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Journal of Cerebral Blood Flow and Metabolism

Ibrahim Jalloh, Adel Helmy, Duncan J Howe, Richard J Shannon, Peter Grice, Andrew Mason, Clare N Gallagher, Matthew G Stovell, Susan van der Heide, Michael P Murphy, John D Pickard, David K Menon, T Adrian Carpenter, Peter J Hutchinson, Keri Lh Carpenter
Following traumatic brain injury, complex cerebral energy perturbations occur. Correlating with unfavourable outcome, high brain extracellular lactate/pyruvate ratio suggests hypoxic metabolism and/or mitochondrial dysfunction. We investigated whether focal administration of succinate, a tricarboxylic acid cycle intermediate interacting directly with the mitochondrial electron transport chain, could improve cerebral metabolism. Microdialysis perfused disodium 2,3-(13)C2 succinate (12 mmol/L) for 24 h into nine sedated traumatic brain injury patients' brains, with simultaneous microdialysate collection for ISCUS analysis of energy metabolism biomarkers (nine patients) and nuclear magnetic resonance of (13)C-labelled metabolites (six patients)...
July 2017: Journal of Cerebral Blood Flow and Metabolism
Alexandre Courchesne-Loyer, Etienne Croteau, Christian-Alexandre Castellano, Valérie St-Pierre, Marie Hennebelle, Stephen C Cunnane
Ketones (principally β-hydroxybutyrate and acetoacetate (AcAc)) are an important alternative fuel to glucose for the human brain, but their utilisation by the brain remains poorly understood. Our objective was to use positron emission tomography (PET) to assess the impact of diet-induced moderate ketosis on cerebral metabolic rate of acetoacetate (CMRa) and glucose (CMRglc) in healthy adults. Ten participants (35 ± 15 y) received a very high fat ketogenic diet (KD) (4.5:1; lipid:protein plus carbohydrates) for four days...
July 2017: Journal of Cerebral Blood Flow and Metabolism
Minshu Li, Zhiguo Li, Honglei Ren, Wei-Na Jin, Kristofer Wood, Qiang Liu, Kevin N Sheth, Fu-Dong Shi
Microglia are the first responders to intracerebral hemorrhage, but their precise role in intracerebral hemorrhage remains to be defined. Microglia are the only type of brain cells expressing the colony-stimulating factor 1 receptor, a key regulator for myeloid lineage cells. Here, we determined the effects of a colony-stimulating factor 1 receptor inhibitor (PLX3397) on microglia and the outcome in the context of experimental mouse intracerebral hemorrhage. We show that PLX3397 effectively depleted microglia, and the depletion of microglia was sustained after intracerebral hemorrhage...
July 2017: Journal of Cerebral Blood Flow and Metabolism
Gilles Bonvento, Julien Valette, Julien Flament, Fanny Mochel, Emmanuel Brouillet
Changes in energy metabolism are generally considered to play an important role in neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. Whether these changes are causal or simply a part of self-defense mechanisms is a matter of debate. Furthermore, energy defects have often been discussed solely in the context of their probable neuronal origin without considering the cellular heterogeneity of the brain. Recent data point towards the existence of a tri-cellular compartmentation of brain energy metabolism between neurons, astrocytes, and oligodendrocytes, each cell type having a distinctive metabolic profile...
June 2017: Journal of Cerebral Blood Flow and Metabolism
Ingrid Digernes, Atle Bjørnerud, Svein Are S Vatnehol, Grete Løvland, Frédéric Courivaud, Einar Vik-Mo, Torstein R Meling, Kyrre E Emblem
Mapping the complex heterogeneity of vascular tissue in the brain is important for understanding cerebrovascular disease. In this translational study, we build on previous work using vessel architectural imaging (VAI) and present a theoretical framework for determining cerebral vascular function and heterogeneity from dynamic susceptibility contrast magnetic resonance imaging (MRI). Our tissue model covers realistic structural architectures for vessel branching and orientations, as well as a range of hemodynamic scenarios for blood flow, capillary transit times and oxygenation...
