salvageable penumbra after reperfusion. These stalls, which are different from permanent cellular plugs of no-reflow, were temporarily and repetitively occurring in the capillary network, impairing the overall circulation like small focal traffic jams. In vivo microscopy in the ischemic penumbra revealed leukocytes traveling slowly through capillary lumen or getting stuck, while red blood cell flow was being disturbed in the neighboring segments under reperfused conditions. Stall dynamics could be modulated, by injection of an anti-Ly6G antibody specifically targeting neutrophils. Decreased number and duration of stalls were associated with improvement in penumbral blood flow within 2-24 h after reperfusion along with increased capillary oxygenation, decreased cellular damage and improved functional outcome. Thereby, dynamic microcirculatory stall phenomenon can be a contributing factor to ongoing penumbral injury and is a potential hyperacute mechanism adding on previous observations of detrimental effects of activated neutrophils in ischemic stroke.



J Cereb Blood Flow Metab: 30 Jan 2021; 41:236-252
Erdener ŞE, Tang J, Kılıç K, Postnov D, ... Schaffer CB, Boas DA
J Cereb Blood Flow Metab: 30 Jan 2021; 41:236-252 | PMID: 32237951
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Abstract

Sexual differences in mitochondrial and related proteins in rat cerebral microvessels: A proteomic approach.

Cikic S, Chandra PK, Harman JC, Rutkai I, ... Gidday JM, Busija DW

Sex differences in mitochondrial numbers and function are present in large cerebral arteries, but it is unclear whether these differences extend to the microcirculation. We performed an assessment of mitochondria-related proteins in cerebral microvessels (MVs) isolated from young, male and female, Sprague-Dawley rats. MVs composed of arterioles, capillaries, and venules were isolated from the cerebrum and used to perform a 3 versus 3 quantitative, multiplexed proteomics experiment utilizing tandem mass tags (TMT), coupled with liquid chromatography/mass spectrometry (LC/MS). MS data and bioinformatic analyses were performed using Proteome Discoverer version 2.2 and Ingenuity Pathway Analysis. We identified a total of 1969 proteins, of which 1871 were quantified by TMT labels. Sixty-four proteins were expressed significantly ( < 0.05) higher in female samples compared with male samples. Females expressed more mitochondrial proteins involved in energy production, mitochondrial membrane structure, anti-oxidant enzyme proteins, and those involved in fatty acid oxidation. Conversely, males had higher expression levels of mitochondria-destructive proteins. Our findings reveal, for the first time, the full extent of sexual dimorphism in the mitochondrial metabolic protein profiles of MVs, which may contribute to sex-dependent cerebrovascular and neurological pathologies.



J Cereb Blood Flow Metab: 30 Jan 2021; 41:397-412
Cikic S, Chandra PK, Harman JC, Rutkai I, ... Gidday JM, Busija DW
J Cereb Blood Flow Metab: 30 Jan 2021; 41:397-412 | PMID: 32241204
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Abstract

The role of spreading depolarizations and electrographic seizures in early injury progression of the rat photothrombosis stroke model.

Schoknecht K, Kikhia M, Lemale CL, Liotta A, ... Friedman A, Dreier JP

Spreading depolarization (SD) and seizures are pathophysiological events associated with cerebral ischemia. Here, we investigated their role for injury progression in the cerebral cortex. Cerebral ischemia was induced in anesthetized male Wistar rats using the photothrombosis (PT) stroke model. SD and spontaneous neuronal activity were recorded in the presence of either urethane or ketamine/xylazine anesthesia. Blood-brain barrier (BBB) permeability, cerebral perfusion, and cellular damage were assessed through a cranial window and repeated intravenous injection of fluorescein sodium salt and propidium iodide until 4 h after PT. Neuronal injury and early lesion volume were quantified by stereological cell counting and manual and automated assessment of ex vivo T2-weighted magnetic resonance imaging. Onset SDs originated at the thrombotic core and invaded neighboring cortex, whereas delayed SDs often showed opposite propagation patterns. Seizure induction by 4-aminopyridine caused no increase in lesion volume or neuronal injury in urethane-anesthetized animals. Ketamine/xylazine anesthesia was associated with a lower number of onset SDs, reduced lesion volume, and neuronal injury despite a longer duration of seizures. BBB permeability increase inversely correlated with the number of SDs at 3 and 4 h after PT. Our results provide further evidence that ketamine may counteract the early progression of ischemic injury.



J Cereb Blood Flow Metab: 30 Jan 2021; 41:413-430
Schoknecht K, Kikhia M, Lemale CL, Liotta A, ... Friedman A, Dreier JP
J Cereb Blood Flow Metab: 30 Jan 2021; 41:413-430 | PMID: 32241203
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Abstract

Repetitive mTBI is associated with age-related reductions in cerebral blood flow but not cortical thickness.

Clark AL, Weigand AJ, Bangen KJ, Merritt VC, Bondi MW, Delano-Wood L

Mild traumatic brain injury (mTBI) is a risk factor for Alzheimer\'s disease (AD), and evidence suggests cerebrovascular dysregulation initiates deleterious neurodegenerative cascades. We examined whether mTBI history alters cerebral blood flow (CBF) and cortical thickness in regions vulnerable to early AD-related changes. Seventy-four young to middle-aged Veterans (mean age = 34, range = 23-48) underwent brain scans. Participants were divided into: (1) Veteran Controls (=27), (2) 1-2 mTBIs (=26), and (2) 3+ mTBIs (=21) groups. Resting CBF was measured using MP-PCASL. T1 structural scans were processed with FreeSurfer. CBF and cortical thickness estimates were extracted from nine AD-vulnerable regions. Regression analyses examined whether mTBI moderated the association between age, CBF, and cortical thickness. Regressions adjusting for sex and posttraumatic stress revealed mTBI moderated the association between age and CBF of the precuneus as well as superior and inferior parietal cortices ( < .05); increasing age was associated with lower CBF in the 3+ mTBIs group, but not in the VCs or 1-2 mTBIs groups. mTBI did not moderate associations between age and cortical thickness ( >.05). Repetitive mTBI is associated with cerebrovascular dysfunction in AD-vulnerable regions and may accelerate pathological aging trajectories.



J Cereb Blood Flow Metab: 30 Jan 2021; 41:431-444
Clark AL, Weigand AJ, Bangen KJ, Merritt VC, Bondi MW, Delano-Wood L
J Cereb Blood Flow Metab: 30 Jan 2021; 41:431-444 | PMID: 32248731
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Abstract

4D flow MRI for non-invasive measurement of blood flow in the brain: A systematic review.

Morgan AG, Thrippleton MJ, Wardlaw JM, Marshall I

The brain\'s vasculature is essential for brain health and its dysfunction contributes to the onset and development of many dementias and neurological disorders. While numerous in vivo imaging techniques exist to investigate cerebral haemodynamics in humans, phase-contrast magnetic resonance imaging (MRI) has emerged as a reliable, non-invasive method of quantifying blood flow within intracranial vessels. In recent years, an advanced form of this method, known as 4D flow, has been developed and utilised in patient studies, where its ability to capture complex blood flow dynamics within any major vessel across the acquired volume has proved effective in collecting large amounts of information in a single scan. While extremely promising as a method of examining the vascular system\'s role in brain-related diseases, the collection of 4D data can be time-consuming, meaning data quality has to be traded off against the acquisition time. Here, we review the available literature to examine 4D flow\'s capabilities in assessing physiological and pathological features of the cerebrovascular system. Emerging techniques such as dynamic velocity-encoding and advanced undersampling methods, combined with increasingly high-field MRI scanners, are likely to bring 4D flow to the forefront of cerebrovascular imaging studies in the years to come.



J Cereb Blood Flow Metab: 30 Jan 2021; 41:206-218
Morgan AG, Thrippleton MJ, Wardlaw JM, Marshall I
J Cereb Blood Flow Metab: 30 Jan 2021; 41:206-218 | PMID: 32936731
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Abstract

Tissue despite full recanalization following thrombectomy for anterior circulation stroke with proximal occlusion: A clinical study.

Schiphorst AT, Charron S, Hassen WB, Provost C, ... Baron JC, Oppenheim C

Despite early thrombectomy, a sizeable fraction of acute stroke patients with large vessel occlusion have poor outcome. Thephenomenon, i.e. impaired microvascular reperfusion despite complete recanalization, may contribute to such \"futile recanalizations\". Although well reported in animal models,is still poorly characterized in man. From a large prospective thrombectomy database, we included all patients with intracranial proximal occlusion, complete recanalization (modified thrombolysis in cerebral infarction score 2c-3), and availability of both baseline and 24 h follow-up MRI including arterial spin labeling perfusion mapping.was operationally defined as i) hypoperfusion ≥40% relative to contralateral homologous region, assessed with both visual (two independent investigators) and automatic image analysis, and ii) infarction on follow-up MRI. Thirty-three patients were eligible (median age: 70 years, NIHSS: 18, and stroke onset-to-recanalization delay: 208 min). The operational criteria were met in one patient only, consistently with the visual and automatic analyses. This patient recanalized 160 min after stroke onset and had excellent functional outcome. In our cohort of patients with complete and stable recanalization following thrombectomy for intracranial proximal occlusion, severe ipsilateral hypoperfusion on follow-up imaging associated with newly developed infarction was a rare occurrence. Thus,may be infrequent in human stroke and may not substantially contribute to futile recanalizations.



J Cereb Blood Flow Metab: 30 Jan 2021; 41:253-266
Schiphorst AT, Charron S, Hassen WB, Provost C, ... Baron JC, Oppenheim C
J Cereb Blood Flow Metab: 30 Jan 2021; 41:253-266 | PMID: 32960688
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Abstract

Parkinson patients have a presynaptic serotonergic deficit: A dynamic deep brain stimulation PET study.

Jørgensen LM, Henriksen T, Mardosiene S, Keller SH, ... Svarer C, Knudsen GM

Patients with Parkinson\'s disease (PD) often suffer from non-motor symptoms, which may be caused by serotonergic dysfunction. Apart from alleviating the motor symptoms, Deep Brain Stimulation (DBS) in the subthalamic nucleus (STN) may also influence non-motor symptoms. The aim of this study is to investigate how turning DBS off affects the serotonergic system. We here exploit a novel functional PET neuroimaging methodology to evaluate the preservation of serotonergic neurons and capacity to release serotonin. We measured cerebral 5-HTR binding in 13 DBS-STN treated PD patients, at baseline and after turning DBS off. Ten age-matched volunteers served as controls. Clinical measures of motor symptoms were assessed under the two conditions and correlated to the PET measures of the static and dynamic integrity of the serotonergic system. PD patients exhibited a significant loss of frontal and parietal 5-HTR, and the loss was significantly correlated to motor symptom severity. We saw a corresponding release of serotonin, but only in brain regions with preserved 5-HTR, suggesting the presence of a presynaptic serotonergic deficit. Our study demonstrates that DBS-STN dynamically regulates the serotonin system in PD, and that preservation of serotonergic functions may be predictive of DBS-STN effects.



J Cereb Blood Flow Metab: 17 Jan 2021:271678X20982389; epub ahead of print
Jørgensen LM, Henriksen T, Mardosiene S, Keller SH, ... Svarer C, Knudsen GM
J Cereb Blood Flow Metab: 17 Jan 2021:271678X20982389; epub ahead of print | PMID: 33461410
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Abstract

Intrathecal and systemic alterations of L-arginine metabolism in patients after intracerebral hemorrhage.

Mader MM, Böger R, Appel D, Schwedhelm E, ... Czorlich P, Hannemann J

Alterations in the concentration of nitric oxide (NO) and L-arginine metabolites have been associated with the pathophysiology of different vascular diseases. Here, we describe striking changes in L-arginine metabolism after hemorrhagic stroke. Blood and cerebrospinal fluid (CSF) samples of patients with intracerebral hemorrhage (ICH) and/or intraventricular hemorrhage were collected over a ten-day period. Liquid chromatography-tandem mass spectrometry was used to quantify key substrates and products of L-arginine metabolizing enzymes as well as asymmetric (ADMA) and symmetric dimethylarginine (SDMA). Changes in the plasma were limited to early reductions in L-ornithine, L-lysine, and L-citrulline concentrations. Intrathecally, we observed signs of early NO synthase (NOS) upregulation followed by a decrease back to baseline accompanied by a rise in the level of its endogenous NOS-inhibitor ADMA. SDMA demonstrated increased levels throughout the observation period. For arginase, a pattern of persistently elevated activity was measured and arginine:glycine amidinotransferase (AGAT) appeared to be reduced in its activity at later time points. An early reduction in CSF L-arginine concentration was an independent risk factor for poor outcome. Together, these findings further elucidate pathophysiological mechanisms after ICH potentially involved in secondary brain injury and may reveal novel therapeutic targets.



