bluuebunny/crossref_metadata_2025 huggingface dataset:
Arterial spin labeling imaging reveals widespread and Aβ-independent reductions in cerebral blood flow in elderly apolipoprotein epsilon-4 carriers
Authors: Michels Lars , Warnock Geoffrey , Buck Alfred , Macauda Gianluca , Leh Sandra E , Kaelin Andrea M , Riese Florian , Meyer Rafael , O’Gorman Ruth , Hock Christoph , Kollias Spyros , Gietl Anton F
Published: December 2015

Changes in cerebral blood flow are an essential feature of Alzheimer’s disease and have been linked to apolipoprotein E-genotype and cerebral amyloid-deposition. These factors could be interdependent or influence cerebral blood flow via different mechanisms. We examined apolipoprotein E-genotype, amyloid beta-deposition, and cerebral blood flow in amnestic mild cognitive impairment using pseudo-continuous arterial spin labeling MRI in 27 cognitively normal elderly and 16 amnestic mild cognitive impairment participants. Subjects underwent Pittsburgh Compound B (PiB) positron emission tomography and apolipoprotein E-genotyping. Global cerebral blood flow was lower in apolipoprotein E ɛ4-allele carriers (apolipoprotein E4+) than in apolipoprotein E4− across all subjects (including cognitively normal participants) and within the group of cognitively normal elderly. Global cerebral blood flow was lower in subjects with mild cognitive impairment compared with cognitively normal. Subjects with elevated cerebral amyloid-deposition (PiB+) showed a trend for lower global cerebral blood flow. Apolipoprotein E-status exerted the strongest effect on global cerebral blood flow. Regional analysis indicated that local cerebral blood flow reductions were more widespread for the contrasts apolipoprotein E4+ versus apolipoprotein E4− compared with the contrasts PiB+ versus PiB− or mild cognitive impairment versus cognitively normal. These findings suggest that apolipoprotein E-genotype exerts its impact on cerebral blood flow at least partly independently from amyloid beta-deposition, suggesting that apolipoprotein E also contributes to cerebral blood flow changes outside the context of Alzheimer’s disease.
Cerebral metabolic rate of oxygen in obstructive sleep apnea at rest and in response to breath-hold challenge
Authors: Rodgers Zachary B , Leinwand Sarah E , Keenan Brendan T , Kini Lohith G , Schwab Richard J , Wehrli Felix W
Published: December 2015

Obstructive sleep apnea (OSA) is associated with extensive neurologic comorbidities. It is hypothesized that the repeated nocturnal apneas experienced in patients with OSA may inhibit the normal apneic response, resulting in hypoxic brain injury and subsequent neurologic dysfunction. In this study, we applied the recently developed OxFlow MRI method for rapid quantification of cerebral metabolic rate of oxygen (CMRO2) during a volitional apnea paradigm. MRI data were analyzed in 11 OSA subjects and 10 controls (mean ± SD apnea-hypopnea index (AHI): 43.9 ± 18.1 vs. 2.9 ± 1.6 events/hour, P < 0.0001; age: 53.8 ± 8.2 vs. 45.3 ± 8.5 years, P = 0.027; BMI: 36.6 ± 4.4 vs. 31.9 ± 2.2 kg/m2, P = 0.0064). Although total cerebral blood flow and arteriovenous oxygen difference were not significantly different between apneics and controls ( P > 0.05), apneics displayed reduced baseline CMRO2 (117.4 ± 37.5 vs. 151.6 ± 29.4 µmol/100 g/min, P = 0.013). In response to apnea, CMRO2 decreased more in apneics than controls (−10.9 ± 8.8 % vs. −4.0 ± 6.7 %, P = 0.036). In contrast, group differences in flow-based cerebrovascular reactivity were not significant. Results should be interpreted with caution given the small sample size, and future studies with larger independent samples should examine the observed associations, including potential independent effects of age or BMI. Overall, these data suggest that dysregulation of the apneic response may be a mechanism for OSA-associated neuropathology.
Cerebrospinal fluid profiles with increasing number of cerebral microbleeds in a continuum of cognitive impairment
Authors: Shams Sara , Granberg Tobias , Martola Juha , Li Xiaozhen , Shams Mana , Fereshtehnejad Seyed-Mohammad , Cavallin Lena , Aspelin Peter , Kristoffersen-Wiberg Maria , Wahlund Lars-Olof
Published: December 2015

Cerebral microbleeds (CMBs) are hypothesised to have an important yet unknown role in the dementia disease pathology. In this study we analysed increasing number of CMBs and their independent associations with routine cerebrospinal fluid (CSF) biomarkers in a continuum of cognitive impairment. A total of 1039 patients undergoing dementia investigation were analysed and underwent lumbar puncture, and an MRI scan. CSF samples were analysed for amyloid β (Aβ) 42, total tau (T-tau), tau phosphorylated at threonine 18 (P-tau) and CSF/serum albumin ratios. Increasing number of CMBs were independently associated with low Aβ42 levels, in the whole cohort, Alzheimer’s disease and mild cognitive impairment ( p < 0.05). CSF/serum albumin ratios were high with multiple CMBs ( p < 0.001), reflecting accompanying blood–brain barrier dysfunction. T-tau and P-tau levels were lower in Alzheimer’s patients with multiple CMBs when compared to zero CMBs, but did not change in the rest of the cohort. White matter hyperintensities were associated with low Aβ42 in the whole cohort and Alzheimer’s disease ( p < 0.05). Aβ42 is the routine CSF-biomarker mainly associated with CMBs in cognitive impairment, and there is an accumulative effect with increasing number of CMBs.
A novel approach to measure local cerebral haematocrit using MRI
Authors: Calamante Fernando , Ahlgren André , van Osch Matthias JP , Knutsson Linda
Published: December 2015

