<div><h4>The negative effect of aging on cerebral venous outflow in acute ischemic stroke.</h4><i>Heitkamp C, Winkelmeier L, Heit JJ, Flottmann F, ... Fiehler J, Faizy TD</i><br /><AbstractText>Cortical venous outflow (VO) represents an imaging biomarker of increasing interest in patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO). We conducted a retrospective multicenter cohort study to investigate the effect of aging on VO. A total of 784 patients met the inclusion criteria. Cortical Vein Opacification Score (COVES) was used to assess VO profiles on admission CT angiography. Cerebral microperfusion was determined using the hypoperfusion intensity ratio (HIR) derived from perfusion imaging. Arterial collaterals were assessed using the Tan scale. Multivariable regression analysis was performed to identify independent determinants of VO, HIR and arterial collaterals. In multivariable regression, higher age correlated with worse VO (adjusted odds ratio [95% CI]; 0.83 [0.73-0.95]; <i>P</i> = 0.006) and poorer HIR (β coefficient [95% CI], 0.014 [0.005-0.024]; <i>P = </i>0.002). The negative effect of higher age on VO was mediated by the extent of HIR (17.3%). We conclude that higher age was associated with worse VO in AIS-LVO, partially explained by the extent of HIR reflecting cerebral microperfusion. Our study underlines the need to assess collateral blood flow beyond the arterial system and provides valuable insights into deteriorated cerebral blood supply in elderly AIS-LVO patients.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 31 May 2023:271678X231179558; epub ahead of print</small></div>

<div><h4>Cerebral multi-autoregulation model based enhanced external counterpulsation treatment planning for cerebral ischemic stroke.</h4><i>Li B, Liu Y, Liu J, Sun H, ... Zhang Z, Zhang L</i><br /><AbstractText>Enhanced external counterpulsation (EECP) treatment for cerebral ischemic stroke patients with differing severity of stenosis, is subject to uncertainties due to the varying effects of the cerebral autoregulation mechanism on haemodynamics. The current study reports the development of a cerebral multi-autoregulation (MR) mathematical model, based on cerebral arteriole regulation of neurogenic, vascular smooth muscle reflex and shear stress mechanisms which takes into account the severity of stenosis. The model was evaluated by comparison to authentic clinical measurements of cerebral autoregulatory efficiency. Then it was applied to a 0D/3D geometric multi-scale haemodynamic model of a cerebral artery. Haemodynamic indicators were calculated under different pressurization durations of EECP to evaluate the efficacy for different stenosis lesions. Moderate stenosis of 50% to 60% produced excessive time-averaged wall shear stress in the distal area of the stenosis (>7 Pa) during prolonged pressurization and may result in damage to vascular endothelial cells. However, prolonged pressurization did not result in haemodynamic risk for severe stenosis of 70% to 80%, indicating that the duration of pressurization may be extended with increasing severity of stenosis. The current MR model accurately simulated cerebral blood flow and has relevance to the simulation of cerebral haemodynamics in a clinical setting.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 31 May 2023:271678X231179542; epub ahead of print</small></div>

<div><h4>Non-human primate models of focal cortical ischemia for neuronal replacement therapy.</h4><i>Mu J, Hao P, Duan H, Zhao W, ... Yang Z, Li X</i><br /><AbstractText>Despite the high prevalence, stroke remains incurable due to the limited regeneration capacity in the central nervous system. Neuronal replacement strategies are highly diverse biomedical fields that attempt to replace lost neurons by utilizing exogenous stem cell transplants, biomaterials, and direct neuronal reprogramming. Although these approaches have achieved encouraging outcomes mostly in the rodent stroke model, further preclinical validation in non-human primates (NHP) is still needed prior to clinical trials. In this paper, we briefly review the recent progress of promising neuronal replacement therapy in NHP stroke studies. Moreover, we summarize the key characteristics of the NHP as highly valuable translational tools and discuss (1) NHP species and their advantages in terms of genetics, physiology, neuroanatomy, immunology, and behavior; (2) various methods for establishing NHP focal ischemic models to study the regenerative and plastic changes associated with motor functional recovery; and (3) a comprehensive analysis of experimentally and clinically accessible outcomes and a potential adaptive mechanism. Our review specifically aims to facilitate the selection of the appropriate NHP cortical ischemic models and efficient prognostic evaluation methods in preclinical stroke research design of neuronal replacement strategies.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 31 May 2023:271678X231179544; epub ahead of print</small></div>

<div><h4>Visualising and semi-quantitatively measuring brain fluid pathways, including meningeal lymphatics, in humans using widely available MRI techniques.</h4><i>Sennfält S, Thrippleton MJ, Stringer M, Reyes CA, ... Cheng Y, Wardlaw J</i><br /><AbstractText>Brain fluid dynamics remains poorly understood with central issues unresolved. In this study, we first review the literature regarding points of controversy, then pilot study if conventional MRI techniques can assess brain fluid outflow pathways and explore potential associations with small vessel disease (SVD). We assessed 19 subjects participating in the Mild Stroke Study 3 who had FLAIR imaging before and 20-30 minutes after intravenous Gadolinium (Gd)-based contrast. Signal intensity (SI) change was assessed semi-quantitatively by placing regions of interest, and qualitatively by a visual scoring system, along dorsal and basal fluid outflow routes. Following i.v. Gd, SI increased substantially along the anterior, middle, and posterior superior sagittal sinus (SSS) (82%, 104%, and 119%, respectively), at basal areas (cribriform plate, 67%; jugular foramina, 72%), and in narrow channels surrounding superficial cortical veins separated from surrounding cerebrospinal fluid (CSF) (96%) (all p < 0.001). The SI increase was associated with higher intraparenchymal perivascular spaces (PVS) scores (Std. Beta 0.71, p = 0.01). Our findings suggests that interstitial fluid drainage is visible on conventional MRI and drains from brain parenchyma via cortical perivenous spaces to dural meningeal lymphatics along the SSS remaining separate from the CSF. An association with parenchymal PVS requires further research, now feasible in humans.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 31 May 2023:271678X231179555; epub ahead of print</small></div>

<div><h4>Antihypertensives in dementia: Good or bad for the brain?</h4><i>Heutz RA, Weijs RW, de Heus RA, Claassen JA</i><br /><AbstractText>We discuss the current evidence for both benefit and harm of antihypertensive treatment in people with dementia. We conclude that there is a lack of evidence to support the claim that there is an increased risk of cerebral hypoperfusion with antihypertensive treatment in dementia, and that there is growing evidence which refutes this claim.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 27 May 2023:271678X231179421; epub ahead of print</small></div>

<div><h4>Cerebrovascular glycocalyx damage and microcirculation impairment in patients with temporal lobe epilepsy.</h4><i>van Lanen RH, Haeren RH, Staals J, Dings JT, ... Vink H, Rijkers K</i><br /><AbstractText>Temporal lobe epilepsy (TLE) is increasingly associated with blood-brain barrier dysfunction and microvascular alterations, yet the pathophysiological link is missing. An important barrier function is exerted by the glycocalyx, a gel-like layer coating the endothelium. To explore such associations, we used intraoperative videomicroscopy to quantify glycocalyx and microcirculation properties of the neocortex and hippocampus of 15 patients undergoing resective brain surgery as treatment for drug-resistant TLE, and 15 non-epileptic controls. Fluorescent lectin staining of neocortex and hippocampal tissue was used for blood vessel surface area quantification. Neocortical perfused boundary region, the thickness of the glycocalyx\' impaired layer, was higher in patients (2.64 ± 0.52 µm) compared to controls (1.31 ± 0.29 µm), <i>P < </i>0.01, indicative of reduced glycocalyx integrity in patients. Moreover, erythrocyte flow velocity analysis revealed an impaired ability of TLE patients to (de-)recruit capillaries in response to changing metabolic demands (<i>R</i><sup>2</sup> = 0.75, <i>P < </i>0.01), indicating failure of neurovascular coupling mechanisms. Blood vessel quantification comparison between intraoperative measurements and resected tissue showed strong correlation (<i>R</i><sup>2</sup> = 0.94, <i>P < </i>0.01). This is the first report on <i>in vivo</i> assessment of glycocalyx and microcirculation properties in TLE patients, confirming the pivotal role of cerebrovascular changes. Further assessment of the cerebral microcirculation in relation to epileptogenesis might open avenues for new therapeutic targets for drug-resistant epilepsy.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 26 May 2023:271678X231179413; epub ahead of print</small></div>

<div><h4>Genetic, vascular, and amyloid components of cerebral blood flow in a preclinical population.</h4><i>Padrela BE, Lorenzini L, Collij LE, García DV, ... Braber AD, Mutsaerts HJ</i><br /><AbstractText>Aging-related cognitive decline can be accelerated by a combination of genetic factors, cardiovascular and cerebrovascular dysfunction, and amyloid-β burden. Whereas cerebral blood flow (CBF) has been studied as a potential early biomarker of cognitive decline, its normal variability in healthy elderly is less known. In this study, we investigated the contribution of genetic, vascular, and amyloid-β components of CBF in a cognitively unimpaired (CU) population of monozygotic older twins. We included 134 participants who underwent arterial spin labeling (ASL) MRI and [<sup>18</sup>F]flutemetamol amyloid-PET imaging at baseline and after a four-year follow-up. Generalized estimating equations were used to investigate the associations of amyloid burden and white matter hyperintensities with CBF. We showed that, in CU individuals, CBF: 1) has a genetic component, as within-pair similarities in CBF values were moderate and significant (ICC > 0.40); 2) is negatively associated with cerebrovascular damage; and 3) is positively associated with the interaction between cardiovascular risk scores and early amyloid-β burden, which may reflect a vascular compensatory response of CBF to early amyloid-β accumulation. These findings encourage future studies to account for multiple interactions with CBF in disease trajectory analyses.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 26 May 2023:271678X231178993; epub ahead of print</small></div>

