Journal: J Cereb Blood Flow Metab

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<div><h4>Cerebral blood flow and cerebrovascular resistance across the adult lifespan: A multimodality approach.</h4><i>Tomoto T, Lu M, Khan AM, Liu J, ... Tarumi T, Zhang R</i><br /><AbstractText>Cerebral blood flow (CBF) decreases across the adult lifespan; however, more studies are needed to understand the underlying mechanisms. This study measured CBF and cerebrovascular resistance (CVR) using a multimodality approach in 185 healthy adults (21-80 years). Color-coded duplex ultrasonography and phase-contrast MRI were used to measure CBF, CBF velocity, and vessel diameters of the internal carotid (ICA) and vertebral arteries (VA). MRI arterial spin labeling was used to measure brain perfusion. Transcranial Doppler was used to measure CBF velocity at the middle cerebral artery. Structural MRI was used to measure brain volume. CBF was presented as total blood flow (mL/min) and normalized CBF (nCBF, mL/100g/min). Mean arterial pressure was measured to calculate CVR. Age was associated with decreased CBF by ∼3.5 mL/min/year and nCBF by ∼0.19 mL/100g/min/year across the methods. CVR increased by ∼0.011 mmHg/mL/100g/min/year. Blood flow velocities in ICA and VA decreased with age ranging from 0.07-0.15 cm/s/year, while the vessel diameters remained similar among age groups. These findings suggest that age-related decreases in CBF can be attributed mainly to decreases in blood flow velocity in the large cerebral arteries and that increased CVR likely reflects the presence of cerebral vasoconstrictions in the small cerebral arterioles and/or capillaries.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 28 Jan 2023:271678X231153741; epub ahead of print</small></div>
Tomoto T, Lu M, Khan AM, Liu J, ... Tarumi T, Zhang R
J Cereb Blood Flow Metab: 28 Jan 2023:271678X231153741; epub ahead of print | PMID: 36708213
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<div><h4>Blood-CNS barrier dysfunction in amyotrophic lateral sclerosis: Proposed mechanisms and clinical implications.</h4><i>Steinruecke M, Lonergan RM, Selvaraj BT, Chandran S, Diaz-Castro B, Stavrou M</i><br /><AbstractText>There is strong evidence for blood-brain and blood-spinal cord barrier dysfunction at the early stages of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Since impairment of the blood-central nervous system barrier (BCNSB) occurs during the pre-symptomatic stages of ALS, the mechanisms underlying this pathology are likely also involved in the ALS disease process. In this review, we explore how drivers of ALS disease, particularly mitochondrial dysfunction, astrocyte pathology and neuroinflammation, may contribute to BCNSB impairment. Mitochondria are highly abundant in BCNSB tissue and mitochondrial dysfunction in ALS contributes to motor neuron death. Likewise, astrocytes adopt key physical, transport and metabolic functions at the barrier, many of which are impaired in ALS. Astrocytes also show raised expression of inflammatory markers in ALS and ablating ALS-causing transgenes in astrocytes slows disease progression. In addition, key drivers of neuroinflammation, including TAR DNA-binding protein 43 (TDP-43) pathology, matrix metalloproteinase activation and systemic inflammation, affect BCNSB integrity in ALS. Finally, we discuss the translational implications of BCNSB dysfunction in ALS, including the development of biomarkers for disease onset and progression, approaches aimed at restoring BCNSB integrity and <i>in vitro</i> modelling of the neurogliovascular system.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 26 Jan 2023:271678X231153281; epub ahead of print</small></div>
Steinruecke M, Lonergan RM, Selvaraj BT, Chandran S, Diaz-Castro B, Stavrou M
J Cereb Blood Flow Metab: 26 Jan 2023:271678X231153281; epub ahead of print | PMID: 36704819
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<div><h4>Point-Counterpoint: Arterial blood pressure response to exercise does relate to exercise-induced improvement in cognitive function.</h4><i>Washio T, Ogoh S</i><br /><AbstractText>Exercise is a beneficial intervention to prevent cognitive dysfunction. However, an optimal exercise prescription for preventing dementia has not been established because the physiological mechanism(s) of exercise-induced improvements in cognitive function remains unclear. Interestingly, our recent study demonstrated that individuals with a higher exercise pressor response exhibit less exercise-induced cognitive improvement, suggesting that individual differences in cardiovascular responses to exercise or its associated physiological factors, may be related to exercise-induced alterations in cognitive function. Therefore, consideration of individual cardiovascular responses is warranted to develop appropriate exercise prescriptions for a given individual to prevent cognitive dysfunction.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 26 Jan 2023:271678X231153734; epub ahead of print</small></div>
Washio T, Ogoh S
J Cereb Blood Flow Metab: 26 Jan 2023:271678X231153734; epub ahead of print | PMID: 36704820
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<div><h4>Impaired damping of cerebral blood flow velocity pulsatility is associated with the number of perivascular spaces as measured with 7T MRI.</h4><i>van den Kerkhof M, van der Thiel MM, van Oostenbrugge RJ, Postma AA, ... Backes WH, Jansen JF</i><br /><AbstractText>Arterial walls stiffen with age, cardiovascular risk factors, and various vascular diseases, which may lead to less damping of the arterial blood flow pulse, subsequent microvascular damage, and enlarged perivascular spaces (PVS). However, the exact interplay between these processes is unclear. This study aimed to investigate the relation between blood flow velocity pulsatility in the small lenticulostriate arteries and their supplying middle cerebral artery and the respective damping factor (DF), with the number of MRI-visible PVS in elderly subjects. Blood flow velocity waveforms were obtained in 45 subjects (median age [range]: 64 [48-81] years, 47% male) using 7T MRI. PVS were scored in the basal ganglia (BG) and centrum semiovale (CSO). Spearman correlation analyses were used to determine associations of the blood flow pulsatility and the DF, with PVS score, adjusted for age and sex. We found a significant association between a lower DF and a higher number of PVS in the BG (<i>r<sub>s</sub></i> = -0.352, <i>P</i> = 0.021), but not in the CSO. This finding supports the supposed pathophysiological mechanism in which excessive kinetic energy deposition leads to damage of small perforating arteries and contributes to the enlargement of PVS at the level of the BG, but possible other pathways might also be of influence.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 26 Jan 2023:271678X231153374; epub ahead of print</small></div>
van den Kerkhof M, van der Thiel MM, van Oostenbrugge RJ, Postma AA, ... Backes WH, Jansen JF
J Cereb Blood Flow Metab: 26 Jan 2023:271678X231153374; epub ahead of print | PMID: 36704826
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<div><h4>Dynamic cerebral autoregulation measured by diffuse correlation spectroscopy.</h4><i>Favilla CG, Mullen MT, Kahn F, Rasheed ID, ... Parthasarathy AB, Yodh AG</i><br /><AbstractText>Dynamic cerebral autoregulation (dCA) can be derived from spontaneous oscillations in arterial blood pressure (ABP) and cerebral blood flow (CBF). Transcranial Doppler (TCD) measures CBF-velocity and is commonly used to assess dCA. Diffuse correlation spectroscopy (DCS) is a promising optical technique for non-invasive CBF monitoring, so here we aimed to validate DCS as a tool for quantifying dCA. In 33 healthy adults and 17 acute ischemic stroke patients, resting-state hemodynamic were monitored simultaneously with high-speed (20 Hz) DCS and TCD. dCA parameters were calcaulated by a transfer function analysis using a Fourier decomposition of ABP and CBF (or CBF-velocity). Strong correlation was found between DCS and TCD measured gain (magnitude of regulation) in healthy volunteers (r = 0.73, p < 0.001) and stroke patients (r = 0.76, p = 0.003). DCS-gain retained strong test-retest reliability in both groups (ICC 0.87 and 0.82, respectively). DCS and TCD-derived phase (latency of regulation) did not significantly correlate in healthy volunteers (r = 0.12, p = 0.50) but moderately correlated in stroke patients (r = 0.65, p = 0.006). DCS-derived phase was reproducible in both groups (ICC 0.88 and 0.90, respectively). High-frequency DCS is a promising non-invasive bedside technique that can be leveraged to quantify dCA from resting-state data, but the discrepancy between TCD and DCS-derived phase requires further investigation.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 26 Jan 2023:271678X231153728; epub ahead of print</small></div>
Favilla CG, Mullen MT, Kahn F, Rasheed ID, ... Parthasarathy AB, Yodh AG
J Cereb Blood Flow Metab: 26 Jan 2023:271678X231153728; epub ahead of print | PMID: 36703572
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<div><h4>Alpha-adrenergic receptor activation after fetal hypoxia-ischaemia suppresses transient epileptiform activity and limits loss of oligodendrocytes and hippocampal neurons.</h4><i>Dhillon SK, Gunn ER, Pedersen MV, Lear CA, ... Gunn AJ, Bennet L</i><br /><AbstractText>Exposure to hypoxic-ischaemia (HI) is consistently followed by a delayed fall in cerebral perfusion. In preterm fetal sheep this is associated with impaired cerebral oxygenation, consistent with mismatch between perfusion and metabolism. In the present study we tested the hypothesis that alpha-adrenergic inhibition after HI would improve cerebral perfusion, and so attenuate mismatch and reduce neural injury. Chronically instrumented preterm (0.7 gestation) fetal sheep received sham-HI (n = 10) or HI induced by complete umbilical cord occlusion for 25 minutes. From 15 minutes to 8 hours after HI, fetuses received either an intravenous infusion of a non-selective alpha-adrenergic antagonist, phentolamine (10 mg bolus, 10 mg/h infusion, n = 10), or saline (n = 10). Fetal brains were processed for histology 72 hours post-HI. Phentolamine infusion was associated with increased epileptiform transient activity and a greater fall in cerebral oxygenation in the early post-HI recovery phase. Histologically, phentolamine was associated with greater loss of oligodendrocytes and hippocampal neurons. In summary, contrary to our hypothesis, alpha-adrenergic inhibition increased epileptiform transient activity with an exaggerated fall in cerebral oxygenation, and increased neural injury, suggesting that alpha-adrenergic receptor activation after HI is an important endogenous neuroprotective mechanism.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 26 Jan 2023:271678X231153723; epub ahead of print</small></div>
Dhillon SK, Gunn ER, Pedersen MV, Lear CA, ... Gunn AJ, Bennet L
J Cereb Blood Flow Metab: 26 Jan 2023:271678X231153723; epub ahead of print | PMID: 36703575
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<div><h4>Endothelial cell CD36 mediates stroke-induced brain injury via BBB dysfunction and monocyte infiltration in normal and obese conditions.</h4><i>Kim ID, Ju H, Minkler J, Jiang R, ... Febbraio M, Cho S</i><br /><AbstractText>CD36 expressed in multiple cell types regulates inflammation, vascular function, and innate immunity. Specifically, CD36 in microvascular endothelial cells (ECs) signals to elicit inflammation and causes EC death. This study investigated roles for EC-CD36 on acute stroke pathology in normal and obese conditions. Obesity induced by a high-fat diet (HD) selectively increased CD36 expression in ECs, not in monocytes/macrophages, in the post-ischemic brain. Mice deficient CD36 in ECs (EC<sup>CD36-/-</sup>) showed reduced injury size and vascular permeability in normal conditions. While control mice fed a HD developed obesity and aggravated stroke injury, EC<sup>CD36-/-</sup> mice were resistant to develop an obesity phenotype. Subjecting EC<sup>CD36-/-</sup> mice to stroke resulted in reduced injury size and BBB disruption. Moreover, the mice had reduced MCP-1 and CCR2 gene expression, resulting in reduced monocyte trafficking with improved survival and acute motor function. Reduced MCP-1 and CCR2 expression was still evident in EC<sup>CD36-/-</sup> mice subjected to severe stroke, suggesting that monocyte trafficking is an infarct-independent metabolic effect associated with specific EC-CD36 deletion. Our findings demonstrate the importance of EC-CD36 in developing vascular comorbidities and suggest that targeting EC-CD36 is a potential preventative strategy to normalize vascular risk factors, leading to improved acute stroke outcomes.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 26 Jan 2023:271678X231154602; epub ahead of print</small></div>