The percentage blood volume occupied by red blood cells is known as haematocrit. While it is straightforward to measure haematocrit in large arteries, it is very challenging to do it in microvasculature (cerebral haematocrit). Currently, this can only be done using invasive methods (e.g. PET), but their use is very limited. Local variations in cerebral haematocrit have been reported in various brain abnormalities (e.g. stroke, tumours). We propose a new approach to image cerebral haematocrit using MRI, which relies on combining data from two measurements: one that provides haematocrit-weighted and other one haematocrit-independent values of the same parameter, thus providing an easily obtainable measurement of this important physiological parameter. Four different implementations are described, with one illustrated as proof-of-concept using data from healthy subjects. Cerebral haematocrit measurements were found to be in general agreement with literature values from invasive techniques (e.g. cerebral/arterial ratios of 0.88 and 0.86 for sub-cortical and cortical regions), and showed good test–retest reproducibility (e.g. coefficient-of-variation: 15% and 13% for those regions). The method was also able to detect statistically significant haematocrit gender differences in cortical regions ( p < 0.01). The proposed MRI technique should have important applications in various neurological diseases, such as in stroke and brain tumours.
Kinetic study of benzyl [1-14C]acetate as a potential probe for astrocytic energy metabolism in the rat brain: Comparison with benzyl [2-14C]acetate
Authors: Okada Maki , Yanamoto Kazuhiko , Kagawa Tomohiko , Yoshino Keiko , Hosoi Rie , Abe Kohji , Zhang Ming-Rong , Inoue Osamu
Published: December 2015

Brain uptake of [14C]acetate has been reported to be a useful marker of astrocytic energy metabolism. In addition to uptake values, the rate of radiolabeled acetate washout from the brain appears to reflect CO2 exhaustion and oxygen consumption in astrocytes. We measured the time–radioactivity curves of benzyl [1-14C]acetate ([1-14C]BA), a lipophilic probe of [1-14C]acetate, and compared it with that of benzyl [2-14C]acetate ([2-14C]BA) in rat brains. The highest brain uptake was observed immediately after injecting either [1-14C]BA or [2-14C]BA, and both subsequently disappeared from the brain in a single-exponential manner. Estimated [1-14C]BA washout rates in the cerebral cortex and cerebellum were higher than those of [2-14C]BA. These results suggested that [1-14C]BA could be a useful probe for estimating the astrocytic oxidative metabolism. The [1-14C]BA washout rate in the cerebral cortex of immature rats was lower than that of mature rats. An autoradiographic study showed that the washout rates of [1-14C]BA from the rat brains of a lithium–pilocarpine-induced status epilepticus model were not significantly different from the values in control rat brains except for the medial septal nucleus. These results implied that the enhancement of amino acid turnover rate rather than astrocytic oxidative metabolism was increased in status epilepticus.
MiR-34a regulates blood–brain barrier permeability and mitochondrial function by targeting cytochrome c
Authors: Bukeirat Mimi , Sarkar Saumyendra N , Hu Heng , Quintana Dominic D , Simpkins James W , Ren Xuefang
Published: December 2015

The blood–brain barrier is composed of cerebrovascular endothelial cells and tight junctions, and maintaining its integrity is crucial for the homeostasis of the neuronal environment. Recently, we discovered that mitochondria play a critical role in maintaining blood–brain barrier integrity. We report for the first time a novel mechanism underlying blood–brain barrier integrity: miR-34a mediated regulation of blood–brain barrier through a mitochondrial mechanism. Bioinformatics analysis suggests miR-34a targets several mitochondria-associated gene candidates. We demonstrated that miR-34a triggers the breakdown of blood–brain barrier in cerebrovascular endothelial cell monolayer in vitro, paralleled by reduction of mitochondrial oxidative phosphorylation and adenosine triphosphate production, and decreased cytochrome c levels.
Detrimental role of pericyte Nox4 in the acute phase of brain ischemia
Authors: Nishimura Ataru , Ago Tetsuro , Kuroda Junya , Arimura Koichi , Tachibana Masaki , Nakamura Kuniyuki , Wakisaka Yoshinobu , Sadoshima Junichi , Iihara Koji , Kitazono Takanari
Published: December 2015

