Journal: J Cereb Blood Flow Metab

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Abstract

Interpretable deep learning for the prognosis of long-term functional outcome post-stroke using acute diffusion weighted imaging.

Moulton E, Valabregue R, Piotin M, Marnat G, ... Clarencon F, Rosso C
Advances in deep learning can be applied to acute stroke imaging to build powerful and explainable prediction models that could supersede traditionally used biomarkers. We aimed to evaluate the performance and interpretability of a deep learning model based on convolutional neural networks (CNN) in predicting long-term functional outcome with diffusion-weighted imaging (DWI) acquired at day 1 post-stroke. Ischemic stroke patients (n = 322) were included from the ASTER and INSULINFARCT trials as well as the Pitié-Salpêtrière registry. We trained a CNN to predict long-term functional outcome assessed at 3 months with the modified Rankin Scale (dichotomized as good [mRS ≤ 2] vs. poor [mRS ≥ 3]) and compared its performance to two logistic regression models using lesion volume and ASPECTS. The CNN contained an attention mechanism, which allowed to visualize the areas of the brain that drove prediction. The deep learning model yielded a significantly higher area under the curve (0.83 95%CI [0.78-0.87]) than lesion volume (0.78 [0.73-0.83]) and ASPECTS (0.77 [0.71-0.83]) (p < 0.05). Setting all classifiers to the specificity as the deep learning model (i.e., 0.87 [0.82-0.92]), the CNN yielded a significantly higher sensitivity (0.67 [0.59-0.73]) than lesion volume (0.48 [0.40-0.56]) and ASPECTS (0.50 [0.41-0.58]) (p = 0.002). The attention mechanism revealed that the network learned to naturally attend to the lesion to predict outcome.



J Cereb Blood Flow Metab: 28 Sep 2022:271678X221129230; epub ahead of print
Moulton E, Valabregue R, Piotin M, Marnat G, ... Clarencon F, Rosso C
J Cereb Blood Flow Metab: 28 Sep 2022:271678X221129230; epub ahead of print | PMID: 36169033
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Abstract

PET imaging studies to investigate functional expression of mGluR2 using [C]mG2P001.

Yuan G, Dhaynaut M, Guehl NJ, Neelamegam R, ... Normandin MD, Brownell AL
Metabotropic glutamate receptor 2 (mGluR2) has been extensively studied for the treatment of various neurological and psychiatric disorders. Understanding of the mGluR2 function is pivotal in supporting the drug discovery targeting mGluR2. Herein, the positive allosteric modulation of mGluR2 was investigated via the in vivo positron emission tomography (PET) imaging using 2-((4-(2-[11C]methoxy-4-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)-1-methyl-1H-imidazo[4,5-b]pyridine ([11C]mG2P001). Distinct from the orthosteric compounds, pretreatment with the unlabeled mG2P001, a potent mGluR2 positive allosteric modulator (PAM), resulted in a significant increase instead of decrease of the [11C]mG2P001 accumulation in rat brain detected by PET imaging. Subsequent in vitro studies with [3H]mG2P001 revealed the cooperative binding mechanism of mG2P001 with glutamate and its pharmacological effect that contributed to the enhanced binding of [3H]mG2P001 in transfected CHO cells expressing mGluR2. The in vivo PET imaging and quantitative analysis of [11C]mG2P001 in non-human primates (NHPs) further validated the characteristics of [11C]mG2P001 as an imaging ligand for mGluR2. Self-blocking studies in primates enhanced accumulation of [11C]mG2P001. Altogether, these studies show that [11C]mG2P001 is a sensitive biomarker for mGluR2 expression and the binding is affected by the tissue glutamate concentration.



J Cereb Blood Flow Metab: 28 Sep 2022:271678X221130387; epub ahead of print
Yuan G, Dhaynaut M, Guehl NJ, Neelamegam R, ... Normandin MD, Brownell AL
J Cereb Blood Flow Metab: 28 Sep 2022:271678X221130387; epub ahead of print | PMID: 36172629
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Abstract

Quantification of the purinergic P2X receptor with [C]SMW139 improves through correction for brain-penetrating radiometabolites.

Brumberg J, Aarnio R, Forsberg A, Marjamäki P, ... Rinne JO, Varrone A
The membrane-based purinergic 7 receptor (P2X7R) is expressed on activated microglia and the target of the radioligand [11C]SMW139 for in vivo assessment of neuroinflammation. This study investigated the contribution of radiolabelled metabolites which potentially affect its quantification. Ex vivo high-performance liquid chromatography with a radio detector (radioHPLC) was used to evaluate the parent and radiometabolite fractions of [11C]SMW139 in the brain and plasma of eleven mice. Twelve healthy humans underwent 90-min [11C]SMW139 brain PET with arterial blood sampling and radiometabolite analysis. The volume of distribution was estimated by using one- and two- tissue compartment (TCM) modeling with single (VT) and dual (VTp) input functions. RadioHPLC showed three major groups of radiometabolite peaks with increasing concentrations in the plasma of all mice and humans. Two radiometabolite peaks were also visible in mice brain homogenates and therefore considered for dual input modeling in humans. 2TCM with single input function provided VT estimates with a wide range (0.10-10.74) and high coefficient of variation (COV: 159.9%), whereas dual input function model showed a narrow range of VTp estimates (0.04-0.24; COV: 33.3%). In conclusion, compartment modeling with correction for brain-penetrant radiometabolites improves the in vivo quantification of [11C]SMW139 binding to P2X7R in the human brain.



J Cereb Blood Flow Metab: 26 Sep 2022:271678X221126830; epub ahead of print
Brumberg J, Aarnio R, Forsberg A, Marjamäki P, ... Rinne JO, Varrone A
J Cereb Blood Flow Metab: 26 Sep 2022:271678X221126830; epub ahead of print | PMID: 36163685
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Abstract

Spatiotemporal analysis of blood plasma and blood cell flow fluctuations of cerebral microcirculation in anesthetized rats.