Kim ID, Ju H, Minkler J, Jiang R, ... Febbraio M, Cho S
J Cereb Blood Flow Metab: 26 Jan 2023:271678X231154602; epub ahead of print | PMID: 36703604
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<div><h4>Spreading depolarization causes reperfusion failure after cerebral ischemia.</h4><i>Törteli A, Tóth R, Berger S, Samardzic S, ... Menyhárt Á, Farkas E</i><br /><AbstractText>Despite successful recanalization, reperfusion failure associated with poor neurological outcomes develops in half of treated stroke patients. We explore here whether spreading depolarization (SD) is a predictor of reperfusion failure. Global forebrain ischemia/reperfusion was induced in male and female C57BL/6 mice (n = 57). SD and cerebral blood flow (CBF) changes were visualized with transcranial intrinsic optical signal and laser speckle contrast imaging. To block SD, MK801 was applied (n = 26). Neurological deficit, circle of Willis (CoW) anatomy and neuronal injury were evaluated 24 hours later. SD emerged after ischemia onset in one or both hemispheres under a perfusion threshold (CBF drop to 21.1 ± 4.6 vs. 33.6 ± 4.4%, SD vs. no SD). The failure of later reperfusion (44.4 ± 12.5%) was invariably linked to previous SD. In contrast, reperfusion was adequate (98.9 ± 7.4%) in hemispheres devoid of SD. Absence of the P1 segment of the posterior cerebral artery in the CoW favored SD occurrence and reperfusion failure. SD occurrence and reperfusion failure were associated with poor neurologic function, and neuronal necrosis 24 hours after ischemia. The inhibition of SD significantly improved reperfusion. SD occurrence during ischemia impairs later reperfusion, prognosticating poor neurological outcomes. The increased likelihood of SD occurrence is predicted by inadequate collaterals.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 26 Jan 2023:271678X231153745; epub ahead of print</small></div>
Törteli A, Tóth R, Berger S, Samardzic S, ... Menyhárt Á, Farkas E
J Cereb Blood Flow Metab: 26 Jan 2023:271678X231153745; epub ahead of print | PMID: 36703609
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<div><h4>Amyloid-PET of the white matter: Relationship to free water, fiber integrity, and cognition in patients with dementia and small vessel disease.</h4><i>Ottoy J, Ozzoude M, Zukotynski K, Kang MS, ... Goubran M, Medical Imaging Trials Network of Canada (MITNEC) and Alzheimer’s Disease Neuroimaging Initiative (ADNI)</i><br /><AbstractText>White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (Aβ-PET) recently gained interest for detecting WM injury. Yet, little is understood about the origin of the altered Aβ-PET signal in WM regions. Here, we investigated the relative contributions of diffusion MRI-based microstructural alterations, including free water and tissue-specific properties, to Aβ-PET in WM and to cognition. We included a unique cohort of 115 participants covering the spectrum of low-to-severe white matter hyperintensity (WMH) burden and cognitively normal to dementia. We applied a bi-tensor diffusion-MRI model that differentiates between (i) the extracellular WM compartment (represented via free water), and (ii) the fiber-specific compartment (via free water-adjusted fractional anisotropy [FA]). We observed that, in regions of WMH, a decrease in Aβ-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in Aβ-PET related more closely to higher cortical Aβ (together with lower free water-adjusted FA). In relation to cognitive impairment, we observed a closer relationship with higher free water than with either free water-adjusted FA or WM PET. Our findings support free water and Aβ-PET as markers of WM abnormalities in patients with mixed dementia, and contribute to a better understanding of processes giving rise to the WM PET signal.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 25 Jan 2023:271678X231152001; epub ahead of print</small></div>
Ottoy J, Ozzoude M, Zukotynski K, Kang MS, ... Goubran M, Medical Imaging Trials Network of Canada (MITNEC) and Alzheimer’s Disease Neuroimaging Initiative (ADNI)
J Cereb Blood Flow Metab: 25 Jan 2023:271678X231152001; epub ahead of print | PMID: 36695071
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<div><h4>Noradrenaline released from locus coeruleus axons contracts cerebral capillary pericytes via adrenergic receptors.</h4><i>Korte N, James G, You H, Hirunpattarasilp C, ... Sethi H, Attwell D</i><br /><AbstractText>Noradrenaline (NA) release from locus coeruleus axons generates vascular contractile tone in arteriolar smooth muscle and contractile capillary pericytes. This tone allows neuronal activity to evoke vasodilation that increases local cerebral blood flow (CBF). Much of the vascular resistance within the brain is located in capillaries and locus coeruleus axons have NA release sites closer to pericytes than to arterioles. In acute brain slices, NA contracted pericytes but did not raise the pericyte cytoplasmic Ca<sup>2+</sup> concentration, while the α<sub>1</sub> agonist phenylephrine did not evoke contraction. Blocking α<sub>2</sub> adrenergic receptors (α<sub>2</sub>Rs, which induce contraction by inhibiting cAMP production), greatly reduced the NA-evoked pericyte contraction, whereas stimulating α<sub>2</sub>Rs using xylazine (a sedative) or clonidine (an anti-hypertensive drug) evoked pericyte contraction. Noradrenaline-evoked pericyte contraction and capillary constriction are thus mediated via α<sub>2</sub>Rs. Consequently, α<sub>2</sub>Rs may not only modulate CBF in health and pathological conditions, but also contribute to CBF changes evoked by α<sub>2</sub>R ligands administered in research, veterinary and clinical settings.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 23 Jan 2023:271678X231152549; epub ahead of print</small></div>
Korte N, James G, You H, Hirunpattarasilp C, ... Sethi H, Attwell D
J Cereb Blood Flow Metab: 23 Jan 2023:271678X231152549; epub ahead of print | PMID: 36688515
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<div><h4>Spontaneous vasomotion propagates along pial arterioles in the awake mouse brain like stimulus-evoked vascular reactivity.</h4><i>Munting LP, Bonnar O, Kozberg MG, Auger CA, ... Bacskai BJ, van Veluw SJ</i><br /><AbstractText>Sensory stimulation evokes a local, vasodilation-mediated blood flow increase to the activated brain region, which is referred to as functional hyperemia. Spontaneous vasomotion is a change in arteriolar diameter that occurs without sensory stimulation, at low frequency (∼0.1 Hz). These vessel diameter changes are a driving force for perivascular soluble waste clearance, the failure of which has been implicated in neurodegenerative disease. Stimulus-evoked vascular reactivity is known to propagate along penetrating arterioles to pial arterioles, but it is unclear whether spontaneous vasomotion propagates similarly. We therefore imaged both stimulus-evoked and spontaneous changes in pial arteriole diameter in awake, head-fixed mice with 2-photon microscopy. By cross-correlating different regions of interest (ROIs) along the length of imaged arterioles, we assessed vasomotion propagation. We found that both during rest and during visual stimulation, one-third of the arterioles showed significant propagation (i.e., a wave), with a median (interquartile range) wave speed of 405 (323) µm/s at rest and 345 (177) µm/s during stimulation. In a second group of mice, with GCaMP expression in their vascular smooth muscle cells, we also found spontaneous propagation of calcium signaling along pial arterioles. In summary, we demonstrate that spontaneous vasomotion propagates along pial arterioles like stimulus-evoked vascular reactivity.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 19 Jan 2023:271678X231152550; epub ahead of print</small></div>
Munting LP, Bonnar O, Kozberg MG, Auger CA, ... Bacskai BJ, van Veluw SJ
J Cereb Blood Flow Metab: 19 Jan 2023:271678X231152550; epub ahead of print | PMID: 36655606
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<div><h4>Molecular mechanism of cerebral edema improvement via IL-1RA released from the stroke-unaffected hindlimb by treadmill exercise after cerebral infarction in rats.</h4><i>Gono R, Sugimoto K, Yang C, Murata Y, ... Katada R, Matsumoto H</i><br /><AbstractText>Cerebral edema following cerebral infarction can be severe and directly affect mortality and mobility. Exercise therapy after cerebral infarction is an effective therapeutic approach; however, the molecular mechanism remains unclear. Myokines such as interleukin-1 receptor antagonist (IL-1RA) are released during skeletal muscle contraction with effects on other organs. We hypothesized that myokine release during exercise might improve brain edema and confirmed the hypothesis using transient middle cerebral artery occlusion (tMCAO) model rats. Rats subjected to tMCAO were divided according to the severity of illness and further assigned to exercise and non-exercise groups. Treadmill exercises were performed at a speed of 2-8 m/min for 10 min from 1-6 days post-reperfusion after tMCAO. Exercise significantly reduced edema and neurological deficits in severely ill rats, with a reduction in aquaporin-4 (AQP4) expression in the ischemic core and increased blood IL-1RA release from the stroke-unaffected hindlimb muscle after tMCAO. Administration of IL-1RA into the lateral ventricles significantly reduced edema and AQP4 expression in the ischemic core. In conclusion, treadmill exercise performed in the early phase of stroke onset alleviated the decrease in blood IL-1RA following ischemic stroke. IL-1RA administration decreased astrocytic AQP4 expression in the ischemic core, suppressing brain edema.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 18 Jan 2023:271678X231151569; epub ahead of print</small></div>
Gono R, Sugimoto K, Yang C, Murata Y, ... Katada R, Matsumoto H
J Cereb Blood Flow Metab: 18 Jan 2023:271678X231151569; epub ahead of print | PMID: 36651110
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<div><h4>Dialysis adequacy and hemoglobin levels predict cerebral atrophy in maintenance-hemodialysis patients.</h4><i>Cao MX, Xiao J, Qin HM, Wang ZH, ... Liu SX, Li S</i><br /><AbstractText>The pathogenesis of cerebral atrophy (CA) is not clear. Previous studies show a high incidence of preterm CA in hemodialysis patients. This study aims to investigate the factors influencing CA and to derive a CA prediction nomogram in maintenance-hemodialysis patients. First, brain volumes of hemodialysis patients (≤55 years) were compared against age- and sex-matched healthy controls, and differences were revealed in bilateral insular cisterns width, maximum cerebral sulci width, Evans index, ventricular-brain ratio, frontal atrophy index, and temporal lobe ratio. Then, the patients were divided equally into \"no or mild\" or \"severe\" CA groups. Potential factors influencing CA were screened. Kt/V (urea removal index) and hemoglobin levels negatively correlated with CA degree, and were used to establish a nomogram within randomly assigned training and validation patient groups. The areas under the receiver operating characteristic curves (AUROC) for training and validation groups were 0.703 and 0.744, respectively. When potassium and calcium were added to the nomogram, the AUROC for training/validation group increased to 0.748/0.806. The nomogram had optimal AUROC for training (0.759) and validation (0.804) groups when albumin was also included. Hemodialysis patients showed reduced anterior brain volumes and the nomogram established herein may have predictive value for developing CA.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 18 Jan 2023:271678X231151621; epub ahead of print</small></div>