<div><h4>Genetic insights into the risk of metabolic syndrome and its components on stroke and its subtypes: Bidirectional Mendelian randomization.</h4><i>He Q, Wang W, Li H, Xiong Y, ... Ma L, You C</i><br /><AbstractText>The role of metabolic syndrome (MetS) on stroke has been explored only in many observational studies. We conducted Mendelian randomization (MR) to clarify whether or not the genetically predicted MetS and its components are causally associated with stroke and its subtypes. Genetic instruments of MetS and its components and outcome data sets for stroke and its subtypes came from the gene-wide association study in the UK Biobank and MEGASTROKE consortium, respectively. Inverse variance weighting was utilized as the main method. Genetically predicted MetS, waist circumference (WC), and hypertension increase the risk of stroke. WC and hypertension are related to increased risk of ischemic stroke. MetS, WC, hypertension, and triglycerides (TG) are causally associated with the increasing of large artery stroke. Hypertension increased the risk of cardioembolic stroke. Hypertension and TG lead to 77.43- and 1.19-fold increases, respectively, in small vessel stroke (SVS) risk. The protective role of high-density lipoprotein cholesterol on SVS is identified. Results of the reverse MR analyses show that stroke is related to hypertension risk. From the genetical variants perspective, our study provides novel evidence that early management of MetS and its components are effective strategies to decrease the risk of stroke and its subtypes.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 18 May 2023:271678X231169838; epub ahead of print</small></div>

<div><h4>Neutrophil-derived cathelicidin promotes cerebral angiogenesis after ischemic stroke.</h4><i>Xie W, Huang T, Guo Y, Zhang Y, ... Chen C, Li P</i><br /><AbstractText>Neutrophils play critical roles in the evolving of brain injuries following ischemic stroke. However, how they impact the brain repair in the late phase after stroke remain uncertain. Using a prospective clinical stroke patient cohort, we found significantly increased cathelicidin antimicrobial peptide (CAMP) in the peripheral blood of stroke patients compared to that of healthy controls. While in the mouse stroke model, CAMP was present in the peripheral blood, brain ischemic core and significantly increased at day 1, 3, 7, 14 after middle cerebral artery occlusion (MCAO). CAMP<sup>-/-</sup> mice exhibited significantly increased infarct volume, exacerbated neurological outcome, reduced cerebral endothelial cell proliferation and vascular density at 7 and 14 days after MCAO. Using bEND3 cells subjected to oxygen-glucose deprivation (OGD), we found significantly increased angiogenesis-related gene expression with the treatment of recombinant CAMP peptide (rCAMP) after reoxygenation. Intracerebroventricular injection (ICV) of AZD-5069, the antagonist of CAMP receptor CXCR2, or knockdown of CXCR2 by shCXCR2 recombinant adeno-associated virus (rAAV) impeded angiogenesis and neurological recovery after MCAO. Administration of rCAMP promoted endothelial proliferation and angiogenesis and attenuated neurological deficits 14 days after MCAO. In conclusion, neutrophil derived CAMP represents an important mediator that could promote post-stroke angiogenesis and neurological recovery in the late phase after stroke.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 17 May 2023:271678X231175190; epub ahead of print</small></div>

<div><h4>The neurovascular unit in healthy and injured spinal cord.</h4><i>Zhou R, Li J, Wang R, Chen Z, Zhou F</i><br /><AbstractText>The neurovascular unit (NVU) reflects the close temporal and spatial link between neurons and blood vessels. However, the understanding of the NVU in the spinal cord is far from clear and largely based on generalized knowledge obtained from the brain. Herein, we review the present knowledge of the NVU and highlight candidate approaches to investigate the NVU, particularly focusing on the spinal cord. Several unique features maintain the highly regulated microenvironment in the NVU. Autoregulation and neurovascular coupling ensure regional blood flow meets the metabolic demand according to the blood supply or local neural activation. The blood-central nervous system barrier partitions the circulating blood from neural parenchyma and facilitates the selective exchange of substances. Furthermore, we discuss spinal cord injury (SCI) as a common injury from the perspective of NVU dysfunction. Hopefully, this review will help expand the understanding of the NVU in the spinal cord and inspire new insights into SCI.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 15 May 2023:271678X231172008; epub ahead of print</small></div>

<div><h4>Metformin attenuates white matter injury and cognitive impairment induced by chronic cerebral hypoperfusion.</h4><i>He Y, Li Z, Shi X, Ding J, Wang X</i><br /><AbstractText>Vascular cognitive impairment and dementia (VCID) is a series of cognitive dysfunction associated with cerebrovascular diseases and currently lacks effective treatments. The white matter, which is essential for neuronal information processing and integration, is nourished by a network of capillaries and is vulnerable to chronic hypoperfusion. Here, we show that metformin, a widely used drug for the treatment of type 2 diabetes, alleviates the white matter damage and improves cognitive impairment in a mouse model of VCID established by bilateral carotid artery stenosis (BCAS)-induced chronic hypoperfusion. Mechanistically, metformin restores the dysfunctions of oligodendrocyte precursor cells (OPCs) under hypoxia. Metformin up-regulates prolyl hydroxylases 2 via activating the AMP-activated protein kinase pathway, leading to hypoxia-inducible factor-1α (HIF-1α) degradation in OPCs. These findings suggest that metformin may have a promising therapeutic role in alleviating cognitive abnormalities by ameliorating white matter damage of VCID.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 12 May 2023:271678X231175189; epub ahead of print</small></div>

<div><h4>The multifaceted roles of activating transcription factor 3 (ATF3) in inflammatory responses - Potential target to regulate neuroinflammation in acute brain injury.</h4><i>Li Y, Fan Q, Li F, Pang R, ... Xuan W, Yu W</i><br /><AbstractText>Activating transcription factor 3 (ATF3) is one of the most important transcription factors that respond to and exert dual effects on inflammatory responses. Recently, the involvement of ATF3 in the neuroinflammatory response to acute brain injury (ABI) has been highlighted. It functions by regulating neuroimmune activation and the production of neuroinflammatory mediators. Notably, recent clinical evidence suggests that ATF3 may serve as a potential ideal biomarker of the long-term prognosis of ABI patients. This mini-review describes the essential inflammation modulatory roles of ATF3 in different disease contexts and summarizes the regulatory mechanisms of ATF3 in the ABI-induced neuroinflammation.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 11 May 2023:271678X231171999; epub ahead of print</small></div>

<div><h4>High-physiological and supra-physiological 1,2-C glucose focal supplementation to the traumatised human brain.</h4><i>Stovell MG, Howe DJ, Thelin EP, Jalloh I, ... Hutchinson PJ, Carpenter KL</i><br /><AbstractText>How to optimise glucose metabolism in the traumatised human brain remains unclear, including whether injured brain can metabolise additional glucose when supplied. We studied the effect of microdialysis-delivered 1,2-<sup>13</sup>C<sub>2</sub> glucose at 4 and 8 mmol/L on brain extracellular chemistry using bedside ISCUS<i>flex</i>, and the fate of the <sup>13</sup>C label in the 8 mmol/L group using high-resolution NMR of recovered microdialysates, in 20 patients. Compared with unsupplemented perfusion, 4 mmol/L glucose increased extracellular concentrations of pyruvate (17%, p = 0.04) and lactate (19%, p = 0.01), with a small increase in lactate/pyruvate ratio (5%, p = 0.007). Perfusion with 8 mmol/L glucose did not significantly influence extracellular chemistry measured with ISCUS<i>flex</i>, compared to unsupplemented perfusion. These extracellular chemistry changes appeared influenced by the underlying metabolic states of patients\' traumatised brains, and the presence of relative neuroglycopaenia. Despite abundant <sup>13</sup>C glucose supplementation, NMR revealed only 16.7% <sup>13</sup>C enrichment of recovered extracellular lactate; the majority being glycolytic in origin. Furthermore, no <sup>13</sup>C enrichment of TCA cycle-derived extracellular glutamine was detected. These findings indicate that a large proportion of extracellular lactate does not originate from local glucose metabolism, and taken together with our earlier studies, suggest that extracellular lactate is an important transitional step in the brain\'s production of glutamine.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 08 May 2023:271678X231173584; epub ahead of print</small></div>

<div><h4>Calcium transients in nNOS neurons underlie distinct phases of the neurovascular response to barrel cortex activation in awake mice.</h4><i>Ahn SJ, Anfray A, Anrather J, Iadecola C</i><br /><AbstractText>Neuronal nitric oxide (NO) synthase (nNOS), a Ca<sup>2+</sup> dependent enzyme, is expressed by distinct populations of neocortical neurons. Although neuronal NO is well known to contribute to the blood flow increase evoked by neural activity, the relationships between nNOS neurons activity and vascular responses in the awake state remain unclear. We imaged the barrel cortex in awake, head-fixed mice through a chronically implanted cranial window. The Ca<sup>2+</sup> indicator GCaMP7f was expressed selectively in nNOS neurons using adenoviral gene transfer in nNOS<sup>cre</sup> mice. Air-puffs directed at the contralateral whiskers or spontaneous motion induced Ca<sup>2+</sup> transients in 30.2 ± 2.2% or 51.6 ± 3.3% of nNOS neurons, respectively, and evoked local arteriolar dilation. The greatest dilatation (14.8 ± 1.1%) occurred when whisking and motion occurred simultaneously. Ca<sup>2+</sup> transients in individual nNOS neurons and local arteriolar dilation showed various degrees of correlation, which was strongest when the activity of whole nNOS neuron ensemble was examined. We also found that some nNOS neurons became active immediately prior to arteriolar dilation, while others were activated gradually after arteriolar dilatation. Discrete nNOS neuron subsets may contribute either to the initiation or to the maintenance of the vascular response, suggesting a previously unappreciated temporal specificity to the role of NO in neurovascular coupling.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 07 May 2023:271678X231173175; epub ahead of print</small></div>