Niizawa T, Sakuraba R, Kusaka T, Kurihara Y, ... Kanno I, Masamoto K
Cerebral hemodynamics fluctuates spontaneously over broad frequency ranges. However, its spatiotemporal coherence of flow oscillations in cerebral microcirculation remains incompletely understood. The objective of this study was to characterize the spatiotemporal fluctuations of red blood cells (RBCs) and plasma flow in the rat cerebral microcirculation by simultaneously imaging their dynamic behaviors. Comparisons of changes in cross-section diameters between RBC and plasma flow showed dissociations in penetrating arterioles. The results indicate that vasomotion has the least effect on the lateral movement of circulating RBCs, resulting in variable changes in plasma layer thickness. Parenchymal capillaries exhibited slow fluctuations in RBC velocity (0.1 to 0.3 Hz), regardless of capillary diameter fluctuations (<0.1 Hz). Temporal fluctuations and the velocity of RBCs decreased significantly at divergent capillary bifurcations. The results indicate that a transit of RBCs generates flow resistance in the capillaries and that slow velocity fluctuations of the RBCs are subject to a number of bifurcations. In conclusion, the high-frequency oscillation of the blood flow is filtered at the bifurcation through the capillary networks. Therefore, a number of bifurcations in the cerebral microcirculation may contribute to the power of low-frequency oscillations.



J Cereb Blood Flow Metab: 22 Sep 2022:271678X221125743; epub ahead of print
Niizawa T, Sakuraba R, Kusaka T, Kurihara Y, ... Kanno I, Masamoto K
J Cereb Blood Flow Metab: 22 Sep 2022:271678X221125743; epub ahead of print | PMID: 36138557
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Abstract

Cerebral O and CO transport in isovolumic haemodilution: Compensation of cerebral delivery of O and maintenance of cerebrovascular reactivity to CO.

Carr JM, Ainslie PN, MacLeod DB, Tremblay JC, ... Green DJ, Hoiland RL
This study investigated the influence of acute reductions in arterial O2 content (CaO2) via isovolumic haemodilution on global cerebral blood flow (gCBF) and cerebrovascular CO2 reactivity (CVR) in 11 healthy males (age; 28 ± 7 years: body mass index; 23 ± 2 kg/m2). Radial artery and internal jugular vein catheters provided measurement of blood pressure and gases, quantification of cerebral metabolism, cerebral CO2 washout, and trans-cerebral nitrite exchange (ozone based chemiluminescence). Prior to and following haemodilution, the partial pressure of arterial CO2 (PaCO2) was elevated with dynamic end-tidal forcing while gCBF was measured with duplex ultrasound. CVR was determined as the slope of the gCBF response and PaCO2. Replacement of ∼20% of blood volume with an equal volume of 5% human serum albumin (Alburex® 5%) reduced haemoglobin (13.8 ± 0.8 vs. 11.3 ± 0.6 g/dL; P < 0.001) and CaO2 (18.9 ± 1.0 vs 15.0 ± 0.8 mL/dL P < 0.001), elevated gCBF (+18 ± 11%; P = 0.002), preserved cerebral oxygen delivery (P = 0.49), and elevated CO2 washout (+11%; P = 0.01). The net cerebral uptake of nitrite (11.6 ± 14.0 nmol/min; P = 0.027) at baseline was abolished following haemodilution (-3.6 ± 17.9 nmol/min; P = 0.54), perhaps underpinning the conservation of CVR (61.7 ± 19.0 vs. 69.0 ± 19.2 mL/min/mmHg; P = 0.23). These findings demonstrate that the cerebrovascular responses to acute anaemia in healthy humans are sufficient to support the maintenance of CVR.



J Cereb Blood Flow Metab: 21 Sep 2022:271678X221119442; epub ahead of print
Carr JM, Ainslie PN, MacLeod DB, Tremblay JC, ... Green DJ, Hoiland RL
J Cereb Blood Flow Metab: 21 Sep 2022:271678X221119442; epub ahead of print | PMID: 36131560
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Abstract

Poor venous outflow profiles increase the risk of reperfusion hemorrhage after endovascular treatment.

Winkelmeier L, Heit JJ, Adusumilli G, Geest V, ... Fiehler J, Faizy TD
To investigate whether unfavorable cerebral venous outflow (VO) predicts reperfusion hemorrhage after endovascular treatment (EVT), we conducted a retrospective multicenter cohort study of patients with acute ischemic stroke and large vessel occlusion (AIS-LVO). 629 AIS-LVO patients met inclusion criteria. VO profiles were assessed on admission CT angiography using the Cortical Vein Opacification Score (COVES). Unfavorable VO was defined as COVES ≤ 2. Reperfusion hemorrhages on follow-up imaging were subdivided into no hemorrhage (noRH), hemorrhagic infarction (HI) and parenchymal hematoma (PH). Patients with PH and HI less frequently achieved good clinical outcomes defined as 90-day modified Rankin Scale scores of ≤ 2 (PH: 13.6% vs. HI: 24.6% vs. noRH: 44.1%; p < 0.001). The occurrence of HI and PH on follow-up imaging was more likely in patients with unfavorable compared to patients with favorable VO (HI: 25.1% vs. 17.4%, p = 0.023; PH: 18.3% vs. 8.5%; p = <0.001). In multivariable regression analyses, unfavorable VO increased the likelihood of PH (aOR: 1.84; 95% CI: 1.03-3.37, p = 0.044) and HI (aOR: 2.05; 95% CI: 1.25-3.43, p = 0.005), independent of age, sex, admission National Institutes Health Stroke Scale scores and arterial collateral status. We conclude that unfavorable VO was associated with the occurrence of HI and PH, both related to worse clinical outcomes.



J Cereb Blood Flow Metab: 20 Sep 2022:271678X221127089; epub ahead of print
Winkelmeier L, Heit JJ, Adusumilli G, Geest V, ... Fiehler J, Faizy TD
J Cereb Blood Flow Metab: 20 Sep 2022:271678X221127089; epub ahead of print | PMID: 36127828
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Abstract

Expedited brain cooling: Persistent temperature management from first aid to interhospital treatment.

Xu S, Ji X, Li M, Wu D
Selective brain cooling is a promising technique for improving outcomes in ischemic stroke in the area of reperfusion. A recent study described the efficacy of a new method of selective brain cooling via active conductive head cooling. This is a major step forward in the administration of hypothermic treatment during pre-hospital transfer. However, to enhance the benefits of selective therapeutic cooling, a more comprehensive strategy preventing delay in hypothermic induction and increasing the accuracy of selectivity in the brain should be considered to mitigate the side effects related to therapeutic hypothermia.