Cao MX, Xiao J, Qin HM, Wang ZH, ... Liu SX, Li S
J Cereb Blood Flow Metab: 18 Jan 2023:271678X231151621; epub ahead of print | PMID: 36651130
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<div><h4>Small-animal PET study for noninvasive quantification of transmembrane AMPA receptor regulatory protein -8 (TARP -8) in the brain.</h4><i>Yamasaki T, Ishii H, Hiraishi A, Kumata K, ... Liang S, Zhang MR</i><br /><AbstractText>Transmembrane AMPA receptor regulatory protein γ-8 (TARP γ-8) mediates various AMPA receptor functions. Recently, [<sup>11</sup>C]TARP-2105 was developed as a PET ligand for TARP γ-8 imaging. We performed a full kinetic analysis of [<sup>11</sup>C]TARP-2105 using PET with [<sup>11</sup>C]TARP-2105 for the first time. The distribution volume (<i>V</i><sub>T</sub>), which is a macro parameter consisting of the <i>K</i><sub>1</sub>-<i>k</i><sub>4</sub> rate constants in the two-tissue compartment model analysis, exhibited the following rank order: hippocampus (1.4 ± 0.3) > amygdala (1.0 ± 0.2) > frontal cortex (0.9 ± 0.2) > striatum (0.8 ± 0.2) ≫ cerebellum (0.5 ± 0.1) ≈ thalamus (0.5 ± 0.1) > pons (0.4 ± 0.1 mL/cm<sup>3</sup>). These heterogenous <i>V</i><sub>T</sub> values corresponded with the order of biological distribution of TARP γ-8 in the brain. To validate the reference tissue model, the binding potential (BP<sub>ND</sub>) of [<sup>11</sup>C]TARP-2105 for TARP γ-8 was estimated using general methods (SRTM, MRTM0, Logan reference model, and ratio method). These BP<sub>ND</sub>s based on reference models indicated excellent correlation (R<sup>2</sup> > 0.9) to the indirect BP<sub>ND</sub>s based on 2TCM with moderate reproducibility (%variability ≈ 10). PET with [<sup>11</sup>C]TARP-2105 enabled noninvasive BP<sub>ND</sub> estimation and visual mapping of TARP γ-8 in the living rat brain.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 18 Jan 2023:271678X231152025; epub ahead of print</small></div>
Yamasaki T, Ishii H, Hiraishi A, Kumata K, ... Liang S, Zhang MR
J Cereb Blood Flow Metab: 18 Jan 2023:271678X231152025; epub ahead of print | PMID: 36655318
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<div><h4>Xanthine oxidase mediates chronic stress-induced cerebrovascular dysfunction and cognitive impairment.</h4><i>Burrage EN, Coblentz T, Prabhu SS, Childers R, ... Kelley EE, Chantler PD</i><br /><AbstractText>Xanthine oxidase (XO) mediates vascular function. Chronic stress impairs cerebrovascular function and increases the risk of stroke and cognitive decline. Our study determined the role of XO on stress-induced cerebrovascular dysfunction and cognitive decline. We measured middle cerebral artery (MCA) function, free radical formation, and working memory in 6-month-old C57BL/6 mice who underwent 8 weeks of control conditions or unpredictable chronic mild stress (UCMS) with or without febuxostat (50 mg/L), a XO inhibitor. UCMS mice had an impaired MCA dilation to acetylcholine vs. controls (p < 0.0001), and increased total free radical formation, XOR protein levels, and hydrogen peroxide production in the liver compared to controls. UCMS increased hydrogen peroxide production in the brain and cerebrovasculature compared to controls. Working memory, using the y-maze test, was impaired (p < 0.05) in UCMS mice compared to control mice. However, blocking XO using febuxostat prevented the UCMS-induced impaired MCA response, while free radical production and hydrogen peroxide levels were similar to controls in the liver and brain of UCMS mice treated with febuxostat. Further, UCMS + Feb mice did not have a significant reduction in working memory. These data suggest that the cerebrovascular dysfunction associated with chronic stress may be driven by XO, which leads to a reduction in working memory.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 18 Jan 2023:271678X231152551; epub ahead of print</small></div>
Burrage EN, Coblentz T, Prabhu SS, Childers R, ... Kelley EE, Chantler PD
J Cereb Blood Flow Metab: 18 Jan 2023:271678X231152551; epub ahead of print | PMID: 36655326
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<div><h4>Neural cortical organoids from self-assembling human iPSC as a model to investigate neurotoxicity in brain ischemia.</h4><i>De Paola M, Pischiutta F, Comolli D, Mariani A, ... Forloni G, Zanier ER</i><br /><AbstractText>Brain ischemia is a common acute injury resulting from impaired blood flow to the brain. Translation of effective drug candidates from experimental models to patients has systematically failed. The use of human induced pluripotent stem cells (iPSC) offers new opportunities to gain translational insights into diseases including brain ischemia. We used a human 3D self-assembling iPSC-derived model (human cortical organoids, hCO) to characterize the effects of ischemia caused by oxygen-glucose deprivation (OGD). hCO exposed to 2 h or 8 h of OGD had neuronal death and impaired neuronal network complexity, measured in whole-mounting microtubule-associated protein 2 (MAP-2) immunostaining. Neuronal vulnerability was reflected by a reduction in <i>MAP-2</i> mRNA levels, and increased release of neurofilament light chain (NfL) in culture media, proportional to OGD severity. Glial fibrillary acidic protein (GFAP) gene or protein levels did not change in hCO, but their release in medium increased after prolonged OGD. In conclusion, this human 3D iPSC-based <i>in vitro</i> model of brain ischemic injury is characterized by marked neuronal injury reflected by the release of the translational biomarker NfL which is relevant for testing neuroprotective strategies.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 18 Jan 2023:271678X231152023; epub ahead of print</small></div>
De Paola M, Pischiutta F, Comolli D, Mariani A, ... Forloni G, Zanier ER
J Cereb Blood Flow Metab: 18 Jan 2023:271678X231152023; epub ahead of print | PMID: 36655331
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<div><h4>Targeted capillary photothrombosis via multiphoton excitation of Rose Bengal.</h4><i>Delafontaine-Martel P, Zhang C, Lu X, Damseh R, Lesage F, Marchand PJ</i><br /><AbstractText>Microvascular stalling, the process occurring when a capillary temporarily loses perfusion, has gained increasing interest in recent years through its demonstrated presence in various neuropathologies. Studying the impact of such stalls on the surrounding brain tissue is of paramount importance to understand their role in such diseases. Despite efforts trying to study the stalling events, investigations are hampered by their elusiveness and scarcity. In an attempt to alleviate these hurdles, we present here a novel methodology enabling transient occlusions of targeted microvascular segments through multiphoton excitation of Rose Bengal, an established photothrombotic agent. With n = 7 mice C57BL/6 J (5 males and 2 females) and 95 photothrombosis trials, we demonstrate the ability of triggering reversible blockages by illuminating a capillary segment during ∼300 s at 1000 nm, using a standard Ti:Sapphire femtosecond laser. Furthermore, we performed concurrent Optical Coherence Microscopy (OCM) angiography imaging of the microvascular network to highlight the specificity of the targeted occlusion and its duration. Through comparison with a control group, we conclude that blood flow cessation is indeed created by the photothrombotic agent via multiphoton excitation and is temporary, followed by a flow recovery in less than 24 h. Moreover, Immunohistology points toward a stalling mechanism driven by adherence of the neutrophil in the vascular lumen. This observation seems to be promoted by the inflammation locally created via multiphoton activation of Rose Bengal.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 17 Jan 2023:271678X231151560; epub ahead of print</small></div>
Delafontaine-Martel P, Zhang C, Lu X, Damseh R, Lesage F, Marchand PJ
J Cereb Blood Flow Metab: 17 Jan 2023:271678X231151560; epub ahead of print | PMID: 36647768
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Abstract
<div><h4>Immunomodulatory role of glycoRNAs in the brain.</h4><i>Chokkalla AK, Jeong S, Subramanian S, Vemuganti R</i><br /><AbstractText>Glycosylation of lipids and proteins significantly increases the molecular diversity in the brain. Membrane-localized glycoconjugates facilitate critical neuro-immune interactions. Therefore, glycodysregulation is increasingly recognized as a novel hallmark of various acute and chronic neurological diseases. Although RNAs are heavily modified, they are never thought to be substrates for glycosylation due to their inaccessibility to the glycosylation machinery in the Golgi apparatus. The astonishing discovery of cell surface glycoRNAs opened new avenues for glycomedicine. This review highlighted the key features of GlycoRNAs and further discussed their potential immunomodulatory role in the brain, particularly focusing on post-stroke neuroinflammation.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 16 Jan 2023:271678X231151995; epub ahead of print</small></div>
Chokkalla AK, Jeong S, Subramanian S, Vemuganti R
J Cereb Blood Flow Metab: 16 Jan 2023:271678X231151995; epub ahead of print | PMID: 36644904
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Abstract
<div><h4>An enriched environment improves long-term functional outcomes in mice after intracerebral hemorrhage by mechanisms that involve the Nrf2/BDNF/glutaminase pathway.</h4><i>Jia P, Wang J, Ren X, He J, ... Chen X, Wang J</i><br /><AbstractText>Post-stroke depression exacerbates neurologic deficits and quality of life. Depression after ischemic stroke is known to some extent. However, depression after intracerebral hemorrhage (ICH) is relatively unknown. Increasing evidence shows that exposure to an enriched environment (EE) after cerebral ischemia/reperfusion injury has neuroprotective effects in animal models, but its impact after ICH is unknown. In this study, we investigated the effect of EE on long-term functional outcomes in mice subjected to collagenase-induced striatal ICH. Mice were subjected to ICH with the standard environment (SE) or ICH with EE for 6 h/day (8:00 am-2:00 pm). Depressive, anxiety-like behaviors and cognitive tests were evaluated on day 28 with the sucrose preference test, tail suspension test, forced swim test, light-dark transition experiment, morris water maze, and novel object recognition test. Exposure to EE improved neurologic function, attenuated depressive and anxiety-like behaviors, and promoted spatial learning and memory. These changes were associated with increased expression of transcription factor Nrf2 and brain-derived neurotrophic factor (BDNF) and inhibited glutaminase activity in the perihematomal tissue. However, EE did not change the above behavioral outcomes in Nrf2<sup>-/-</sup> mice on day 28. Furthermore, exposure to EE did not increase BDNF expression compared to exposure to SE in Nrf2<sup>-/-</sup> mice on day 28 after ICH. These findings indicate that EE improves long-term outcomes in sensorimotor, emotional, and cognitive behavior after ICH and that the underlying mechanism involves the Nrf2/BDNF/glutaminase pathway.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 12 Jan 2023:271678X221135419; epub ahead of print</small></div>
Jia P, Wang J, Ren X, He J, ... Chen X, Wang J
J Cereb Blood Flow Metab: 12 Jan 2023:271678X221135419; epub ahead of print | PMID: 36635875