<div><h4>Candidate neuroinflammatory markers of cerebral autoregulation dysfunction in human acute brain injury.</h4><i>Smith CA, Carpenter KL, Hutchinson PJ, Smielewski P, Helmy A</i><br /><AbstractText>The loss of cerebral autoregulation (CA) is a common and detrimental secondary injury mechanism following acute brain injury and has been associated with worse morbidity and mortality. However patient outcomes have not as yet been conclusively proven to have improved as a result of CA-directed therapy. While CA monitoring has been used to modify CPP targets, this approach cannot work if the impairment of CA is not simply related to CPP but involves other underlying mechanisms and triggers, which at present are largely unknown. Neuroinflammation, particularly inflammation affecting the cerebral vasculature, is an important cascade that occurs following acute injury. We hypothesise that disturbances to the cerebral vasculature can affect the regulation of CBF, and hence the vascular inflammatory pathways could be a putative mechanism that causes CA dysfunction. This review provides a brief overview of CA, and its impairment following brain injury. We discuss candidate vascular and endothelial markers and what is known about their link to disturbance of the CBF and autoregulation. We focus on human traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH), with supporting evidence from animal work and applicability to wider neurologic diseases.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 03 May 2023:271678X231171991; epub ahead of print</small></div>

<div><h4>Blood-brain barrier leakage hotspots collocating with brain lesions due to sporadic and monogenic small vessel disease.</h4><i>Rudilosso S, Stringer MS, Thrippleton M, Chappell F, ... Wardlaw JM, SVDs@target consortium</i><br /><AbstractText>Blood-brain barrier (BBB) is known to be impaired in cerebral small vessel disease (SVD), and is measurable by dynamic-contrast enhancement (DCE)-MRI. In a cohort of 69 patients (42 sporadic, 27 monogenic SVD), who underwent 3T MRI, including DCE and cerebrovascular reactivity (CVR) sequences, we assessed the relationship of BBB-leakage hotspots to SVD lesions (lacunes, white matter hyperintensities (WMH), and microbleeds). We defined as hotspots the regions with permeability surface area product highest decile on DCE-derived maps within the white matter. We assessed factors associated with the presence and number of hotspots corresponding to SVD lesions in multivariable regression models adjusted for age, WMH volume, number of lacunes, and SVD type. We identified hotspots at lacune edges in 29/46 (63%) patients with lacunes, within WMH in 26/60 (43%) and at the WMH edges in 34/60 (57%) patients with WMH, and microbleed edges in 4/11 (36%) patients with microbleeds. In adjusted analysis, lower WMH-CVR was associated with presence and number of hotspots at lacune edges, and higher WMH volume with hotspots within WMH and at WMH edges, independently of the SVD type. In conclusion, SVD lesions frequently collocate with high BBB-leakage in patients with sporadic and monogenic forms of SVD.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 03 May 2023:271678X231173444; epub ahead of print</small></div>

<div><h4>Differential association of cerebral blood flow and anisocytosis in APOE ε4 carriers at midlife.</h4><i>Dounavi ME, Mak E, Swann P, Low A, ... Ritchie CW, O\'Brien JT</i><br /><AbstractText>Cerebral hemodynamic alterations have been observed in apolipoprotein ε4 (APOE4) carriers at midlife, however the physiological underpinnings of this observation are poorly understood. Our goal was to investigate cerebral blood flow (CBF) and its spatial coefficient of variation (CoV) in relation to APOE4 and a measure of erythrocyte anisocytosis (red blood cell distribution width - RDW) in a middle-aged cohort. Data from 563 participants in the PREVENT-Dementia study scanned with 3 T MRI cross-sectionally were analysed. Voxel-wise and region-of-interest analyses within nine vascular regions were run to detect areas of altered perfusion. Within the vascular regions, interaction terms between APOE4 and RDW in predicting CBF were examined. Areas of hyperperfusion in APOE4 carriers were detected mainly in frontotemporal regions. The APOE4 allele differentially moderated the association between RDW and CBF, an association which was more prominent in the distal vascular territories (p - [0.01, 0.05]). The CoV was not different between the considered groups. We provide novel evidence that in midlife, RDW and CBF are differentially associated in APOE4 carriers and non-carriers. This association is consistent with a differential hemodynamic response to hematological alterations in APOE4 carriers.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 03 May 2023:271678X231173587; epub ahead of print</small></div>

<div><h4>Dynamic cerebral autoregulation in Alzheimer\'s disease and mild cognitive impairment: A systematic review.</h4><i>Heutz R, Claassen J, Feiner S, Davies A, ... Heus R, Beishon LC</i><br /><AbstractText>Dynamic cerebral autoregulation (dCA) is a key mechanism that regulates cerebral blood flow (CBF) in response to transient changes in blood pressure (BP). Impairment of dCA could increase vulnerability to hypertensive vascular damage, but also to BP lowering effects of antihypertensive treatment. The literature remains conflicted on whether dCA is altered in Alzheimer\'s disease (AD) and mild cognitive impairment (MCI). We summarized available data on dCA in AD and MCI, by searching PubMed, Embase, PsycINFO and Web of Science databases (inception-January 2022). Eight studies (total n = 443) were included in the qualitative synthesis of which seven were eligible for meta-analysis. All studies used Transcranial Doppler (TCD) ultrasonography and transfer function analysis or the autoregulatory index to assess dCA during spontaneous or induced BP fluctuations. Meta-analysis indicated no significant difference between AD, MCI and healthy controls in dCA parameters for spontaneous fluctuations. For induced fluctuations, the available data were limited, but indicative of at least preserved and possibly better autoregulatory functioning in AD and MCI compared to controls. In summary, current evidence does not suggest poorer dCA efficiency in AD or MCI. Further work is needed to investigate dCA in dementia with induced fluctuations controlling for changes in end-tidal carbon dioxide.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 01 May 2023:271678X231173449; epub ahead of print</small></div>

<div><h4>Quantification and prospective evaluation of serum NfL and GFAP as blood-derived biomarkers of outcome in acute ischemic stroke patients.</h4><i>Ferrari F, Rossi D, Ricciardi A, Morasso C, ... Corsi F, Truffi M</i><br /><AbstractText>Identification of reliable and accessible biomarkers to characterize ischemic stroke patients\' prognosis remains a clinical challenge. Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are markers of brain injury, detectable in blood by high-sensitive technologies. Our aim was to measure serum NfL and GFAP after stroke, and to evaluate their correlation with functional outcome and the scores in rehabilitation scales at 3-month follow-up. Stroke patients were prospectively enrolled in a longitudinal observational study within 24 hours from symptom onset (D1) and monitored after 7 (D7), 30 ± 3 (M1) and 90 ± 5 (M3) days. At each time-point serum NfL and GFAP levels were measured by Single Molecule Array and correlated with National Institute of Health Stroke Scale (NIHSS), modified Rankin scale (mRS), Trunk Control Test (TCT), Functional Ambulation Classification (FAC) and Functional Independence Measure (FIM) scores. Serum NfL and GFAP showed different temporal profiles: NfL increased after stroke with a peak value at D7; GFAP showed an earlier peak at D1. NfL and GFAP concentrations correlated with clinical/rehabilitation outcomes both longitudinally and prospectively. Multivariate analysis revealed that NfL-D7 and GFAP-D1 were independent predictors of 3-month NIHSS, TCT, FAC and FIM scores, with NfL being the biomarker with the best predictive performance.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 27 Apr 2023:271678X231172520; epub ahead of print</small></div>

<div><h4>Insulin resistance and body mass index are associated with TSPO PET in cognitively unimpaired elderly.</h4><i>Ekblad LL, Tuisku J, Koivumäki M, Helin S, Rinne JO, Snellman A</i><br /><AbstractText>Metabolic risk factors are associated with peripheral low-grade inflammation and an increased risk for dementia. We evaluated if metabolic risk factors i.e. insulin resistance, body mass index (BMI), serum cholesterol values, or high sensitivity C-reactive protein associate with central inflammation or beta-amyloid (Aβ) accumulation in the brain, and if these associations are modulated by <i>APOE4</i> gene dose. Altogether 60 cognitively unimpaired individuals (mean age 67.7 years (SD 4.7); 63% women; 21 <i>APOE3/3</i>, 20 <i>APOE3/4</i> and 19 <i>APOE4</i>/<i>4</i>) underwent positron emission tomography with [<sup>11</sup>C]PK11195 targeting TSPO (18 kDa translocator protein) and [<sup>11</sup>C]PIB targeting fibrillar Aβ. [<sup>11</sup>C]PK11195 distribution value ratios and [<sup>11</sup>C]PIB standardized uptake values were calculated in a cortical composite region of interest typical for Aβ accumulation in Alzheimer\'s disease. Associations between metabolic risk factors, [<sup>11</sup>C]PK11195, and [<sup>11</sup>C]PIB uptake were evaluated with linear models adjusted for age and sex. Higher logarithmic HOMA-IR (standardized beta 0.40, p = 0.002) and BMI (standardized beta 0.27, p = 0.048) were associated with higher TSPO availability. Voxel-wise analyses indicated that this association was mainly seen in the parietal cortex. Higher logarithmic HOMA-IR was associated with higher [<sup>11</sup>C]PIB (standardized beta 0.44, p = 0.02), but only in <i>APOE4/4</i> homozygotes. BMI and HOMA-IR seem to influence TSPO availability in the brain.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 27 Apr 2023:271678X231172519; epub ahead of print</small></div>

<div><h4>JCBFM point/counterpoint series : Point/counterpoint: Cerebrovascular resistance is a flawed concept.</h4><i>Ince J, Minhas JS, Panerai RB</i><br /><AbstractText>The relationship between cerebral blood flow and blood pressure is a critical part of investigation of cerebral autoregulation. Conventionally, cerebrovascular resistance (CVR) has been used to describe this relationship, but the underlying principles used for this method is flawed in real-world application for several reasons. Despite this, the use of CVR remains entrenched within current literature. This \'Point/Counterpoint\' review provides a summary of the flaws in using CVR and explains the benefits of calculating the more accurate critical closing pressure (CrCP) and resistance-area product (RAP) parameters, with support of real-world data.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 27 Apr 2023:271678X231172854; epub ahead of print</small></div>