Pericytes are mural cells abundantly present in cerebral microvessels and play important roles, including the formation and maintenance of the blood–brain barrier. Nox4 is a major source of reactive oxygen species in cardiovascular cells and modulate cellular functions, particularly under pathological conditions. In the present study, we found that the expression of Nox4 was markedly induced in microvascular cells, including pericytes, in peri-infarct areas after middle cerebral artery occlusion stroke models in mice. The upregulation of Nox4 was greater in a permanent middle cerebral artery occlusion model compared with an ischemia/reperfusion transient middle cerebral artery occlusion model. We performed permanent middle cerebral artery occlusion on mice with Nox4 overexpression in pericytes (Tg-Nox4). Infarct volume was significantly greater with enhanced reactive oxygen species production and blood–brain barrier breakdown in peri-infarct areas in Tg-Nox4, compared with littermate controls. In cultured brain pericytes, Nox4 was significantly upregulated by hypoxia and was promptly downregulated by reoxygenation. Phosphorylation of NFκB and production of matrix metalloproteinase 9 were significantly increased in both cultured pericytes overexpressing Nox4 and in peri-infarct areas in Tg-Nox4. Collectively, Nox4 is upregulated in pericytes in peri-infarct areas after acute brain ischemia and may enhance blood–brain barrier breakdown through activation of NFκB and matrix metalloproteinase 9, thereby causing enlargement of infarct volume.
Hypothermia protects brain mitochondrial function from hypoxemia in a murine model of sepsis
Authors: Chisholm Kim I , Ida Keila K , Davies Andrew L , Tachtsidis Ilias , Papkovsky Dmitri B , Dyson Alex , Singer Mervyn , Duchen Michael R , Smith Kenneth J
Published: December 2015

Sepsis is commonly associated with brain dysfunction, but the underlying mechanisms remain unclear, although mitochondrial dysfunction and microvascular abnormalities have been implicated. We therefore assessed whether cerebral mitochondrial dysfunction during systemic endotoxemia in mice increased mitochondrial sensitivity to a further bioenergetic insult (hyoxemia), and whether hypothermia could improve outcome. Mice (C57bl/6) were injected intraperitoneally with lipopolysaccharide (LPS) (5 mg/kg; n = 85) or saline (0.01 ml/g; n = 47). Six, 24 and 48 h later, we used confocal imaging in vivo to assess cerebral mitochondrial redox potential and cortical oxygenation in response to changes in inspired oxygen. The fraction of inspired oxygen (FiO2) at which the cortical redox potential changed was compared between groups. In a subset of animals, spontaneous hypothermia was maintained or controlled hypothermia induced during imaging. Decreasing FiO2 resulted in a more reduced cerebral redox state around veins, but preserved oxidation around arteries. This pattern appeared at a higher FiO2 in LPS-injected animals, suggesting an increased sensitivity of cortical mitochondria to hypoxemia. This increased sensitivity was accompanied by a decrease in cortical oxygenation, but was attenuated by hypothermia. These results suggest that systemic endotoxemia influences cortical oxygenation and mitochondrial function, and that therapeutic hypothermia can be protective.
Perfusion-weighted imaging and dynamic 4D angiograms for the estimation of collateral blood flow in lacunar infarction
Authors: Förster Alex , Mürle Bettina , Böhme Johannes , Al-Zghloul Mansour , Kerl Hans U , Wenz Holger , Groden Christoph
Published: December 2015

Although lacunar infarction accounts for approximately 25% of ischemic strokes, collateral blood flow through anastomoses is not well evaluated in lacunar infarction. In 111 lacunar infarction patients, we analyzed diffusion-weighted images, perfusion-weighted images, and blood flow on dynamic four-dimensional angiograms generated by use of Signal Processing In NMR-Software. Blood flow was classified as absent (type 1), from periphery to center (type 2), from center to periphery (type 3), and combination of type 2 and 3 (type 4). On diffusion-weighted images, lacunar infarction was found in the basal ganglia (11.7%), internal capsule (24.3%), corona radiata (30.6%), thalamus (24.3%), and brainstem (9.0%). In 58 (52.2%) patients, perfusion-weighted image showed a circumscribed hypoperfusion, in one (0.9%) a circumscribed hyperperfusion, whereas the remainder was normal. In 36 (62.1%) patients, a larger perfusion deficit (>7 mm) was observed. In these, blood flow was classified type 1 in four (11.1%), 2 in 17 (47.2%), 3 in 9 (25.0%), and 4 in six (16.7%) patients. Patients with lacunar infarction in the posterior circulation more often demonstrated blood flow type 2 and less often type 3 (p = 0.01). Detailed examination and graduation of blood flow in lacunar infarction by use of dynamic four-dimensional angiograms is feasible and may serve for a better characterization of this stroke subtype.
Acute hypoxia increases the cerebral metabolic rate – a magnetic resonance imaging study
Authors: Vestergaard Mark B , Lindberg Ulrich , Aachmann-Andersen Niels Jacob , Lisbjerg Kristian , Christensen Søren Just , Law Ian , Rasmussen Peter , Olsen Niels V , Larsson Henrik BW
Published: December 2015