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<div><h4> imaging of cerebral glucose metabolism informs on subacute to chronic post-stroke tissue status - A pilot study combining PET and deuterium metabolic imaging.</h4><i>Meerwaldt AE, Straathof M, Oosterveld W, van Heijningen CL, ... Mulder WJ, Dijkhuizen RM</i><br /><AbstractText>Recanalization therapy after acute ischemic stroke enables restoration of cerebral perfusion. However, a significant subset of patients has poor outcome, which may be caused by disruption of cerebral energy metabolism. To assess changes in glucose metabolism subacutely and chronically after recanalization, we applied two complementary imaging techniques, fluorodeoxyglucose (FDG) positron emission tomography (PET) and deuterium (<sup>2</sup>H) metabolic imaging (DMI), after 60-minute transient middle cerebral artery occlusion (tMCAO) in C57BL/6 mice. Glucose uptake, measured with FDG PET, was reduced at 48 hours after tMCAO and returned to baseline value after 11 days. DMI revealed effective glucose supply as well as elevated lactate production and reduced glutamate/glutamine synthesis in the lesion area at 48 hours post-tMCAO, of which the extent was dependent on stroke severity. A further decrease in oxidative metabolism was evident after 11 days. Immunohistochemistry revealed significant glial activation in and around the lesion, which may play a role in the observed metabolic profiles. Our findings indicate that imaging (altered) active glucose metabolism in and around reperfused stroke lesions can provide substantial information on (secondary) pathophysiological changes in post-ischemic brain tissue.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 06 Jan 2023:271678X221148970; epub ahead of print</small></div>
Meerwaldt AE, Straathof M, Oosterveld W, van Heijningen CL, ... Mulder WJ, Dijkhuizen RM
J Cereb Blood Flow Metab: 06 Jan 2023:271678X221148970; epub ahead of print | PMID: 36606595
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<div><h4>Depression, stress, and regional cerebral blood flow.</h4><i>Chiappelli J, Adhikari BM, Kvarta MD, Bruce HA, ... Wang DJ, Hong LE</i><br /><AbstractText>Decreased cerebral blood flow (CBF) may be an important mechanism associated with depression. In this study we aimed to determine if the association of CBF and depression is dependent on current level of depression or the tendency to experience depression over time (trait depression), and if CBF is influenced by depression-related factors such as stressful life experiences and antidepressant medication use. CBF was measured in 254 participants from the Amish Connectome Project (age 18-76, 99 men and 154 women) using arterial spin labeling. All participants underwent assessment of symptoms of depression measured with the Beck Depression Inventory and Maryland Trait and State Depression scales. Individuals diagnosed with a unipolar depressive disorder had significantly lower average gray matter CBF compared to individuals with no history of depression or to individuals with a history of depression that was in remission at time of study. Trait depression was significantly associated with lower CBF, with the associations strongest in cingulate gyrus and frontal white matter. Use of antidepressant medication and more stressful life experiences were also associated with significantly lower CBF. Resting CBF in specific brain regions is associated with trait depression, experience of stressful life events, and current antidepressant use, and may provide a valuable biomarker for further studies.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 06 Jan 2023:271678X221148979; epub ahead of print</small></div>
Chiappelli J, Adhikari BM, Kvarta MD, Bruce HA, ... Wang DJ, Hong LE
J Cereb Blood Flow Metab: 06 Jan 2023:271678X221148979; epub ahead of print | PMID: 36606600
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<div><h4>The central role of peripheral inflammation in ischemic stroke.</h4><i>Monsour M, Borlongan CV</i><br /><AbstractText>Stroke pathology and its treatments conventionally focus on the brain. Probing inflammation, a critical secondary cell death mechanism in stroke, has been largely relegated to the brain. To this end, peripheral inflammation has emerged as an equally potent contributor to the onset and progression of stroke secondary cell death. Here, we review novel concepts on peripheral organs displaying robust inflammatory response to stroke. These inflammation-plagued organs include the spleen, cervical lymph nodes, thymus, bone marrow, gastrointestinal system, and adrenal glands, likely converging their inflammatory effects through B and T-cells. Recognizing the significant impact of this systemic inflammation, we also discuss innovative stroke therapeutics directed at sequestration of peripheral inflammation. This review paper challenges the paradigm of a brain-centered disease pathology and treatment and offers a peripheral approach to our stroke understanding.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 05 Jan 2023:271678X221149509; epub ahead of print</small></div>
Monsour M, Borlongan CV
J Cereb Blood Flow Metab: 05 Jan 2023:271678X221149509; epub ahead of print | PMID: 36601776
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<div><h4>Counterpoint: Arterial blood pressure response to exercise does not relate to exercise-induced improvement in cognitive function.</h4><i>Lefferts WK, Smart N</i><br /><AbstractText>Acute exercise has been shown to transiently improve specific aspects of cognitive function, however the mechanism governing these effects remain unclear. Blood pressure responses during exercise have been hypothesized to be a primary contributing factor, in part through its influence on cerebral blood flow. In this counterpoint, we highlight the inconsistent and weak associations between changes in blood pressure, cerebral blood flow and cognitive responses during and following acute exercise. Despite sound theoretical foundation, cognitive responses to exercise do not appear strongly related to blood pressure and more likely stem from a complex integration of multiple mechanisms.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 03 Jan 2023:271678X221149654; epub ahead of print</small></div>
Lefferts WK, Smart N
J Cereb Blood Flow Metab: 03 Jan 2023:271678X221149654; epub ahead of print | PMID: 36597573
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Abstract
<div><h4>Twenty-four hour blood pressure variability and the prevalence and the progression of cerebral white matter hyperintensities.</h4><i>Starmans NL, Wolters FJ, Leeuwis AE, Bron EE, ... Kappelle LJ, Heart-Brain Connection Consortium</i><br /><AbstractText>Blood pressure variability (BPV) is related to cerebral white matter hyperintensities (WMH), but longitudinal studies assessing WMH progression are scarce. Patients with cardiovascular disease and control participants of the Heart-Brain Connection Study underwent 24-hour ambulatory blood pressure monitoring and repeated brain MRI at baseline and after 2 years. Using linear regression, we determined whether different measures of BPV (standard deviation, coefficient of variation, average real variability (ARV), variability independent of the mean) and nocturnal dipping were associated with WMH and whether this association was mediated or moderated by baseline cerebral perfusion. Among 177 participants (mean age: 65.9 ± 8.1 years, 33.9% female), the absence of diastolic nocturnal dipping was associated with higher WMH volume at baseline (β = 0.208, 95%CI: 0.025-0.392), but not with WMH progression among 91 participants with follow-up imaging. None of the BPV measures were associated with baseline WMH. Only 24-hour diastolic ARV was significantly associated with WMH progression (β = 0.144, 95%CI: 0.030-0.258), most profound in participants with low cerebral perfusion at baseline (p-interaction = 0.042). In conclusion, absent diastolic nocturnal dipping and 24-hour diastolic ARV were associated with higher WMH volume. Whilst requiring replication, these findings suggest that blood pressure patterns and variability may be a target for prevention of small vessel disease.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 03 Jan 2023:271678X221149937; epub ahead of print</small></div>
Starmans NL, Wolters FJ, Leeuwis AE, Bron EE, ... Kappelle LJ, Heart-Brain Connection Consortium
J Cereb Blood Flow Metab: 03 Jan 2023:271678X221149937; epub ahead of print | PMID: 36597406
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<div><h4>Altered hemodynamics and vascular reactivity in a mouse model with severe pericyte deficiency.</h4><i>Stobart JL, Erlebach E, Glück C, Huang SF, ... Keller A, Weber B</i><br /><AbstractText>Pericytes are the mural cells of the microvascular network that are in close contact with underlying endothelial cells. Endothelial-secreted PDGFB leads to recruitment of pericytes to the vessel wall, but this is disrupted in <i>Pdgfb<sup>ret/ret</sup></i> mice when the PDGFB retention motif is deleted. This results in severely reduced pericyte coverage on blood vessels. In this study, we investigated vascular abnormalities and hemodynamics in <i>Pdgfb</i><sup>ret/ret</sup> mice throughout the cerebrovascular network and in different cortical layers by <i>in vivo</i> two-photon microscopy. We confirmed that <i>Pdgfb</i><sup>ret/ret</sup> mice are severely deficient in pericytes throughout the vascular network, with enlarged brain blood vessels and a reduced number of vessel branches. Red blood cell velocity, linear density, and tube hematocrit were reduced in <i>Pdgfb</i><sup>ret/ret</sup> mice, which may impair oxygen delivery to the tissue. We also measured intravascular PO<sub>2</sub> and found that concentrations were higher in cortical Layer 2/3 in <i>Pdgfb</i><sup>ret/ret</sup> mice, indicative of reduced blood oxygen extraction. Finally, we found that <i>Pdgfb</i><sup>ret/ret</sup> mice had a reduced capacity for vasodilation in response to an acetazolamide challenge during functional MRI imaging. Taken together, these results suggest that severe pericyte deficiency can lead to vascular abnormalities and altered cerebral blood flow, reminiscent of pathologies such as arteriovenous malformations.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 22 Dec 2022:271678X221147366; epub ahead of print</small></div>
Stobart JL, Erlebach E, Glück C, Huang SF, ... Keller A, Weber B
J Cereb Blood Flow Metab: 22 Dec 2022:271678X221147366; epub ahead of print | PMID: 36545806
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Abstract
<div><h4>Germinal matrix hemorrhage induces immune responses, brain injury, and motor impairment in neonatal rats.</h4><i>Zhang X, Yuan J, Zhang S, Li W, ... Wang X, Zhu C</i><br /><AbstractText>Germinal matrix hemorrhage (GMH) is a major complication of prematurity that causes secondary brain injury and is associated with long-term neurological disabilities. This study used a postnatal day 5 rat model of GMH to explore immune response, brain injury, and neurobehavioral changes after hemorrhagic injury. The results showed that CD45<sup>high</sup>/CD11b<sup>+</sup> immune cells increased in the brain after GMH and were accompanied by increased macrophage-related chemokine/cytokines and inflammatory mediators. Hematoma formed as early as 2 h after injection of collagenase VII and white matter injury appeared not only in the external capsule and hippocampus, but also in the thalamus. In addition, GMH caused abnormal motor function as revealed by gait analysis, and locomotor hyperactivity in the elevated plus maze, though no other obvious anxiety or recognition/memory function changes were noted when examined by the open field test and novel object recognition test. The animal model used here partially reproduces the GMH-induced brain injury and motor dysfunction seen in human neonates and therefore can be used as a valid tool in experimental studies for the development of effective therapeutic strategies for GMH-induced brain injury.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 22 Dec 2022:271678X221147091; epub ahead of print</small></div>
Zhang X, Yuan J, Zhang S, Li W, ... Wang X, Zhu C
J Cereb Blood Flow Metab: 22 Dec 2022:271678X221147091; epub ahead of print | PMID: 36545808