<div><h4>Isoflurane and ketamine-xylazine modify pharmacokinetics of [F]SynVesT-1 in the mouse brain.</h4><i>Miranda A, Bertoglio D, De Weerdt C, Staelens S, Verhaeghe J</i><br /><AbstractText>We investigated the effect of isoflurane and ketamine-xylazine anesthesia on the positron emission tomography (PET) tracer [<sup>18</sup>F]SynVesT-1 in the mouse brain. [<sup>18</sup>F]SynVesT-1 PET scans were performed in C57BL/6J mice in five conditions: isoflurane anesthesia (ANISO), ketamine-xylazine (ANKX), awake freely moving (AW), awake followed by isoflurane administration (AW/ANISO) or followed by ketamine-xylazine (AW/ANKX) 20 min post tracer injection. ANISO, ANKX and AW scans were also performed in mice administered with levetiracetam (LEV, 200 mg/kg) to assess non-displaceable binding. Metabolite analysis was performed in ANISO, ANKX and AW mice. Finally, <i>in vivo</i> autoradiography in ANISO, ANKX and AW mice at 30 min post-injection was performed for validation. Kinetic modeling, with a metabolite corrected image derived input function, was performed to calculate total and non-displaceable volume of distribution (<i>V</i><sub>T(IDIF)</sub>). <i>V</i><sub>T(IDIF)</sub> was higher in ANISO compared to AW (p < 0.0001) while <i>V</i><sub>T(IDIF)</sub> in ANKX was lower compared with AW (p < 0.0001). Non-displaceable <i>V</i><sub>T(IDIF)</sub> was significantly different between ANISO and AW, but not between ANKX and AW. Change in the TAC washout was observed after administration of either isoflurane or ketamine-xylazine. Observed changes in tracer kinetics and volume of distribution might be explained by physiological changes due to anesthesia, as well as by induced cellular effects.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 27 Apr 2023:271678X231173185; epub ahead of print</small></div>

<div><h4>Characteristics of activation of monocyte-derived macrophages versus microglia after mouse experimental intracerebral hemorrhage.</h4><i>Ye F, Yang J, Holste KG, Koduri S, ... Garton HJ, Xi G</i><br /><AbstractText>Both monocyte-derived macrophages (MDMs) and brain resident microglia participate in hematoma resolution after intracerebral hemorrhage (ICH). Here, we utilized a transgenic mouse line with enhanced green fluorescent protein (EGFP) labeled microglia (Tmem119-EGFP mice) combined with a F4/80 immunohistochemistry (a pan-macrophage marker) to visualize changes in MDMs and microglia after ICH. A murine model of ICH was used in which autologous blood was stereotactically injected into the right basal ganglia. The autologous blood was co-injected with CD47 blocking antibodies to enhance phagocytosis or clodronate liposomes for phagocyte depletion. In addition, Tmem119-EGFP mice were injected with the blood components peroxiredoxin 2 (Prx2) or thrombin. MDMs entered the brain and formed a peri-hematoma cell layer by day 3 after ICH and giant phagocytes engulfed red blood cells were found. CD47 blocking antibody increased the number of MDMs around and inside the hematoma and extended MDM phagocytic activity to day 7. Both MDMs and microglia could be diminished by clodronate liposomes. Intracerebral injection of Prx2 but not thrombin attracted MDMs into brain parenchyma. In conclusion, MDMs play an important role in phagocytosis after ICH which can be enhanced by CD47 blocking antibody, suggesting the modulation of MDMs after ICH could be a future therapeutic target.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 27 Apr 2023:271678X231173187; epub ahead of print</small></div>

<div><h4>Metabolic implications of axonal demyelination and its consequences for synchronized network activity: An and study.</h4><i>Gerevich Z, Kovács R, Liotta A, Hasam-Henderson LA, ... Wallach I, Berndt N</i><br /><AbstractText>Myelination enhances the conduction velocity of action potentials (AP) and increases energy efficiency. Thick myelin sheaths are typically found on large-distance axonal connections or in fast-spiking interneurons, which are critical for synchronizing neuronal networks during gamma-band oscillations. Loss of myelin sheath is associated with multiple alterations in axonal architecture leading to impaired AP propagation. While numerous studies are devoted to the effects of demyelination on conduction velocity, the metabolic effects and the consequences for network synchronization have not been investigated. Here we present a unifying computational model for electrophysiology and metabolism of the myelinated axon. The computational model suggested that demyelination not only decreases the AP speed but AP propagation in demyelinated axons requires compensatory processes like mitochondrial mass increase and a switch from saltatory to continuous propagation to rescue axon functionality at the cost of reduced AP propagation speed and increased energy expenditure. Indeed, these predictions were proven to be true in a culture model of demyelination where the pharmacologically-induced loss of myelin was associated with increased oxygen consumption rates, and a significant broadening of bandwidth as well as a decrease in the power of gamma oscillations.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 26 Apr 2023:271678X231170746; epub ahead of print</small></div>

<div><h4>CRTC1 is a potential target to delay aging-induced cognitive deficit by protecting the integrity of the blood-brain barrier via inhibiting inflammation.</h4><i>Wang Y, Du W, Sun Y, Zhang J, Ma C, Jin X</i><br /><AbstractText>Aging can cause attenuation in the functioning of multiple organs, and blood-brain barrier (BBB) breakdown could promote the occurrence of disorders of the central nervous system during aging. Since inflammation is considered to be an important factor underlying BBB injury during aging, vascular endothelial cell senescence serves as a critical pathological basis for the destruction of BBB integrity. In the current review, we have first introduced the concepts related to aging-induced cognitive deficit and BBB integrity damage. Thereafter, we reviewed the potential relationship between disruption of BBB integrity and cognition deficit and the role of inflammation, vascular endothelial cell senescence, and BBB injury. We have also briefly introduced the function of CREB-regulated transcription co-activator 1 (CRTC1) in cognition and aging-induced CRTC1 changes as well as the critical roles of CRTC1/cyclooxygenase-2 (COX-2) in regulating inflammation, endothelial cell senescence, and BBB injury. Finally, the underlying mechanisms have been summarized and we propose that CRTC1 could be a promising target to delay aging-induced cognitive deficit by protecting the integrity of BBB through promoting inhibition of inflammation-mediated endothelial cell senescence.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 22 Apr 2023:271678X231169133; epub ahead of print</small></div>

<div><h4>Multi-layered adaptive neoangiogenesis Intra-Operative quantification (MANIOQ).</h4><i>Lacoin G, Zemmoura I, Gennisson JL, Kouamé D, Remenieras JP</i><br /><AbstractText>Quantification of vascularization volume can provide valuable information for diagnosis and prognosis in vascular pathologies. It can be adapted to inform the surgical management of gliomas, aggressive brain tumors characterized by exuberant sprouting of new blood vessels (neoangiogenesis). Filtered ultrafast Doppler data can provide two main parameters: vascularization index (VI) and fractional moving blood volume (FMBV) that clinically reflect tumor micro vascularization. Current protocols lack robust, automatic, and repeatable filtering methods. We present a filtrating method called Multi-layered Adaptive Neoangiogenesis Intra-Operative Quantification (MANIOQ). First, an adaptive clutter filtering is implemented, based on singular value decomposition (SVD) and hierarchical clustering. Second a method for noise equalization is applied, based on the subtraction of a weighted noise profile. Finally, an <i>in vivo</i> analysis of the periphery of the B-mode hyper signal area allows to measure the vascular infiltration extent of the brain tumors. Ninety ultrasound acquisitions were processed from 23 patients. Compared to reference methods in the literature, MANIOQ provides a more robust tissue filtering, and noise equalization allows for the first time to keep axial and lateral gain compensation (TGC and LGC). MANIOQ opens the way to an intra-operative clinical analysis of gliomas micro vascularization.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 18 Apr 2023:271678X231170504; epub ahead of print</small></div>

<div><h4>Kinetic models for estimating occupancy from single-scan PET displacement studies.</h4><i>Laurell GL, Plavén-Sigray P, Johansen A, Raval NR, ... Svarer C, Schain M</i><br /><AbstractText>The traditional design of PET target engagement studies is based on a baseline scan and one or more scans after drug administration. We here evaluate an alternative design in which the drug is administered during an on-going scan (i.e., a displacement study). This approach results both in lower radiation exposure and lower costs. Existing kinetic models assume steady state. This condition is not present during a drug displacement and consequently, our aim here was to develop kinetic models for analysing PET displacement data. We modified existing compartment models to accommodate a time-variant increase in occupancy following the pharmacological in-scan intervention. Since this implies the use of differential equations that cannot be solved analytically, we developed instead one approximate and one numerical solution. Through simulations, we show that if the occupancy is relatively high, it can be estimated without bias and with good accuracy. The models were applied to PET data from six pigs where [<sup>11</sup>C]UCB-J was displaced by intravenous brivaracetam. The dose-occupancy relationship estimated from these scans showed good agreement with occupancies calculated with Lassen plot applied to baseline-block scans of two pigs. In summary, the proposed models provide a framework to determine target occupancy from a single displacement scan.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 18 Apr 2023:271678X231168591; epub ahead of print</small></div>

<div><h4>Potential role of plasma branched-chain amino acids in the differential diagnosis of acute cerebral venous thrombosis.</h4><i>Jiang H, Zhou C, Wei H, Wu Y, ... Meng R, Ji X</i><br /><AbstractText>Cerebral venous thrombosis (CVT) is a special and easily misdiagnosed or undiagnosed subtype of stroke. To identify specific biomarkers with a high predictive ability for the diagnosis of acute CVT, we performed metabolomic analysis in plasma samples from acute CVT patients and healthy controls and confirmed the results in validation cohorts. In the discovery stage, there were 343 differential metabolites, and the caffeine metabolism pathway and the biosynthesis pathway for the branched chain amino acids (BCAAs) valine, leucine, and isoleucine were two significant pathways between the CVT and healthy cohorts. The area under the curve (AUC) for metabolites associated with valine, leucine, and isoleucine biosynthesis was 0.934. In the validation stage, the BCAA concentrations demonstrated an AUC of 0.935 to differentiate patients with acute CVT from the control cohort. In addition, BCAAs combined with D-dimer levels were used to establish a diagnostic model for CVT, and the AUC was 0.951, showing good diagnostic efficacy of separating CVT patients from the control cohort. BCAAs as plasma biomarkers deserve to be further studied and even developed in clinical CVT management.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 17 Apr 2023:271678X231170037; epub ahead of print</small></div>