J Cereb Blood Flow Metab: 20 Sep 2022:271678X221127088; epub ahead of print
Xu S, Ji X, Li M, Wu D
J Cereb Blood Flow Metab: 20 Sep 2022:271678X221127088; epub ahead of print | PMID: 36127836
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Abstract

Point/counterpoint: We should not take the direction of blood pressure change into consideration for dynamic cerebral autoregulation quantification.

Kostoglou K, Simpson DM, Payne SJ
Over the past years, a wide range of studies have provided evidence of asymmetry in the response of static and dynamic cerebral autoregulation (CA) during increasing and decreasing pressure challenges. The main message is that CA is stronger during transient increases of arterial blood pressure rather than decreases. Here we do not argue against the presence of CA asymmetry but we seek to raise questions regarding the measurement of the effect and whether this effect needs to be taken into account, especially in clinical settings.



J Cereb Blood Flow Metab: 13 Sep 2022:271678X221123442; epub ahead of print
Kostoglou K, Simpson DM, Payne SJ
J Cereb Blood Flow Metab: 13 Sep 2022:271678X221123442; epub ahead of print | PMID: 36113047
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Abstract

Cerebral perfusion in untreated, controlled, and uncontrolled hypertension.

Christie IN, Windsor R, Mutsaerts HJ, Tillin T, ... Gourine AV, Hosford PS
This study evaluated the association between systemic arterial blood pressure and cerebral perfusion in 740 participants of the UK\'s largest tri-ethnic study with measurements of cerebral blood flow (CBF) performed using arterial spin labelling MRI. A significant negative correlation between blood pressure, age and CBF was observed across the patient cohort. The lowest CBF values were recorded in the group of patients with hypertension that were prescribed with anti-hypertensive drugs, but uncontrolled on medication. These findings confirm that hypertension is associated with reduced cerebral perfusion and highlight the importance of blood pressure control for the benefit of maintaining brain blood flow.



J Cereb Blood Flow Metab: 13 Sep 2022:271678X221124644; epub ahead of print
Christie IN, Windsor R, Mutsaerts HJ, Tillin T, ... Gourine AV, Hosford PS
J Cereb Blood Flow Metab: 13 Sep 2022:271678X221124644; epub ahead of print | PMID: 36113055
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Abstract

Increased rates of brain protein synthesis during [N1,N2] sleep: L-[1-C]leucine PET studies in human subjects.

Picchioni D, Schmidt KC, Loutaev I, Pavletic AJ, ... Balkin TJ, Smith CB
During sleep, reduced brain energy demands provide an opportunity for biosynthetic processes like protein synthesis. Sleep is required for some forms of memory consolidation which requires de novo protein synthesis. We measured regional cerebral protein synthesis rates (rCPS) in human subjects to ascertain how rCPS is affected during sleep. Subjects underwent three consecutive L-[1-11C]leucine PET scans with simultaneous polysomnography: 1. rested awake, 2. sleep-deprived awake, 3. sleep. Measured rCPS were similar across the three conditions. Variations in sleep stage times during sleep scans were used to estimate rCPS in sleep stages under the assumption that measured rCPS is the weighted sum of rCPS in each stage, with weights reflecting time and availability of [11C]leucine in that stage. During sleep scans, subjects spent most of the time in N2, N3, and awake and very little time in N1 and REM; rCPS in N1 and REM could not be reliably estimated. When stages N1 and N2 were combined [N1,N2], estimates of rCPS were more robust. In selective regions, estimated rCPS were statistically significantly higher (30-39%) in [N1,N2] compared with N3; estimated rCPS in N3 were similar to values measured in sleep-deprived awake scans. Results indicate increased rates of protein synthesis linked to [N1,N2] sleep.



J Cereb Blood Flow Metab: 07 Sep 2022:271678X221121873; epub ahead of print
Picchioni D, Schmidt KC, Loutaev I, Pavletic AJ, ... Balkin TJ, Smith CB
J Cereb Blood Flow Metab: 07 Sep 2022:271678X221121873; epub ahead of print | PMID: 36071616
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Abstract

Reduced brain oxygen metabolism in patients with multiple sclerosis: Evidence from dual-calibrated functional MRI.

Chandler HL, Stickland RC, Patitucci E, Germuska M, ... Tomassini V, Wise RG
Cerebral energy deficiency is increasingly recognised as an important feature of multiple sclerosis (MS). Until now, we have lacked non-invasive imaging methods to quantify energy utilisation and mitochondrial function in the human brain. Here, we used novel dual-calibrated functional magnetic resonance imaging (dc-fMRI) to map grey-matter (GM) deoxy-haemoglobin sensitive cerebral blood volume (CBVdHb), cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen consumption (CMRO2) in patients with MS (PwMS) and age/sex matched controls. By integrating a flow-diffusion model of oxygen transport, we evaluated the effective oxygen diffusivity of the capillary network (DC) and the partial pressure of oxygen at the mitochondria (PmO2). Significant between-group differences were observed as decreased CBF (p = 0.010), CMRO2 (p < 0.001) and DC (p = 0.002), and increased PmO2 (p = 0.043) in patients compared to controls. No significant differences were observed for CBVdHb (p = 0.389), OEF (p = 0.358), or GM volume (p = 0.302). Regional analysis showed widespread reductions in CMRO2 and DC for PwMS. Our findings may be indicative of reduced oxygen demand or utilisation in the MS brain and mitochondrial dysfunction. Our results suggest changes in brain physiology may precede MRI-detectable GM loss and may contribute to disease progression and neurodegeneration.



J Cereb Blood Flow Metab: 07 Sep 2022:271678X221121849; epub ahead of print
Chandler HL, Stickland RC, Patitucci E, Germuska M, ... Tomassini V, Wise RG
J Cereb Blood Flow Metab: 07 Sep 2022:271678X221121849; epub ahead of print | PMID: 36071645
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Abstract

The variant in methylenetetrahydrofolate reductase causes morphological and functional cerebrovascular deficits in mice.