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<div><h4>Role of post-ischemic phase-dependent modulation of anti-inflammatory M2-type macrophages against rat brain damage.</h4><i>Kurashiki Y, Kagusa H, Yagi K, Kinouchi T, ... Uto Y, Takagi Y</i><br /><AbstractText>Cerebral ischemia triggers inflammatory changes, and early complications and unfavorable outcomes of endovascular thrombectomy for brain occlusion promote the recruitment of various cell types to the ischemic area. Although anti-inflammatory M2-type macrophages are thought to exert protective effects against cerebral ischemia, little has been clarified regarding the significance of post-ischemic phase-dependent modulation of M2-type macrophages. To test our hypothesis that post-ischemic phase-dependent modulation of macrophages represents a potential therapy against ischemic brain damage, the effects on rats of an M2-type macrophage-specific activator, Gc-protein macrophage-activating factor (GcMAF), were compared with vehicle-treated control rats in the acute (day 0-6) or subacute (day 7-13) phase after ischemia induction. Acute-phase GcMAF treatment augmented both anti-inflammatory CD163<sup>+</sup> M2-type- and pro-inflammatory CD16<sup>+</sup> M1-type macrophages, resulting in no beneficial effects. Conversely, subacute-phase GcMAF injection increased only CD163<sup>+</sup> M2-type macrophages accompanied by elevated mRNA levels of arginase-1 and interleukin-4. M2-type macrophages co-localized with CD36<sup>+</sup> phagocytic cells led to clearance of the infarct area, which were abrogated by clodronate-liposomes. Expression of survival-related molecules on day 28 at the infarct border was augmented by GcMAF. These data provide new and important insights into the significance of M2-type macrophage-specific activation as post-ischemic phase-dependent therapy.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 22 Dec 2022:271678X221147090; epub ahead of print</small></div>
Kurashiki Y, Kagusa H, Yagi K, Kinouchi T, ... Uto Y, Takagi Y
J Cereb Blood Flow Metab: 22 Dec 2022:271678X221147090; epub ahead of print | PMID: 36545833
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<div><h4>Cerebral blood flow regulates iron overload in the cerebral nuclei of hemodialysis patients with anemia.</h4><i>Wang H, Chai C, Wu G, Li J, ... Shen W, Xia S</i><br /><AbstractText>Hemodialysis patients exhibit anemia-related cerebral hyperperfusion and iron deposition (ID). However, the mechanisms underlying the pathology of cerebral ID are not clear. We investigated the role of cerebral blood flow (CBF) in the pathophysiology of cerebral ID in hemodialysis patients with anemia. This study recruited 33 hemodialysis patients with anemia and thirty-three healthy controls (HCs). All the subjects underwent quantitative susceptibility mapping (QSM) and arterial spin labeling (ASL) to measure ID and CBF in the cerebral nuclei. Furthermore, we evaluated lacunar infarction (LI), cerebral microbleeds, and total white matter hyperintensity volume (TWMHV). Hemodialysis patients with anemia showed significantly higher ID and CBF in some nuclei compared to the HCs after adjusting for age, sex, and total intracranial volume (TIV) [<i>P</i> < 0.05, false discovery rate (FDR) corrected]. CBF showed a positive correlation with ID in both patients and HCs after adjustments for age, gender, and TIV (<i>P < </i>0.05, FDR corrected). Serum phosphorus, calcium, TWMHV, hypertension, and dialysis duration were independently associated with ID (<i>P < </i>0.05). Hemoglobin, serum phosphorus, and LI were independently associated with CBF (<i>P < </i>0.05). Mediation analysis demonstrated that CBF mediated the effects between hemoglobin and ID. Our study demonstrated that CBF mediated aberrant cerebral ID in hemodialysis patients with anemia.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 22 Dec 2022:271678X221147363; epub ahead of print</small></div>
Wang H, Chai C, Wu G, Li J, ... Shen W, Xia S
J Cereb Blood Flow Metab: 22 Dec 2022:271678X221147363; epub ahead of print | PMID: 36545834
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<div><h4>Chronic cerebral hypoperfusion alters the CypA-EMMPRIN-gelatinase pathway: Implications for vascular dementia.</h4><i>Chai YL, Rajeev V, Poh L, Selvaraji S, ... Arumugam TV, Lai MK</i><br /><AbstractText>Chronic cerebral hypoperfusion (CCH) is postulated to underlie multiple pathophysiological processes in vascular dementia (VaD), including extracellular matrix dysfunction. While several extracellular matrix proteins, namely cyclophilin A (CypA), extracellular matrix metalloproteinase inducer (EMMPRIN) and gelatinases (matrix metalloproteinases, MMP-2 and -9) have been investigated in acute stroke, their involvement in CCH and VaD remains unclear. In this study, CypA-EMMPRIN-gelatinase proteins were analysed in a clinical cohort of 36 aged, cognitively unimpaired subjects and 48 VaD patients, as well as in a bilateral carotid artery stenosis mouse model of CCH. Lower CypA and higher EMMPRIN levels were found in both VaD serum and CCH mouse brain. Furthermore, gelatinases were differentially altered in CCH mice and VaD patients, with significant MMP-2 increase in CCH brain and serum, whilst serum MMP-9 was elevated in VaD but reduced in CCH, suggesting complex CypA-EMMPRIN-gelatinase regulatory mechanisms. Interestingly, subjects with cortical infarcts had higher serum MMP-2, while white matter hyperintensities, cortical infarcts and lacunes were associated with higher serum MMP-9. Taken together, our data indicate that perturbations of CypA-EMMPRIN signalling may be associated with gelatinase-mediated vascular sequelae, highlighting the potential utility of the CypA-EMMPRIN-gelatinase pathway as clinical biomarkers and therapeutic targets in VaD.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 19 Dec 2022:271678X221146401; epub ahead of print</small></div>
Chai YL, Rajeev V, Poh L, Selvaraji S, ... Arumugam TV, Lai MK
J Cereb Blood Flow Metab: 19 Dec 2022:271678X221146401; epub ahead of print | PMID: 36537035
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<div><h4>Activin A alleviates neuronal injury through inhibiting cGAS-STING-mediated autophagy in mice with ischemic stroke.</h4><i>Liu M, Li Y, Han S, Wang H, Li J</i><br /><AbstractText>Activin A plays an essential role in ischemic stroke as a well-known neuroprotective factor. We previously reported that Activin A could promote white matter remyelination. However, the exact molecular mechanism of Activin A in neuronal protection post-stroke is still unclear. In this study, the middle cerebral artery occlusion/reperfusion (MCAO/R)-induced ischemic stroke mouse model and oxygen-glucose deprivation/reoxygenation (OGD/R)-treated primary neurons were used to explore the molecular mechanism of Activin A-mediated neuroprotection against ischemic injuries. We found that Activin A significantly inhibits cGAS-STING-mediated excessive autophagy through the PI3K-PKB pathway, but not mTOR-dependent autophagy. Consequently, Activin A protected neurons against OGD/R-induced ischemic injury and improved cell survival in a dose-dependent manner. In addition, Activin A improved neurological functions and reduced infarct size of mice with MCAO/R-induced ischemic stroke by inhibiting autophagy. Furthermore, Activin A depended on ACVR1C receptor to exert neuroprotective effects in 1 h MCAO/R treated mice. Our findings showed that Activin A alleviated neuronal ischemic injury through inhibiting cGAS-STING-mediated excessive autophagy in mice with ischemic stroke, which may suggest a potential therapeutic target for ischemic stroke.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 19 Dec 2022:271678X221147056; epub ahead of print</small></div>
Liu M, Li Y, Han S, Wang H, Li J
J Cereb Blood Flow Metab: 19 Dec 2022:271678X221147056; epub ahead of print | PMID: 36537048
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<div><h4>A systematic observation of vasodynamics from different segments along the cerebral vasculature in the penumbra zone of awake mice following cerebral ischemia and recanalization.</h4><i>Qiu B, Zhao Z, Wang N, Feng Z, ... Ge WP, Wang Y</i><br /><AbstractText>Different segments of the cerebral vascular network may react distinctly to brain ischemia and recanalization. However, there are limited systematic observations of these vascular responses in mice under a physiological state following ischemic stroke. Herein, we aimed to investigate the vasodynamics among several segments along the cerebral vessels in awake mice following cerebral ischemia/recanalization via two-photon imaging. Plasma in the blood vessels were labelled with fluorescein isothiocyanate dextran. Smooth muscle cells and pericytes were labelled via a genetic mouse line (PDGFRβ-tdTomato). We observed a no-reflow phenomenon in downstream microcirculation, and the vasodynamics of different segments of larger cerebral vessels varied in the penumbra area following cerebral ischemia-reperfusion. Despite obtaining reperfusion from the middle cerebral artery, there were significant constrictions of the downstream blood vessels in the ischemic penumbra zone. Interestingly, we observed an extensive constriction of the capillaries 3 hours following recanalization, both at the site covered by pericyte soma and by the pericyte process alone. In addition, we did not observe a significant positive correlation between the changed capillary diameter and pericyte coverage along the capillary. Taken together, abnormal constrictions and vasodynamics of cerebral large and small vessels may directly contribute to microcirculation failure following recanalization in ischemic stroke.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 16 Dec 2022:271678X221146128; epub ahead of print</small></div>
Qiu B, Zhao Z, Wang N, Feng Z, ... Ge WP, Wang Y
J Cereb Blood Flow Metab: 16 Dec 2022:271678X221146128; epub ahead of print | PMID: 36524693
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<div><h4>Blood-brain barrier disruption measured by albumin index correlates with inflammatory fluid biomarkers.</h4><i>Hillmer L, Erhardt EB, Caprihan A, Adair JC, ... Hobson S, Rosenberg GA</i><br /><AbstractText>Blood-brain barrier (BBB) permeability can be measured by the ratio of albumin in cerebrospinal fluid (CSF) and blood and by dynamic contrast-enhanced MRI (DCEMRI). Albumin is a large molecule measured in CSF and blood to form the albumin index (Q<sub>alb</sub>), which is a global measure of BBB permeability, while the smaller Gadolinium molecule measures regional transfer (K<sub>trans</sub>); few studies have directly compared them in the same patients. We used both methods as part of a study of mechanisms of white matter injury in patients with different forms of dementia. In addition, we also measured biomarkers for inflammation, including proteases, angiogenic growth factors, and cytokines, and correlated them with the BBB results. We found that there was no correlation between Q<sub>alb</sub> and K<sub>trans</sub>. The Q<sub>alb</sub> was associated with the matrix metalloproteinases (MMP-2, MMP-3, and MMP-10), the angiogenic factors (VEGF-C and PlGF), and the cytokines (IL-6, IL-8 and TNF-α). On the other hand, K<sub>trans</sub> was associated with the diffusion measures, mean free water and PSMD, which indicate white matter injury. Our results show that the Q<sub>alb</sub> and K<sub>trans</sub> measure different aspects of BBB permeability, with albumin being a measure of inflammatory BBB opening and K<sub>trans</sub> indicating white matter injury.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 15 Dec 2022:271678X221146127; epub ahead of print</small></div>
Hillmer L, Erhardt EB, Caprihan A, Adair JC, ... Hobson S, Rosenberg GA
J Cereb Blood Flow Metab: 15 Dec 2022:271678X221146127; epub ahead of print | PMID: 36522849
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<div><h4>Red blood cells as glucose carriers to the human brain: Modulation of cerebral activity by erythrocyte exchange transfusion in Glut1 deficiency (G1D).</h4><i>Wang RC, Lee EE, De Simone N, Kathote G, ... Holland AA, Pascual JM</i><br /><AbstractText>Red blood cells circulating through the brain are briefly but closely apposed to the capillary endothelium. We hypothesized that this contact provides a nearly direct pathway for metabolic substrate transfer to neural cells that complements the better characterized plasma to endothelium transfer. While brain function is considered independent of normal fluctuations in blood glucose concentration, this is not borne out by persons with glucose transporter I (GLUT1) deficiency (G1D). In them, encephalopathy is often ameliorated by meal or carbohydrate administration, and this enabled us to test our hypothesis: Since red blood cells contain glucose, and since the red cells of G1D individuals are also deficient in GLUT1, replacing them with normal donor cells via exchange transfusion could augment erythrocyte to neural cell glucose transport via mass action in the setting of unaltered erythrocyte count or plasma glucose abundance. This motivated us to perform red blood cell exchange in 3 G1D persons. There were rapid, favorable and unprecedented changes in cognitive, electroencephalographic and quality-of-life measures. The hypothesized transfer mechanism was further substantiated by <i>in vitro</i> measurement of direct erythrocyte to endothelial cell glucose flux. The results also indicate that the adult intellect is capable of significant enhancement without deliberate practice.      ClinicalTrials.gov registration: NCT04137692 https://clinicaltrials.gov/ct2/show/NCT04137692.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 15 Dec 2022:271678X221146121; epub ahead of print</small></div>