June 2017: Journal of Cerebral Blood Flow and Metabolism
Wei-Na Jin, Samuel Xiang-Yu Shi, Zhiguo Li, Minshu Li, Kristofer Wood, Rayna J Gonzales, Qiang Liu
Brain ischemia elicits microglial activation and microglia survival depend on signaling through colony-stimulating factor 1 receptor (CSF1R). Although depletion of microglia has been linked to worse stroke outcomes, it remains unclear to what extent and by what mechanisms activated microglia influence ischemia-induced inflammation and injury in the brain. Using a mouse model of transient focal cerebral ischemia and reperfusion, we demonstrated that depletion of microglia via administration of the dual CSF1R/c-Kit inhibitor PLX3397 exacerbates neurodeficits and brain infarction...
June 2017: Journal of Cerebral Blood Flow and Metabolism
TaeHee Kim, Raghu Vemuganti
Both Parkinson's disease (PD) and stroke are debilitating conditions that result in neuronal death and loss of neurological functions. These two conditions predominantly affect aging populations with the deterioration of the quality of life for the patients themselves and a tremendous burden to families. While the neurodegeneration and symptomology of PD develop chronically over the years, post-stroke neuronal death and dysfunction develop rapidly in days. Despite the discrepancy in the pathophysiological time frame and severity, both conditions share common molecular mechanisms that include oxidative stress, mitochondrial dysfunction, inflammation, endoplasmic reticulum stress, and activation of various cell death pathways (apoptosis/necrosis/autophagy) that synergistically modulate the neuronal death...
June 2017: Journal of Cerebral Blood Flow and Metabolism
Hitoshi Gotoh, Tadashi Nomura, Katsuhiko Ono
Large amounts of energy are required when cells undergo cell proliferation and differentiation for mammalian neuronal development. Early neonatal mice face transient starvation and use stored energy for survival or to support development. Glycogen is a branched polysaccharide that is formed by glucose, and serves as an astrocytic energy store for rapid energy requirements. Although it is present in radial glial cells and astrocytes, the role of glycogen during development remains unclear. In the present study, we demonstrated that glycogen accumulated in glutamate aspartate transporter (GLAST)+ astrocytes in the subventricular zone and rostral migratory stream...
June 2017: Journal of Cerebral Blood Flow and Metabolism
Boeun Lee, Yu Kyeong Kim, Ji Youn Lee, Young Joo Kim, Yun-Sang Lee, Dong Soo Lee, June-Key Chung, Jae Min Jeong
Metabotropic glutamate receptor type 1 (mGluR1) is related with various neurological and psychiatric diseases, such as anxiety, depression, epilepsy, Parkinson's disease, and neuropathic pain. Hence, mGluR1 is an important target for drug development and imaging. We synthesized [(18)F]cEFQ (3-ethyl-2-[(18)F]fluoroquinolin-6-yl cis-(4-methoxycyclohexyl)methanone) as a PET tracer for selective mGluR1 imaging and evaluated its properties in rodents. A chloroquinoline precursor was labeled by a nucleophilic substitution reaction, and the resulting [(18)F]cEFQ was obtained with high radiochemical purity (>99%) and specific activity (63-246 GBq/µmol)...
June 2017: Journal of Cerebral Blood Flow and Metabolism
Ararat Chakhoyan, Aurélien Corroyer-Dulmont, Marine M Leblond, Aurélie Gérault, Jérôme Toutain, Laurent Chazaviel, Didier Divoux, Edwige Petit, Eric T MacKenzie, François Kauffmann, Nicolas Delcroix, Myriam Bernaudin, Omar Touzani, Samuel Valable
The alleviation of hypoxia in glioblastoma with carbogen to improve treatment has met with limited success. Our hypothesis is that the eventual benefits of carbogen depend on the capacity for vasodilation. We examined, with MRI, changes in fractional cerebral blood volume, blood oxygen saturation, and blood oxygenation level dependent signals in response to carbogen. The analyses were performed in two xenograft models of glioma (U87 and U251) recognized to have different vascular patterns. Carbogen increased fractional cerebral blood volume, blood oxygen saturation, and blood oxygenation level dependent signals in contralateral tissues...