J Cereb Blood Flow Metab: 17 Jan 2021:271678X20983216; epub ahead of print
Mader MM, Böger R, Appel D, Schwedhelm E, ... Czorlich P, Hannemann J
J Cereb Blood Flow Metab: 17 Jan 2021:271678X20983216; epub ahead of print | PMID: 33461409
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Abstract

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

Kylkilahti TM, Berends E, Ramos M, Shanbhag NC, ... Bloch KM, Lundgaard I

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



J Cereb Blood Flow Metab: 17 Jan 2021:271678X20982388; epub ahead of print
Kylkilahti TM, Berends E, Ramos M, Shanbhag NC, ... Bloch KM, Lundgaard I
J Cereb Blood Flow Metab: 17 Jan 2021:271678X20982388; epub ahead of print | PMID: 33461408
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Abstract

Regional and depth-dependence of cortical blood-flow assessed with high-resolution Arterial Spin Labeling (ASL).

Taso M, Munsch F, Zhao L, Alsop DC

Methods for imaging of cerebral blood flow do not typically resolve the cortex and thus underestimate flow. However, recent work with high-resolution MRI has emphasized the regional and depth-dependent structural, functional and relaxation times variations within the cortex. Using high-resolution Arterial Spin Labeling (ASL) and T mapping acquisitions, we sought to probe the effects of spatial resolution and tissue heterogeneity on cortical cerebral blood flow (CBF) measurements with ASL. We acquired high-resolution (1.6mm) whole brain ASL data in a cohort of 10 volunteers at 3T, along with T and transit-time (ATT) mapping, followed by group cortical surface-based analysis using FreeSurfer of the different measured parameters. Fully resolved regional analysis showed higher than average mid-thickness CBF in primary motor areas (+15%,p<0.002), frontal regions (+17%,p<0.01) and auditory cortex, while occipital regions had lower average CBF (-20%,p<10). ASL signal was higher towards the pial surface but correction for the shorter T near the white matter surface reverses this gradient, at least when using the low-resolution ATT map. Similar to structural measures, fully-resolved ASL CBF measures show significant differences across cortical regions. Depth-dependent variation of T in the cortex complicates interpretation of depth-dependent ASL signal and may have implications for the accurate CBF quantification at lower resolutions.



J Cereb Blood Flow Metab: 13 Jan 2021:271678X20982382; epub ahead of print
Taso M, Munsch F, Zhao L, Alsop DC
J Cereb Blood Flow Metab: 13 Jan 2021:271678X20982382; epub ahead of print | PMID: 33444098
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Abstract

Understanding the brain uptake and permeability of small molecules through the BBB: A technical overview.

Chowdhury EA, Noorani B, Alqahtani F, Bhalerao A, ... Sivandzade F, Cucullo L

The brain is the most important organ in our body requiring its unique microenvironment. By the virtue of its function, the blood-brain barrier poses a significant hurdle in drug delivery for the treatment of neurological diseases. There are also different theories regarding how molecules are typically effluxed from the brain. In this review, we comprehensively discuss how the different pharmacokinetic techniques used for measuring brain uptake/permeability of small molecules have evolved with time. We also discuss the advantages and disadvantages associated with these different techniques as well as the importance to utilize the right method to properly assess CNS exposure to drug molecules. Even though very strong advances have been made we still have a long way to go to ensure a reduction in failures in central nervous system drug development programs.



J Cereb Blood Flow Metab: 13 Jan 2021:271678X20985946; epub ahead of print
Chowdhury EA, Noorani B, Alqahtani F, Bhalerao A, ... Sivandzade F, Cucullo L
J Cereb Blood Flow Metab: 13 Jan 2021:271678X20985946; epub ahead of print | PMID: 33444097
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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: 13 Jan 2021:271678X20982383; epub ahead of print
Bracko O, Cruz Hernández JC, Park L, Nishimura N, Schaffer CB
J Cereb Blood Flow Metab: 13 Jan 2021:271678X20982383; epub ahead of print | PMID: 33444096
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Abstract

Normative distribution of posterior circulation tissue time-to-maximum: Effects of anatomic variation, tracer kinetics, and implications for patient selection in posterior circulation ischemic stroke.

Goldman-Yassen AE, Straka M, Uhouse M, Dehkharghani S

The generalization of perfusion-based, anterior circulation large vessel occlusion selection criteria to posterior circulation stroke is not straightforward due to physiologic delay, which we posit produces physiologic prolongation of the posterior circulation perfusion time-to-maximum (Tmax). To assess normative Tmax distributions, patients undergoing CTA/CTP for suspected ischemic stroke between 1/2018-3/2019 were retrospectively identified. Subjects with any cerebrovascular stenoses, or with follow-up MRI or final clinical diagnosis of stroke were excluded. Posterior circulation anatomic variations were identified. CTP were processed in RAPID and segmented in a custom pipeline permitting manually-enforced arterial input function (AIF) and perfusion estimations constrained to pre-specified vascular territories. Seventy-one subjects (mean 64 ± 19 years) met inclusion. Median Tmax was significantly greater in the cerebellar hemispheres (right: 3.0 s, left: 2.9 s) and PCA territories (right: 2.9 s; left: 3.3 s) than in the anterior circulation (right: 2.4 s; left: 2.3 s, p < 0.001). Fetal PCA disposition eliminated ipsilateral PCA Tmax delays (p = 0.012). Median territorial Tmax was significantly lower with basilar versus any anterior circulation AIF for all vascular territories (p < 0.001). Significant baseline delays in posterior circulation Tmax are observed even without steno-occlusive disease and vary with anatomic variation and AIF selection. The potential for overestimation of at-risk volumes in the posterior circulation merits caution in future trials.



J Cereb Blood Flow Metab: 13 Jan 2021:271678X20982395; epub ahead of print
Goldman-Yassen AE, Straka M, Uhouse M, Dehkharghani S
J Cereb Blood Flow Metab: 13 Jan 2021:271678X20982395; epub ahead of print | PMID: 33444095
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Abstract

In vivo synaptic density relates to glucose metabolism at rest in healthy subjects, but is strongly modulated by regional differences.

Aalst JV, Ceccarini J, Sunaert S, Dupont P, Koole M, Laere KV

Preclinical and postmortem studies have suggested that regional synaptic density and glucose consumption (CMRGlc) are strongly related. However, the relation between synaptic density and cerebral glucose metabolism in the human brain has not directly been assessed in vivo. Using [C]UCB-J binding to synaptic vesicle glycoprotein 2 A (SV2A) as indicator for synaptic density and [F]FDG for measuring cerebral glucose consumption, we studied twenty healthy female subjects (age 29.6 ± 9.9 yrs) who underwent a single-day dual-tracer protocol (GE Signa PET-MR). Global measures of absolute and relative CMRGlc and specific binding of [C]UCB-J were indeed highly significantly correlated ( > 0.47,  < 0.001). However, regional differences in relative [F]FDG and [C]UCB-J uptake were observed, with up to 19% higher [C]UCB-J uptake in the medial temporal lobe (MTL) and up to 17% higher glucose metabolism in frontal and motor-related areas and thalamus. This pattern has a considerable overlap with the brain regions showing different levels of aerobic glycolysis. Regionally varying energy demands of inhibitory and excitatory synapses at rest may also contribute to this difference. Being unaffected by astroglial and/or microglial energy demands, changes in synaptic density in the MTL may therefore be more sensitive to early detection of pathological conditions compared to changes in glucose metabolism.



J Cereb Blood Flow Metab: 13 Jan 2021:271678X20981502; epub ahead of print
Aalst JV, Ceccarini J, Sunaert S, Dupont P, Koole M, Laere KV
J Cereb Blood Flow Metab: 13 Jan 2021:271678X20981502; epub ahead of print | PMID: 33444094
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Abstract

β2 glycoprotein I participates in phagocytosis of apoptotic neurons and in vascular injury in experimental brain stroke.

Grossi C, Artusi C, Meroni P, Borghi MO, ... De Simoni MG, Fumagalli S

Beta-2 Glycoprotein I (β2-GPI) is the main target of anti-phospholipid antibodies (aPL) in the autoimmune anti-phospholipid syndrome, characterized by increased risk of stroke. We here investigated the antibody independent role of β2-GPI after ischemia/reperfusion, modeledby transient middle cerebral artery occlusion (tMCAo) in male C57Bl/6J mice;by subjecting immortalized human brain microvascular endothelial cells (ihBMEC) to 16 h hypoxia and 4 h re-oxygenation.(coding for β2-GPI) was upregulated selectively in the liver at 48 h after tMCAo. At the same time β2-GPI circulating levels increased. β2-GPI was detectable in brain parenchyma and endothelium at all time points after tMCAo. Parenchymal β2-GPI recognized apoptotic neurons (positive for annexin V, C3 and TUNEL) cleared by CD68+ brain macrophages. Hypoxic ihBMEC showed increased release of IL-6, over-expression ofandafter re-oxygenation with β2-GPI alone. β2-GPI interacted with mannose-binding lectin in mouse plasma and ihBMEC medium, potentially involved in formation of thrombi. We show for the first time that brain ischemia triggers the hepatic production of β2-GPI. β2-GPI is present in the ischemic endothelium, enhancing vascular inflammation, and extravasates binding stressed neurons before their clearance by phagocytosis. Thus β2-GPI may be a new mediator of brain injury following ischemic stroke.



J Cereb Blood Flow Metab: 13 Jan 2021:271678X20984551; epub ahead of print
Grossi C, Artusi C, Meroni P, Borghi MO, ... De Simoni MG, Fumagalli S
J Cereb Blood Flow Metab: 13 Jan 2021:271678X20984551; epub ahead of print | PMID: 33444093
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Abstract

Imaging biomarkers of vascular and axonal injury are spatially distinct in chronic traumatic brain injury.

Haber M, Amyot F, Lynch CE, Sandsmark DK, ... Pham D, Diaz-Arrastia R

Traumatic Brain Injury (TBI) is associated with both diffuse axonal injury (DAI) and diffuse vascular injury (DVI), which result from inertial shearing forces. These terms are often used interchangeably, but the spatial relationships between DAI and DVI have not been carefully studied. Multimodal magnetic resonance imaging (MRI) can help distinguish these injury mechanisms: diffusion tensor imaging (DTI) provides information about axonal integrity, while arterial spin labeling (ASL) can be used to measure cerebral blood flow (CBF), and the reactivity of the Blood Oxygen Level Dependent (BOLD) signal to a hypercapnia challenge reflects cerebrovascular reactivity (CVR). Subjects with chronic TBI (n = 27) and healthy controls (n = 14) were studied with multimodal MRI. Mean values of mean diffusivity (MD), fractional anisotropy (FA), CBF, and CVR were extracted for pre-determined regions of interest (ROIs). Normalized z-score maps were generated from the pool of healthy controls. Abnormal ROIs in one modality were not predictive of abnormalities in another. Approximately 9-10% of abnormal voxels for CVR and CBF also showed an abnormal voxel value for MD, while only 1% of abnormal CVR and CBF voxels show a concomitant abnormal FA value. These data indicate that DAI and DVI represent two distinct TBI endophenotypes that are spatially independent.



J Cereb Blood Flow Metab: 13 Jan 2021:271678X20985156; epub ahead of print
Haber M, Amyot F, Lynch CE, Sandsmark DK, ... Pham D, Diaz-Arrastia R
J Cereb Blood Flow Metab: 13 Jan 2021:271678X20985156; epub ahead of print | PMID: 33444092
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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: 13 Jan 2021:271678X20980652; epub ahead of print
Vikner T, Eklund A, Karalija N, Malm J, ... Nyberg L, Wåhlin A
J Cereb Blood Flow Metab: 13 Jan 2021:271678X20980652; epub ahead of print | 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: 13 Jan 2021:271678X20984565; epub ahead of print
Imai T, Matsubara H, Hara H
J Cereb Blood Flow Metab: 13 Jan 2021:271678X20984565; epub ahead of print | PMID: 33444090
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Abstract

Role of perivascular and meningeal macrophages in outcome following experimental subarachnoid hemorrhage.

Wan H, Brathwaite S, Ai J, Hynynen K, Macdonald RL

The distribution and clearance of erythrocytes after subarachnoid hemorrhage (SAH) is poorly understood. We aimed to characterize the distribution of erythrocytes after SAH and the cells involved in their clearance. To visualize erythrocyte distribution, we injected fluorescently-labelled erythrocytes into the prechiasmatic cistern of mice. 10 minutes after injection, we found labelled erythrocytes in the subarachnoid space and ventricular system, and also in the perivascular spaces surrounding large penetrating arterioles. 2 and 5 days after SAH, fluorescence was confined within leptomeningeal and perivascular cells. We identified the perivascular cells as perivascular macrophages based on their morphology, location, Iba-1 immunoreactivity and preferential uptake of FITC-dextran. We subsequently depleted meningeal and perivascular macrophages 2 days before or 3 hours after SAH with clodronate liposomes. At day 5 after SAH, we found increased blood deposition in mice treated prior to SAH, but not those treated after. Treatment post-SAH improved neurological scoring, reduced neuronal cell death and perivascular inflammation, whereas pre-treatment only reduced perivascular inflammation. Our data indicate that after SAH, erythrocytes are distributed throughout the subarachnoid space extending into the perivascular spaces of parenchymal arterioles. Furthermore, meningeal and perivascular macrophages are involved in erythrocyte uptake and play an important role in outcome after SAH.