Wang RC, Lee EE, De Simone N, Kathote G, ... Holland AA, Pascual JM
J Cereb Blood Flow Metab: 15 Dec 2022:271678X221146121; epub ahead of print | PMID: 36523131
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<div><h4>PDGFR-positive cell-mediated post-stroke remodeling of fibronectin and laminin 2 for tissue repair and functional recovery.</h4><i>Shibahara T, Nakamura K, Wakisaka Y, Shijo M, ... Kitazono T, Ago T</i><br /><AbstractText>Post-stroke intra-infarct repair promotes peri-infarct neural reorganization leading to functional recovery. Herein, we examined the remodeling of extracellular matrix proteins (ECM) that constitute the intact basal membrane after permanent middle cerebral artery occlusion (pMCAO) in mice. Among ECM, collagen type IV remained localized on small vessel walls surrounding CD31-positive endothelial cells within infarct areas. Fibronectin was gradually deposited from peri-infarct areas to the ischemic core, in parallel with the accumulation of PDGFRβ-positive cells. Cultured PDGFRβ-positive pericytes produced fibronectin, which was enhanced by the treatment with PDGF-BB. Intra-infarct deposition of fibronectin was significantly attenuated in pericyte-deficient <i>Pdgfrb<sup>+/-</sup></i>mice. Phagocytic activity of macrophages against myelin debris was significantly enhanced on fibronectin-coated dishes. In contrast, laminin α2, produced by GFAP- and aquaporin 4-positive astrocytes, accumulated strongly in the boundary of peri-infarct areas. Pericyte-conditioned medium increased the expression of laminin α2 in cultured astrocytes, partly through TGFβ1. Laminin α2 increased the differentiation of oligodendrocyte precursor cells into oligodendrocytes and the expression of myelin-associated proteins. Peri-infarct deposition of laminin α2 was significantly reduced in <i>Pdgfrb<sup>+/-</sup></i>mice, with attenuated oligodendrogenesis in peri-infarct areas. Collectively, intra-infarct PDGFRβ-positive cells may orchestrate post-stroke remodeling of key ECM that create optimal environments promoting clearance of myelin debris and peri-infarct oligodendrogenesis.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 14 Dec 2022:271678X221145092; epub ahead of print</small></div>
Shibahara T, Nakamura K, Wakisaka Y, Shijo M, ... Kitazono T, Ago T
J Cereb Blood Flow Metab: 14 Dec 2022:271678X221145092; epub ahead of print | PMID: 36514952
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<div><h4>Progranulin released from microglial lysosomes reduces neuronal ferroptosis after cerebral ischemia in mice.</h4><i>Chen T, Shi R, Suo Q, Wu S, ... Yang GY, Zhang Z</i><br /><AbstractText>The cellular redox state is essential for inhibiting ferroptosis. Progranulin (PGRN) plays an important role in maintaining the cellular redox state after ischemic brain injury. However, the effect of PGRN on ferroptosis and its underlying mechanism after cerebral ischemia remains unclear. This study assesses whether PGRN affects ferroptosis and explores its mechanism of action on ferroptosis after cerebral ischemia. We found endogenous <i>PGRN</i> expression in microglia increased on day 3 after ischemia. In addition, PGRN agonists chloroquine and trehalose upregulated <i>PGRN</i> expression, reduced brain infarct volume, and improved neurobehavioral outcomes after cerebral ischemia compared to controls (<i>p</i> < 0.05). Moreover, <i>PGRN</i> upregulation attenuated ferroptosis by decreasing malondialdehyde and increasing <i>Gpx4</i>, <i>Nrf2</i>, and <i>Slc7a11</i> expression and glutathione content (<i>p < </i>0.05). Furthermore, chloroquine induced microglial lysosome PGRN release, which was associated with increased neuron survival. Our results indicate that PGRN derived from microglial lysosomes effectively inhibits ferroptosis during ischemic brain injury, identifying it as a promising target for ischemic stroke therapy.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 14 Dec 2022:271678X221145090; epub ahead of print</small></div>
Chen T, Shi R, Suo Q, Wu S, ... Yang GY, Zhang Z
J Cereb Blood Flow Metab: 14 Dec 2022:271678X221145090; epub ahead of print | PMID: 36514959
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<div><h4>Measuring capillary flow dynamics using interlaced two-photon volumetric scanning.</h4><i>Giblin JT, Park SW, Jiang J, Kılıç K, ... Boas DA, Chen IA</i><br /><AbstractText>Two photon microscopy and optical coherence tomography (OCT) are two standard methods for measuring flow speeds of red blood cells in microvessels, particularly in animal models. However, traditional two photon microscopy lacks the depth of field to adequately capture the full volumetric complexity of the cerebral microvasculature and OCT lacks the specificity offered by fluorescent labeling. In addition, the traditional raster scanning technique utilized in both modalities requires a balance of image frame rate and field of view, which severely limits the study of RBC velocities in the microvascular network. Here, we overcome this by using a custom two photon system with an axicon based Bessel beam to obtain volumetric images of the microvascular network with fluorescent specificity. We combine this with a novel scan pattern that generates pairs of frames with short time delay sufficient for tracking red blood cell flow in capillaries. We track RBC flow speeds in 10 or more capillaries simultaneously at 1 Hz in a 237 µm × 237 µm × 120 µm volume and quantified both their spatial and temporal variability in speed. We also demonstrate the ability to track flow speed changes around stalls in capillary flow and measure to 300 µm in depth.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 10 Dec 2022:271678X221145091; epub ahead of print</small></div>
Giblin JT, Park SW, Jiang J, Kılıç K, ... Boas DA, Chen IA
J Cereb Blood Flow Metab: 10 Dec 2022:271678X221145091; epub ahead of print | PMID: 36495178
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<div><h4>CNS-peripheral immune interactions in hemorrhagic stroke.</h4><i>Li X, Chen G</i><br /><AbstractText>Stroke is a sudden and rapidly progressing ischemic or hemorrhagic cerebrovascular disease. When stroke damages the brain, the immune system becomes hyperactive, leading to systemic inflammatory response and immunomodulatory disorders, which could significantly impact brain damage, recovery, and prognosis of stroke. Emerging researches suggest that ischemic stroke-induced spleen contraction could activate a peripheral immune response, which may further aggravate brain injury. This review focuses on hemorrhagic strokes including intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) and discusses the central nervous system-peripheral immune interactions after hemorrhagic stroke induction. First, inflammatory progression after ICH and SAH is investigated. As a part of this review, we summarize the various kinds of inflammatory cell infiltration to aggravate brain injury after blood-brain barrier interruption induced by hemorrhagic stroke. Then, we explore hemorrhagic stroke-induced systemic inflammatory response syndrome (SIRS) and discuss the interactions of CNS and peripheral inflammatory response. In addition, potential targets related to inflammatory response for ICH and SAH are discussed in this review, which may lead to novel therapeutic strategies for hemorrhagic stroke.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 07 Dec 2022:271678X221145089; epub ahead of print</small></div>
Li X, Chen G
J Cereb Blood Flow Metab: 07 Dec 2022:271678X221145089; epub ahead of print | PMID: 36476130
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<div><h4>Endothelial progenitor cell transplantation attenuates synaptic loss associated with enhancing complement receptor 3-dependent microglial/macrophage phagocytosis in ischemic mice.</h4><i>Ma Y, Liu Z, Jiang L, Wang L, ... Ding J, Zhang Z</i><br /><AbstractText>Endothelial progenitor cell (EPC) transplantation has therapeutic effects in cerebral ischemia. However, how EPCs modulate microglial activity remains unclear. In the study, we explored whether EPCs modulated microglial/macrophage activity and facilitated injured brain repair. Adult male mice (n = 184) underwent transient middle cerebral artery occlusion, and EPCs were transplanted into the brain immediately after ischemia. Microglial/macrophage activity and complement receptor 3 (CR3) expression were evaluated in ischemic brains and cultured microglia. CR3 agonist leukadherin-1 was administrated into mice immediately after ischemia to imitate the effects of EPCs. Synaptophysin and postsynaptic density protein 95 (PSD-95) expressions were detected in EPC- and leukadherin-1 treated mice. We found that EPC transplantation increased the number of M2 microglia/macrophage-phagocytizing apoptotic cells and CR3 expression in ischemic brains at 3 days after ischemia (<i>p</i> < 0.05). EPC-conditional medium or cultured EPCs increased microglial migration and phagocytosis and upregulated CR3 expression in cultured microglia under oxygen-glucose deprivation condition (<i>p < </i>0.05). Leukadherin-1 reduced brain atrophy volume and neurological deficits at 14 days after ischemia (<i>p < </i>0.05). Both EPC transplantation and leukadherin-1 increased synaptophysin and PSD-95 expression at 14 days after ischemia (<i>p < </i>0.05). EPC transplantation promoted CR3-mediated microglial/macrophage phagocytosis and subsequently attenuated synaptic loss. Our study provided a novel therapeutic mechanism for EPCs.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 01 Dec 2022:271678X221135841; epub ahead of print</small></div>
Ma Y, Liu Z, Jiang L, Wang L, ... Ding J, Zhang Z
J Cereb Blood Flow Metab: 01 Dec 2022:271678X221135841; epub ahead of print | PMID: 36457150
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<div><h4>Neuronal Serpina3n is an endogenous protector against blood brain barrier damage following cerebral ischemic stroke.</h4><i>Li F, Zhang Y, Li R, Li Y, ... Li P, Wan J</i><br /><AbstractText>Ischemic stroke results in blood-brain barrier (BBB) disruption, during which the reciprocal interaction between ischemic neurons and components of the BBB appears to play a critical role. However, the underlying mechanisms for BBB protection remain largely unknown. In this study, we found that Serpina3n, a serine protease inhibitor, was significantly upregulated in the ischemic brain, predominantly in ischemic neurons from 6 hours to 3 days after stroke. Using neuron-specific adeno-associated virus (AAV), intranasal delivery of recombinant protein, and immune-deficient Rag1<sup>-/-</sup> mice, we demonstrated that Serpina3n attenuated BBB disruption and immune cell infiltration following stroke by inhibiting the activity of granzyme B (GZMB) and neutrophil elastase (NE) secreted by T cells and neutrophils. Furthermore, we found that intranasal delivery of rSerpina3n significantly attenuated the neurologic deficits after stroke. In conclusion, Serpina3n is a novel ischemic neuron-derived proteinase inhibitor that counterbalances BBB disruption induced by peripheral T cell and neutrophil infiltration after ischemic stroke. These findings reveal a novel endogenous protective mechanism against BBB damage with Serpina3n being a potential therapeutic target in ischemic stroke.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 01 Dec 2022:271678X221113897; epub ahead of print</small></div>
Li F, Zhang Y, Li R, Li Y, ... Li P, Wan J
J Cereb Blood Flow Metab: 01 Dec 2022:271678X221113897; epub ahead of print | PMID: 36457151