Reagan AM, Christensen KE, Graham LC, Bedwell AA, ... Rozen R, Howell GR
Vascular contributions to cognitive impairment and dementia (VCID) particularly Alzheimer\'s disease and related dementias (ADRDs) are increasing; however, mechanisms driving cerebrovascular decline are poorly understood. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate and methionine cycles. Variants in MTHFR, notably 677 C> T, are associated with dementias, but no mouse model existed to identify mechanisms by which MTHFR677C > T increases risk. Therefore, MODEL-AD created a novel knock-in (KI) strain carrying the Mthfr677C > T allele on the C57BL/6J background (Mthfr677C > T) to characterize morphology and function perturbed by the variant. Consistent with human clinical data, Mthfr677C > T mice have reduced enzyme activity in the liver and elevated plasma homocysteine levels. MTHFR enzyme activity is also reduced in the Mthfr677C > T brain. Mice showed reduced tissue perfusion in numerous brain regions by PET/CT as well as significantly reduced vascular density, pericyte number and increased GFAP-expressing astrocytes in frontal cortex. Electron microscopy revealed cerebrovascular damage including endothelial and pericyte apoptosis, reduced luminal size, and increased astrocyte and microglial presence in the microenvironment. Collectively, these data support a mechanism by which variations in MTHFR perturb cerebrovascular health laying the foundation to incorporate our new Mthfr677C > T mouse model in studies examining genetic susceptibility for cerebrovascular dysfunction in ADRDs.



J Cereb Blood Flow Metab: 01 Sep 2022:271678X221122644; epub ahead of print
Reagan AM, Christensen KE, Graham LC, Bedwell AA, ... Rozen R, Howell GR
J Cereb Blood Flow Metab: 01 Sep 2022:271678X221122644; epub ahead of print | PMID: 36050860
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Abstract

Diagnostic and prognostic performance of Mxa and transfer function analysis-based dynamic cerebral autoregulation metrics.

Olsen MH, Riberholt C, Plovsing RR, Berg RM, Møller K
Dynamic cerebral autoregulation is often assessed by continuously recorded arterial blood pressure (ABP) and transcranial Doppler-derived mean cerebral blood flow velocity followed by analysis in the time and frequency domain, respectively. Sequential correlation (in the time domain, yielding e.g., the measure mean flow index, Mxa) and transfer function analysis (TFA) (in the frequency domain, yielding, e.g., normalised and non-normalised gain as well as phase in the low frequency domain) are commonly used approaches. This study investigated the diagnostic and prognostic performance of these metrics. We included recordings from 48 healthy volunteers, 19 patients with sepsis, 36 with traumatic brain injury (TBI), and 14 patients admitted to a neurorehabilitation unit. The diagnostic (between healthy volunteers and patients) and prognostic performance (to predict death or poor functional outcome) of Mxa and the TFA measures were assessed by area under the receiver-operating characteristic (AUROC) curves. AUROC curves generally indicated that the measures were \'no better than chance\' (AUROC ∼0.5) both for distinguishing between healthy volunteers and patient groups, and for predicting outcomes in our cohort. No metric emerged as superior for distinguishing between healthy volunteers and different patient groups, for assessing the effect of interventions, or for predicting mortality or functional outcome.



J Cereb Blood Flow Metab: 25 Aug 2022:271678X221121841; epub ahead of print
Olsen MH, Riberholt C, Plovsing RR, Berg RM, Møller K
J Cereb Blood Flow Metab: 25 Aug 2022:271678X221121841; epub ahead of print | PMID: 36008917
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Abstract

Abnormal cerebral microvascular perfusion and reactivity in female offspring of reduced uterine perfusion pressure (RUPP) mice model.

Lara E, Rivera N, González-Bernal A, Rojas D, ... Rodríguez A, Escudero C
Children born from women with preeclampsia have alterations in cerebral neurovascular development and a high risk for developing cognitive alterations. Because cerebral blood vessels are critical components in cerebrovascular development, we evaluated the brain microvascular perfusion and microvascular reactivity (exposed to external stimuli of warm and cold) in pups born to preeclampsia-like syndrome based on the reduction of uterine perfusion (RUPP). Also, we evaluate the angiogenic proteomic profile in those brains. Pregnant mice showed a reduction in uterine flow after RUPP surgery (-40 to 50%) associated with unfavorable perinatal results compared to sham mice. Furthermore, offspring of the RUPP mice exhibited reduced brain microvascular perfusion at postnatal day 5 (P5) compared with offspring from sham mice. This reduction was preferentially observed in females. Also, brain microvascular reactivity to external stimuli (warm and cold) was reduced in pups of RUPP mice. Furthermore, a differential expression of the angiogenic profile associated with inflammation, extrinsic apoptotic, cancer, and cellular senescence processes as the primary signaling impaired process was found in the brains of RUPP-offspring. Then, offspring (P5) from preeclampsia-like syndrome exhibit impaired brain perfusion and microvascular reactivity, particularly in female mice, associated with differential expression of angiogenic proteins in the brain tissue.



J Cereb Blood Flow Metab: 25 Aug 2022:271678X221121872; epub ahead of print
Lara E, Rivera N, González-Bernal A, Rojas D, ... Rodríguez A, Escudero C
J Cereb Blood Flow Metab: 25 Aug 2022:271678X221121872; epub ahead of print | PMID: 36008921
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Abstract

Disturbed microcirculation and hyperaemic response in a murine model of systemic inflammation.

Fruekilde SK, Bailey CJ, Lambertsen KL, Clausen BH, ... Drasbek KR, Gutiérrez-Jiménez E
Systemic inflammation affects cognitive functions and increases the risk of dementia. This phenomenon is thought to be mediated in part by cytokines that promote neuronal survival, but the continuous exposure to which may lead to neurodegeneration. The effects of systemic inflammation on cerebral blood vessels, and their provision of adequate oxygen to support critical brain parenchymal cell functions, remains unclear. Here, we demonstrate that neurovascular coupling is profoundly disturbed in lipopolysaccharide (LPS) induced systemic inflammation in awake mice. In the 24 hours following LPS injection, the hyperaemic response of pial vessels to functional activation was attenuated and delayed. Concurrently, under steady-state conditions, the capillary network displayed a significant increase in the number of capillaries with blocked blood flow, as well as increased duration of \'capillary stalls\'-a phenomenon previously reported in animal models of stroke and Alzheimer\'s disease pathology. We speculate that vascular changes and impaired oxygen availability may affect brain functions following acute systemic inflammation and contribute to the long-term risk of neurodegenerative changes associated with chronic, systemic inflammation.



J Cereb Blood Flow Metab: 23 Aug 2022:271678X221112278; epub ahead of print
Fruekilde SK, Bailey CJ, Lambertsen KL, Clausen BH, ... Drasbek KR, Gutiérrez-Jiménez E
J Cereb Blood Flow Metab: 23 Aug 2022:271678X221112278; epub ahead of print | PMID: 35999817
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Abstract

Transfer function analysis of dynamic cerebral autoregulation: a CARNet white paper 2022 update.