The aim of the present study was to examine changes in cerebral metabolism by magnetic resonance imaging of healthy subjects during inhalation of 10% O2 hypoxic air. Hypoxic exposure elevates cerebral perfusion, but its effect on energy metabolism has been less investigated. Magnetic resonance imaging techniques were used to measure global cerebral blood flow and the venous oxygen saturation in the sagittal sinus. Global cerebral metabolic rate of oxygen was quantified from cerebral blood flow and arteriovenous oxygen saturation difference. Concentrations of lactate, glutamate, N-acetylaspartate, creatine and phosphocreatine were measured in the visual cortex by magnetic resonance spectroscopy. Twenty-three young healthy males were scanned for 60 min during normoxia, followed by 40 min of breathing hypoxic air. Inhalation of hypoxic air resulted in an increase in cerebral blood flow of 15.5% ( p = 0.058), and an increase in cerebral metabolic rate of oxygen of 8.5% ( p = 0.035). Cerebral lactate concentration increased by 180.3% ([Formula: see text]), glutamate increased by 4.7% ([Formula: see text]) and creatine and phosphocreatine decreased by 15.2% ( p[Formula: see text]). The N-acetylaspartate concentration was unchanged ( p = 0.36). In conclusion, acute hypoxia in healthy subjects increased perfusion and metabolic rate, which could represent an increase in neuronal activity. We conclude that marked changes in brain homeostasis occur in the healthy human brain during exposure to acute hypoxia.
Inhibition of prostaglandin E2 receptor EP3 mitigates thrombin-induced brain injury
Authors: Han Xiaoning , Lan Xi , Li Qiang , Gao Yufeng , Zhu Wei , Cheng Tian , Maruyama Takayuki , Wang Jian
Published: December 2015

Prostaglandin E2 EP3 receptor is the only prostaglandin E2 receptor that couples to multiple G-proteins, but its role in thrombin-induced brain injury is unclear. In the present study, we exposed mouse hippocampal slice cultures to thrombin in vitro and injected mice with intrastriatal thrombin in vivo to investigate the role of EP3 receptor in thrombin-induced brain injury and explore its underlying cellular and molecular mechanisms. In vitro, EP3 receptor inhibition reduced thrombin-induced hippocampal CA1 cell death. In vivo, EP3 receptor was expressed in astrocytes and microglia in the perilesional region. EP3 receptor inhibition reduced lesion volume, neurologic deficit, cell death, matrix metalloproteinase-9 activity, neutrophil infiltration, and the number of CD68+ microglia, but increased the number of Ym-1+ M2 microglia. RhoA-Rho kinase levels were increased after thrombin injection and were decreased by EP3 receptor inhibition. In mice that received an intrastriatal injection of autologous arterial blood, inhibition of thrombin activity with hirudin decreased RhoA expression compared with that in vehicle-treated mice. However, EP3 receptor activation reversed this effect of hirudin. These findings show that prostaglandin E2 EP3 receptor contributes to thrombin-induced brain damage via Rho-Rho kinase–mediated cytotoxicity and proinflammatory responses.
Oxygen extraction fraction measurement using quantitative susceptibility mapping: Comparison with positron emission tomography
Authors: Kudo Kohsuke , Liu Tian , Murakami Toshiyuki , Goodwin Jonathan , Uwano Ikuko , Yamashita Fumio , Higuchi Satomi , Wang Yi , Ogasawara Kuniaki , Ogawa Akira , Sasaki Makoto
Published: December 2015

The purposes of this study are to establish oxygen extraction fraction (OEF) measurements using quantitative susceptibility mapping (QSM) of magnetic resonance imaging (MRI), and to compare QSM–OEF data with the gold standard 15O positron emission tomography (PET). Twenty-six patients with chronic unilateral internal carotid artery or middle cerebral artery stenosis or occlusion, and 15 normal subjects were included. MRI scans were conducted using a 3.0 Tesla scanner with a three-dimensional spoiled gradient recalled sequence. QSM images were created using the morphology-enabled dipole inversion method, and OEF maps were generated from QSM images using extraction of venous susceptibility induced by deoxygenated hemoglobin. Significant correlation of relative OEF ratio to contra-lateral hemisphere between QSM–OEF and PET–OEF was observed (r = 0.62, p < 0.001). The local (intra-section) correlation was also significant (r = 0.52, p < 0.001) in patients with increased PET–OEF. The sensitivity and specificity of OEF increase in QSM was 0.63 (5/8) and 0.89 (16/18), respectively, in comparison with PET. In conclusion, good correlation was achieved between QSM–OEF and PET–OEF in the identification of elevated OEF in affected hemispheres of patients with unilateral chronic steno-occlusive disease.
A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke
Authors: Maysami Samaneh , Wong Raymond , Pradillo Jesus M , Denes Adam , Dhungana Hiramani , Malm Tarja , Koistinaho Jari , Orset Cyrille , Rahman Mahbubur , Rubio Marina , Schwaninger Markus , Vivien Denis , Bath Philip M , Rothwell Nancy J , Allan Stuart M
Published: December 2015

Stroke represents a global challenge and is a leading cause of permanent disability worldwide. Despite much effort, translation of research findings to clinical benefit has not yet been successful. Failure of neuroprotection trials is considered, in part, due to the low quality of preclinical studies, low level of reproducibility across different laboratories and that stroke co-morbidities have not been fully considered in experimental models. More rigorous testing of new drug candidates in different experimental models of stroke and initiation of preclinical cross-laboratory studies have been suggested as ways to improve translation. However, to our knowledge, no drugs currently in clinical stroke trials have been investigated in preclinical cross-laboratory studies. The cytokine interleukin 1 is a key mediator of neuronal injury, and the naturally occurring interleukin 1 receptor antagonist has been reported as beneficial in experimental studies of stroke. In the present paper, we report on a preclinical cross-laboratory stroke trial designed to investigate the efficacy of interleukin 1 receptor antagonist in different research laboratories across Europe. Our results strongly support the therapeutic potential of interleukin 1 receptor antagonist in experimental stroke and provide further evidence that interleukin 1 receptor antagonist should be evaluated in more extensive clinical stroke trials.
Gradual cerebral hypoperfusion in spontaneously hypertensive rats induces slowly evolving white matter abnormalities and impairs working memory
Authors: Kitamura Akihiro , Saito Satoshi , Maki Takakuni , Oishi Naoya , Ayaki Takashi , Hattori Yorito , Yamamoto Yumi , Urushitani Makoto , Kalaria Raj N , Fukuyama Hidenao , Horsburgh Karen , Takahashi Ryosuke , Ihara Masafumi
Published: December 2015