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<div><h4>Putative neurochemical and cell type contributions to hemodynamic activity in the rodent caudate putamen.</h4><i>Katz BM, Walton LR, Houston KM, Cerri DH, Shih YI</i><br /><AbstractText>Functional magnetic resonance imaging (fMRI) is widely used by researchers to noninvasively monitor brain-wide activity. The traditional assumption of a uniform relationship between neuronal and hemodynamic activity throughout the brain has been increasingly challenged. This relationship is now believed to be impacted by heterogeneously distributed cell types and neurochemical signaling. To date, most cell-type- and neurotransmitter-specific influences on hemodynamics have been examined within the cortex and hippocampus of rodent models, where glutamatergic signaling is prominent. However, neurochemical influences on hemodynamics are relatively unknown in largely GABAergic brain regions such as the rodent caudate putamen (CPu). Given the extensive contribution of CPu function and dysfunction to behavior, and the increasing focus on this region in fMRI studies, improved understanding of CPu hemodynamics could have broad impacts. Here we discuss existing findings on neurochemical contributions to hemodynamics as they may relate to the CPu with special consideration for how these contributions could originate from various cell types and circuits. We hope this review can help inform the direction of future studies as well as interpretation of fMRI findings in the CPu.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 30 Nov 2022:271678X221142533; epub ahead of print</small></div>
Katz BM, Walton LR, Houston KM, Cerri DH, Shih YI
J Cereb Blood Flow Metab: 30 Nov 2022:271678X221142533; epub ahead of print | PMID: 36448509
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<div><h4>Kinetic evaluation and assessment of longitudinal changes in reference region and extracerebral [F]MK-6240 PET uptake.</h4><i>Fu JF, Lois C, Sanchez J, Becker JA, ... Johnson KA, Price JC</i><br /><AbstractText>[<sup>18</sup>F]MK-6240 meningeal/extracerebral off-target binding may impact tau quantification. We examined the kinetics and longitudinal changes of extracerebral and reference regions. [<sup>18</sup>F]MK-6240 PET was performed in 24 cognitively-normal and eight cognitively-impaired subjects, with arterial samples in 13 subjects. Follow-up scans at 6.1 ± 0.5 (n = 25) and 13.3 ± 0.9 (n = 16) months were acquired. Extracerebral and reference region (cerebellar gray matter (CerGM)-based, cerebral white matter (WM), pons) uptake were evaluated using standardized uptake values (SUV<sub>90-110</sub>), spectral analysis, and distribution volume. Longitudinal changes in SUV<sub>90-110</sub> were examined. The impact of reference region on target region outcomes, partial volume correction (PVC) and regional erosion were evaluated. Eroded WM and pons showed lower variability, lower extracerebral contamination, and lower longitudinal changes than CerGM-based regions. CerGM-based regions resulted larger cross-sectional effect sizes for group differentiation. Extracerebral signal was high in 50% of subjects and exhibited irreversible kinetics and nonsignificant longitudinal changes over one-year but was highly variable at subject-level. PVC resulted in higher variability in reference region uptake and longitudinal changes. Our results suggest that eroded CerGM may be preferred for cross-sectional, whilst eroded WM or pons may be preferred for longitudinal [<sup>18</sup>F]MK-6240 studies. For CerGM, erosion was necessary (preferred over PVC) to address the heterogenous nature of extracerebral signal.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 24 Nov 2022:271678X221142139; epub ahead of print</small></div>
Fu JF, Lois C, Sanchez J, Becker JA, ... Johnson KA, Price JC
J Cereb Blood Flow Metab: 24 Nov 2022:271678X221142139; epub ahead of print | PMID: 36420769
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<div><h4>Directional sensitivity of dynamic cerebral autoregulation during spontaneous fluctuations in arterial blood pressure at rest.</h4><i>Panerai RB, Barnes SC, Batterham AP, Robinson TG, Haunton VJ</i><br /><AbstractText>Directional sensitivity, the more efficient response of cerebral autoregulation to increases, compared to decreases, in mean arterial pressure (MAP), has been demonstrated with repeated squat-stand maneuvers (SSM). In 43 healthy subjects (26 male, 23.1 ± 4.2 years old), five min. recordings of cerebral blood velocity (bilateral Doppler ultrasound), MAP (Finometer), end-tidal CO<sub>2</sub> (capnograph), and heart rate (ECG) were obtained during sitting (SIT), standing (STA) and SSM. A new analytical procedure, based on autoregressive-moving average models, allowed distinct estimates of the autoregulation index (ARI) by separating the MAP signal into its positive (MAP<sub>+D</sub>) and negative (MAP<sub>-D</sub>) derivatives. ARI<sub>+D</sub> was higher than ARI<sub>-D</sub> (p < 0.0001), SIT: 5.61 ± 1.58 vs 4.31 ± 2.16; STA: 5.70 ± 1.24 vs 4.63 ± 1.92; SSM: 4.70 ± 1.11 vs 3.31 ± 1.53, but the difference ARI<sub>+D</sub>-ARI<sub>-D</sub> was not influenced by the condition. A bootstrap procedure determined the critical number of subjects needed to identify a significant difference between ARI<sub>+D</sub> and ARI<sub>-D</sub>, corresponding to 24, 37 and 38 subjects, respectively, for SSM, STA and SIT. Further investigations are needed on the influences of sex, aging and other phenotypical characteristics on the phenomenon of directional sensitivity of dynamic autoregulation.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 24 Nov 2022:271678X221142527; epub ahead of print</small></div>
Panerai RB, Barnes SC, Batterham AP, Robinson TG, Haunton VJ
J Cereb Blood Flow Metab: 24 Nov 2022:271678X221142527; epub ahead of print | PMID: 36420777
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<div><h4>Leukocyte indicators and variations predict worse outcomes after intravenous thrombolysis in patients with acute ischemic stroke.</h4><i>Xie J, Pang C, Yu H, Zhang W, Ren C, Deng B</i><br /><AbstractText>Leukocytes are systematic inflammation indicators related to stroke prognosis and can exhibit large dynamic waves before and after recombinant tissue plasminogen activator (r-tPA) therapy. However, additional evidence is needed to determine the prognostic significance of various leukocytes including both static and dynamic data among patients who underwent r-tPA therapy. A total of 251 patients treated with r-tPA were included; their leukocyte data were collected at two time points, and patients were followed up for three months. Analysis revealed the following findings. (i) Patients with hemorrhagic transformation (HT) and unfavorable outcomes had a higher level of leukocytes after r-tPA therapy (leukocyte count (adjusted OR (aOR) 1.191 for HT and 1.184 for unfavorable outcomes), neutrophil count (aOR 1.215 and 1.214), neutrophil-to-lymphocyte ratio (NLR; aOR 1.084 and 1.091)) and larger dynamic leukocyte changes. (ii)Among all leukocytes, the NLR after r-tPA administration demonstrated the strongest correlation with HT and unfavorable outcomes. (iii) Patients with an NLR ≥ 3.322 had a 3.492-fold increased risk for HT, and those with an NLR ≥ 5.511 had a 3.024-fold increased risk for functional outcomes. Overall, this study shows that leukocytes, especially leukocyte count, neutrophil count and the NLR, are independently associated with HT and functional outcomes in stroke patients.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 24 Nov 2022:271678X221142694; epub ahead of print</small></div>
Xie J, Pang C, Yu H, Zhang W, Ren C, Deng B
J Cereb Blood Flow Metab: 24 Nov 2022:271678X221142694; epub ahead of print | PMID: 36420778
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<div><h4>Gray matter hypoperfusion is a late pathological event in the course of Alzheimer\'s disease.</h4><i>Ahmadi K, Pereira JB, Berron D, Vogel J, ... Mutsaerts HJ, Hansson O</i><br /><AbstractText>Several studies have shown decreased cerebral blood flow (CBF) in Alzheimer\'s disease (AD). However, the role of hypoperfusion in the disease pathogenesis remains unclear. Combining arterial spin labeling MRI, PET, and CSF biomarkers, we investigated the associations between gray matter (GM)-CBF and the key mechanisms in AD including amyloid-β (Aβ) and tau pathology, synaptic and axonal degeneration. Further, we applied a disease progression modeling to characterize the temporal sequence of different AD biomarkers. Lower perfusion was observed in temporo-occipito-parietal cortex in the Aβ-positive cognitively impaired compared to both Aβ-negative and Aβ-positive cognitively unimpaired individuals. In participants along the AD spectrum, GM-CBF was associated with tau, synaptic and axonal dysfunction, but not Aβ in similar cortical regions. Axonal degeneration was further associated with hypoperfusion in cognitively unimpaired individuals. Disease progression modeling revealed that GM-CBF disruption Followed the abnormality of biomarkers of Aβ, tau and brain atrophy. These findings indicate that tau tangles and neurodegeneration are more closely connected with GM-CBF changes than Aβ pathology. Although subjected to the sensitivity of the employed neuroimaging techniques and the modeling approach, these findings suggest that hypoperfusion might not be an early event associated with the build-up of Aβ in preclinical phase of AD.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 22 Nov 2022:271678X221141139; epub ahead of print</small></div>
Ahmadi K, Pereira JB, Berron D, Vogel J, ... Mutsaerts HJ, Hansson O
J Cereb Blood Flow Metab: 22 Nov 2022:271678X221141139; epub ahead of print | PMID: 36412244
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<div><h4>Revascularization improves vascular hemodynamics - a study assessing cerebrovascular reserve and transit time in Moyamoya patients using MRI.</h4><i>Zhao MY, Armindo RD, Gauden AJ, Yim B, ... Steinberg GK, Zaharchuk G</i><br /><AbstractText>Cerebrovascular reserve (CVR) reflects the capacity of cerebral blood flow (CBF) to change. Decreased CVR implies poor hemodynamics and is linked to a higher risk for stroke. Revascularization has been shown to improve CBF in patients with vasculopathy such as Moyamoya disease. Dynamic susceptibility contrast (DSC) can measure transit time to evaluate patients suspected of stroke. Arterial spin labeling (ASL) is a non-invasive technique for CBF, CVR, and arterial transit time (ATT) measurements. Here, we investigate the change in hemodynamics 4-12 months after extracranial-to-intracranial direct bypass in 52 Moyamoya patients using ASL with single and multiple post-labeling delays (PLD). Images were collected using ASL and DSC with acetazolamide. CVR, CBF, ATT, and time-to-maximum (Tmax) were measured in different flow territories. Results showed that hemodynamics improved significantly in regions affected by arterial occlusions after revascularization. CVR increased by 16 ± 11% (p < 0.01) and 25 ± 13% (p < 0.01) for single- and multi-PLD ASL, respectively. Transit time measured by multi-PLD ASL and post-vasodilation DSC reduced by 13 ± 7% (p < 0.01) and 9 ± 5% (p < 0.01), respectively. For all regions, ATT correlated significantly with Tmax (R<sup>2 </sup> = <sup> </sup>0.59, p < 0.01). Thus, revascularization improved CVR and decreased transit times. Multi-PLD ASL can serve as an effective and non-invasive modality to examine vascular hemodynamics in Moyamoya patients.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 20 Nov 2022:271678X221140343; epub ahead of print</small></div>
Zhao MY, Armindo RD, Gauden AJ, Yim B, ... Steinberg GK, Zaharchuk G
J Cereb Blood Flow Metab: 20 Nov 2022:271678X221140343; epub ahead of print | PMID: 36408536