Panerai RB, Brassard P, Burma JS, Castro P, ... Simpson DM, Cerebrovascular Research Network (CARNet)
Cerebral autoregulation (CA) refers to the control of cerebral tissue blood flow (CBF) in response to changes in perfusion pressure. Due to the challenges of measuring intracranial pressure, CA is often described as the relationship between mean arterial pressure (MAP) and CBF. Dynamic CA (dCA) can be assessed using multiple techniques, with transfer function analysis (TFA) being the most common. A 2016 white paper by members of an international Cerebrovascular Research Network (CARNet) that is focused on CA strove to improve TFA standardization by way of introducing data acquisition, analysis, and reporting guidelines. Since then, additional evidence has allowed for the improvement and refinement of the original recommendations, as well as for the inclusion of new guidelines to reflect recent advances in the field. This second edition of the white paper contains more robust, evidence-based recommendations, which have been expanded to address current streams of inquiry, including optimizing MAP variability, acquiring CBF estimates from alternative methods, estimating alternative dCA metrics, and incorporating dCA quantification into clinical trials. Implementation of these new and revised recommendations is important to improve the reliability and reproducibility of dCA studies, and to facilitate inter-institutional collaboration and the comparison of results between studies.



J Cereb Blood Flow Metab: 12 Aug 2022:271678X221119760; epub ahead of print
Panerai RB, Brassard P, Burma JS, Castro P, ... Simpson DM, Cerebrovascular Research Network (CARNet)
J Cereb Blood Flow Metab: 12 Aug 2022:271678X221119760; epub ahead of print | PMID: 35962478
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Abstract

Effects of increased intracranial pressure on cerebrospinal fluid influx, cerebral vascular hemodynamic indexes, and cerebrospinal fluid lymphatic efflux.

Xiang T, Feng D, Zhang X, Chen Y, ... Zhang J, Jiang R
The glymphatic-lymphatic fluid transport system (GLFTS) consists of glymphatic pathway and cerebrospinal fluid (CSF) lymphatic outflow routes, allowing biological liquids from the brain parenchyma to access the CSF along with perivascular space and to be cleaned out of the skull through lymphatic vessels. It is known that increased local pressure due to physical compression of tissue improves lymphatic transport in peripheral organs, but little is known about the exact relationship between increased intracranial pressure (IICP) and GLFTS. In this study, we verify our hypothesis that IICP significantly impacts GLFTS, and this effect depends on severity of the IICP. Using a previously developed inflating balloon model to induce IICP and inject fluorescent tracers into the cisterna magna, we found significant impairment of the glymphatic circulation after IICP. We further found that cerebrovascular occlusion occurred, and cerebrovascular pulsation decreased after IICP. IICP also interrupted the drainage of deep cervical lymph nodes and dorsal meningeal lymphatic function, enhancing spinal lymphatic outflow to the sacral lymph nodes. Notably, these effects were associated with the severity of IICP. Thus, our findings proved that the intensity of IICP significantly impacts GLFTS. This may have translational applications for preventing and treating related neurological disorders.



J Cereb Blood Flow Metab: 12 Aug 2022:271678X221119855; epub ahead of print
Xiang T, Feng D, Zhang X, Chen Y, ... Zhang J, Jiang R
J Cereb Blood Flow Metab: 12 Aug 2022:271678X221119855; epub ahead of print | PMID: 35962479
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Abstract

Persistent neuroinflammation and behavioural deficits after single mild traumatic brain injury.

Drieu A, Lanquetin A, Prunotto P, Gulhan Z, ... Vivien D, Ali C
Despite an apparently silent imaging, some patients with mild traumatic brain injury (TBI) experience cognitive dysfunctions, which may persist chronically. Brain changes responsible for these dysfunctions are unclear and commonly overlooked. It is thus crucial to increase our understanding of the mechanisms linking the initial event to the functional deficits, and to provide objective evidence of brain tissue alterations underpinning these deficits. We first set up a murine model of closed-head controlled cortical impact, which provoked persistent cognitive and sensorimotor deficits, despite no evidence of brain contusion or bleeding on MRI, thus recapitulating features of mild TBI. Molecular MRI for P-selectin, a key adhesion molecule, detected no sign of cerebrovascular inflammation after mild TBI, as confirmed by immunostainings. By contrast, in vivo PET imaging with the TSPO ligand [18F]DPA-714 demonstrated persisting signs of neuroinflammation in the ipsilateral cortex and hippocampus after mild TBI. Interestingly, immunohistochemical analyses confirmed these spatio-temporal profiles, showing a robust parenchymal astrogliosis and microgliosis, at least up to 3 weeks post-injury in both the cortex and hippocampus. In conclusion, we show that even one single mild TBI induces long-term behavioural deficits, associated with a persistent neuro-inflammatory status that can be detected by PET imaging.



J Cereb Blood Flow Metab: 09 Aug 2022:271678X221119288; epub ahead of print
Drieu A, Lanquetin A, Prunotto P, Gulhan Z, ... Vivien D, Ali C
J Cereb Blood Flow Metab: 09 Aug 2022:271678X221119288; epub ahead of print | PMID: 35945692
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Abstract

Microglia: Active participants in brain capillary function.

Dufort C, Wang Y, Hu X
A recent study by Bisht, Okojie, and Sharma, et al. characterizes a population of capillary-associated microglia (CAM) whose cell bodies are positioned along small blood vessels in the healthy mouse brain. Through elegant, longitudinal intravital imaging of brain vasculature and CAMs, the authors have uncovered the significance of microglia in cerebral blood flow regulation. Further investigation into the functions of this CAM population and how they interact with surrounding cells within the neurovascular unit will improve our understanding of vascular regulation and cerebrovascular diseases.



J Cereb Blood Flow Metab: 08 Aug 2022:271678X221119292; epub ahead of print
Dufort C, Wang Y, Hu X
J Cereb Blood Flow Metab: 08 Aug 2022:271678X221119292; epub ahead of print | PMID: 35942567
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Abstract

Unique expression of the atypical mitochondrial subunit NDUFA4L2 in cerebral pericytes fine tunes HIF activity in response to hypoxia.