Rats subjected to bilateral common carotid arteries (CCAs) occlusion or 2-vessel occlusion (2VO) have been used as animal models of subcortical ischemic vascular dementia (SIVD). However, these models possess an inherent limitation in that cerebral blood flow (CBF) drops sharply and substantially after ligation of CCAs without vascular risk factors and causative small vessel changes. We previously reported a novel rat model of 2-vessel gradual occlusion (2VGO) in which ameroid constrictors (ACs) were placed bilaterally in the CCAs of Wistar-Kyoto rats. To simulate SIVD pathology more closely, we applied ACs in spontaneously hypertensive rats (SHRs), which naturally develop small vessel pathology, and compared their phenotypes with SHR-2VO and sham-operated rats. The mortality rate of the SHR-2VGO was 0% while that of the SHR-2VO was 56.5%. The CBF of the SHR-2VO dropped to 50% of the baseline level at 3 h, whereas the SHR-2VGO showed a gradual CBF reduction reaching only 68% of the baseline level at seven days. The SHR-2VGO showed slowly evolving white matter abnormalities and subsequent spatial working memory impairments of a similar magnitude to the remaining SHR-2VO at 28 days. We suggest the SHR-2VGO robustly replicates selective aspects of the pathophysiology of SIVD with low mortality rate.
Experimental hypertension increases spontaneous intracerebral hemorrhages in a mouse model of cerebral amyloidosis
Authors: Passos Giselle F , Kilday Kelley , Gillen Daniel L , Cribbs David H , Vasilevko Vitaly
Published: December 2015

Hypertension and cerebral amyloid angiopathy (CAA) are major risk factors for intracerebral hemorrhage (ICH); however the mechanisms of interplay between the two are not fully understood. We investigated the effect of hypertension in a transgenic mouse model with Alzheimer’s-like pathology (Tg2576) treating them with angiontensin II and L-NG-nitroarginine methyl ester. A similar increase in systolic blood pressure was observed in both Tg2576 and control mice; however Tg2576 mice developed signs of stroke with a markedly shorter latency. Cerebral deposition of amyloid beta promotes the hypertension-induced ICH, thus supporting the notion that hypertension is a risk factor for ICH among patients with CAA.
The transient intraluminal filament middle cerebral artery occlusion model as a model of endovascular thrombectomy in stroke
Authors: Sutherland Brad A , Neuhaus Ain A , Couch Yvonne , Balami Joyce S , DeLuca Gabriele C , Hadley Gina , Harris Scarlett L , Grey Adam N , Buchan Alastair M
Published: December 2015

The clinical relevance of the transient intraluminal filament model of middle cerebral artery occlusion (tMCAO) has been questioned due to distinct cerebral blood flow profiles upon reperfusion between tMCAO (abrupt reperfusion) and alteplase treatment (gradual reperfusion), resulting in differing pathophysiologies. Positive results from recent endovascular thrombectomy trials, where the occluding clot is mechanically removed, could revolutionize stroke treatment. The rapid cerebral blood flow restoration in both tMCAO and endovascular thrombectomy provides clinical relevance for this pre-clinical model. Any future clinical trials of neuroprotective agents as adjuncts to endovascular thrombectomy should consider tMCAO as the model of choice to determine pre-clinical efficacy.
Cerebral small vessel disease: Capillary pathways to stroke and cognitive decline
Authors: Østergaard Leif , Engedal Thorbjørn S , Moreton Fiona , Hansen Mikkel B , Wardlaw Joanna M , Dalkara Turgay , Markus Hugh S , Muir Keith W
Published: December 2015

Cerebral small vessel disease (SVD) gives rise to one in five strokes worldwide and constitutes a major source of cognitive decline in the elderly. SVD is known to occur in relation to hypertension, diabetes, smoking, radiation therapy and in a range of inherited and genetic disorders, autoimmune disorders, connective tissue disorders, and infections. Until recently, changes in capillary patency and blood viscosity have received little attention in the aetiopathogenesis of SVD and the high risk of subsequent stroke and cognitive decline. Capillary flow patterns were, however, recently shown to limit the extraction efficacy of oxygen in tissue and capillary dysfunction therefore proposed as a source of stroke-like symptoms and neurodegeneration, even in the absence of physical flow-limiting vascular pathology. In this review, we examine whether capillary flow disturbances may be a shared feature of conditions that represent risk factors for SVD. We then discuss aspects of capillary dysfunction that could be prevented or alleviated and therefore might be of general benefit to patients at risk of SVD, stroke or cognitive decline.
Caloric restriction improves diabetes-induced cognitive deficits by attenuating neurogranin-associated calcium signaling in high-fat diet-fed mice
Authors: Kim Hwajin , Kang Heeyoung , Heo Rok Won , Jeon Byeong Tak , Yi Chin-ok , Shin Hyun Joo , Kim Jeonghyun , Jeong Seon-Yong , Kwak Woori , Kim Won-Ho , Kang Sang Soo , Roh Gu Seob
Published: December 2015