June 2017: Journal of Cerebral Blood Flow and Metabolism
Leonardo A Rivera-Rivera, Tilman Schubert, Patrick Turski, Kevin M Johnson, Sara E Berman, Howard A Rowley, Cynthia M Carlsson, Sterling C Johnson, Oliver Wieben
Cerebral blood flow, arterial pulsation, and vasomotion may be important indicators of cerebrovascular health in aging and diseases of aging such as Alzheimer's disease. Noninvasive markers that assess these characteristics may be helpful in the study of co-occurrence of these diseases and potential additive and interacting effects. In this study, 4D flow MRI was used to measure intra-cranial flow features with cardiac-gated phase contrast MRI in cranial arteries and veins. Mean blood flow and pulsatility index as well as the transit time of the peak flow from the middle cerebral artery to the superior sagittal sinus were measured in a total of 104 subjects comprising of four groups: (a) subjects with Alzheimer's disease, (b) age-matched controls, (c) subjects with mild cognitive impairment, and (d) a group of late middle-aged with parental history of sporadic Alzheimer's disease...
June 2017: Journal of Cerebral Blood Flow and Metabolism
Thiruma V Arumugam, Silvia Manzanero, Milena Furtado, Patrick J Biggins, Yu-Hsuan Hsieh, Mathias Gelderblom, Kelli Pa MacDonald, Ekaterina Salimova, Yu-I Li, Othmar Korn, Deborah Dewar, I Mhairi Macrae, Robert B Ashman, Sung-Chun Tang, Nadia A Rosenthal, Marc J Ruitenberg, Tim Magnus, Christine A Wells
The C-type lectin Mincle is implicated in innate immune responses to sterile inflammation, but its contribution to associated pathologies is not well understood. Herein, we show that Mincle exacerbates neuronal loss following ischemic but not traumatic spinal cord injury. Loss of Mincle was beneficial in a model of transient middle cerebral artery occlusion but did not alter outcomes following heart or gut ischemia. High functional scores in Mincle KO animals using the focal cerebral ischemia model were accompanied by reduced lesion size, fewer infiltrating leukocytes and less neutrophil-derived cytokine production than isogenic controls...
June 2017: Journal of Cerebral Blood Flow and Metabolism
Pavitra Kannan, Martin Schain, Warren W Kretzschmar, Lora Weidner, Nicholas Mitsios, Balázs Gulyás, Hans Blom, Michael M Gottesman, Robert B Innis, Matthew D Hall, Jan Mulder
Changes in P-glycoprotein and ABCG2 densities may play a role in amyloid-beta accumulation in Alzheimer's disease. However, previous studies report conflicting results from different brain regions, without correcting for changes in vessel density. We developed an automated method to measure transporter density exclusively within the vascular space, thereby correcting for vessel density. We then examined variability in transporter density across brain regions, matter, and disease using two cohorts of post-mortem brains from Alzheimer's disease patients and age-matched controls...
June 2017: Journal of Cerebral Blood Flow and Metabolism
Sylvain Auvity, Hélène Chapy, Sébastien Goutal, Fabien Caillé, Benoit Hosten, Maria Smirnova, Xavier Declèves, Nicolas Tournier, Salvatore Cisternino
Diphenhydramine, a sedative histamine H1-receptor (H1R) antagonist, was evaluated as a probe to measure drug/H(+)-antiporter function at the blood-brain barrier. In situ brain perfusion experiments in mice and rats showed that diphenhydramine transport at the blood-brain barrier was saturable, following Michaelis-Menten kinetics with a Km = 2.99 mM and Vmax = 179.5 nmol s(-1) g(-1). In the pharmacological plasma concentration range the carrier-mediated component accounted for 77% of diphenhydramine influx while passive diffusion accounted for only 23%...