Mesa-Ciller C, Turiel G, Guajardo-Grence A, Lopez-Rodriguez AB, ... Aragonés J, Urrutia AA
A central response to insufficient cerebral oxygen delivery is a profound reprograming of metabolism, which is mainly regulated by the Hypoxia Inducible Factor (HIF). Among other responses, HIF induces the expression of the atypical mitochondrial subunit NDUFA4L2. Surprisingly, NDUFA4L2 is constitutively expressed in the brain in non-hypoxic conditions. Analysis of publicly available single cell transcriptomic (scRNA-seq) data sets coupled with high-resolution multiplexed fluorescence RNA in situ hybridization (RNA F.I.S.H.) revealed that in the murine and human brain NDUFA4L2 is exclusively expressed in mural cells with the highest levels found in pericytes and declining along the arteriole-arterial smooth muscle cell axis. This pattern was mirrored by COX4I2, another atypical mitochondrial subunit. High NDUFA4L2 expression was also observed in human brain pericytes in vitro, decreasing when pericytes are muscularized and further induced by HIF stabilization in a PHD2/PHD3 dependent manner. In vivo, Vhl conditional inactivation in pericyte targeting Ng2-cre transgenic mice dramatically induced NDUFA4L2 expression. Finally NDUFA4L2 inactivation in pericytes increased oxygen consumption and therefore the degree of HIF pathway induction in hypoxia. In conclusion our work reveals that NDUFA4L2 together with COX4I2 is a key hypoxic-induced metabolic marker constitutively expressed in pericytes coupling mitochondrial oxygen consumption and cellular hypoxia response.



J Cereb Blood Flow Metab: 04 Aug 2022:271678X221118236; epub ahead of print
Mesa-Ciller C, Turiel G, Guajardo-Grence A, Lopez-Rodriguez AB, ... Aragonés J, Urrutia AA
J Cereb Blood Flow Metab: 04 Aug 2022:271678X221118236; epub ahead of print | PMID: 35929074
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Abstract

Vascular topology and blood flow are acutely impacted by experimental febrile status epilepticus.

Salehi A, Salari S, Jullienne A, Daglian J, ... Baram TZ, Obenaus A
Febrile status epilepticus (FSE) is an important risk factor for temporal lobe epilepsy and early identification of those at high risk for epilepsy is vital. In a rat model of FSE, we identified an acute (2 hrs) novel MRI signal where reduced T2 relaxation values in the basolateral amygdala (BLA) predicted epilepsy in adulthood; this T2 signal remains incompletely understood and we hypothesized that it may be influenced by vascular topology. Experimental FSE induced in rat pups reduced blood vessel density of the cortical vasculature in a lateralized manner at 2 hrs post FSE. Middle cerebral artery (MCA) exhibited abnormal topology in FSE pups but not in controls. In the BLA, significant vessel junction reductions and decreased vessel diameter were observed, together with a strong trend for reduced vessel length. Perfusion weighted MRI (PWI) was acutely increased cerebral blood flow (CBF) in cortex, amygdala and hippocampus of FSE pups that correlated to decreased T2 relaxation values compared to controls. This is consistent with increased levels of deoxyhemoglobin associated with increased metabolic demand. In summary, FSE acutely modifies vascular topological and CBF in cortex and BLA that may underlie acute MRI signal changes that predict progression to future epilepsy.



J Cereb Blood Flow Metab: 01 Aug 2022:271678X221117625; epub ahead of print
Salehi A, Salari S, Jullienne A, Daglian J, ... Baram TZ, Obenaus A
J Cereb Blood Flow Metab: 01 Aug 2022:271678X221117625; epub ahead of print | PMID: 35912523
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Abstract

Whole-brain perfusion mapping in mice by dynamic BOLD MRI with transient hypoxia.

Lee D, Le TT, Im GH, Kim SG
Non-invasive mapping of cerebral perfusion is critical for understanding neurovascular and neurodegenerative diseases. However, perfusion MRI methods cannot be easily implemented for whole-brain studies in mice because of their small size. To overcome this issue, a transient hypoxia stimulus was applied to induce a bolus of deoxyhemoglobins as an endogenous paramagnetic contrast in blood oxygenation level-dependent (BOLD) MRI. Based on stimulus-duration-dependent studies, 5 s anoxic stimulus was chosen, which induced a decrease in arterial oxygenation to 59%. Dynamic susceptibility changes were acquired with whole-brain BOLD MRI using both all-vessel-sensitive gradient-echo and microvascular-sensitive spin-echo readouts. Cerebral blood flow (CBF) and cerebral blood volume (CBV) were quantified by modeling BOLD dynamics using a partial-volume-corrected arterial input function. In the mouse under ketamine/xylazine anesthesia, total CBF and CBV were 112.0 ± 15.0 ml/100 g/min and 3.39 ± 0.59 ml/100 g (n = 15 mice), respectively, whereas microvascular CBF and CBV were 85.8 ± 6.9 ml/100 g/min and 2.23 ± 0.27 ml/100 g (n = 7 mice), respectively. Regional total vs. microvascular perfusion metrics were highly correlated but a slight mismatch was observed in the large-vessel areas and cortical depth profiles. Overall, this non-invasive, repeatable, simple hypoxia BOLD-MRI approach is viable for perfusion mapping of rodents.



J Cereb Blood Flow Metab: 28 Jul 2022:271678X221117008; epub ahead of print
Lee D, Le TT, Im GH, Kim SG
J Cereb Blood Flow Metab: 28 Jul 2022:271678X221117008; epub ahead of print | PMID: 35903000
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Abstract

Evidence for the beneficial effect of ketamine in the treatment of patients with post-traumatic stress disorder: A systematic review and meta-analysis.

Albuquerque TR, Macedo LFR, Delmondes GA, Rolim Neto ML, ... Lisboa KWSC, Menezes IRA
Post-traumatic stress disorder (PTSD) is an anxiety disorder with manifestations somatic resulting from reliving the trauma. The therapy for the treatment of PTSD has limitations, between reduced efficacy and \"PTSD pharmacotherapeutic crisis\". Scientific evidence has shown that the use of ketamine has benefits for the treatment of depressive disorders and other symptoms present in PTSD compared to other conventional therapies. Therefore, this study aims to analyze the available evidence on the effect of ketamine in the treatment of post-traumatic stress. The systematic review and the meta-analysis were conducted following PRISMA guidelines and RevManager software, using randomized controlled trials and eligible studies of quality criteria for data extraction and analysis. The sample design evaluated included the last ten years, whose search resulted in 594 articles. After applying the exclusion criteria, 35 articles were selected, of which 14 articles were part of the sample, however, only six articles were selected the meta-analysis. The results showed that the ketamine is a promising drug in the management of PTSD with effect more evident performed after 24 h evaluated by MADRS scale. However, the main limitations of the present review demonstrate that more high-quality studies are needed to investigate the influence of therapy, safety, and efficacy.