Diabetes-induced cognitive decline has been recognized in human patients of type 2 diabetes mellitus and mouse model of obesity, but the underlying mechanisms or therapeutic targets are not clearly identified. We investigated the effect of caloric restriction on diabetes-induced memory deficits and searched a molecular mechanism of caloric restriction-mediated neuroprotection. C57BL/6 mice were fed a high-fat diet for 40 weeks and RNA-seq analysis was performed in the hippocampus of high-fat diet-fed mice. To investigate caloric restriction effect on differential expression of genes, mice were fed high-fat diet for 20 weeks and continued on high-fat diet or subjected to caloric restriction (2 g/day) for 12 weeks. High-fat diet-fed mice exhibited insulin resistance, glial activation, blood–brain barrier leakage, and memory deficits, in that we identified neurogranin, a down-regulated gene in high-fat diet-fed mice using RNA-seq analysis; neurogranin regulates Ca2+/calmodulin-dependent synaptic function. Caloric restriction increased insulin sensitivity, reduced high-fat diet-induced blood–brain barrier leakage and glial activation, and improved memory deficit. Furthermore, caloric restriction reversed high-fat diet-induced expression of neurogranin and the activation of Ca2+/calmodulin-dependent protein kinase II and calpain as well as the downstream effectors. Our results suggest that neurogranin is an important factor of high-fat diet-induced memory deficits on which caloric restriction has a therapeutic effect by regulating neurogranin-associated calcium signaling.
Cannabinoid receptor activation in the juvenile rat brain results in rapid biomechanical alterations: Neurovascular mechanism as a putative confounding factor
Authors: Chatelin Simon , Humbert-Claude Marie , Garteiser Philippe , Ricobaraza Ana , Vilgrain Valérie , Van Beers Bernard E , Sinkus Ralph , Lenkei Zsolt
Published: December 2015

We have recently reported cannabinoid-induced rapid changes in the structure of individual neurons. In order to investigate the presence of similar effects at the regional level, measures of brain tissue biomechanics are required. However, cannabinoids are known to alter cerebral blood flow (CBF), putatively resulting in presently unexplored changes in cerebral tissue biomechanics. Here we used magnetic resonance elastography (MRE) and flow-sensitive alternating inversion recovery (FAIR) imaging to measure in vivo alterations of mechanical properties and CBF, respectively, in the rat hippocampus, a brain region with a high density of type-1 cannabinoid receptors (CB1R). Systemic injection of the cannabinoid agonist CP55,940 (0.7 mg/kg) induced a significant stiffness decrease of 10.5 ± 1.2% at 15 minutes. FAIR imaging indicated a comparable decrease (11.3 ± 1.9%) in CBF. Both effects were specific to CB1R activation, as shown by pretreatment with the CB1R-specific antagonist AM251. Strikingly, similar rapid parallel changes of brain elasticity and CBF were also observed after systemic treatment with the hypotensive drug nicardipine. Our results reveal important drug-induced parallel changes in CBF and brain mechanical characteristics, and show that blood flow-dependent tissue softening has to be considered as an important putative confounding factor when cerebral viscoelastic changes are investigated.
Internalization of targeted quantum dots by brain capillary endothelial cells in vivo
Authors: Paris-Robidas Sarah , Brouard Danny , Emond Vincent , Parent Martin , Calon Frédéric
Published: December 2015

Receptors located on brain capillary endothelial cells forming the blood–brain barrier are the target of most brain drug delivery approaches. Yet, direct subcellular evidence of vectorized transport of nanoformulations into the brain is lacking. To resolve this question, quantum dots were conjugated to monoclonal antibodies (Ri7) targeting the murine transferrin receptor. Specific transferrin receptor-mediated endocytosis of Ri7-quantum dots was first confirmed in N2A and bEnd5 cells. After intravenous injection in mice, Ri7-quantum dots exhibited a fourfold higher volume of distribution in brain tissues, compared to controls. Immunofluorescence analysis showed that Ri7-quantum dots were sequestered throughout the cerebral vasculature 30 min, 1 h, and 4 h post injection, with a decline of signal intensity after 24 h. Transmission electron microscopic studies confirmed that Ri7-quantum dots were massively internalized by brain capillary endothelial cells, averaging 37 ± 4 Ri7-quantum dots/cell 1 h after injection. Most quantum dots within brain capillary endothelial cells were observed in small vesicles (58%), with a smaller proportion detected in tubular structures or in multivesicular bodies. Parenchymal penetration of Ri7-quantum dots was extremely low and comparable to control IgG. Our results show that systemically administered Ri7-quantum dots complexes undergo extensive endocytosis by brain capillary endothelial cells and open the door for novel therapeutic approaches based on brain endothelial cell drug delivery.
Microvascular basis for growth of small infarcts following occlusion of single penetrating arterioles in mouse cortex
Authors: Taylor Zachary J , Hui Edward S , Watson Ashley N , Nie Xingju , Deardorff Rachael L , Jensen Jens H , Helpern Joseph A , Shih Andy Y
Published: December 2015