June 2017: Journal of Cerebral Blood Flow and Metabolism
Siobhan M Hoscheidt, J Mikhail Kellawan, Sara E Berman, Leonardo A Rivera-Rivera, Rachel A Krause, Jennifer M Oh, Michal S Beeri, Howard A Rowley, Oliver Wieben, Cynthia M Carlsson, Sanjay Asthana, Sterling C Johnson, William G Schrage, Barbara B Bendlin
Insulin resistance (IR) is associated with poor cerebrovascular health and increased risk for dementia. Little is known about the unique effect of IR on both micro- and macrovascular flow particularly in midlife when interventions against dementia may be most effective. We examined the effect of IR as indexed by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) on cerebral blood flow in macro- and microvessels utilizing magnetic resonance imaging (MRI) among cognitively asymptomatic middle-aged individuals...
June 2017: Journal of Cerebral Blood Flow and Metabolism
Saima Hilal, Xin Xu, M Kamran Ikram, Henri Vrooman, Narayanaswamy Venketasubramanian, Christopher Chen
Intracranial stenosis is a common vascular lesion observed in Asian and other non-Caucasian stroke populations. However, its role in cognitive impairment and dementia has been under-studied. We, therefore, examined the association of intracranial stenosis with cognitive impairment, dementia and their subtypes in a memory clinic case-control study, where all subjects underwent detailed neuropsychological assessment and 3 T neuroimaging including three-dimensional time-of-flight magnetic resonance angiography...
June 2017: Journal of Cerebral Blood Flow and Metabolism
Johanna A Gutiérrez-Vargas, Herman Moreno, Gloria P Cardona-Gómez
Post-stroke cognitive impairment is a major cause of long-term neurological disability. The prevalence of post-stroke cognitive deficits varies between 20% and 80% depending on brain region, country, and diagnostic criteria. The biochemical mechanisms underlying post-stroke cognitive impairment are not known in detail. Cyclin-dependent kinase 5 is involved in neurodegeneration, and its dysregulation contributes to cognitive disorders and dementia. Here, we administered cyclin-dependent kinase 5-targeting gene therapy to the right hippocampus of ischemic rats after transient right middle cerebral artery occlusion...
June 2017: Journal of Cerebral Blood Flow and Metabolism
Iben Lundgaard, Minh Lon Lu, Ezra Yang, Weiguo Peng, Humberto Mestre, Emi Hitomi, Rashid Deane, Maiken Nedergaard
Brain lactate concentration is higher during wakefulness than in sleep. However, it is unknown why arousal is linked to an increase in brain lactate and why lactate declines within minutes of sleep. Here, we show that the glymphatic system is responsible for state-dependent changes in brain lactate concentration. Suppression of glymphatic function via acetazolamide treatment, cisterna magna puncture, aquaporin 4 deletion, or changes in body position reduced the decline in brain lactate normally observed when awake mice transition into sleep or anesthesia...
June 2017: Journal of Cerebral Blood Flow and Metabolism
Jim Fm Myers, Robert A Comley, Roger N Gunn
[(11)C]Ro15-4513 has been introduced as a positron emission tomography radioligand to image the GABAAα5 receptor subtype thought to be important in learning, memory and addiction. However, the in vivo selectivity of the ligand remains unknown and a full assessment of different analysis approaches has yet to be performed. Using human heterologous competition data, with [(11)C]Ro15-4513 and the highly selective GABAAα5 selective negative allosteric modulator Basmisanil (RG1662), we quantify the GABAAα5 selectivity of [(11)C]Ro15-4513, assess the validity of reference tissues and evaluate the performance of four different kinetic analysis methods...
June 2017: Journal of Cerebral Blood Flow and Metabolism
Maria Sancho, Nina C Samson, Bjorn O Hald, Ahmed M Hashad, Sean P Marrelli, Suzanne E Brett, Donald G Welsh
The conducted vasomotor response reflects electrical communication in the arterial wall and the distance signals spread is regulated by three factors including resident ion channels. This study defined the role of inward-rectifying K(+) channels (KIR) in governing electrical communication along hamster cerebral arteries. Focal KCl application induced a vasoconstriction that conducted robustly, indicative of electrical communication among cells. Inhibiting dominant K(+) conductances had no attenuating effect, the exception being Ba(2+) blockade of KIR...
June 2017: Journal of Cerebral Blood Flow and Metabolism
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