J Cereb Blood Flow Metab: 13 Jan 2021:271678X20980296; epub ahead of print
Wan H, Brathwaite S, Ai J, Hynynen K, Macdonald RL
J Cereb Blood Flow Metab: 13 Jan 2021:271678X20980296; epub ahead of print | PMID: 33444089
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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: 13 Jan 2021:271678X20970059; epub ahead of print
Chen S, Lachance BB, Gao L, Jia X
J Cereb Blood Flow Metab: 13 Jan 2021:271678X20970059; epub ahead of print | PMID: 33444088
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Abstract

A novel method of quantifying hemodynamic delays to improve hemodynamic response, and CVR estimates in CO2 challenge fMRI.

Yao JF, Yang HS, Wang JH, Liang Z, ... Jang I, Tong Y

Elevated carbon dioxide (CO2) in breathing air is widely used as a vasoactive stimulus to assess cerebrovascular functions under hypercapnia (i.e., \"stress test\" for the brain). Blood-oxygen-level-dependent (BOLD) is a contrast mechanism used in functional magnetic resonance imaging (fMRI). BOLD is used to study CO2-induced cerebrovascular reactivity (CVR), which is defined as the voxel-wise percentage BOLD signal change per mmHg change in the arterial partial pressure of CO2 (PaCO2). Besides the CVR, two additional important parameters reflecting the cerebrovascular functions are the arrival time of arterial CO2 at each voxel, and the waveform of the local BOLD signal. In this study, we developed a novel analytical method to accurately calculate the arrival time of elevated CO2 at each voxel using the systemic low frequency oscillations (sLFO: 0.01-0.1 Hz) extracted from the CO2 challenge data. In addition, 26 candidate hemodynamic response functions (HRF) were used to quantitatively describe the temporal brain reactions to a CO2 stimulus. We demonstrated that our approach improved the traditional method by allowing us to accurately map three perfusion-related parameters: the relative arrival time of blood, the hemodynamic response function, and CVR during a CO2 challenge.



J Cereb Blood Flow Metab: 13 Jan 2021:271678X20978582; epub ahead of print
Yao JF, Yang HS, Wang JH, Liang Z, ... Jang I, Tong Y
J Cereb Blood Flow Metab: 13 Jan 2021:271678X20978582; epub ahead of print | PMID: 33444087
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Abstract

Targeted tPA overexpression in denervated spinal motor neurons promotes stroke recovery in mice.

Gan X, Chopp M, Xin H, Wang F, ... He L, Liu Z

Our previous studies demonstrated that axonal remodeling of the corticospinal tract (CST) contributes to neurological recovery after stroke in rodents. The present study employed a novel non-invasive peripheral approach, to over-express tPA in denervated spinal motor neurons via recombinant adeno-associated virus (AAV) intramuscular injection in transgenic mice subjected to permanent middle cerebral artery occlusion (MCAo), in which the CST axons are specifically and completely labeled with yellow fluorescent protein (YFP). One day after surgery, mice were randomly selected to receive saline, AAV5-RFP, or tPA (1 × 10 viral particles) injected into the stroke-impaired forelimb muscles ( = 10/group). Functional deficits and recovery were monitored with foot-fault and single pellet reaching tests. At day 28 after MCAo, mice received intramuscular injection of PRV-614-mRFP (1.52 × 10 pfu) as above, and were euthanized four days later. Compared with saline or AAV-RFP-treated mice, AAV-tPA significantly enhanced behavioral recovery ( < 0.01, both tests), as well as increased CST axonal density in the denervated gray matter of the cervical cord ( < 0.001), and RFP-positive pyramidal neurons in both ipsilesional and contralesional cortices ( < 0.001). Behavioral outcomes were significantly correlated to neural remodeling ( < 0.05). Our results provide a fundamental basis for the development of therapeutic approaches aimed at promoting corticospinal innervation for stroke treatment.



J Cereb Blood Flow Metab: 30 Dec 2020; 41:92-104
Gan X, Chopp M, Xin H, Wang F, ... He L, Liu Z
J Cereb Blood Flow Metab: 30 Dec 2020; 41:92-104 | PMID: 31987011
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Abstract

In vivo characterization of spontaneous microhemorrhage formation in mice with cerebral amyloid angiopathy.

van Veluw SJ, Frosch MP, Scherlek AA, Lee D, Greenberg SM, Bacskai BJ

The pathophysiology of microhemorrhages in the context of cerebral amyloid angiopathy (CAA) remains poorly understood. Here we used in vivo two-photon microscopy in aged APP/PS1 mice with mild-to-moderate CAA to assess the formation of microhemorrhages and their spatial relationship with vascular Aβ depositions in the surrounding microvascular network. Mice with chronic cranial windows were intravenously injected with fluorescent dextran to visualize the vessels and a fluorescently labeled anti-fibrin antibody to visualize microhemorrhages. Focal vessel irradiations resulted in extravascular fibrin-positive clots at individual rupture sites that remained visible for weeks. Spontaneous extravascular fibrin-positive clots were more often observed in 19-month-old transgenic APP/PS1 mice compared to their wild-type littermate controls ( = 0.039), after heparin administration. In the transgenic mice, these spontaneous leakage sites frequently occurred at arteriolar segments without CAA at bifurcations or vessel bends. These findings suggest that the presence of vascular Aβ per se does not directly predispose vessels to leak, but that complex flow dynamics within CAA-affected vascular networks likely play a role. Our in vivo approach for the detection of individual spontaneous leakage sites may be used in longitudinal studies aimed to assess structural and functional alterations at the single-vessel level leading up to microhemorrhage formation.



J Cereb Blood Flow Metab: 30 Dec 2020; 41:82-91
van Veluw SJ, Frosch MP, Scherlek AA, Lee D, Greenberg SM, Bacskai BJ
J Cereb Blood Flow Metab: 30 Dec 2020; 41:82-91 | PMID: 31987010
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Abstract

DSC perfusion-based collateral imaging and quantitative T2 mapping to assess regional recruitment of leptomeningeal collaterals and microstructural cortical tissue damage in unilateral steno-occlusive vasculopathy.

Seiler A, Brandhofe A, Gracien RM, Pfeilschifter W, ... Nöth U, Wagner M

Leptomeningeal collateral supply is considered pivotal in steno-occlusive vasculopathy to prevent chronic microstructural ischaemic tissue damage. The aim of this study was to assess the alleged protective role of leptomeningeal collaterals in patients with unilateral high-grade steno-occlusive vasculopathy using quantitative (q)T2 mapping and perfusion-weighted imaging (PWI)-based collateral abundance. High-resolution qT2 was used to estimate microstructural damage of the segmented normal-appearing cortex. Volumetric abundance of collaterals was assessed based on PWI source data. The ratio relative cerebral blood flow/relative cerebral blood volume (rCBF/rCBV) as a surrogate of relative cerebral perfusion pressure (rCPP) was used to investigate the intravascular hemodynamic competency of pial collateral vessels and the hemodynamic state of brain parenchyma. Within the dependent vascular territory with increased cortical qT2 values ( = 0.0001) compared to the contralateral side, parenchymal rCPP was decreased ( = 0.0001) and correlated negatively with increase of qT2 (  < 0.05). Furthermore, volumetric abundance of adjacent leptomeningeal collaterals was significantly increased ( < 0.01) and negatively correlated with changes of parenchymal rCPP ( = 0.01). Microstructural cortical damage is closely related to restrictions of antegrade blood flow despite increased pial collateral vessel abundance. Therefore, increased leptomeningeal collateral supply cannot necessarily be regarded as a sign of effective compensation in patients with high-grade steno-occlusive vasculopathy.



J Cereb Blood Flow Metab: 30 Dec 2020; 41:67-81
Seiler A, Brandhofe A, Gracien RM, Pfeilschifter W, ... Nöth U, Wagner M
J Cereb Blood Flow Metab: 30 Dec 2020; 41:67-81 | PMID: 31987009
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Abstract

Cerebral microinfarcts affect brain structural network topology in cognitively impaired patients.

Zhang L, Biessels GJ, Hilal S, Chong JSX, ... Chen CL, Zhou JH

Cerebral microinfarcts (CMIs), a novel cerebrovascular marker, are prevalent in Alzheimer\'s disease (AD) and associated with cognitive impairment. Nonetheless, the underlying mechanism of how CMIs influence cognition remains uncertain. We hypothesized that cortical-CMIs disrupted structural connectivity in the higher-order cognitive networks, leading to cognitive impairment. We analyzed diffusion-MRI data of 92 AD (26 with cortical-CMIs) and 110 cognitive impairment no dementia patients (CIND, 28 with cortical-CMIs). We compared structural network topology between groups with and without cortical-CMIs in AD/CIND, and tested whether structural connectivity mediated the association between cortical-CMIs and cognition. Cortical-CMIs correlated with impaired structural network topology (i.e. lower efficiency/degree centrality in the executive control/dorsal attention networks in CIND, and lower clustering coefficient in the default mode/dorsal attention networks in AD), which mediated the association of cortical-CMIs with visuoconstruction dysfunction. Our findings provide the first in vivo human evidence that cortical-CMIs impair cognition in elderly via disrupting structural connectivity.



J Cereb Blood Flow Metab: 30 Dec 2020; 41:105-115
Zhang L, Biessels GJ, Hilal S, Chong JSX, ... Chen CL, Zhou JH
J Cereb Blood Flow Metab: 30 Dec 2020; 41:105-115 | PMID: 31986957
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Abstract

Impact of physiological noise in characterizing the functional MRI default-mode network in Alzheimer\'s disease.

Li YT, Chang CY, Hsu YC, Fuh JL, ... Yeh JT, Lin FH

The functional connectivity of the default-mode network (DMN) monitored by functional magnetic resonance imaging (fMRI) in Alzheimer\'s disease (AD) patients has been found weaker than that in healthy participants. Since breathing and heart beating can cause fluctuations in the fMRI signal, these physiological activities may affect the fMRI data differently between AD patients and healthy participants. We collected resting-state fMRI data from AD patients and age-matched healthy participants. With concurrent cardiac and respiratory recordings, we estimated both physiological responses phase-locked and non-phase-locked to heart beating and breathing. We found that the cardiac and respiratory physiological responses in AD patients were 3.00 ± 0.51 s and 3.96 ± 0.52 s later (both <0.0001) than those in healthy participants, respectively. After correcting the physiological noise in the resting-state fMRI data by population-specific physiological response functions, the DMN estimated by seed-correlation was more localized to the seed region. The DMN difference between AD patients and healthy controls became insignificant after suppressing physiological noise. Our results indicate the importance of controlling physiological noise in the resting-state fMRI analysis to obtain clinically related characterizations in AD.



J Cereb Blood Flow Metab: 30 Dec 2020; 41:166-181
Li YT, Chang CY, Hsu YC, Fuh JL, ... Yeh JT, Lin FH
J Cereb Blood Flow Metab: 30 Dec 2020; 41:166-181 | PMID: 32070180
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Abstract

A Monte Carlo approach for improving transient dopamine release detection sensitivity.

Bevington CW, Cheng JK, Klyuzhin IS, Cherkasova MV, Winstanley CA, Sossi V

Current methods using a single PET scan to detect voxel-level transient dopamine release-using F-test (significance) and cluster size thresholding-have limited detection sensitivity for clusters of release small in size and/or having low release levels. Specifically, simulations show that voxels with release near the peripheries of such clusters are often rejected-becoming false negatives and ultimately distorting the F-distribution of rejected voxels. We suggest a Monte Carlo method that incorporates these two observations into a cost function, allowing erroneously rejected voxels to be accepted under specified criteria. In simulations, the proposed method improves detection sensitivity by up to 50% while preserving the cluster size threshold, or up to 180% when optimizing for sensitivity. A further parametric-based voxelwise thresholding is then suggested to better estimate the release dynamics in detected clusters. We apply the Monte Carlo method to a pilot scan from a human gambling study, where additional parametrically unique clusters are detected as compared to the current best methods-results consistent with our simulations.



J Cereb Blood Flow Metab: 30 Dec 2020; 41:116-131
Bevington CW, Cheng JK, Klyuzhin IS, Cherkasova MV, Winstanley CA, Sossi V
J Cereb Blood Flow Metab: 30 Dec 2020; 41:116-131 | PMID: 32050828
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Abstract

Tight junctions in the blood-brain barrier promote edema formation and infarct size in stroke - Ambivalent effects of sealing proteins.