<div><h4>CD31 as a probable responding and gate-keeping protein of the blood-brain barrier and the risk of Alzheimer\'s disease.</h4><i>Zhang Z, Gan Q, Han J, Tao Q, Qiu WQ, Madri JA</i><br /><AbstractText>Several studies have shown that an abnormal vascular-immunity link could increase Alzheimer\'s disease (AD) risk; however, the mechanism is unclear. CD31, also named platelet endothelial cell adhesion molecule (PECAM), is a surface membrane protein of both endothelial and immune cells and plays important roles in the interaction between the vascular and immune systems. In this review, we focus on research regarding CD31 biological actions in the pathological process that may contribute to AD based on the following rationales. First, endothelial, leukocyte and soluble forms of CD31 play multi-roles in regulating transendothelial migration, increasing blood-brain barrier (BBB) permeability and resulting in neuroinflammation. Second, CD31 expressed by endothelial and immune cells dynamically modulates numbers of signaling pathways, including Src family kinases, selected G proteins, and β-catenin which in turn affect cell-matrix and cell-cell attachment, activation, permeability, survival, and ultimately neuronal cell injury. In endothelia and immune cells, these diverse CD31-mediated pathways act as a critical regulator in the immunity-endothelia-brain axis, thereby mediating AD pathogenesis in ApoE4 carriers, which is the major genetic risk factor for AD. This evidence suggests a novel mechanism and potential drug target for CD31 in the background of genetic vulnerabilities and peripheral inflammation for AD development and progression.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 12 Apr 2023:271678X231170041; epub ahead of print</small></div>

<div><h4>Hemoglobin and cerebral hypoxic vasodilation in humans: Evidence for nitric oxide-dependent and -nitrosothiol mediated signal transduction.</h4><i>Hoiland RL, MacLeod DB, Stacey BS, Caldwell HG, ... Bailey DM, Ainslie PN</i><br /><AbstractText>Cerebral hypoxic vasodilation is poorly understood in humans, which undermines the development of therapeutics to optimize cerebral oxygen delivery. Across four investigations (total n = 195) we investigated the role of nitric oxide (NO) and hemoglobin-based <i>S</i>-nitrosothiol (RSNO) and nitrite (<mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\"><mml:msubsup><mml:mrow><mml:mi>NO</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow><mml:mrow><mml:mo>-</mml:mo></mml:mrow></mml:msubsup></mml:math>) signaling in the regulation of cerebral hypoxic vasodilation. We conducted hemodilution (n = 10) and NO synthase inhibition experiments (n = 11) as well as hemoglobin oxygen desaturation protocols, wherein we measured cerebral blood flow (CBF), intra-arterial blood pressure, and in subsets of participants trans-cerebral release/uptake of RSNO and <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\"><mml:msubsup><mml:mrow><mml:mi>NO</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow><mml:mrow><mml:mo>-</mml:mo></mml:mrow></mml:msubsup></mml:math>. Higher CBF during hypoxia was associated with greater trans-cerebral RSNO release but not <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\"><mml:msubsup><mml:mrow><mml:mi>NO</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow><mml:mrow><mml:mo>-</mml:mo></mml:mrow></mml:msubsup></mml:math>, while NO synthase inhibition reduced cerebral hypoxic vasodilation. Hemodilution increased the magnitude of cerebral hypoxic vasodilation following acute hemodilution, while in 134 participants tested under normal conditions, hypoxic cerebral vasodilation was inversely correlated to arterial hemoglobin concentration. These studies were replicated in a sample of polycythemic high-altitude native Andeans suffering from excessive erythrocytosis (n = 40), where cerebral hypoxic vasodilation was inversely correlated to hemoglobin concentration, and improved with hemodilution (n = 6). Collectively, our data indicate that cerebral hypoxic vasodilation is partially NO-dependent, associated with trans-cerebral RSNO release, and place hemoglobin-based NO signaling as a central mechanism of cerebral hypoxic vasodilation in humans.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 12 Apr 2023:271678X231169579; epub ahead of print</small></div>

<div><h4>The GHB analogue HOCPCA improves deficits in cognition and sensorimotor function after MCAO via CaMKIIα.</h4><i>Griem-Krey N, Klein AB, Clausen BH, Namini MR, ... Clarkson AN, Wellendorph P</i><br /><AbstractText>Ca<sup>2+</sup>/calmodulin-dependent protein kinase II alpha (CaMKIIα) is a major contributor to physiological and pathological glutamate-mediated Ca<sup>2+</sup> signals, and its involvement in various critical cellular pathways demands specific pharmacological strategies. We recently presented γ-hydroxybutyrate (GHB) ligands as the first small molecules selectively targeting and stabilizing the CaMKIIα hub domain. Here, we report that the cyclic GHB analogue 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA), improves sensorimotor function after experimental stroke in mice when administered at a clinically relevant time and in combination with alteplase. Further, we observed improved hippocampal neuronal activity and working memory after stroke. On the biochemical level, we observed that hub modulation by HOCPCA results in differential effects on distinct CaMKII pools, ultimately alleviating aberrant CaMKII signalling after cerebral ischemia. As such, HOCPCA normalised cytosolic Thr286 autophosphorylation after ischemia in mice and downregulated ischemia-specific expression of a constitutively active CaMKII kinase proteolytic fragment. Previous studies suggest holoenzyme stabilisation as a potential mechanism, yet a causal link to <i>in vivo</i> findings requires further studies. Similarly, HOCPCA\'s effects on dampening inflammatory changes require further investigation as an underlying protective mechanism. HOCPCA\'s selectivity and absence of effects on physiological CaMKII signalling highlight pharmacological modulation of the CaMKIIα hub domain as an attractive neuroprotective strategy.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 07 Apr 2023:271678X231167920; epub ahead of print</small></div>

<div><h4>An automatic analysis framework for FDOPA PET neuroimaging.</h4><i>Nordio G, Easmin R, Giacomel A, Dipasquale O, ... Matthews J, Talbot PS</i><br /><AbstractText>In this study we evaluate the performance of a fully automated analytical framework for FDOPA PET neuroimaging data, and its sensitivity to demographic and experimental variables and processing parameters. An instance of XNAT imaging platform was used to store the King\'s College London institutional brain FDOPA PET imaging archive, alongside individual demographics and clinical information. By re-engineering the historical Matlab-based scripts for FDOPA PET analysis, a fully automated analysis pipeline for imaging processing and data quantification was implemented in Python and integrated in XNAT. The final data repository includes 892 FDOPA PET scans organized from 23 different studies. We found good reproducibility of the data analysis by the automated pipeline (in the striatum for the Ki<sup>cer</sup>: for the controls ICC = 0.71, for the psychotic patients ICC = 0.88). From the demographic and experimental variables assessed, gender was found to most influence striatal dopamine synthesis capacity (F = 10.7, p < 0.001), with women showing greater dopamine synthesis capacity than men. Our automated analysis pipeline represents a valid resourse for standardised and robust quantification of dopamine synthesis capacity using FDOPA PET data. Combining information from different neuroimaging studies has allowed us to test it comprehensively and to validate its replicability and reproducibility performances on a large sample size.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 07 Apr 2023:271678X231168687; epub ahead of print</small></div>

<div><h4>Effectiveness of butylphthalide on cerebral autoregulation in ischemic stroke patients with large artery atherosclerosis (EBCAS study): A randomized, controlled, multicenter trial.</h4><i>Guo ZN, Yue BH, Fan L, Liu J, ... Sun X, Yang Y</i><br /><AbstractText>Finding appropriate drugs to improve cerebral autoregulation (CA) in patients with acute ischemic stroke (AIS) is necessary to improve prognosis. We aimed to investigate the effect of butylphthalide on CA in patients with AIS. In this randomized controlled trial, 99 patients were 2:1 randomized to butylphthalide or placebo group. The butylphthalide group received intravenous infusion with a preconfigured butylphthalide-sodium chloride solution for 14 days and an oral butylphthalide capsule for additional 76 days. The placebo group synchronously received an intravenous infusion of 100 mL 0.9% saline and an oral butylphthalide simulation capsule. The transfer function parameter, phase difference (PD), and gain were used to quantify CA. The primary outcomes were CA levels on the affected side on day 14 and day 90. Eighty patients completed the follow-up (52 in the butylphthalide group and 28 in the placebo group). The PD of the affected side on 14 days or discharge and on 90 days was higher in the butylphthalide group than in the placebo group. The differences in safety outcomes were not significant. Therefore, butylphthalide treatment for 90 days can significantly improve CA in patients with AIS.<b>Trial registration:</b> ClinicalTrial.gov: NCT03413202.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 06 Apr 2023:271678X231168507; epub ahead of print</small></div>

<div><h4>Zfp580 inactivation as a new therapeutic target to enhance recovery after stroke in mice.</h4><i>Hoffmann CJ, Kuffner MT, Koschützke L, Lorenz S, ... Endres M, Harms C</i><br /><AbstractText>Paracrine cerebral Interleukin 6 (Il6) is relevant for stroke recovery, but systemic Il6 elevation may worsen outcome. Hence, paracrine Il6 response modulation within the neurovascular unit has emerged as an attractive therapeutic approach. Lithium modulates Il6 responses and improves stroke outcome. However, lithium may cause serious adverse effects. Here, we report that Zincfinger protein 580 (Zfp580) mediates the effects of lithium on Il6 signaling. In contrast to lithium, Zfp580 inactivation had no neurotoxic effects, and Zfp580 knock out mice showed no phenotypic changes in cognitive and motor function behavioral tests. We discovered that lithium and hypoxia disinhibited Il6 via Zfp580 suppression and post-translational modification by small ubiquitin-like modifier (SUMO). After transient middle cerebral artery occlusion, loss of Zfp580 reduced paracrine Il6 and increased Il6 trans-signaling. Aside from modulating Il6 signaling, Zfp580 loss improved endothelial resilience to ischemia, was highly neuroprotective resulting in smaller infarcts and enhanced use-dependent neuroplasticity, all of which led to improved functional outcome. In conclusion, inactivation of Zfp580 exerts positive effects on multiple key mechanisms without exhibiting relevant adverse side effects, making it potentially a more specific and effective treatment target for stroke recovery than lithium. To fully assess its potential, Zfp580 inhibitors must be developed.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 06 Apr 2023:271678X231168499; epub ahead of print</small></div>