Small cerebral infarcts, i.e. microinfarcts, are common in the aging brain and linked to vascular cognitive impairment. However, little is known about the acute growth of these minute lesions and their effect on blood flow in surrounding tissues. We modeled microinfarcts in the mouse cortex by inducing photothrombotic clots in single penetrating arterioles. The resultant hemodynamic changes in tissues surrounding the occluded vessel were then studied using in vivo two-photon microscopy. We were able to generate a spectrum of infarct volumes by occluding arterioles that carried a range of blood fluxes. Those resulting from occlusion of high-flux penetrating arterioles (flux of 2 nL/s or higher) exhibited a radial outgrowth that encompassed unusually large tissue volumes. The gradual expansion of these infarcts was propagated by an evolving insufficiency in capillary flow that encroached on territories of neighboring penetrating arterioles, leading to the stagnation and recruitment of their perfusion domains into the final infarct volume. Our results suggest that local collapse of microvascular function contributes to tissue damage incurred by single penetrating arteriole occlusions in mice, and that a similar mechanism may add to pathophysiology induced by microinfarcts of the human brain.
Cerebral microcirculatory failure after subarachnoid hemorrhage is reversed by hyaluronidase
Authors: McConnell Evan D , Wei Helen S , Reitz Katherine M , Kang Hongyi , Takano Takahiro , Vates G Edward , Nedergaard Maiken
Published: December 2015

Aneurysmal subarachnoid hemorrhage remains one of the more devastating forms of stroke due in large part to delayed cerebral ischemia that appears days to weeks following the initial hemorrhage. Therapies exclusively targeting large caliber arterial vasospasm have fallen short, and thus we asked whether capillary dysfunction contributes to delayed cerebral ischemia after subarachnoid hemorrhage. Using a mouse model of subarachnoid hemorrhage and two-photon microscopy we showed capillary dysfunction unrelated to upstream arterial constriction. Subarachnoid hemorrhage decreased RBC velocity by 30%, decreased capillary pulsatility by 50%, and increased length of non-perfusing capillaries by 15%. This was accompanied by severe brain hypoxia and neuronal loss. Hyaluronidase, an enzyme that alters capillary blood flow by removing the luminal glycocalyx, returned RBC velocity and pulsatility to normal. Hyaluronidase also reversed brain hypoxia and prevented neuron loss typically seen after subarachnoid hemorrhage. Thus, subarachnoid hemorrhage causes specific changes in capillary RBC flow independent of arterial spasm, and hyaluronidase treatment that normalizes capillary blood flow can prevent brain hypoxia and injury after subarachnoid hemorrhage. Prevention or treatment of capillary dysfunction after subarachnoid hemorrhage may reduce the incidence or severity of subarachnoid hemorrhage-induced delayed cerebral ischemia.
Graph theoretical analysis of functional networks and its relationship to cognitive decline in patients with carotid stenosis
Authors: Chang Ting-Yu , Huang Kuo-Lun , Ho Meng-Yang , Ho Pei-Shan , Chang Chien-Hung , Liu Chi-Hung , Chang Yeu-Jhy , Wong Ho-Fai , Hsieh I-Chang , Lee Tsong-Hai , Liu Ho-Ling
Published: December 2015

Significant carotid stenosis compromises hemodynamics and impairs cognitive functions. The interplay between these changes and brain connectivity has rarely been investigated. We aimed to discover the changes of functional connectivity and its relation to cognitive decline in carotid stenosis patients. Twenty-seven patients with unilateral carotid stenosis (≥60%) and 20 age- and sex-matched controls underwent neuropsychological tests and resting-state functional magnetic resonance imaging. The patients also received perfusion magnetic resonance imaging. The relationships between cognitive function and functional networks among the patients and controls were evaluated. Graph theory was applied on resting-state functional magnetic resonance imaging network analysis, which revealed that the hemispheres ipsilateral to the stenosis were significantly impaired in “degree” and “global efficiency.” The neuropsychological performances were positively correlated with degree, clustering coefficient, local efficiency, and global efficiency, and negatively correlated with characteristic path length, modularity, and small-worldness in the patients, whereas these relationships were not observed in the controls. In this study, we identified the networks that were impaired in the affected hemispheres in patients with carotid stenosis. Specific indices (global efficiency, characteristic path length, and modularity) were highly correlated with neuropsychological performance in our patients. Analysis of brain connectivity may help to elucidate the relationship between hemodynamic impairment and cognitive decline.
Quantification of the novel N-methyl-d-aspartate receptor ligand [11C]GMOM in man
Authors: van der Doef Thalia F , Golla Sandeep SV , Klein Pieter J , Oropeza-Seguias Gisela M , Schuit Robert C , Metaxas Athanasios , Jobse Ellen , Schwarte Lothar A , Windhorst Albert D , Lammertsma Adriaan A , van Berckel Bart NM , Boellaard Ronald
Published: December 2015