Winkler L, Blasig R, Breitkreuz-Korff O, Berndt P, ... Blasig IE, Haseloff RF

The outcome of stroke is greatly influenced by the state of the blood-brain barrier (BBB). The BBB endothelium is sealed paracellularly by tight junction (TJ) proteins, i.e., claudins (Cldns) and the redox regulator occludin. Functions of Cldn3 and occludin at the BBB are largely unknown, particularly after stroke. We address the effects of Cldn3 deficiency and stress factors on the BBB and its TJs. Cldn3 tightened the BBB for small molecules and ions, limited endothelial endocytosis, strengthened the TJ structure and controlled Cldn1 expression. After middle cerebral artery occlusion (MCAO) and 3-h reperfusion or hypoxia of isolated brain capillaries, Cldn1, Cldn3 and occludin were downregulated. In Cldn3 knockout mice (C3KO), the reduction in Cldn1 was even greater and TJ ultrastructure was impaired; 48 h after MCAO of wt mice, infarct volumes were enlarged and edema developed, but endothelial TJs were preserved. In contrast, junctional localization of Cldn5 and occludin, TJ density, swelling and infarction size were reduced in affected brain areas of C3KO. Taken together, Cldn3 and occludin protect TJs in stroke, and this keeps the BBB intact. However, functional Cldn3, Cldn3-regulated TJ proteins and occludin promote edema and infarction, which suggests that TJ modulation could improve the outcome of stroke.



J Cereb Blood Flow Metab: 30 Dec 2020; 41:132-145
Winkler L, Blasig R, Breitkreuz-Korff O, Berndt P, ... Blasig IE, Haseloff RF
J Cereb Blood Flow Metab: 30 Dec 2020; 41:132-145 | PMID: 32054373
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Abstract

Venous disruption affects white matter integrity through increased interstitial fluid in cerebral small vessel disease.

Zhang R, Huang P, Jiaerken Y, Wang S, ... Lou M, Zhang M

Deep medullary veins (DMVs) participate in the drainage of surrounding white matter. In cerebral small vessel disease (CSVD), disrupted DMVs were often observed together with damaged white matter, but the phenomenon lacked validation and explanation. We hypothesized that venous disruption might cause white matter damage through increased interstitial fluid resulting from hemodynamic alteration, and we designed a comprehensive multi-modality MRI study to testify our hypothesis. Susceptibility-weighted imaging was used to investigate the characteristics of DMVs and derive DMVs scores. Free water elimination diffusion tensor imaging model was used to analyze interstitial fluid fraction (fraction of free water, fFW) and white matter integrity (tissue fractional anisotropy, FAt). Totally, 104 CSVD patients were included. Total DMVs score was associated with FAt of DMVs drainage area. The effect of total DMVs score on FAt was mediated by fFW, after controlling for age, sex, hypertension, regional cerebral blood flow and lacune numbers. The relationships between DMVs score, fFW and FAt were also significant in most DMVs drainage subregions. Therefore, we discovered the DMVs disruption - increased interstitial fluid - white matter damage link in CSVD patients, which was independent of arterial perfusion variations.



J Cereb Blood Flow Metab: 30 Dec 2020; 41:157-165
Zhang R, Huang P, Jiaerken Y, Wang S, ... Lou M, Zhang M
J Cereb Blood Flow Metab: 30 Dec 2020; 41:157-165 | PMID: 32065078
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Abstract

Visualizing prolonged hyperperfusion in post-stroke epilepsy using postictal subtraction SPECT.

Fukuma K, Kajimoto K, Tanaka T, Takaya S, ... Toyoda K, Ihara M

Diagnosis of post-stroke epilepsy is often challenging because of a low incidence of epileptiform abnormalities on electroencephalography (EEG). Hence, this study evaluated whether postictal subtraction single-photon emission computed tomography (SPECT) could visualize epileptic activity and act as a diagnostic modality in post-stroke epilepsy. Fifty post-stroke epilepsy patients, who had undergone Tc-99m-ECD SPECT twice (postictal and interictal), were enrolled. The postictal hyperperfusion area was identified by subtraction (postictal-interictal) SPECT and classified into two distribution types: superficial or deep-seated. Laterality and distribution of postictal hyperperfusion on subtraction SPECT were compared with stroke lesions, seizure symptoms, and epileptiform EEG findings. Forty-three of the 50 patients (86%) had hyperperfusion on subtraction SPECT and 26 (52%) had epileptiform EEG findings. Subtraction SPECT showed prolonged postictal hyperperfusion despite the relatively long interval between seizure end and postictal SPECT (median: 19.1 h, range: 2.2-112.5 h). The laterality of the hyperperfusion area had a high concordance rate with the laterality of stroke lesions (97.7%), seizure symptoms (91.9%), and epileptiform EEG findings (100%). Scalp EEG identified epileptiform activity more frequently in superficial type of SPECT, but less frequently in deep-seated type (both,  = 0.03). Postictal SPECT can be complementary to scalp EEG in endorsing the diagnosis and location of post-stroke epilepsy.



J Cereb Blood Flow Metab: 30 Dec 2020; 41:146-156
Fukuma K, Kajimoto K, Tanaka T, Takaya S, ... Toyoda K, Ihara M
J Cereb Blood Flow Metab: 30 Dec 2020; 41:146-156 | PMID: 32065077
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Abstract

Meprin β: A novel regulator of blood-brain barrier integrity.

Gindorf M, Storck SE, Ohler A, Scharfenberg F, Becker-Pauly C, Pietrzik CU

The metalloprotease meprin β (Mep1b) is capable of cleaving cell-adhesion molecules in different tissues (e.g. skin, kidney and intestine) and is dysregulated in several diseases associated with barrier breakdown (Alzheimer´s disease, kidney disruption, inflammatory bowel disease). In this study, we demonstrate that Mep1b is a novel regulator of tight junction (TJ) composition and blood-brain barrier (BBB) integrity in brain endothelium. In Mep1b-transfected mouse brain endothelial cells (bEnd.3), we observed a reduction of the TJ protein claudin-5, decreased transendothelial electrical resistance (TEER) and an elevated permeability to paracellular diffusion marker [C]-inulin. Analysis of global Mep1b knock-out (Mep1b) mice showed increased TJ protein expression (claudin-5, occludin, ZO-1) in cerebral microvessels and increased TEER in cultivated primary mouse brain endothelial compared to wild-type (wt) mice. Furthermore, we investigated the IgG levels in cerebrospinal fluid (CSF) and the brain water content as additional permeability markers and detected lower IgG levels and reduced brain water content in Mep1b mice compared to wt mice. Showing opposing features in overexpression and knock-out, we conclude that Mep1b plays a role in regulating brain endothelial TJ-proteins and therefore affecting BBB tightness in vitro and in vivo.



J Cereb Blood Flow Metab: 30 Dec 2020; 41:31-44
Gindorf M, Storck SE, Ohler A, Scharfenberg F, Becker-Pauly C, Pietrzik CU
J Cereb Blood Flow Metab: 30 Dec 2020; 41:31-44 | PMID: 32065075
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Abstract

Altered task-induced cerebral blood flow and oxygen metabolism underlies motor impairment in multiple sclerosis.

West KL, Sivakolundu DK, Zuppichini MD, Turner MP, ... Okuda DT, Rypma B

The neural mechanisms underlying motor impairment in multiple sclerosis (MS) remain unknown. Motor cortex dysfunction is implicated in blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies, but the role of neural-vascular coupling underlying BOLD changes remains unknown. We sought to independently measure the physiologic factors (i.e., cerebral blood flow (ΔCBF), cerebral metabolic rate of oxygen (ΔCMRO), and flow-metabolism coupling (ΔCBF/ΔCMRO), utilizing dual-echo calibrated fMRI (cfMRI) during a bilateral finger-tapping task. We utilized cfMRI to measure physiologic responses in 17 healthy volunteers and 32 MS patients (MSP) with and without motor impairment during a thumb-button-press task in thumb-related (task-central) and surrounding primary motor cortex (task-surround) regions of interest (ROIs). We observed significant ΔCBF and ΔCMRO increases in all MSP compared to healthy volunteers in the task-central ROI and increased flow-metabolism coupling (ΔCBF/ΔCMRO) in the MSP without motor impairment. In the task-surround ROI, we observed decreases in ΔCBF and ΔCMRO in MSP with motor impairment. Additionally, ΔCBF and ΔCMRO responses in the task-surround ROI were associated with motor function and white matter damage in MSP. These results suggest an important role for task-surround recruitment in the primary motor cortex to maintain motor dexterity and its dependence on intact white matter microstructure and neural-vascular coupling.



J Cereb Blood Flow Metab: 30 Dec 2020; 41:182-193
West KL, Sivakolundu DK, Zuppichini MD, Turner MP, ... Okuda DT, Rypma B
J Cereb Blood Flow Metab: 30 Dec 2020; 41:182-193 | PMID: 32126873
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Abstract

Ischemic lesion water homeostasis after thrombectomy for large vessel occlusion stroke within the anterior circulation: The impact of age.

Meyer L, Schönfeld M, Bechstein M, Hanning U, ... Fiehler J, Broocks G

The effect of age on lesion pathophysiology in the context of thrombectomy has been poorly investigated. We aimed to investigate the impact of age on ischemic lesion water homeostasis measured with net water uptake (NWU) within a multicenter cohort of patients receiving thrombectomy for anterior circulation large vessel occlusion (LVO) stroke. Lesion-NWU was quantified in multimodal CT on admission and 24 h for calculating Δ-NWU as their difference. The impact of age and procedural parameters on Δ-NWU was analyzed. Multivariable regression analysis was performed to identify significant predictors for Δ-NWU. Two hundred and four patients with anterior circulation stroke were included in the retrospective analysis. Comparison of younger and elderly patients showed no significant differences in NWU on admission but significantly higher Δ-NWU ( = 0.005) on follow-up CT in younger patients. In multivariable regression analysis, higher age was independently associated with lowered Δ-NWU (95% confidence interval: -0.59 to -0.16,  < 0.001). Although successful recanalization (TICI ≥ 2b) significantly reduced Δ-NWU progression by 6.4% ( < 0.001), younger age was still independently associated with higher Δ-NWU ( < 0.001). Younger age is significantly associated with increased brain edema formation after thrombectomy for LVO stroke. Younger patients might be particularly receptive targets for future adjuvant neuroprotective drugs that influence ischemic edema formation.



J Cereb Blood Flow Metab: 30 Dec 2020; 41:45-52
Meyer L, Schönfeld M, Bechstein M, Hanning U, ... Fiehler J, Broocks G
J Cereb Blood Flow Metab: 30 Dec 2020; 41:45-52 | PMID: 32248730
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Abstract

Optimized lactoferrin as a highly promising treatment for intracerebral hemorrhage: Pre-clinical experience.

Zhao X, Kruzel M, Ting SM, Sun G, Savitz SI, Aronowski J

Intracerebral hemorrhage (ICH) is the deadliest form of stroke for which there is no effective treatment, despite an endless number of pre-clinical studies and clinical trials. The obvious therapeutic target is the neutralization of toxic products of red blood cell (RBC) lysis that lead to cytotoxicity, inflammation, and oxidative damage. We used rigorous approaches and translationally relevant experimental ICH models to show that lactoferrin-(LTF)-based monotherapy is uniquely robust in reducing brain damage after ICH. Specifically, we designed, produced, and pharmacokinetically/toxicologically characterized an optimized LTF, a fusion of human LTF and the Fc domain of human IgG (FcLTF) that has a 5.8-fold longer half-life in the circulation than native LTF. Following dose-optimization studies, we showed that FcLTF reduces neurological injury caused by ICH in aged male/female mice, and in young male Sprague Dawley (SD) and spontaneously hypertensive rats (SHR). FcLTF showed a remarkably long 24-h therapeutic window. In tissue culture systems, FcLTF protected neurons from the toxic effects of RBCs and promoted microglia toward phagocytosis of RBCs and dead neurons, documenting its pleotropic effect. Our findings indicate that FcLTF is safe and effective in reducing ICH-induced damage in animal models used in this study.



J Cereb Blood Flow Metab: 30 Dec 2020; 41:53-66
Zhao X, Kruzel M, Ting SM, Sun G, Savitz SI, Aronowski J
J Cereb Blood Flow Metab: 30 Dec 2020; 41:53-66 | PMID: 32438861
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Abstract

A meta-analysis of remote ischaemic conditioning in experimental stroke.

Weir P, Maguire R, O\'Sullivan SE, England TJ

Remote ischaemic conditioning (RIC) is achieved by repeated transient ischaemia of a distant organ/limb and is neuroprotective in experimental ischaemic stroke. However, the optimal time and methods of administration are unclear. Systematic review identified relevant preclinical studies; two authors independently extracted data on infarct volume, neurological deficit, RIC method (administration time, site, cycle number, length of limb occlusion (dose)), species and quality. Data were analysed using random effects models; results expressed as standardised mean difference (SMD). In 57 publications incorporating 99 experiments (1406 rats, 101 mice, 14 monkeys), RIC reduced lesion volume in transient (SMD -2.0; 95% CI -2.38, -1.61;  < 0.00001) and permanent (SMD -1.54; 95% CI -2.38, -1.61;  < 0.00001) focal models of ischaemia and improved neurological deficit (SMD -1.63; 95% CI -1.97, -1.29,  < 0.00001). In meta-regression, cycle length and number, dose and limb number did not interact with infarct volume, although country and physiological monitoring during anaesthesia did. In all studies, RIC was ineffective if the dose was <10 or ≥50 min. Median study quality was 7 (range 4-9/10); Egger\'s test suggested publication bias ( < 0.001). RIC is most effective in experimental stroke using a dose between 10 and 45 min. Further studies using repeated dosing in animals with co-morbidities are warranted.