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<div><h4>Association of cognitive function and hypoperfusion in Moyamoya disease patients without stroke.</h4><i>Shen XX, Zhang HD, Fu HG, Xu JL, ... Duan L, Han C</i><br /><AbstractText>The influence of hypoperfusion on cognition in patients with Moyamoya disease (MMD) is unclear. This study investigated cognitive function changes in MMD patients without stroke and illustrated the relationship between cognitive impairment and hypoperfusion. We prospectively performed a structured battery of seven neurocognitive tests on 115 adult MMD patients without stroke and 82 healthy controls. Hemodynamic assessment was performed using dynamic susceptibility contrast-enhanced MRI. The best subset regression (BSR) strategy was used to identify risk factors. Global cognition (MoCA), speed of information processing (TMT-A), executive function (TMT-B), visuospatial function (CDT), and verbal memory (CAVLT) were significantly poorer in MMD patients without stroke than in healthy controls. The TMT-B score significantly correlated with cerebral blood flow (CBF) in the bilateral lateral frontal lobes, centrum semiovale, and temporal lobes. The TMT-A and CAVLT scores significantly correlated with CBF in the left centrum semiovale (L-CSO) and temporal lobes. According to the BSR results, age, education, white matter lesions, and hypoperfusion of the L-CSO were risk factors for cognitive impairment. Hypoperfusion leads to multiple cognitive impairments in MMD patients without stroke. The perfusion of particular areas may help evaluate the cognitive function of MMD patients and guide therapeutic strategies.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 17 Nov 2022:271678X221140349; epub ahead of print</small></div>
Shen XX, Zhang HD, Fu HG, Xu JL, ... Duan L, Han C
J Cereb Blood Flow Metab: 17 Nov 2022:271678X221140349; epub ahead of print | PMID: 36397212
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<div><h4>Post cardiac arrest physical exercise mitigates cell death in the septal and thalamic nuclei and ameliorates contextual fear conditioning deficits in rats.</h4><i>Ferrier FJ, Saul I, Khoury N, Ruiz AJ, ... Young JI, Perez-Pinzon MA</i><br /><AbstractText>A major concern for cardiac arrest (CA) survivors is the manifestation of long-term cognitive impairments. Physical exercise (PE) is a well-established approach to improve cognitive functions under certain pathological conditions. We previously showed that PE post-CA mitigates cognitive deficits, but the underlying mechanisms remain unknown. To define neuroprotective mechanisms, we analyzed whether PE post-CA protects neurons involved in memory. We first performed a contextual fear conditioning (CFC) test to confirm that PE post-CA preserves memory in rats. We then conducted a cell-count analysis and determined the number of live cells in the hippocampus, and septal and thalamic nuclei, all areas involved in cognitive functions. Lastly, we performed RNA-seq to determine PE post-CA effect on gene expression. Following CA, exercised rats had preserved CFC memory than sham PE animals. Despite this outcome, PE post-CA did not protect hippocampal cells from dying. However, PE ameliorated cell death in septal and thalamic nuclei compared to sham PE animals, suggesting that these nuclei are crucial in mitigating cognitive decline post-CA. Interestingly, PE affected regulation of genes related to neuroinflammation, plasticity, and cell death. These findings reveal potential mechanisms whereby PE post-CA preserves cognitive functions by protecting septal and thalamic cells via gene regulation.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 11 Nov 2022:271678X221137539; epub ahead of print</small></div>
Ferrier FJ, Saul I, Khoury N, Ruiz AJ, ... Young JI, Perez-Pinzon MA
J Cereb Blood Flow Metab: 11 Nov 2022:271678X221137539; epub ahead of print | PMID: 36369732
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<div><h4>Dualistic roles and mechanistic insights of macrophage migration inhibitory factor in brain injury and neurodegenerative diseases.</h4><i>Xuan W, Xie W, Li F, Huang D, ... Li Y, Li P</i><br /><AbstractText>Macrophage migration inhibitory factor (MIF) is involved in various immune-mediated pathologies and regulates both innate and adaptive immune reactions, thus being related to several acute and chronic inflammatory diseases such as rheumatoid arthritis, septic shock, and atherosclerosis. Its role in acute and chronic brain pathologies, such as stroke and neurodegenerative diseases, has attracted increasing attention in recent years. In response to stimuli like hypoxia, inflammation or infection, different cell types can rapidly release MIF, including immune cells, endothelial cells, and neuron cells. Notably, clinical data from past decades also suggested a possible link between serum MIF levels and the severity of stroke and the evolving of neurodegenerative diseases. In this review, we summarize the major and recent findings focusing on the mechanisms of MIF modulating functions in brain injury and neurodegenerative diseases, which may provide important therapeutic targets meriting further investigation.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 11 Nov 2022:271678X221138412; epub ahead of print</small></div>
Xuan W, Xie W, Li F, Huang D, ... Li Y, Li P
J Cereb Blood Flow Metab: 11 Nov 2022:271678X221138412; epub ahead of print | PMID: 36369735
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<div><h4>Considerations on gradual glutamate accumulation related to cognitive task performance.</h4><i>Möller HE</i><br /><AbstractText>Long-lasting activities with high demand in cognitive control are known to result in cognitive fatigue. However, the reason for control cost inflation remains elusive. A neurometabolic account was proposed in a recent study combining magnetic resonance spectroscopy (MRS) with daylong execution of behavioral tasks. It suggests that control cost during high-demand work is related to the necessity of recycling potentially toxic substances, specifically glutamate, which may accumulate extracellularly. As MRS provides estimates of metabolite concentrations, further evaluations are possible how well this hypothesis fits with fundamental consequences from the dynamic equilibrium of intercompartmental glutamate distributions.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 11 Nov 2022:271678X221139550; epub ahead of print</small></div>
Möller HE
J Cereb Blood Flow Metab: 11 Nov 2022:271678X221139550; epub ahead of print | PMID: 36369737
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<div><h4>Capillary transit time heterogeneity inhibits cerebral oxygen metabolism in patients with reduced cerebrovascular reserve capacity from steno-occlusive disease.</h4><i>Vestergaard MB, Iversen HK, Simonsen SA, Lindberg U, ... Andersen UB, Larsson HB</i><br /><AbstractText>The healthy cerebral perfusion demonstrates a homogenous distribution of capillary transit times. A disruption of this homogeneity may inhibit the extraction of oxygen. A high degree of capillary transit time heterogeneity (CTH) describes that some capillaries have very low blood flows, while others have excessively high blood flows and consequently short transit times. Very short transit times could hinder the oxygen extraction due to insufficient time for diffusion of oxygen into the tissue. CTH could be a consequence of cerebral vessel disease. We examined whether patients with cerebral steno-occlusive vessel disease demonstrate high CTH and if elevation of cerebral blood flow (CBF) by administration of acetazolamide (ACZ) increases the cerebral metabolic rate of oxygen (CMRO<sub>2</sub>), or if some patients demonstrate reduced CMRO<sub>2</sub> related to detrimental CTH. Thirty-four patients and thirty-one healthy controls participated. Global CBF and CMRO<sub>2</sub> were acquired using phase-contrast MRI. Regional brain maps of CTH were acquired using dynamic contrast-enhanced MRI. Patients with impaired cerebrovascular reserve capacity demonstrated elevated CTH and a significant reduction of CMRO<sub>2</sub> after administration of ACZ, which could be related to high CTH. Impaired oxygen extraction from CTH could be a contributing part of the declining brain health observed in patients with cerebral vessel disease.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 11 Nov 2022:271678X221139084; epub ahead of print</small></div>
Vestergaard MB, Iversen HK, Simonsen SA, Lindberg U, ... Andersen UB, Larsson HB
J Cereb Blood Flow Metab: 11 Nov 2022:271678X221139084; epub ahead of print | PMID: 36369740
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Abstract
<div><h4>Stroke-prone salt-sensitive spontaneously hypertensive rats show higher susceptibility to spreading depolarization (SD) and altered hemodynamic responses to SD.</h4><i>Kang EJ, Prager O, Lublinsky S, Oliveira-Ferreira AI, ... Friedman A, Dreier JP</i><br /><AbstractText>Spreading depolarization (SD) occurs in a plethora of clinical conditions including migraine aura, delayed ischemia after subarachnoid hemorrhage and malignant hemispheric stroke. It describes waves of near-breakdown of ion homeostasis, particularly Na<sup>+</sup> homeostasis in brain gray matter. SD induces tone alterations in resistance vessels, causing either hyperperfusion in healthy tissue; or hypoperfusion (inverse hemodynamic response = spreading ischemia) in tissue at risk. Observations from mice with genetic dysfunction of the ATP1A2-encoded α<sub>2</sub>-isoform of Na<sup>+</sup>/K<sup>+</sup>-ATPase (α<sub>2</sub>NaKA) suggest a mechanistic link between (1) SD, (2) vascular dysfunction, and (3) salt-sensitive hypertension via α<sub>2</sub>NaKA. Thus, α<sub>2</sub>NaKA-dysfunctional mice are more susceptible to SD and show a shift toward more inverse hemodynamic responses. α<sub>2</sub>NaKA-dysfunctional patients suffer from familial hemiplegic migraine type 2, a Mendelian model disease of SD. α<sub>2</sub>NaKA-dysfunctional mice are also a genetic model of salt-sensitive hypertension. To determine whether SD thresholds and hemodynamic responses are also altered in other genetic models of salt-sensitive hypertension, we examined these variables in stroke-prone spontaneously hypertensive rats (SHRsp). Compared with Wistar Kyoto control rats, we found in SHRsp that electrical SD threshold was significantly reduced, propagation speed was increased, and inverse hemodynamic responses were prolonged. These results may have relevance to both migraine with aura and stroke.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 03 Nov 2022:271678X221135085; epub ahead of print</small></div>
Kang EJ, Prager O, Lublinsky S, Oliveira-Ferreira AI, ... Friedman A, Dreier JP
J Cereb Blood Flow Metab: 03 Nov 2022:271678X221135085; epub ahead of print | PMID: 36329390
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Abstract
<div><h4>The roles of microglia and astrocytes in myelin phagocytosis in the central nervous system.</h4><i>Xu T, Liu C, Deng S, Gan L, ... Tian H, Tang Y</i><br /><AbstractText>Myelination is an important process in the central nervous system (CNS). Oligodendrocytes (OLs) extend multiple layers to densely sheath on axons, composing the myelin to achieve efficient electrical signal conduction. The myelination during developmental stage maintains a balanced state. However, numerous CNS diseases including neurodegenerative and cerebrovascular diseases cause demyelination and disrupt the homeostasis, resulting in inflammation and white matter deficits. Effective clearance of myelin debris is needed in the region of demyelination, which is a key step for remyelination and tissue regeneration. Microglia and astrocytes are the major resident phagocytic cells in the brain, which may play different or collaborative roles in myelination. Microglia and astrocytes participate in developmental myelination through engulfing excessive unneeded myelin. They are also involved in the clearance of degenerated myelin debris for accelerating remyelination, or engulfing healthy myelin sheath for inhibiting remyelination. This review focuses on the roles of microglia and astrocytes in phagocytosing myelin in the developmental brain and diseased brain. In addition, the interaction between microglia and astrocytes to mediate myelin engulfment is also summarized.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 02 Nov 2022:271678X221137762; epub ahead of print</small></div>
Xu T, Liu C, Deng S, Gan L, ... Tian H, Tang Y
J Cereb Blood Flow Metab: 02 Nov 2022:271678X221137762; epub ahead of print | PMID: 36324281
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