J Cereb Blood Flow Metab: 26 Jul 2022:271678X221116477; epub ahead of print
Albuquerque TR, Macedo LFR, Delmondes GA, Rolim Neto ML, ... Lisboa KWSC, Menezes IRA
J Cereb Blood Flow Metab: 26 Jul 2022:271678X221116477; epub ahead of print | PMID: 35891578
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Abstract

Ischemia preconditioning induces an adaptive response that defines a circulating metabolomic signature in ischemic stroke patients.

Sol J, Colàs-Campàs L, Mauri-Capdevila G, Molina-Seguin J, ... Jové M, Purroy F
Transient ischemic attacks (TIAs) before an acute ischemic stroke (AIS) could induce ischemic tolerance (IT) phenomena. with an endogenous neuroprotective role (Ischemic preconditioning. IPC). A consecutive prospective cohort of patients with AIS were recruited from 8 different hospitals. Participants were classified by those with non-previous recent TIA vs. previous TIA (within seven days. TIA ≤7d). A total of 541 AIS patients were recruited. 40 (7.4%). of them had previous TIA ≤7d. In line with IPC. patients with TIA ≤7d showed: 1) a significantly less severe stroke at admission by NIHSS score. 2) a better outcome at 7-90 days follow-up and reduced infarct volumes. 3) a specific upregulated metabolomics/lipidomic profile composed of diverse lipid categories. Effectively. IPC activates an additional adaptive response on increasing circulation levels of structural and bioactive lipids to facilitate functional recovery after AIS which may support biochemical machinery for neuronal survival. Furthermore. previous TIA before AIS seems to facilitate the production of anti-inflammatory mediators that contribute to a better immune response. Thus. the IT phenomena contributes to a better adaptation of further ischemia. Our study provides first-time evidence of a metabolomics/lipidomic signature related to the development of stroke tolerance in AIS patients induced by recent TIA.



J Cereb Blood Flow Metab: 22 Jul 2022:271678X221116288; epub ahead of print
Sol J, Colàs-Campàs L, Mauri-Capdevila G, Molina-Seguin J, ... Jové M, Purroy F
J Cereb Blood Flow Metab: 22 Jul 2022:271678X221116288; epub ahead of print | PMID: 35869638
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Abstract

Brain-derived programmed death-ligand 1 mediates immunosuppression post intracerebral hemorrhage.

Cheng N, Wang H, Zou M, Jin WN, Shi FD, Shi K
Immunosuppression commonly occurs after a stroke, which is believed to be associated with the increased risk of infectious comorbidities of stroke patients, while the mechanisms underlying post-stroke immunosuppression is yet to be elucidated. In the brains of intracerebral hemorrhage (ICH) patients and murine ICH models, we identified that neuron-derived programmed death-ligand 1 (PD-L1) is reduced in the perihematomal area, associating increased soluble PD-L1 level in the peripheral blood. ICH induced a significant decrease of T and natural killer (NK) cell numbers in the periphery with an upregulation of programed death-1 (PD-1) in these cells. Blocking PD-1 pathway with an anti-PD1 monoclonal antibody prevented the T and NK cell compartment contraction and spleen atrophy post-ICH, with reduced pulmonary bacterial burden and improved neurological outcome. Thus, we here identified that brain-derived PD-L1 as a new mechanism driving post-stroke immunosuppression, and anti-PD1 treatment could be potentially developed to reducing the risk of post-stroke infections.



J Cereb Blood Flow Metab: 21 Jul 2022:271678X221116048; epub ahead of print
Cheng N, Wang H, Zou M, Jin WN, Shi FD, Shi K
J Cereb Blood Flow Metab: 21 Jul 2022:271678X221116048; epub ahead of print | PMID: 35861238
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Abstract

Epigenetic mechanisms and potential therapeutic targets in stroke.

Morris-Blanco KC, Chokkalla AK, Arruri V, Jeong S, Probelsky SM, Vemuganti R
Accumulating evidence indicates a central role for epigenetic modifications in the progression of stroke pathology. These epigenetic mechanisms are involved in complex and dynamic processes that modulate post-stroke gene expression, cellular injury response, motor function, and cognitive ability. Despite decades of research, stroke continues to be classified as a leading cause of death and disability worldwide with limited clinical interventions. Thus, technological advances in the field of epigenetics may provide innovative targets to develop new stroke therapies. This review presents the evidence on the impact of epigenomic readers, writers, and erasers in both ischemic and hemorrhagic stroke pathophysiology. We specifically explore the role of DNA methylation, DNA hydroxymethylation, histone modifications, and epigenomic regulation by long non-coding RNAs in modulating gene expression and functional outcome after stroke. Furthermore, we highlight promising pharmacological approaches and biomarkers in relation to epigenetics for translational therapeutic applications.



J Cereb Blood Flow Metab: 19 Jul 2022:271678X221116192; epub ahead of print
Morris-Blanco KC, Chokkalla AK, Arruri V, Jeong S, Probelsky SM, Vemuganti R
J Cereb Blood Flow Metab: 19 Jul 2022:271678X221116192; epub ahead of print | PMID: 35854641
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Abstract

Resuscitation with epinephrine worsens cerebral capillary no-reflow after experimental pediatric cardiac arrest: An multiphoton microscopy evaluation.