J Cereb Blood Flow Metab: 30 Dec 2020; 41:3-13
Weir P, Maguire R, O'Sullivan SE, England TJ
J Cereb Blood Flow Metab: 30 Dec 2020; 41:3-13 | PMID: 32538284
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Abstract

Glucagon-like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: a systematic scoping review.

Maskery MP, Holscher C, Jones SP, Price CI, ... Werring DJ, Emsley HC

Stroke mortality and morbidity is expected to rise. Despite considerable recent advances within acute ischemic stroke treatment, scope remains for development of widely applicable neuroprotective agents. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally licensed for the management of Type 2 Diabetes Mellitus, have demonstrated pre-clinical neuroprotective efficacy in a range of neurodegenerative conditions. This systematic scoping review reports the pre-clinical basis of GLP-1RAs as neuroprotective agents in acute ischemic stroke and their translation into clinical trials. We included 35 pre-clinical studies, 11 retrospective database studies, 7 cardiovascular outcome trials and 4 prospective clinical studies. Pre-clinical neuroprotection was demonstrated in normoglycemic models when administration was delayed by up to 24 h following stroke induction. Outcomes included reduced infarct volume, apoptosis, oxidative stress and inflammation alongside increased neurogenesis, angiogenesis and cerebral blood flow. Improved neurological function and a trend towards increased survival were also reported. Cardiovascular outcomes trials reported a significant reduction in stroke incidence with semaglutide and dulaglutide. Retrospective database studies show a trend towards neuroprotection. Prospective interventional clinical trials are on-going, but initial indicators of safety and tolerability are favourable. Ultimately, we propose that repurposing GLP-1RAs is potentially advantageous but appropriately designed trials are needed to determine clinical efficacy and cost-effectiveness.



J Cereb Blood Flow Metab: 30 Dec 2020; 41:14-30
Maskery MP, Holscher C, Jones SP, Price CI, ... Werring DJ, Emsley HC
J Cereb Blood Flow Metab: 30 Dec 2020; 41:14-30 | PMID: 32954901
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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 using2-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 Dec 2020:271678X20973787; epub ahead of print
Lenz IJ, Plesnila N, Terpolilli NA
J Cereb Blood Flow Metab: 29 Dec 2020:271678X20973787; epub ahead of print | PMID: 33256507
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Abstract

Circadian effects on stroke outcome - Did we not wake up in time for neuroprotection?

Boltze J, Didwischus N, Merrow M, Dallmann R, Plesnila N

The occurrence of stroke in humans peaks in the morning. A recent study revealed that time of day mitigates the therapeutic impact of neuroprotective paradigms. These findings might not only explain the previous failure of translation of neuroprotective therapies but inspire new paradigms in stroke chronopathophysiology research. Taking chronotype into account may complement the many factors that influence efficacy of experimental therapies in stroke.



J Cereb Blood Flow Metab: 17 Dec 2020:271678X20978711; epub ahead of print
Boltze J, Didwischus N, Merrow M, Dallmann R, Plesnila N
J Cereb Blood Flow Metab: 17 Dec 2020:271678X20978711; epub ahead of print | PMID: 33337257
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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,  = 0.04) and higher ASL SCoV (0.32 SD, 95%CI = 0.12|0.52,  = 0.002). These results warrant future research on the potential relations between antihypertensive use and cerebral perfusion.



J Cereb Blood Flow Metab: 15 Dec 2020:271678X20966975; epub ahead of print
van Dalen JW, Mutsaerts HJ, Petr J, Caan MW, ... Nederveen AJ, Richard E
J Cereb Blood Flow Metab: 15 Dec 2020:271678X20966975; epub ahead of print | PMID: 33325767
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Abstract

Characterisation of microvessel blood velocity and segment length in the brain using multi-diffusion-time diffusion-weighted MRI.

Scott LA, Dickie BR, Rawson SD, Coutts G, ... Parker GJ, Parkes LM

Multi-diffusion-time diffusion-weighted MRI can probe tissue microstructure, but the method has not been widely applied to the microvasculature. At long diffusion-times, blood flow in capillaries is in the diffusive regime, and signal attenuation is dependent on blood velocity () and capillary segment length (). It is described by the pseudo-diffusion coefficient () of intravoxel incoherent motion (IVIM). At shorter diffusion-times, blood flow is in the ballistic regime, and signal attenuation depends on , and not . In theory,could be estimated usingand . In this study, we compare the accuracy and repeatability of three approaches to estimating , and therefore : the IVIM ballistic model, the velocity autocorrelation model, and the ballistic approximation to the velocity autocorrelation model. Twenty-nine rat datasets from two strains were acquired at 7 T, with -values between 0 and 1000 smm and diffusion times between 11.6 and 50 ms. Five rats were scanned twice to assess scan-rescan repeatability. Measurements ofwere validated using corrosion casting and micro-CT imaging. The ballistic approximation of the velocity autocorrelation model had lowest bias relative to corrosion cast estimates of , and had highest repeatability.



J Cereb Blood Flow Metab: 15 Dec 2020:271678X20978523; epub ahead of print
Scott LA, Dickie BR, Rawson SD, Coutts G, ... Parker GJ, Parkes LM
J Cereb Blood Flow Metab: 15 Dec 2020:271678X20978523; epub ahead of print | PMID: 33325766
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Abstract

Evolution of the stroke paradigm: A review of delayed recanalization.

Camara R, Matei N, Zhang JH

While the time window for reperfusion after ischemic stroke continues to increase, many patients are not candidates for reperfusion under current guidelines that allow for reperfusion within 24 h after last known well time; however, many case studies report favorable outcomes beyond 24 h after symptom onset for both spontaneous and medically induced recanalization. Furthermore, modern imaging allows for identification of penumbra at extended time points, and reperfusion risk factors and complications are becoming better understood. Taken together, continued urgency exists to better understand the pathophysiologic mechanisms and ideal setting of delayed recanalization beyond 24 h after onset of ischemia.



J Cereb Blood Flow Metab: 15 Dec 2020:271678X20978861; epub ahead of print
Camara R, Matei N, Zhang JH
J Cereb Blood Flow Metab: 15 Dec 2020:271678X20978861; epub ahead of print | PMID: 33325765
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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: 15 Dec 2020:271678X20973119; epub ahead of print
Yu Z, Li W, Lan J, Hayakawa K, ... Lo EH, Wang X
J Cereb Blood Flow Metab: 15 Dec 2020:271678X20973119; epub ahead of print | 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 T 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 T relaxometry and DTI sequences, as well as comprehensive cognitive assessment. Averaged quantitative T, 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 T 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. T 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: 15 Dec 2020:271678X20972511; epub ahead of print
Brandhofe A, Stratmann C, Schüre JR, Pilatus U, ... Gracien RM, Seiler A
J Cereb Blood Flow Metab: 15 Dec 2020:271678X20972511; epub ahead of print | PMID: 33327818
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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 ( = 0.009) after controlling for covariates. This association was found for periventricular WMH ( = 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: 30 Nov 2020:271678X20974170; epub ahead of print
Mayer C, Frey BM, Schlemm E, Petersen M, ... Thomalla G, Cheng B
J Cereb Blood Flow Metab: 30 Nov 2020:271678X20974170; epub ahead of print | PMID: 33259747
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Abstract

Test-retest repeatability of [F]Flortaucipir PET in Alzheimer\'s disease and cognitively normal individuals.

Timmers T, Ossenkoppele R, Visser D, Tuncel H, ... Golla SS, van Berckel BN

The aim of this study was to investigate the test-retest (TRT) repeatability of various parametric quantification methods for [F]Flortaucipir positron emission tomography (PET). We included eight subjects with dementia or mild cognitive impairment due to Alzheimer\'s disease and six cognitively normal subjects. All underwent two 130-min dynamic [F]Flortaucipir PET scans within 3 ± 1 weeks. Data were analyzed using reference region models receptor parametric mapping (RPM), simplified reference tissue method 2 (SRTM2) and reference logan (RLogan), as well as standardized uptake value ratios (SUVr, time intervals 40-60, 80-100 and 110-130 min post-injection) with cerebellar gray matter as reference region. We obtained distribution volume ratio or SUVr, first for all brain regions and then in three tau-specific regions-of-interest (ROIs). TRT repeatability (%) was defined as |retest-test|/(average (test + retest)) × 100. For all methods and across ROIs, TRT repeatability ranged from (median (IQR)) 0.84% (0.68-2.15) to 6.84% (2.99-11.50). TRT repeatability was good for all reference methods used, although semi-quantitative models (i.e. SUVr) performed marginally worse than quantitative models, for instance TRT repeatability of RPM: 1.98% (0.78-3.58) vs. SUVr: 3.05% (1.28-5.52),  < 0.001. Furthermore, for SUVr and SUVr, with higher average SUVr, more variation was observed. In conclusion, while TRT repeatability was good for all models used, quantitative methods performed slightly better than semi-quantitative methods.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:2464-2474
Timmers T, Ossenkoppele R, Visser D, Tuncel H, ... Golla SS, van Berckel BN
J Cereb Blood Flow Metab: 29 Nov 2020; 40:2464-2474 | PMID: 31575335
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Abstract

Characterizing pulsatility in distal cerebral arteries using 4D flow MRI.

Vikner T, Nyberg L, Holmgren M, Malm J, Eklund A, Wåhlin A

Recent reports have suggested that age-related arterial stiffening and excessive cerebral arterial pulsatility cause blood-brain barrier breakdown, brain atrophy and cognitive decline. This has spurred interest in developing non-invasive methods to measure pulsatility in distal vessels, closer to the cerebral microcirculation. Here, we report a method based on four-dimensional (4D) flow MRI to estimate a global composite flow waveform of distal cerebral arteries. The method is based on finding and sampling arterial waveforms from thousands of cross sections in numerous small vessels of the brain, originating from cerebral cortical arteries. We demonstrate agreement with internal and external reference methods and show the ability to capture significant increases in distal cerebral arterial pulsatility as a function of age. The proposed approach can be used to advance our understanding regarding excessive arterial pulsatility as a potential trigger of cognitive decline and dementia.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:2429-2440
Vikner T, Nyberg L, Holmgren M, Malm J, Eklund A, Wåhlin A
J Cereb Blood Flow Metab: 29 Nov 2020; 40:2429-2440 | PMID: 31722598
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Abstract

Mild metabolic stress is sufficient to disturb the formation of pyramidal cell ensembles during gamma oscillations.

Elzoheiry S, Lewen A, Schneider J, Both M, ... Hollnagel JO, Kann O

Disturbances of cognitive functions occur rapidly during acute metabolic stress. However, the underlying mechanisms are not fully understood. Cortical gamma oscillations (30-100 Hz) emerging from precise synaptic transmission between excitatory principal neurons and inhibitory interneurons, such as fast-spiking GABAergic basket cells, are associated with higher brain functions, like sensory perception, selective attention and memory formation. We investigated the alterations of cholinergic gamma oscillations at the level of neuronal ensembles in the CA3 region of rat hippocampal slice cultures. We combined electrophysiology, calcium imaging (CamKII.GCaMP6f) and mild metabolic stress that was induced by rotenone, a lipophilic and highly selective inhibitor of complex I in the respiratory chain of mitochondria. The detected pyramidal cell ensembles showing repetitive patterns of activity were highly sensitive to mild metabolic stress. Whereas such synchronised multicellular activity diminished, the overall activity of individual pyramidal cells was unaffected. Additionally, mild metabolic stress had no effect on the rate of action potential generation in fast-spiking neural units. However, the partial disinhibition of slow-spiking neural units suggests that disturbances of ensemble formation likely result from alterations in synaptic inhibition. Our study bridges disturbances on the (multi-)cellular and network level to putative cognitive impairment on the system level.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:2401-2415
Elzoheiry S, Lewen A, Schneider J, Both M, ... Hollnagel JO, Kann O
J Cereb Blood Flow Metab: 29 Nov 2020; 40:2401-2415 | PMID: 31842665
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Abstract

Involvement of the basal nucleus of Meynert on regional cerebral cortical vasodilation associated with masticatory muscle activity in rats.

Hotta H, Suzuki H, Inoue T, Stewart M

We examined the neural mechanisms for increases in regional cerebral blood flow (rCBF) in the neocortex associated with mastication, focusing on the cortical vasodilative system derived from the nucleus basalis of Meynert (NBM). In pentobarbital-anesthetized rats, parietal cortical rCBF was recorded simultaneously with electromyogram (EMG) of jaw muscles, local field potentials of frontal cortex, multi-unit activity of NBM neurons, and systemic mean arterial pressure (MAP). When spontaneous rhythmic EMG activity was observed with cortical desynchronization, an increase in NBM activity and a marked rCBF increase independent of MAP changes were observed. A similar rCBF increase was elicited by repetitive electrical stimulation of unilateral cortical masticatory areas. The magnitude of rCBF increase was partially attenuated by administration of the GABAergic agonist muscimol into the NBM. The rCBF increase persisted after immobilization with systemic muscle relaxant (vecuronium). rCBF did not change when jaw muscle activity was induced by electrical stimulation of the pyramidal tract. The results suggest that activation of NBM vasodilator neurons contributes at least in part to the rCBF increase associated with masticatory muscle activity, and that the NBM activation is induced by central commands from the motor cortex, independently of feedback from brainstem central pattern generator or contracting muscles.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:2416-2428
Hotta H, Suzuki H, Inoue T, Stewart M
J Cereb Blood Flow Metab: 29 Nov 2020; 40:2416-2428 | PMID: 31847668
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Abstract

Reduced cerebral blood flow in an -synuclein transgenic mouse model of Parkinson\'s disease.