<div><h4>Role of intravenous alteplase on late lesion growth and clinical outcome after stroke treatment.</h4><i>Konduri P, Cavalcante F, van Voorst H, Rinkel L, ... Marquering H, MR CLEAN-NO IV Trial Investigators (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands)</i><br /><AbstractText>Several acute ischemic stroke mechanisms that cause lesion growth continue after treatment which is detrimental to long-term clinical outcome. The potential role of intravenous alteplase treatment (IVT), a standard in stroke care, in cessing the physiological processes causing post-treatment lesion development is understudied. We analyzed patients from the MR CLEAN-NO IV trial with good quality 24-hour and 1-week follow-up Non-Contrast CT scans. We delineated hypo- and hyper-dense regions on the scans as lesion. We performed univariable logistic and linear regression to estimate the influence of IVT on the presence (growth > 0 ml) and extent of late lesion growth. The association between late lesion growth and mRS was assessed using ordinal logistic regression. Interaction analysis was performed to evaluate the influence of IVT on this association. Of the 63/116 were randomized to included patients, IVT. Median growth was 8.4(-0.88-26) ml. IVT was not significantly associated with the presence (OR: 1.24 (0.57-2.74, p = 0.59) or extent (β = 5.1(-8.8-19), p = 0.47) of growth. Late lesion growth was associated with worse clinical outcome (aOR: 0.85(0.76-0.95), p < 0.01; per 10 ml). IVT did not influence this association (p = 0.18). We did not find evidence that IVT influences late lesion growth or the relationship between growth and worse clinical outcome. Therapies to reduce lesion development are necessary.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 05 Apr 2023:271678X231167755; epub ahead of print</small></div>

<div><h4>Sex modifies the relationship between age and neurovascular coupling in healthy adults.</h4><i>Koep JL, Bond B, Barker AR, Ruediger SL, ... Coombes JS, Bailey TG</i><br /><AbstractText>Neurovascular coupling (NVC) is the matching between local neuronal activity and regional cerebral blood flow (CBF), but little is known about the effects of age and sex on NVC. This study aimed to investigate the relationships and interaction between age and sex on NVC. Sixty-four healthy adults (18-85 years, N = 34 female) completed a visual stimulus evoked NVC assessment to a flashing checkerboard. NVC responses were measured in the posterior cerebral artery (PCAv) using transcranial Doppler ultrasound. A hierarchical multiple regression was used to determine the relationships between age, sex, and the age by sex interaction on NVC. There was a significant age by sex interaction for baseline (P = 0.001) and peak PCAv (P = 0.01), with a negative relationship with age in females (P < 0.005), and no relationship in males (P ≥ 0.17). NVC responses as a percent increase from baseline showed a significant age by sex interaction (P = 0.014), with a positive relationship with age in females (P = 0.04) and no relationship in males (P = 0.17), even after adjusting for baseline PCAv. These data highlight important sex differences, with an association between age and NVC only apparent in females but not males, and thus a need to account for sex dependent effects of ageing when investigating cerebrovascular regulation.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 05 Apr 2023:271678X231167753; epub ahead of print</small></div>

<div><h4>Preceding transient ischemic attack was associated with functional outcome after stroke thrombectomy: A propensity score matching study.</h4><i>Xu J, Guo W, Ma J, Ma Q, ... Zhao W, Ji X</i><br /><AbstractText>Whether preceding transient ischemic attack (TIA) can provide neuroprotective benefits in subsequent acute ischemic stroke (AIS) caused by large vessel occlusion remains unclarified. This study aimed to investigate the association between preceding TIA and functional outcomes in AIS patients with endovascular therapy (EVT). Eligible patients were divided into TIA and non-TIA groups according to whether they experienced TIA within 96 hours prior to stroke. Two groups were balanced using propensity score matching (PSM) analysis at a 1:3 ratio. Onset stroke severity and 3-month functional independence were evaluated. A total of 887 patients were included. After PSM, 73 patients with and 217 patients without preceding TIA were well matched. Onset stroke severity was not different between the groups (p > 0.05). However, the TIA group had a lower systemic immune-inflammation index (SII) (median, 1091 versus 1358, p < 0.05). Preceding TIA was significantly associated with 3-month functional independence (adjusted odds ratio, 2.852; 95% confidence interval [CI], 1.481-5.495; adjusted p < 0.01). The effects of preceding TIA on functional independence were partially mediated by SII (average causal mediation effects 0.02; 95% CI, 0.001-0.06, p < 0.05). In AIS patients treated by EVT, preceding TIA within 96 hours was associated with three-month functional independence but not with reduced onset stroke severity.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 05 Apr 2023:271678X231167924; epub ahead of print</small></div>

<div><h4>Reversal of the detrimental effects of social isolation on ischemic cerebral injury and stroke-associated pneumonia by inhibiting small intestinal T-cell migration into the brain and lung.</h4><i>Xie B, Zhang Y, Han M, Wang M, ... Shang Y, Zhang J</i><br /><AbstractText>Social isolation (ISO) is associated with an increased risk and poor outcomes of ischemic stroke. However, the roles and mechanisms of ISO in stroke-associated pneumonia (SAP) remain unclear. Adult male mice were single- or pair-housed with an ovariectomized female mouse and then subjected to transient middle cerebral artery occlusion. Isolated mice were treated with the natriuretic peptide receptor A antagonist A71915 or anti-gamma-delta (γδ) TCR monoclonal antibody, whereas pair-housed mice were treated with recombinant human atrial natriuretic peptide (rhANP). Subdiaphragmatic vagotomy (SDV) was performed 14 days before single- or pair-housed conditions. We found that ISO significantly worsened brain and lung injuries relative to pair housing, which was partially mediated by elevated interleukin (IL)-17A levels and the migration of small intestine-derived inflammatory γδ T-cells into the brain and lung. However, rhANP treatment or SDV could ameliorate ISO-exacerbated post-stroke brain and lung damage by reducing IL-17A levels and inhibiting the migration of inflammatory γδ T-cells into the brain and lung. Our results suggest that rhANP mitigated ISO-induced exacerbation of SAP and ischemic cerebral injury by inhibiting small intestine-derived γδ T-cell migration into the lung and brain, which could be mediated by the subdiaphragmatic vagus nerve.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 05 Apr 2023:271678X231167946; epub ahead of print</small></div>

<div><h4>An optical clearing imaging window: Realization of mouse brain imaging and manipulation through scalp and skull.</h4><i>Feng W, Liu CJ, Wang L, Zhang C</i><br /><AbstractText>Cortical visualization is essential to understand the dynamic changes in brain microenvironment under physiopathological conditions. However, the turbid scalp and skull severely limit the imaging depth and resolution. Existing cranial windows require invasive scalp excision and various subsequent skull treatments. Non-invasive in vivo imaging of skull bone marrow, meninges, and cortex through scalp and skull with high resolution yet remains a challenge. In this work, a non-invasive trans-scalp/skull optical clearing imaging window is proposed for cortical and calvarial imaging, which is achieved by applying a novel skin optical clearing reagent. The imaging depth and resolution are greatly enhanced in near infrared imaging and optical coherence tomography imaging. Combining this imaging window with adaptive optics, we achieve the visualization and manipulation of the calvarial and cortical microenvironment through the scalp and skull using two-photon imaging for the first time. Our method provides a well-performed imaging window and paves the way for intravital brain studies with the advantages of easy-operation, convenience and non-invasiveness.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 31 Mar 2023:271678X231167729; epub ahead of print</small></div>

<div><h4>A pilot study of lymphoscintigraphy with tracer injection into the human brain.</h4><i>Coxon AT, Desai R, Patel PR, Vellimana AK, ... Siegel BA, Dunn GP</i><br /><AbstractText>Many groups have reported lymphatic and glymphatic structures in animal and human brains, but tracer injection into the human brain to demonstrate real-time lymphatic drainage and mapping has not been described. We enrolled patients undergoing standard-of-care resection or stereotactic biopsy for suspected intracranial tumors. Patients received peritumoral injections of <sup>99m</sup>Tc-tilmanocept followed by planar or tomographic imaging. Fourteen patients with suspected brain tumors were enrolled. One was excluded from analysis because of tracer leakage during injection. There was no drainage of <sup>99m</sup>Tc-tilmanocept to regional lymph nodes in any of the patients. On average, after correcting for radioactive decay, 70.7% (95% CI: 59.9%, 81.6%) of the tracer in the injection site and 78.1% (95% CI: 71.1%, 85.1%) in the whole-head on the day of surgery remained the morning after, with variable radioactivity in the subarachnoid space. The retained fraction was much greater than expected based on the clearance rate from non-brain injection sites. In this pilot study, the lymphatic tracer <sup>99m</sup>Tc-tilmanocept was injected into the brain parenchyma, and there was no drainage outside the brain to the cervical lymph nodes. Our work demonstrates an inefficiency of drainage from peritumoral brain parenchyma and highlights a therapeutic opportunity to improve immunosurveillance of the brain.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 30 Mar 2023:271678X231160891; epub ahead of print</small></div>