Oghifobibi OA, Toader AE, Nicholas MA, Nelson BP, ... Vazquez AL, Manole MD
Epinephrine is the principal resuscitation therapy for pediatric cardiac arrest (CA). Clinical data suggest that although epinephrine increases the rate of resuscitation, it fails to improve neurological outcome, possibly secondary to reductions in microvascular flow. We characterized the effect of epinephrine vs. placebo administered at resuscitation from pediatric asphyxial CA on microvascular and macrovascular cortical perfusion assessed using in vivo multiphoton microscopy and laser speckle flowmetry, respectively, and on brain tissue oxygenation (PbO2), behavioral outcomes, and neuropathology in 16-18-day-old rats. Epinephrine-treated rats had a more rapid return of spontaneous circulation and brisk immediate cortical reperfusion during 1-3 min post-CA vs. placebo. However, at the microvascular level, epinephrine-treated rats had penetrating arteriole constriction and increases in both capillary stalling (no-reflow) and cortical capillary transit time 30-60 min post-CA vs. placebo. Placebo-treated rats had increased capillary diameters post-CA. The cortex was hypoxic post-CA in both groups. Epinephrine treatment worsened reference memory performance vs. shams. Hippocampal neuron counts did not differ between groups. Resuscitation with epinephrine enhanced immediate reperfusion but produced microvascular alterations during the first hour post-resuscitation, characterized by vasoconstriction, capillary stasis, prolonged cortical transit time, and absence of compensatory cortical vasodilation. Targeted therapies mitigating the deleterious microvascular effects of epinephrine are needed.



J Cereb Blood Flow Metab: 19 Jul 2022:271678X221113022; epub ahead of print
Oghifobibi OA, Toader AE, Nicholas MA, Nelson BP, ... Vazquez AL, Manole MD
J Cereb Blood Flow Metab: 19 Jul 2022:271678X221113022; epub ahead of print | PMID: 35854408
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Abstract

Cell-specific expression and function of laminin at the neurovascular unit.

Nirwane A, Yao Y
Laminin, a major component of the basal lamina (BL), is a heterotrimeric protein with many isoforms. In the CNS, laminin is expressed by almost all cell types, yet different cells synthesize distinct laminin isoforms. By binding to its receptors, laminin exerts a wide variety of important functions. However, due to the reciprocal and cell-specific expression of laminin in different cells at the neurovascular unit, its functions in blood-brain barrier (BBB) maintenance and BBB repair after injury are not fully understood. In this review, we focus on the expression and functions of laminin and its receptors in the neurovascular unit under both physiological and pathological conditions. We first briefly introduce the structures of laminin and its receptors. Next, the expression and functions of laminin and its receptors in the CNS are summarized in a cell-specific manner. Finally, we identify the knowledge gap in the field and discuss key questions that need to be answered in the future. Our goal is to provide a comprehensive overview on cell-specific expression of laminin and its receptors in the CNS and their functions on BBB integrity.



J Cereb Blood Flow Metab: 07 Jul 2022:271678X221113027; epub ahead of print
Nirwane A, Yao Y
J Cereb Blood Flow Metab: 07 Jul 2022:271678X221113027; epub ahead of print | PMID: 35796497
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Abstract

Impaired neuronal integrity in traumatic brain injury detected by I-iomazenil single photon emission computed tomography and MRI.

Kato H, Nakagawara J, Hachisuka K, Hatazawa J, ... Shiga T, Mori E
This study was aiming at investigating the extent of neuronal damage in cases of traumatic brain injury (TBI) with diffuse axonal injury (DAI) using 123I-iomazenil(IMZ) SPECT and MRI. We compared the findings in 31 patients with TBI without any major focal brain lesions and 25 age-matched normal controls. Subjects underwent 123I-IMZ SPECT and MRI, and also assessment by cognitive function tests. The partial volume effect of 123I-IMZ SPECT was corrected using MRI. In the patients with TBI, decreased spatial concentration of 123I-IMZ binding was detected in the medial frontal/orbitofrontal cortex, posterior cingulate gyrus, cuneus, precuneus, and superior region of the cerebellum. ROC analysis of 123I-IMZ SPECT for the detection of neuronal injury showed a high diagnostic ability of 123I-IMZ binding density for TBI in these areas. The decreased 123I-IMZ uptake density in the cuneus and precuneus was associated with cognitive decline after the injury. In the patients with TBI, brain atrophy was detected in the frontal lobe, anterior temporal and parietal cortex, corpus callosum, and posterior part of the cerebellum. Evaluation of the neuronal integrity by 123I-IMZ SPECT and MRI provides important information for the diagnosis and pathological interpretation in cases of TBI with DAI.



J Cereb Blood Flow Metab: 07 Jul 2022:271678X221113001; epub ahead of print
Kato H, Nakagawara J, Hachisuka K, Hatazawa J, ... Shiga T, Mori E
J Cereb Blood Flow Metab: 07 Jul 2022:271678X221113001; epub ahead of print | PMID: 35796498
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Abstract

Association between the time of day at stroke onset and functional outcome of acute ischemic stroke patients treated with endovascular therapy.

Wang X, Wang X, Ma J, Jia M, ... Zhao W, Ji X
To investigate the association between time-of-day of stroke onset and functional outcome in patients with acute ischemic stroke(AIS) treated with endovascular thrombectomy(EVT). AIS patients treated with EVT between January 2013 and December 2018 were recruited and divided them into four 6-h interval groups according to the time-of-day of stroke onset. A total of 438 patients were enrolled, 3-month favorable outcome were achieved in 58.6%, 43.7%, 36.6%, and 30.5% of patients in the 00:00-06:00, 06:00-12:00, 12:00-18:00, and 18:00-24:00 groups, respectively (adjusted OR 0.61, 95% CI 0.40-0.93; p = 0.020). Compared with the 18:00-24:00 interval, patients in the 00:00-06:00 interval (adjusted OR 4.01, 95%CI 1.02-15.80, p = 0.047) and the 06:00-12:00 interval (adjusted OR 3.24, 95% CI 1.09-9.64, p = 0.034) were more likely to achieve favorable outcome. The time-of-day of stroke onset was not associated with 3-month mortality (adjusted p = 0.829), symptomatic intracerebral hemorrhage (sICH, adjusted p = 0.296), or early successful recanalization (adjusted p = 0.074). In conclusion, in AIS patients treated with EVT, those onsets either between 00:00 and 06:00 or between 06:00 and 12:00 appeared to be associated with a higher proportion of favorable outcomes at 3 months, but the time-of-day at stroke onset was not associated with the incidence of sICH, rate of early successful recanalization, or 3-month mortality.



J Cereb Blood Flow Metab: 05 Jul 2022:271678X221111852; epub ahead of print
Wang X, Wang X, Ma J, Jia M, ... Zhao W, Ji X
J Cereb Blood Flow Metab: 05 Jul 2022:271678X221111852; epub ahead of print | PMID: 35791272
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This program is still in alpha version.