Biju KC, Shen Q, Hernandez ET, Mader MJ, Clark RA

There is increasing evidence that widespread cortical cerebral blood flow deficits occur early in the course of Parkinson\'s disease. Although cerebral blood flow measurement has been suggested as a potential biomarker for early diagnosis of Parkinson\'s disease, as well as a means for tracking response to treatment, the relationship of cerebral blood flow to α-synucleinopathy, a major pathological hallmark of Parkinson\'s disease, remains unclear. Therefore, we performed arterial spin-labeling magnetic resonance imaging and diffusion tensor imaging on transgenic mice overexpressing human wild-type α-synuclein and age-matched controls to measure cerebral blood flow and degenerative changes. As reported for early-stage Parkinson\'s disease, α-synuclein mice exhibited a significant reduction in cortical cerebral blood flow, which was accompanied by motor coordination deficits and olfactory dysfunction. Although no overt degenerative changes were apparent in diffusion tensor imaging images, magnetic resonance imaging volumetric analysis revealed a significant reduction in olfactory bulb volume, similar to that seen in Parkinson\'s disease patients. Our data, representing the first report of cerebral blood flow deficit in an animal model of Parkinson\'s disease, suggest a causative role for α-synucleinopathy in cerebral blood flow deficits in Parkinson\'s disease. Thus, α-synuclein transgenic mice comprise a promising model to study Parkinson\'s disease-related mechanisms of cerebral blood flow deficits and to investigate further its utility as a potential biomarker for Parkinson\'s disease.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:2441-2453
Biju KC, Shen Q, Hernandez ET, Mader MJ, Clark RA
J Cereb Blood Flow Metab: 29 Nov 2020; 40:2441-2453 | PMID: 31856640
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Abstract

Endothelial progenitor cell transplantation alleviated ischemic brain injury via inhibiting C3/C3aR pathway in mice.

Ma Y, Jiang L, Wang L, Li Y, ... Zhang Z, Yang GY

Endothelial progenitor cell transplantation is a potential therapeutic approach in brain ischemia. However, whether the therapeutic effect of endothelial progenitor cells is via affecting complement activation is unknown. We established a mouse focal ischemia model ( = 111) and transplanted endothelial progenitor cells into the peri-infarct region immediately after brain ischemia. Neurological outcomes and brain infarct/atrophy volume were examined after ischemia. Expression of C3, C3aR and pro-inflammatory factors were further examined to explore the role of endothelial progenitor cells in ischemic brain. We found that endothelial progenitor cells improved neurological outcomes and reduced brain infarct/atrophy volume after 1 to 14 days of ischemia compared to the control (<0.05). C3 and C3aR expression in the brain was up-regulated at 1 day up to 14 days (<0.05). Endothelial progenitor cells reduced astrocyte-derived C3 (<0.05) and C3aR expression (<0.05) after ischemia. Endothelial progenitor cells also reduced inflammatory response after ischemia (<0.05). Endothelial progenitor cell transplantation reduced astrocyte-derived C3 expression in the brain after ischemic stroke, together with decreased C3aR and inflammatory response contributing to neurological function recovery. Our results indicate that modulating complement C3/C3aR pathway is a novel therapeutic target for the ischemic stroke.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:2374-2386
Ma Y, Jiang L, Wang L, Li Y, ... Zhang Z, Yang GY
J Cereb Blood Flow Metab: 29 Nov 2020; 40:2374-2386 | PMID: 31865842
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Abstract

Severity of white matter hyperintensities: Lesion patterns, cognition, and microstructural changes.

Zeng W, Chen Y, Zhu Z, Gao S, ... Jia J, Zhang Z

White matter hyperintensity (WMH) is a common finding in aging population and considered to be a contributor to cognitive decline. Our study aimed to characterize the spatial patterns of WMH in different severities and explore its impact on cognition and brain microstructure in non-demented elderly. Lesions were both qualitatively (Fazekas scale) and quantitatively assessed among 321 community-dwelled individuals with MRI scanning. Voxel- and atlas-based analyses of the whole-brain white matter microstructure were performed. The WMH of the same severities was found to occur uniformly with a specific pattern of lesions. The severity of WMH had a significant negative association with the performance of working and episodic memory, beginning to appear in Fazekas 3 and 4. The white matter tracts presented significant impairments in Fazekas 3, which showed brain-wide changes above Fazekas 4. Lower FA in the superior cerebellar peduncle and left posterior thalamic radiation was mainly associated with episodic memory, and the middle cerebellar peduncle was significantly associated with working memory. These results support that memory is the primary domain to be affected by WMH, and the effect may potentially be influenced by tract-specific WM abnormalities. Fazekas scale 3 might be the critical stage predicting a future decline in cognition.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:2454-2463
Zeng W, Chen Y, Zhu Z, Gao S, ... Jia J, Zhang Z
J Cereb Blood Flow Metab: 29 Nov 2020; 40:2454-2463 | PMID: 31865841
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Abstract

Persistent alterations in cerebrovascular reactivity in response to hypercapnia following pediatric mild traumatic brain injury.

Dodd AB, Lu H, Wertz CJ, Ling JM, ... Liu P, Mayer AR

Much attention has been paid to the effects of mild traumatic brain injury (mTBI) on cerebrovascular reactivity in adult populations, yet it remains understudied in pediatric injury. In this study, 30 adolescents (12-18 years old) with pediatric mTBI (pmTBI) and 35 age- and sex-matched healthy controls (HC) underwent clinical and neuroimaging assessments during sub-acute (6.9 ± 2.2 days) and early chronic (120.4 ± 11.7 days) phases of injury. Relative to controls, pmTBI reported greater initial post-concussion symptoms, headache, pain, and anxiety, resolving by four months post-injury. Patients reported increased sleep issues and exhibited deficits in processing speed and attention across both visits. In grey-white matter interface areas throughout the brain, pmTBI displayed increased maximal fit/amplitude of a time-shifted end-tidal CO regressor to blood oxygen-level dependent response relative to HC, as well as increased latency to maximal fit. The alterations persisted through the early chronic phase of injury, with maximal fit being associated with complaints of ongoing sleep disturbances during post hoc analyses but not cognitive measures of processing speed or attention. Collectively, these findings suggest that deficits in the speed and degree of cerebrovascular reactivity may persist longer than current conceptualizations about clinical recovery within 30 days.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:2491-2504
Dodd AB, Lu H, Wertz CJ, Ling JM, ... Liu P, Mayer AR
J Cereb Blood Flow Metab: 29 Nov 2020; 40:2491-2504 | PMID: 31903838
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Abstract

Susceptibility to capillary plugging can predict brain region specific vessel loss with aging.

Schager B, Brown CE

Vessel loss in the aging brain is commonly reported, yet important questions remain concerning whether there are regional vulnerabilities and what mechanisms could account for these regional differences, if they exist. Here we imaged and quantified vessel length, tortuosity and width in 15 brain regions in young adult and aged mice. Our data indicate that vessel loss was most pronounced in white matter followed by cortical, then subcortical grey matter regions, while some regions (visual cortex, amygdala, thalamus) showed no decline with aging. Regions supplied by the anterior cerebral artery were more vulnerable to loss than those supplied by middle or posterior cerebral arteries. Vessel width and tortuosity generally increased with age but neither reliably predicted regional vessel loss. Since capillaries are naturally prone to plugging and prolonged obstructions often lead to vessel pruning, we hypothesized that regional susceptibilities to plugging could help predict vessel loss. By mapping the distribution of microsphere-induced capillary obstructions, we discovered that regions with a higher density of persistent obstructions were more likely to show vessel loss with aging and vice versa. These findings indicate that age-related vessel loss is region specific and can be explained, at least partially, by regional susceptibilities to capillary plugging.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:2475-2490
Schager B, Brown CE
J Cereb Blood Flow Metab: 29 Nov 2020; 40:2475-2490 | PMID: 31903837
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Abstract

Metabolic endotoxemia promotes neuroinflammation after focal cerebral ischemia.

Kurita N, Yamashiro K, Kuroki T, Tanaka R, ... Asahara T, Hattori N

Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria and a potent inflammatory stimulus for the innate immune response via toll-like receptor (TLR) 4 activation. Type 2 diabetes is associated with changes in gut microbiota and impaired intestinal barrier functions, leading to translocation of microbiota-derived LPS into the circulatory system, a condition referred to as metabolic endotoxemia. We investigated the effects of metabolic endotoxemia after experimental stroke with transient middle cerebral artery occlusion (MCAO) in a murine model of type 2 diabetes () and phenotypically normal littermates (). Compared tomice,mice exhibited an altered gut microbial composition, increased intestinal permeability, and higher plasma LPS levels. In addition,mice presented increased infarct volumes and higher expression levels of LPS, TLR4, and inflammatory cytokines in the ischemic brain, as well as more severe neurological impairments and reduced survival rates after MCAO. Oral administration of a non-absorbable antibiotic modulated the gut microbiota and improved metabolic endotoxemia and stroke outcomes inmice; these effects were associated with reduction of LPS levels and neuroinflammation in the ischemic brain. These data suggest that targeting metabolic endotoxemia may be a novel potential therapeutic strategy to improve stroke outcomes.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:2505-2520
Kurita N, Yamashiro K, Kuroki T, Tanaka R, ... Asahara T, Hattori N
J Cereb Blood Flow Metab: 29 Nov 2020; 40:2505-2520 | PMID: 31910709
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Abstract

Imaging mitochondrial complex I activation during a vibrotactile stimulation: A PET study using [F]BCPP-EF in the conscious monkey brain.

Fang J, Ohba H, Hashimoto F, Tsukada H, Chen F, Liu H

In order to evaluate the capability of 2--butyl-4-chloro-5-{6-[2-(2-[F]fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([F]BCPP-EF), a novel positron emission tomography (PET) probe for mitochondrial complex I (MC-I) activity, to assess neuronal activation, an activation PET study was conducted in the conscious monkey brain with a continuous unilateral vibrotactile stimulation. PET scans with [O]HO, [F]BCPP-EF, or 2-deoxy-2-[F]fluoroglucose ([F]FDG) were conducted under: (1) resting conditions; (2) a continuous vibration stimulation; (3) a continuous vibration stimulation after 15-min pre-vibration; and (4) a continuous vibration stimulation after 30-min pre-vibration. The contralateral/ipsilateral ratio (CIR) in the somatosensory cortex showed significant increases in the uptake of [O]HO, [F]BCPP-EF, and [F]FDG with the vibration stimulation. The longer pre-vibration duration induced significantly lower CIR in regional cerebral blood flow (rCBF) measured using [O]HO, whereas it did not affect the CIR in [F]BCPP-EF or the regional cerebral metabolic rate of glucose (rCMRglc) measured using [F]FDG 30-60 min after the injection. These results suggest that the [F]BCPP-EF response in the later phase of scans was not influenced by the increase in rCBF, indicating the capability of [F]BCPP-EF to detect acute changes in MC-I activity induced by neuronal activation. However, the metabolic shift from glycolysis to oxidation was not observed under the stimulation used here.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:2521-2532
Fang J, Ohba H, Hashimoto F, Tsukada H, Chen F, Liu H
J Cereb Blood Flow Metab: 29 Nov 2020; 40:2521-2532 | PMID: 31948325
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Abstract

Microglia alter the threshold of spreading depolarization and related potassium uptake in the mouse brain.

Varga DP, Menyhárt Á, Pósfai B, Császár E, ... Farkas E, Dénes Á

Selective elimination of microglia from the brain was shown to dysregulate neuronal Ca signaling and to reduce the incidence of spreading depolarization (SD) during cerebral ischemia. However, the mechanisms through which microglia interfere with SD remained unexplored. Here, we identify microglia as essential modulators of the induction and evolution of SD in the physiologically intact brain in vivo. Confocal- and super-resolution microscopy revealed that a series of SDs induced rapid morphological changes in microglia, facilitated microglial process recruitment to neurons and increased the density of P2Y12 receptors (P2Y12R) on recruited microglial processes. In line with this, depolarization and hyperpolarization during SD were microglia- and P2Y12R-dependent. An absence of microglia was associated with altered potassium uptake after SD and increased the number of c-fos-positive neurons, independently of P2Y12R. Thus, the presence of microglia is likely to be essential to maintain the electrical elicitation threshold and to support the full evolution of SD, conceivably by interfering with the extracellular potassium homeostasis of the brain through sustaining [K] re-uptake mechanisms.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:S67-S80
Varga DP, Menyhárt Á, Pósfai B, Császár E, ... Farkas E, Dénes Á
J Cereb Blood Flow Metab: 29 Nov 2020; 40:S67-S80 | PMID: 31987008
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Abstract

Mild pericyte deficiency is associated with aberrant brain microvascular flow in aged PDGFRβ mice.