<div><h4>Microvascular dysfunction associated with unfavorable venous outflow in acute ischemic stroke patients.</h4><i>Li X, Lin L, Zhang J, Fan Y, ... Zhao J, Li J</i><br /><AbstractText>Unfavorable venous outflow (VO) is associated with cerebral edema, which represents microvascular dysfunction. This study estimated the relationship between VO and microvascular function in acute ischemic stroke patients. We retrospectively included 102 MCA/ICA occluded patients with anterior circulation infarction who underwent reperfusion therapy between July 2017 and April 2022. Unfavorable VO was defined as a cortical vein opacification score of 0-3 and favorable VO as that of 4-6. The clinical characteristics, collateral status, microvascular integrity, and outcomes were compared between patients with favorable and unfavorable VO. Multivariate analysis and receiver operator characteristic (ROC) analysis were used. The patients with unfavorable VO had higher extravascular-extracellular volume fraction (Ve) in the infarct core and a lower percentage of robust arterial collateral circulation. ROC analysis revealed that Ve in the infarct core predicts unfavorable VO (AUC = 0.67, sensitivity = 65.08%, specificity = 69.23%). The higher Ve in the infarct core (odds ratio = 1.011, 95% CI = 1.000-1.021, <i>P = </i>0.046) and poor arterial collateral flow (odds ratio = 0.102, 95% CI = 0.032-0.327, <i>P</i> < 0.001) were independent predictors of unfavorable VO. This suggests that microvascular dysfunction may be one of the mechanisms underlying impaired VO.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 27 Mar 2023:271678X231165606; epub ahead of print</small></div>

<div><h4>H3K9 trimethylation dictates neuronal ferroptosis through repressing .</h4><i>Lan T, Hu L, Sun T, Wang X, ... Zhang C, Li Q</i><br /><AbstractText>Spontaneous intracerebral hemorrhage (ICH) is a devastating disease with high morbidity and mortality worldwide. We have previously shown that ferroptosis contributes to neuronal loss in ICH mice. The overload of iron and dysfunction of glutathione peroxidase 4 (GPx4) promote neuronal ferroptosis post-ICH. However, how epigenetic regulatory mechanisms affect the ferroptotic neurons in ICH remains unclear. In the current study, hemin was used to induce ferroptosis in N2A and SK-N-SH neuronal cells to mimic ICH. The results showed that hemin-induced ferroptosis was accompanied by an increment of global level of trimethylation in histone 3 lysine 9 (H3K9me3) and its methyltransferase Suv39h1. Transcriptional target analyses indicated that H3K9me3 was enriched at the promoter region and gene body of transferrin receptor gene 1 (<i>Tfr1</i>) and repressed its expression upon hemin stimulation. Inhibition of H3K9me3 with inhibitor or siRNA against Suv39h1 aggravated hemin- and RSL3-induced ferroptosis by upregulating <i>Tfr1</i> expression. Furthermore, Suv39h1-H3K9me3 mediated repression of <i>Tfr1</i> contributes to the progression of ICH in mice. These data suggest a protective role of H3K9me3 in ferroptosis post ICH. The knowledge gained from this study will improve the understanding of epigenetic regulation in neuronal ferroptosis and shed light on future clinical research after ICH.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 24 Mar 2023:271678X231165653; epub ahead of print</small></div>

<div><h4>The relationship between cytochrome c oxidase, CBF and CMRO in mouse cortex: A NIRS-MRI study.</h4><i>Hashem M, Wu Y, Dunn JF</i><br /><AbstractText>Quantifying relationships between cerebral blood flow (CBF), mitochondrial function (cytochrome c oxidase oxidation state), and metabolic rate of oxygen (CMRO<sub>2</sub>) could provide useful insight into normal neurovascular coupling, as well as regulation of oxidative metabolism in neurological disorders. This paper uses a multimodal NIRS-MRI method to quantify these parameters in rodent brain and, in so doing, provides novel information on the regulation of oxygen metabolism by stimulating with hypercapnia or variations in oxygenation. Under hypercapnia, although oxygenation, oxidation state, and CBF increased, there was no increase in CMRO<sub>2</sub>. Also, there was no correlation between CBF and CCO oxidation state. Conversely, changing oxygenation resulted in a strong correlation between the oxidation of CCO and CBF. This proves that the association between CBF and the redox state of CCO is not fixed and depends on the type of perturbation. Having a means to measure CBF and CCO oxidation state simultaneously will help understanding their contribution to intact neurovascular coupling and detecting abnormal cellular oxygen metabolism in many neurological disorders.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 23 Mar 2023:271678X231165842; epub ahead of print</small></div>

<div><h4>Reduced coupling of global brain function and cerebrospinal fluid dynamics in Parkinson\'s disease.</h4><i>Wang Z, Song Z, Zhou C, Fang Y, ... Zhang B, Pu J</i><br /><AbstractText>Dysfunction of the glymphatic system, an intracranial clearance pathway that drains misfolded proteins, has been implicated in the onset of Parkinson\'s disease (PD). Recently, the coupling strength of global blood-oxygen-level-dependent (gBOLD) signals and cerebrospinal fluid (CSF) inflow dynamics have been suggested to be an indicator of glymphatic function. Using resting-state functional magnetic resonance imaging (MRI), we quantified gBOLD-CSF coupling strength as the cross-correlation between baseline gBOLD and CSF inflow signals to evaluate glymphatic function and its association with the clinical manifestations of PD. We found that gBOLD-CSF coupling in drug-naïve PD patients was significantly weaker than that in normal controls, but significantly stronger in patients less affected by sleep disturbances than in those more affected by sleep disturbances, based on the PD sleep scale. Furthermore, we collected longitudinal data from patients and found that baseline gBOLD-CSF coupling negatively correlated with the rate of change over time, but positively correlated with the rate of change in UPDRS-III scores. In conclusion, severe gBOLD-CSF decoupling in PD patients may reflect longitudinal motor impairment, thereby providing a potential marker of glymphatic dysfunction in PD.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 16 Mar 2023:271678X231164337; epub ahead of print</small></div>

<div><h4>Superior sagittal sinus flow as a proxy for tracking global cerebral blood flow dynamics during wakefulness and sleep.</h4><i>Caporale AS, Barclay AM, Xu J, Rao H, ... Detre JA, Wehrli FW</i><br /><AbstractText>Sleep, a state of reduced consciousness, affects brain oxygen metabolism and lowers cerebral metabolic rate of oxygen (CMRO<sub>2</sub>). Previously, we quantified CMRO<sub>2</sub> during sleep via Fick\'s Principle, with a single-band MRI sequence measuring both hemoglobin O<sub>2</sub> saturation (SvO<sub>2</sub>) and superior sagittal sinus (SSS) blood flow, which was upscaled to obtain total cerebral blood flow (tCBF). The procedure involves a brief initial calibration scan to determine the upscaling factor (f<sub>c</sub>), assumed state-invariant. Here, we used a dual-band sequence to simultaneously provide SvO<sub>2</sub> in SSS and tCBF in the neck every 16 seconds, allowing quantification of f<sub>c</sub> dynamically. Ten healthy subjects were scanned by MRI with simultaneous EEG for 80 minutes, yielding 300 temporal image frames per subject. Four volunteers achieved slow-wave sleep (SWS), as evidenced by increased δ-wave activity (per American Academy of Sleep Medicine criteria). SWS was maintained for 13.5 ± 7.0 minutes, with CMRO<sub>2</sub> 28.6 ± 5.5% lower than pre-sleep wakefulness. Importantly, there was negligible bias between tCBF obtained by upscaling SSS-blood flow, and tCBF measured directly in the inflowing arteries of the neck (intra-class correlation 0.95 ± 0.04, averaged across all subjects), showing that the single-band approach is a valid substitute for quantifying tCBF, simplifying image data collection and analysis without sacrificing accuracy.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 16 Mar 2023:271678X231164423; epub ahead of print</small></div>

<div><h4>Therapeutic effect of 7 nicotinic receptor activation after ischemic stroke in rats.</h4><i>Aguado L, Joya A, Garbizu M, Plaza-García S, ... Llop J, Martín A</i><br /><AbstractText>Nicotinic acetylcholine α7 receptors (α7 nAChRs) have a well-known modulator effect in neuroinflammation. Yet, the therapeutical effect of α7 nAChRs activation after stroke has been scarcely evaluated to date. The role of α7 nAChRs activation with PHA 568487 on inflammation after brain ischemia was assessed with positron emission tomography (PET) using [<sup>18</sup>F]DPA-714 and [<sup>18</sup>F]BR-351 radiotracers after transient middle cerebral artery occlusion (MCAO) in rats. The assessment of brain oedema, blood brain barrier (BBB) disruption and neurofunctional progression after treatment was evaluated with T<sub>2</sub> weighted and dynamic contrast-enhanced magnetic resonance imaging (T<sub>2</sub> W and DCE-MRI) and neurological evaluation. The activation of α7 nAChRs resulted in a decrease of ischemic lesion, midline displacement and cell neurodegeneration from days 3 to 7 after ischemia. Besides, the treatment with PHA 568487 improved the neurofunctional outcome. Treated ischemic rats showed a significant [<sup>18</sup>F]DPA-714-PET uptake reduction at day 7 together with a decrease of activated microglia/infiltrated macrophages. Likewise, the activation of α7 receptors displayed an increase of [<sup>18</sup>F]BR-351-PET signal in ischemic cortical regions, which resulted from the overactivation of MMP-2. Finally, the treatment with PHA 568487 showed a protective effect on BBB disruption and blood brain vessel integrity after cerebral ischemia.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 13 Mar 2023:271678X231161207; epub ahead of print</small></div>

<div><h4>Striatal dopamine transporter and receptor availability correlate with relative cerebral blood flow measured with [C]PE2I, [F]FE-PE2I and [C]raclopride PET in healthy individuals.</h4><i>Jonasson M, Frick A, Fazio P, Hjorth O, ... Varrone A, Lubberink M</i><br /><AbstractText>The aim of this retrospective study was to investigate relationships between relative cerebral blood flow and striatal dopamine transporter and dopamine D2/3 availability in healthy subjects. The data comprised dynamic PET scans with two dopamine transporter tracers [<sup>11</sup>C]PE2I (n = 20) and [<sup>18</sup>F]FE-PE2I (n = 20) and the D2/3 tracer [<sup>11</sup>C]raclopride (n = 18). Subjects with a [<sup>11</sup>C]PE2I scan also underwent a dynamic scan with the serotonin transporter tracer [<sup>11</sup>C]DASB. Binding potential (BP<sub>ND</sub>) and relative tracer delivery (R<sub>1</sub>) values were calculated on regional and voxel-level. Striatal R<sub>1</sub> and BP<sub>ND</sub> values were correlated, using either an MRI-based volume of interest (VOI) or an isocontour VOI based on the parametric BP<sub>ND</sub> image. An inter-tracer comparison between [<sup>11</sup>C]PE2I BP<sub>ND</sub> and [<sup>11</sup>C]DASB R<sub>1</sub> was done on a VOI-level and simulations were performed to investigate whether the constraints of the modeling could cause correlation of the parameters. A positive association was found between BP<sub>ND</sub> and R<sub>1</sub> for all three dopamine tracers. A similar correlation was found for the inter-tracer correlation between [<sup>11</sup>C]PE2I BP<sub>ND</sub> and [<sup>11</sup>C]DASB R<sub>1</sub>. Simulations showed that this relationship was not caused by cross-correlation between parameters in the kinetic model. In conclusion, these results suggest an association between resting-state striatal dopamine function and relative blood flow in healthy subjects.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 13 Mar 2023:271678X231160881; epub ahead of print</small></div>