Watson AN, Berthiaume AA, Faino AV, McDowell KP, ... Hartmann DA, Shih AY

The receptor tyrosine kinase PDGFRβ is essential for pericyte migration to the endothelium. In mice lacking one allele of PDGFRβ (PDGFRβ), previous reports have described an age-dependent loss of pericytes in the brain, leading to cerebrovascular dysfunction and subsequent neurodegeneration reminiscent of that seen in Alzheimer\'s disease and vascular dementia. We examined 12-20-month-old PDGFRβ mice to better understand how pericyte loss affects brain microvascular structure and perfusion in vivo. We observed a mild reduction of cortical pericyte number in PDGFRβ mice (27% fewer cell bodies) compared to controls, but no decrease in pericyte coverage of the endothelium. This mild degree of pericyte loss caused no discernable change in cortical microvascular density, length, basal diameter or reactivity to hypercapnia. Yet, it was associated with an increase in basal blood cell velocity, primarily in pre-capillary arterioles. Taken together, our results suggest that mild pericyte loss can lead to aberrant cerebral blood flow despite a lack of apparent effect on microvascular structure and reactivity.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:2387-2400
Watson AN, Berthiaume AA, Faino AV, McDowell KP, ... Hartmann DA, Shih AY
J Cereb Blood Flow Metab: 29 Nov 2020; 40:2387-2400 | PMID: 31987006
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Abstract

Transcriptomic and functional studies reveal undermined chemotactic and angiostimulatory properties of aged microglia during stroke recovery.

Jiang L, Mu H, Xu F, Xie D, ... Chen J, Hu X

Age-dependent alterations in microglia behavior have been implicated in neurodegeneration and CNS injuries. Here, we compared the transcriptional profiles of young versus aged microglia during stroke recovery. CD45CD11b microglia were FACS-isolated from the brains of young (10-week-old) and aged (18-month-old) male mice with sham operation or 14 days after distal middle cerebral artery occlusion and subjected to RNA-sequencing analysis. Functional groups enriched in young microglia are indicative of upregulation in cell movement, cell interactions, inflammatory responses and angiogenesis, while aged microglia exhibited a reduction or no change in these features. We confirmed reduced chemoattractive capacities of aged microglia toward ischemic brain tissue in organotypic slide co-cultures, and delayed accumulation of aged microglia around dead neurons injected into the striatum . In addition, aging is associated with an overall failure to increase the expression of microglial genes involved in cell-cell interactions, such as CXCL10. Finally, impaired upregulation of pro-angiogenic genes in aged microglia was associated with a decline in neovascularization in aged mice compared to young mice after distal middle cerebral artery occlusion. This study provides a new resource to understand the mechanisms underlying microglial alterations in the aged brain milieu and sheds light on new strategies to improve microglial functions in aged stroke victims.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:S81-S97
Jiang L, Mu H, Xu F, Xie D, ... Chen J, Hu X
J Cereb Blood Flow Metab: 29 Nov 2020; 40:S81-S97 | PMID: 32065074
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Abstract

CCR2 deficiency in monocytes impairs angiogenesis and functional recovery after ischemic stroke in mice.

Pedragosa J, Miró-Mur F, Otxoa-de-Amezaga A, Justicia C, ... Pasparakis M, Planas AM

Inflammatory Ly6CCCR2 monocytes infiltrate the brain after stroke but their functions are not entirely clear. We report that CCR2 monocytes and CCR2 lymphocytes infiltrate the brain after permanent ischemia. To underscore the role of CCR2 monocytes, we generated mice with selective CCR2 deletion in monocytes. One day post-ischemia, these mice showed less infiltrating monocytes and reduced expression of pro-inflammatory cytokines, markers of alternatively macrophage activation, and angiogenesis. Accordingly, Ly6C monocytes sorted from the brain of wild type mice 24 h post-ischemia expressed pro-inflammatory genes, M2 genes, and pro-angiogenic genes. Flow cytometry showed heterogeneous phenotypes within the infiltrating Ly6CCCR2 monocytes, including a subgroup of Arginase-1 cells. Mice with CCR2-deficient monocytes displayed a delayed inflammatory rebound 15 days post-ischemia that was not found in wild type mice. Furthermore, they showed reduced angiogenesis and worse behavioral performance. Administration of CCR2 bone-marrow monocytes to mice with CCR2-deficient monocytes did not improve the behavioral performance suggesting that immature bone-marrow monocytes lack pro-reparative functions. The results show that CCR2 monocytes contribute to acute post-ischemic inflammation and participate in functional recovery. The study unravels heterogeneity in the population of CCR2 monocytes infiltrating the ischemic brain and suggests that pro-reparative monocyte subsets promote functional recovery after ischemic stroke.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:S98-S116
Pedragosa J, Miró-Mur F, Otxoa-de-Amezaga A, Justicia C, ... Pasparakis M, Planas AM
J Cereb Blood Flow Metab: 29 Nov 2020; 40:S98-S116 | PMID: 32151226
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Abstract

Biomechanics and hemodynamics of stent-retrievers.

Kühn AL, Vardar Z, Kraitem A, King RM, ... Puri AS, Gounis MJ

In 2015, multiple randomized clinical trials showed an unparalleled treatment benefit of stent-retriever thrombectomy as compared to standard medical therapy for the treatment of a large artery occlusion causing acute ischemic stroke. A short time later, the HERMES collaborators presented the patient-level pooled analysis of five randomized clinical trials, establishing class 1, level of evidence A for stent-retriever thrombectomy, in combination with intravenous thrombolysis when indicated to treat ischemic stroke. In the years following, evidence continues to mount for expanded use of this therapy for a broader category of patients. The enabling technology that changed the tide to support endovascular treatment of acute ischemic stroke is the stent-retriever. This review summarizes the history of intra-arterial treatment of stroke, introduces the biomechanics of embolus extraction with stent-retrievers, describes technical aspects of the intervention, provides a description of hemodynamic implications of stent-retriever embolectomy, and proposes future directions for a more comprehensive, multi-modal endovascular approach for the treatment of acute ischemic stroke.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:2350-2365
Kühn AL, Vardar Z, Kraitem A, King RM, ... Puri AS, Gounis MJ
J Cereb Blood Flow Metab: 29 Nov 2020; 40:2350-2365 | PMID: 32428424
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Abstract

Genome-wide transcriptomic analysis of microglia reveals impaired responses in aged mice after cerebral ischemia.

Shi L, Rocha M, Zhang W, Jiang M, ... Chen J, Shi Y

Senescence-associated alterations in microglia may have profound impact on cerebral homeostasis and stroke outcomes. However, the lack of a transcriptome-wide comparison between young and aged microglia in the context of ischemia limits our understanding of aging-related mechanisms. Herein, we performed RNA sequencing analysis of microglia purified from cerebral hemispheres of young adult (10-week-old) and aged (18-month-old) mice five days after distal middle cerebral artery occlusion or after sham operation. Considerable transcriptional differences were observed between young and aged microglia in healthy brains, indicating heightened chronic inflammation in aged microglia. Following stroke, the overall transcriptional activation was more robust (>13-fold in the number of genes upregulated) in young microglia than in aged microglia. Gene clusters with functional implications in immune inflammatory responses, immune cell chemotaxis, tissue remodeling, and cell-cell interactions were markedly activated in microglia of young but not aged stroke mice. Consistent with the genomic profiling predictions, post-stroke cerebral infiltration of peripheral immune cells was markedly decreased in aged mice compared to young mice. Moreover, post-ischemic aged microglia demonstrated reduced interaction with neighboring neurons and diminished polarity toward the infarct lesion. These alterations in microglial gene response and behavior may contribute to aging-driven vulnerability and poorer recovery after ischemic stroke.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:S49-S66
Shi L, Rocha M, Zhang W, Jiang M, ... Chen J, Shi Y
J Cereb Blood Flow Metab: 29 Nov 2020; 40:S49-S66 | PMID: 32438860
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Abstract

Regulation of blood-brain barrier integrity by microglia in health and disease: A therapeutic opportunity.

Ronaldson PT, Davis TP

The blood-brain barrier (BBB) is a critical regulator of CNS homeostasis. It possesses physical and biochemical characteristics (i.e. tight junction protein complexes, transporters) that are necessary for the BBB to perform this physiological role. Microvascular endothelial cells require support from astrocytes, pericytes, microglia, neurons, and constituents of the extracellular matrix. This intricate relationship implies the existence of a neurovascular unit (NVU). NVU cellular components can be activated in disease and contribute to dynamic remodeling of the BBB. This is especially true of microglia, the resident immune cells of the brain, which polarize into distinct proinflammatory (M1) or anti-inflammatory (M2) phenotypes. Current data indicate that M1 pro-inflammatory microglia contribute to BBB dysfunction and vascular \"leak\", while M2 anti-inflammatory microglia play a protective role at the BBB. Understanding biological mechanisms involved in microglia activation provides a unique opportunity to develop novel treatment approaches for neurological diseases. In this review, we highlight characteristics of M1 proinflammatory and M2 anti-inflammatory microglia and describe how these distinct phenotypes modulate BBB physiology. Additionally, we outline the role of other NVU cell types in regulating microglial activation and highlight how microglia can be targeted for treatment of disease with a focus on ischemic stroke and Alzheimer\'s disease.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:S6-S24
Ronaldson PT, Davis TP
J Cereb Blood Flow Metab: 29 Nov 2020; 40:S6-S24 | PMID: 32928017
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Abstract

The rise of pericytes in neurovascular research.

Beard DJ, Brown LS, Sutherland BA

The popularity of pericyte research is increasing, and this was not more evident than at the recent 2019 Brain meeting in Yokohama which featured a large number of presentations focused on brain pericyte research, including the Presidential Symposium. In this article, we will provide a history of brain pericyte research, present the results of our analysis showing a substantial increase in brain pericyte research presented at Brain meetings since 2005, suggest reasons for their increased popularity, and comment on what the future holds for brain pericyte research.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:2366-2373
Beard DJ, Brown LS, Sutherland BA
J Cereb Blood Flow Metab: 29 Nov 2020; 40:2366-2373 | PMID: 32955956
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Abstract

Longitudinal monitoring of microglial/macrophage activation in ischemic rat brain using Iba-1-specific nanoparticle-enhanced magnetic resonance imaging.

Sillerud LO, Yang Y, Yang LY, Duval KB, Thompson J, Yang Y

Microglial/macrophage activation plays a dual role in response to brain injury after a stroke, promoting early neuroinflammation and benefit for neurovascular recovery. Therefore, the dynamics of stroke-induced cerebral microglial/macrophage activation are of substantial interest. This study used novel anti-Iba-1-targeted superparamagnetic iron-platinum (FePt) nanoparticles in conjunction with magnetic resonance imaging (MRI) to measure the spatiotemporal changes of the microglial/macrophage activation in living rat brain for four weeks post-stroke. Ischemic lesion areas were identified and measured using T-weighted MR images. After injection of the FePt-nanoparticles, T*-weighted MR images showed that the nanoparticles were seen solely in brain regions that coincided with areas of active microglia/macrophages detected by post-mortem immunohistochemistry. Good agreement in morphological and distributive dynamic changes was also observed between the Fe-cells and the Iba-1-microglia/macrophages. The spatiotemporal changes of nanoparticle detected by T*-weighted images paralleled the changes of microglial/macrophage activation and phenotypes measured by post-mortem immunohistochemistry over the four weeks post-stroke. Maximum microglial/macrophage activation occurred seven days post-stroke for both measures, and the diminished activation found after two weeks continued to four weeks. Our results suggest that nanoparticle-enhanced MRI may constitute a novel approach for monitoring the dynamic development of neuroinflammation in living animals during the progression and treatment of stroke.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:S117-S133
Sillerud LO, Yang Y, Yang LY, Duval KB, Thompson J, Yang Y
J Cereb Blood Flow Metab: 29 Nov 2020; 40:S117-S133 | PMID: 32960690
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Abstract

Epitranscriptomic regulation by mA RNA methylation in brain development and diseases.

Chokkalla AK, Mehta SL, Vemuganti R

Cellular RNAs are pervasively tagged with diverse chemical moieties, collectively called epitranscriptomic modifications. The methylation of adenosine at N position generates N-methyladenosine (mA), which is the most abundant and reversible epitranscriptomic modification in mammals. The mA signaling is mediated by a dedicated set of proteins comprised of writers, erasers, and readers. Contrary to the activation-repression binary view of gene regulation, emerging evidence suggests that the mA methylation controls multiple aspects of mRNA metabolism, such as splicing, export, stability, translation, and degradation, culminating in the fine-tuning of gene expression. Brain shows the highest abundance of mA methylation in the body, which is developmentally altered. Within the brain, mA methylation is biased toward neuronal transcripts and sensitive to neuronal activity. In a healthy brain, mA maintains several developmental and physiological processes such as neurogenesis, axonal growth, synaptic plasticity, circadian rhythm, cognitive function, and stress response. The mA imbalance contributes to the pathogenesis of acute and chronic CNS insults, brain cancer, and neuropsychiatric disorders. This review discussed the molecular mechanisms of mA regulation and its implication in the developmental, physiological, and pathological processes of the brain.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:2331-2349
Chokkalla AK, Mehta SL, Vemuganti R
J Cereb Blood Flow Metab: 29 Nov 2020; 40:2331-2349 | PMID: 32967524
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Abstract

Microglia/macrophage polarization: Fantasy or evidence of functional diversity?

Hu X

Microglia and non-parenchymal macrophages are increasingly recognized to play critical roles in the central nervous system (CNS) health and disease. Accumulating evidence suggests that these mononuclear phagocytes do not constitute stereotypical cell populations, but rather polarize into a variety of phenotypes at different stages of CNS development, stresses, and diseases. This commentary aims to discuss our current consensus and controversy on microglia/macrophage phenotypes. Collective single-cell level evidence validates the concept of microglia/macrophage polarization, while suggests multi-polarity instead of dichotomic polarization. Characterizing the functions of a specific microglia/macrophage phenotype is challenging yet essential to translate our scientific discoveries into clinical application.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:S134-S136
Hu X
J Cereb Blood Flow Metab: 29 Nov 2020; 40:S134-S136 | PMID: 33023387
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Abstract

Neuroinflammatory responses of microglia in central nervous system trauma.

Shields DC, Haque A, Banik NL

Although relatively few in number compared to astrocytes and neurons, microglia demonstrate multiple, varied neuroimmunological functions in the central nervous system during normal and pathological states. After injury to the brain or spinal cord, microglia express beneficial pro- and anti-inflammatory phenotypes at various stages of recovery. However, prolonged microglial activation following injury has been linked to impaired parenchymal healing and functional restoration. The nature and magnitude of microglial response to injury relates in part to peripheral immune cell invasion, extent of tissue damage, and the local microenvironment.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:S25-S33
Shields DC, Haque A, Banik NL
J Cereb Blood Flow Metab: 29 Nov 2020; 40:S25-S33 | PMID: 33086921
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Abstract

Transcriptomic characterization of microglia activation in a rat model of ischemic stroke.

Deng W, Mandeville E, Terasaki Y, Li W, ... Lo EH, Xing C

Microglia are key regulators of inflammatory response after stroke and brain injury. To better understand activation of microglia as well as their phenotypic diversity after ischemic stroke, we profiled the transcriptome of microglia after 75 min transient focal cerebral ischemia in 3-month- and 12-month-old male spontaneously hypertensive rats. Microglia were isolated from the brains by FACS sorting on days 3 and 14 after cerebral ischemia. GeneChip Rat 1.0ST microarray was used to profile the whole transcriptome of sorted microglia. We identified an evolving and complex pattern of activation from 3 to 14 days after stroke onset. M2-like patterns were extensively and persistently upregulated over time. M1-like patterns were only mildly upregulated, mostly at day 14. Younger 3-month-old brains showed a larger microglial response in both pro- and anti-inflammatory pathways, compared to older 12-month-old brains. Importantly, our data revealed that after stroke, most microglia are activated towards a wide spectrum of novel polarization states beyond the standard M1/M2 dichotomy, especially in pathways related to TLR2 and dietary fatty acid signaling. Finally, classes of transcription factors that might potentially regulate microglial activation were identified. These findings should provide a comprehensive database for dissecting microglial mechanisms and pursuing neuroinflammation targets for acute ischemic stroke.



J Cereb Blood Flow Metab: 29 Nov 2020; 40:S34-S48
Deng W, Mandeville E, Terasaki Y, Li W, ... Lo EH, Xing C
J Cereb Blood Flow Metab: 29 Nov 2020; 40:S34-S48 | PMID: 33208001
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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 O-PET. In ten healthy adult brains, PET and MRI were acquired simultaneously on a PET/MR scanner. PET was acquired using C[O], O[O], and H[O]. 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: 26 Nov 2020:271678X20973951; epub ahead of print
Cho J, Lee J, An H, Goyal MS, Su Y, Wang Y
J Cereb Blood Flow Metab: 26 Nov 2020:271678X20973951; epub ahead of print | PMID: 33243071
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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 ([C]DASB; N = 100) or the 5-HT receptor ([C]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: 25 Nov 2020:271678X20974961; epub ahead of print
Ganz M, Nørgaard M, Beliveau V, Svarer C, Knudsen GM, Greve DN
J Cereb Blood Flow Metab: 25 Nov 2020:271678X20974961; epub ahead of print | PMID: 33241770
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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 × 10 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: 21 Nov 2020:271678X20972656; epub ahead of print
Suzuki T, Sato Y, Kushida Y, Tsuji M, ... Borlongan CV, Hayakawa M
J Cereb Blood Flow Metab: 21 Nov 2020:271678X20972656; epub ahead of print | PMID: 33222596
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Abstract

Cerebrovascular and neurological perspectives on adrenoceptor and calcium channel modulating pharmacotherapies.

Gezalian MM, Mangiacotti L, Rajput P, Sparrow N, Schlick K, Lahiri S

Adrenoceptor and calcium channel modulating medications are widely used in clinical practice for acute neurological and systemic conditions. It is generally assumed that the cerebrovascular effects of these drugs mirror that of their systemic effects - and this is reflected in how these medications are currently used in clinical practice. However, recent research suggests that there are distinct cerebrovascular-specific effects of these medications that are related to the unique characteristics of the cerebrovascular anatomy including the regional heterogeneity in density and distribution of adrenoceptor subtypes and calcium channels along the cerebrovasculature. In this review, we critically evaluate existing basic science and clinical research to discuss known and putative interactions between adrenoceptor and calcium channel modulating pharmacotherapies, the neurovascular unit, and cerebrovascular anatomy. In doing so, we provide a rationale for selecting vasoactive medications based on lesion location and lay a foundation for future investigations that will define neuroprotective paradigms of adrenoceptor and calcium channel modulating therapies to improve neurological outcomes in acute neurological and systemic disorders.



J Cereb Blood Flow Metab: 18 Nov 2020:271678X20972869; epub ahead of print
Gezalian MM, Mangiacotti L, Rajput P, Sparrow N, Schlick K, Lahiri S
J Cereb Blood Flow Metab: 18 Nov 2020:271678X20972869; epub ahead of print | PMID: 33210576
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Abstract

Effect of uric acid in animal models of ischaemic stroke: A systematic review and meta-analysis.

Aliena-Valero A, Baixauli-Martín J, Castelló-Ruiz M, Torregrosa G, Hervás D, Salom JB

Addition of uric acid (UA) to thrombolytic therapy, although safe, showed limited efficacy in improving patients\' stroke outcome, despite alleged neuroprotective effects of UA in preclinical research. This systematic review assessed the effects of UA on brain structural and functional outcomes in animal models of ischaemic stroke. We searched Medline, Embase and Web of Science to identify 16 and 14 eligible rodent studies for qualitative and quantitative synthesis, respectively. Range of evidence met 10 of a possible 13 STAIR criteria. Median (Q1, Q3) quality score was 7.5 (6, 10) on the CAMARADES 15-item checklist. For each outcome, we used standardised mean difference (SMD) as effect size and random-effects modelling. Meta-analysis showed that UA significantly reduced infarct size (SMD: -1.18; 95% CI [-1.47, -0.88];  < 0.001), blood-brain barrier (BBB) impairment/oedema (SMD: -0.72; 95% CI [-0.97, -0.48];  < 0.001) and neurofunctional deficit (SMD: -0.98; 95% CI [-1.32, -0.63];  < 0.001). Overall, there was low to moderate between-study heterogeneity and sizeable publication bias. In conclusion, published rodent data suggest that UA improves outcome following ischaemic stroke by reducing infarct size, improving BBB integrity and ameliorating neurofunctional condition. Specific recommendations are given for further high-quality preclinical research required to better inform clinical research.



J Cereb Blood Flow Metab: 18 Nov 2020:271678X20967459; epub ahead of print
Aliena-Valero A, Baixauli-Martín J, Castelló-Ruiz M, Torregrosa G, Hervás D, Salom JB
J Cereb Blood Flow Metab: 18 Nov 2020:271678X20967459; epub ahead of print | PMID: 33210575
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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 Iii 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 () 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 () 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: 18 Nov 2020:271678X20973609; epub ahead of print
Lule S, Wu L, Sarro-Schwartz A, Edmiston Iii WJ, ... Degterev A, Whalen MJ
J Cereb Blood Flow Metab: 18 Nov 2020:271678X20973609; epub ahead of print | 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 K channel opener diazoxide were investigated in 3xTgAD, WT and mutant Presenilin 1(PS1) 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 N-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 PS1 mice, the rCBF response to dizoxide reduced and high molecular weight Abeta oligomers were increased indicating PS1 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 PS1 mutation.



J Cereb Blood Flow Metab: 16 Nov 2020:271678X20964233; epub ahead of print
Liu D, Ahmet I, Griess B, Tweedie D, Greig NH, Mattson MP
J Cereb Blood Flow Metab: 16 Nov 2020:271678X20964233; epub ahead of print | PMID: 33203296
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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 exploretheir 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 cm). 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 PVSunder physiological conditions, offering a valuable foundation to future studies aimed at understanding the physiology of perivascular flow.



J Cereb Blood Flow Metab: 11 Nov 2020:271678X20972856; epub ahead of print
Barisano G, Sheikh-Bahaei N, Law M, Toga AW, Sepehrband F
J Cereb Blood Flow Metab: 11 Nov 2020:271678X20972856; epub ahead of print | PMID: 33183133
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Abstract

Principles and requirements for stroke recovery science.

Sommer CJ, Schäbitz WR

The disappointing results in bench-to-bedside translation of neuroprotective strategies caused a certain shift in stroke research towards enhancing the endogenous recovery potential of the brain. One reason for this focus on recovery is the much wider time window for therapeutic interventions which is open for at least several months. Since recently two large clinical studies using d-amphetamine or fluoxetine, respectively, to enhance post-stroke neurological outcome failed again it is a good time for a critical reflection on principles and requirements for stroke recovery science. In principal, stroke recovery science deals with all events from the molecular up to the functional and behavioral level occurring after brain ischemia eventually ending up with any measurable improvement of various clinical parameters. A detailed knowledge of the spontaneously occurring post-ischemic regeneration processes is the indispensable prerequisite for any therapeutic approaches aiming to modify these responses to enhance post-stroke recovery. This review will briefly illuminate the molecular mechanisms of post-ischemic regeneration and the principle possibilities to foster post-stroke recovery. In this context, recent translational approaches are analyzed. Finally, the principal and specific requirements and pitfalls in stroke recovery research as well as potential explanations for translational failures will be discussed.



J Cereb Blood Flow Metab: 10 Nov 2020:271678X20970048; epub ahead of print
Sommer CJ, Schäbitz WR
J Cereb Blood Flow Metab: 10 Nov 2020:271678X20970048; epub ahead of print | PMID: 33175596
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Abstract

Targeting axon guidance cues for neural circuit repair after spinal cord injury.

Zou Y

At least two-thirds of spinal cord injury cases are anatomically incomplete, without complete spinal cord transection, although the initial injuries cause complete loss of sensory and motor functions. The malleability of neural circuits and networks allows varied extend of functional restoration in some individuals after successful rehabilitative training. However, in most cases, the efficiency and extent are both limited and uncertain, largely due to the many obstacles of repair. The restoration of function after anatomically incomplete injury is in part made possible by the growth of new axons or new axon branches through the spared spinal cord tissue and the new synaptic connections they make, either along the areas they grow through or in the areas they terminate. This review will discuss new progress on the understanding of the role of axon guidance molecules, particularly the Wnt family proteins, in spinal cord injury and how the knowledge and tools of axon guidance can be applied to increase the potential of recovery. These strategies, combined with others, such as neuroprotection and rehabilitation, may bring new promises. The recovery strategies for anatomically incomplete spinal cord injuries are relevant and may be applicable to traumatic brain injury and stroke.



J Cereb Blood Flow Metab: 08 Nov 2020:271678X20961852; epub ahead of print
Zou Y
J Cereb Blood Flow Metab: 08 Nov 2020:271678X20961852; epub ahead of print | PMID: 33167744
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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 . Binding specificity of ALCAM-MPIO was demonstratedunder 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 T*-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 ALCAMwith ALCAM-MPIO. Given reports of endothelial ALCAM upregulation in numerous neurological diseases, this advance in our ability to image ALCAMmay yield substantial improvements for both diagnosis and targeted therapy.



J Cereb Blood Flow Metab: 04 Nov 2020:271678X20968943; epub ahead of print
Zarghami N, Soto MS, Perez-Balderas F, Khrapitchev AA, ... Larkin JR, Sibson NR
J Cereb Blood Flow Metab: 04 Nov 2020:271678X20968943; epub ahead of print | PMID: 33153376
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