<div><h4>A brief overview of a mouse model of cerebral hypoperfusion by bilateral carotid artery stenosis.</h4><i>Ishikawa H, Shindo A, Mizutani A, Tomimoto H, Lo EH, Arai K</i><br /><AbstractText>Vascular cognitive impairment (VCI) refers to all forms of cognitive disorder related to cerebrovascular diseases, including vascular mild cognitive impairment, post-stroke dementia, multi-infarct dementia, subcortical ischemic vascular dementia (SIVD), and mixed dementia. Among the causes of VCI, more attention has been paid to SIVD because the causative cerebral small vessel pathologies are frequently observed in elderly people and because the gradual progression of cognitive decline often mimics Alzheimer\'s disease. In most cases, small vessel diseases are accompanied by cerebral hypoperfusion. In mice, prolonged cerebral hypoperfusion is induced by bilateral carotid artery stenosis (BCAS) with surgically implanted metal micro-coils. This cerebral hypoperfusion BCAS model was proposed as a SIVD mouse model in 2004, and the spreading use of this mouse SIVD model has provided novel data regarding cognitive dysfunction and histological/genetic changes by cerebral hypoperfusion. Oxidative stress, microvascular injury, excitotoxicity, blood-brain barrier dysfunction, and secondary inflammation may be the main mechanisms of brain damage due to prolonged cerebral hypoperfusion, and some potential therapeutic targets for SIVD have been proposed by using transgenic mice or clinically used drugs in BCAS studies. This review article overviews findings from the studies that used this hypoperfused-SIVD mouse model, which were published between 2004 and 2021.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 08 Mar 2023:271678X231154597; epub ahead of print</small></div>

<div><h4>Temperature dysregulation during therapeutic hypothermia predicts long-term outcome in neonates with HIE.</h4><i>Mietzsch U, Flibotte JJ, Law JB, Puia-Dumitrescu M, Juul SE, Wood TR</i><br /><AbstractText>Few reliable or easily obtainable biomarkers to predict long-term outcome in infants with hypoxic-ischemic encephalopathy (HIE) have been identified. We previously showed that mattress temperature (MT), as proxy for disturbed temperature regulation during therapeutic hypothermia (TH), predicts injury on early MRI and holds promise as physiologic biomarker. To determine whether MT in neonates treated with TH for moderate-severe HIE is associated with long-term outcome at 18-22 months, we performed a secondary analysis of the Optimizing Cooling trial using MT data from 167 infants treated at a core temperature of 33.5°C. Median MTs from four time-epochs (0-6 h, 6-24 h, 24-48 h, and 48-72 h of TH) were used to predict death or moderate-severe neurodevelopmental impairment (NDI), using epoch-specific derived and validated MT cutoffs. Median MT of infants who died or survived with NDI was consistently 1.5-3.0°C higher throughout TH. Infants requiring a median MT above the derived cut-offs had a significantly increased odds of death or NDI, most notably at 0-6 h (aOR 17.0, 95%CI 4.3-67.4). By contrast, infants who remained below cut-offs across all epochs had 100% NDI-free survival. MTs in neonates with moderate-severe HIE during TH are highly predictive of long-term outcome and can be used as physiologic biomarker.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 08 Mar 2023:271678X231162174; epub ahead of print</small></div>

<div><h4>RNA profiling of sEV (small extracellular vesicles)/exosomes reveals biomarkers and vascular endothelial dysplasia with moyamoya disease.</h4><i>He S, Liang J, Xue G, Wang Y, ... Zhao Y, Ye X</i><br /><AbstractText>The association of exosomal RNA profiling and pathogenesis of moyamoya disease (MMD) and intracranial Atherosclerotic disease (ICAD) is unknown. In this study, we investigated the RNA profiles of sEV (small extracellular vesicles)/exosomes in patients with MMD and ICAD. Whole blood samples were collected from 30 individuals, including 10 patients with MMD, 10 patients with ICAD, and 10 healthy individuals. Whole transcriptome analysis was performed using the GeneChip WT Pico Reagent kit. Transcriptional correlation was verified using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The association between functional dysregulation and candidate RNAs was studied <i>in vitro</i>. In total, 1,486 downregulated and 2,405 upregulated RNAs differed significantly between patients with MMD and healthy controls. Differential expression of six circRNAs was detected using qPCR. Among these significantly differentially expressed RNAs, IPO11 and PRMT1 circRNAs were upregulated, whereas CACNA1F circRNA was downregulated. This is the first study showing that the differential expression of exosomal RNAs associated with MMD pathogenesis, such as overexpression of IPO11 and PRMT1 circRNAs, may be related to angiogenesis in MMD. The downregulation of CACNA1F circRNA may be related to vascular occlusion. These results propose the utility of exosomal RNAs as biological markers in MMD.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 08 Mar 2023:271678X231162184; epub ahead of print</small></div>

<div><h4>Gut microbiota-associated metabolites and risk of ischemic stroke in REGARDS.</h4><i>Ament Z, Patki A, Bhave VM, Chaudhary NS, ... Irvin MR, Kimberly WT</i><br /><AbstractText>Several metabolite markers are independently associated with incident ischemic stroke. However, prior studies have not accounted for intercorrelated metabolite networks. We used exploratory factor analysis (EFA) to determine if metabolite factors were associated with incident ischemic stroke. Metabolites (n = 162) were measured in a case-control cohort nested in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, which included 1,075 ischemic stroke cases and 968 random cohort participants. Cox models were adjusted for age, gender, race, and age-race interaction (base model) and further adjusted for the Framingham stroke risk factors (fully adjusted model). EFA identified fifteen metabolite factors, each representing a well-defined metabolic pathway. Of these, factor 3, a gut microbiome metabolism factor, was associated with an increased risk of stroke in the base (hazard ratio per one-unit standard deviation, HR = 1.23; 95%CI = 1.15-1.31; P = 1.98 × 10<sup>-10</sup>) and fully adjusted models (HR = 1.13; 95%CI = 1.06-1.21; P = 4.49 × 10<sup>-4</sup>). The highest tertile had a 45% increased risk relative to the lowest (HR = 1.45; 95%CI = 1.25-1.70; P = 2.24 × 10<sup>-6</sup>). Factor 3 was also associated with the Southern diet pattern, a dietary pattern previously linked to increased stroke risk in REGARDS (β = 0.11; 95%CI = 0.03-0.18; P = 8.75 × 10<sup>-3</sup>). These findings highlight the role of diet and gut microbial metabolism in relation to incident ischemic stroke.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 08 Mar 2023:271678X231162648; epub ahead of print</small></div>

<div><h4>Predicting brain temperature in humans using bioheat models: Progress and outlook.</h4><i>Sung D, Rejimon A, Allen JW, Fedorov AG, Fleischer CC</i><br /><AbstractText>Brain temperature, regulated by the balance between blood circulation and metabolic heat generation, is an important parameter related to neural activity, cerebral hemodynamics, and neuroinflammation. A key challenge for integrating brain temperature into clinical practice is the lack of reliable and non-invasive brain thermometry. The recognized importance of brain temperature and thermoregulation in both health and disease, combined with limited availability of experimental methods, has motivated the development of computational thermal models using bioheat equations to predict brain temperature. In this mini-review, we describe progress and the current state-of-the-art in brain thermal modeling in humans and discuss potential avenues for clinical applications.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 08 Mar 2023:271678X231162173; epub ahead of print</small></div>

<div><h4>Manipulation of iron status on cerebral blood flow at high altitude in lowlanders and adapted highlanders.</h4><i>Patrician A, Willie C, Hoiland RL, Gasho C, ... Tymko MM, Ainslie PN</i><br /><AbstractText>Cerebral blood flow (CBF) increases during hypoxia to counteract the reduction in arterial oxygen content. The onset of tissue hypoxemia coincides with the stabilization of hypoxia-inducible factor (HIF) and transcription of downstream HIF-mediated processes. It has yet to be determined, whether HIF down- or upregulation can modulate hypoxic vasodilation of the cerebral vasculature. Therefore, we examined whether: 1) CBF would increase with iron depletion (via chelation) and decrease with repletion (via iron infusion) at high-altitude, and 2) explore whether genotypic advantages of highlanders extend to HIF-mediated regulation of CBF. In a double-blinded and block-randomized design, CBF was assessed in 82 healthy participants (38 lowlanders, 20 Sherpas and 24 Andeans), before and after the infusion of either: iron(III)-hydroxide sucrose, desferrioxamine or saline. Across both lowlanders and highlanders, baseline iron levels contributed to the variability in cerebral hypoxic reactivity at high altitude (R<sup>2</sup> = 0.174, P < 0.001). At 5,050 m, CBF in lowlanders and Sherpa were unaltered by desferrioxamine or iron. At 4,300 m, iron infusion led to 4 ± 10% reduction in CBF (main effect of time p = 0.043) in lowlanders and Andeans. Iron status may provide a novel, albeit subtle, influence on CBF that is potentially dependent on the severity and length-of-stay at high altitude.</AbstractText><br /><br /><br /><br /><small>J Cereb Blood Flow Metab: 08 Mar 2023:271678X231152734; epub ahead of print</small></div>