[11C]GMOM (carbon-11 labeled N-(2-chloro-5-thiomethylphenyl)- N′-(3-[11C]methoxy-phenyl)- N′-methylguanidine) is a PET ligand that binds to the N-methyl-d-aspartate receptor with high specificity and affinity. The purpose of this first in human study was to evaluate kinetics of [11C]GMOM in the healthy human brain and to identify the optimal pharmacokinetic model for quantifying these kinetics, both before and after a pharmacological dose of S-ketamine. Dynamic 90 min [11C]GMOM PET scans were obtained from 10 subjects. In six of the 10 subjects, a second PET scan was performed following an S-ketamine challenge. Metabolite corrected plasma input functions were obtained for all scans. Regional time activity curves were fitted to various single- and two-tissue compartment models. Best fits were obtained using a two-tissue irreversible model with blood volume parameter. The highest net influx rate (Ki) of [11C]GMOM was observed in regions with high N-methyl-d-aspartate receptor density, such as hippocampus and thalamus. A significant reduction in the Ki was observed for the entire brain after administration of ketamine, suggesting specific binding to the N-methyl-d-aspartate receptors. This initial study suggests that the [11C]GMOM could be used for quantification of N-methyl-d-aspartate receptors.
O-linked β-N-acetylglucosamine modification of proteins is activated in post-ischemic brains of young but not aged mice: Implications for impaired functional recovery from ischemic stress
Authors: Liu Shuai , Sheng Huaxin , Yu Zhui , Paschen Wulf , Yang Wei
Published: December 2015

To evaluate the effect of age on the response of brains to an ischemic challenge, we subjected young and aged mice to transient forebrain ischemia, and analyzed the heat shock response and unfolded protein response, ubiquitin conjugation and SUMO conjugation, and O-linked β-N-acetylglucosamine modification of proteins (O-GlcNAcylation). The most prominent age-related difference was an inability of aged mice to activate O-GlcNAcylation. Considering many reports on the protective role of O-GlcNAcylation in various stress conditions including myocardial ischemia, this pathway could be a promising target for therapeutic intervention to improve functional recovery of aged patients following brain ischemia.
Pre-and postoperative cerebral blood flow changes in patients with idiopathic normal pressure hydrocephalus measured by computed tomography (CT)-perfusion
Authors: Ziegelitz Doerthe , Arvidsson Jonathan , Hellström Per , Tullberg Mats , Wikkelsø Carsten , Starck Göran
Published: December 2015

In idiopathic normal pressure hydrocephalus (iNPH), the cerebral blood flow (CBF) is of pathophysiological interest and a potential biomarker. Computed tomography perfusion (CTP), an established technique with high spatial resolution and quantitative measurements, has not yet been used in the iNPH context. If CTP were sensitive to the CBF levels and changes in iNPH, this technique might provide diagnostic and prognostic absolute perfusion thresholds. The aim of this work was to determine the applicability of CTP to iNPH. CBF measurements of 18 patients pre- and 17 three months postoperatively, and six healthy individuals (HI) were evaluated in 12 cortical and subcortical regions of interest. Correlations between CBF and symptomatology were analyzed in shunt-responders. Compared to HI, the preoperative CBF in iNPH was significantly reduced in normal appearing and periventricular white matter (PVWM), the lentiform nucleus and the global parenchyma. No CBF differences were shown between responders and non-responders. In responders, the CBF recovered postoperatively by 2.5–32% to approximately the level of HI, but remained significantly decreased in the PVWM of non-responders. The pre- and postoperative CBF of cortical and subcortical regions correlated with the intensity of symptoms. In spite of limited spatial coverage, CTP can measure CBF changes in iNPH.
Immediate remote ischemic postconditioning after hypoxia ischemia in piglets protects cerebral white matter but not grey matter
Authors: Ezzati Mojgan , Bainbridge Alan , Broad Kevin D , Kawano Go , Oliver-Taylor Aaron , Rocha-Ferreira Eridan , Alonso-Alconada Daniel , Fierens Igor , Rostami Jamshid , Jane Hassell K , Tachtsidis Ilias , Gressens Pierre , Hristova Mariya , Bennett Kate , Lebon Sophie , Fleiss Bobbi , Yellon Derek , Hausenloy Derek J , Golay Xavier , Robertson Nicola J
Published: December 2015

Remote ischemic postconditioning (RIPostC) is a promising therapeutic intervention whereby brief episodes of ischemia/reperfusion of one organ (limb) mitigate damage in another organ (brain) that has experienced severe hypoxia-ischemia. Our aim was to assess whether RIPostC is protective following cerebral hypoxia-ischemia in a piglet model of neonatal encephalopathy (NE) using magnetic resonance spectroscopy (MRS) biomarkers and immunohistochemistry. After hypoxia-ischemia (HI), 16 Large White female newborn piglets were randomized to: (i) no intervention ( n = 8); (ii) RIPostC – with four, 10-min cycles of bilateral lower limb ischemia/reperfusion immediately after HI ( n = 8). RIPostC reduced the hypoxic-ischemic-induced increase in white matter proton MRS lactate/N acetyl aspartate ( p = 0.005) and increased whole brain phosphorus-31 MRS ATP ( p = 0.039) over the 48 h after HI. Cell death was reduced with RIPostC in the periventricular white matter ( p = 0.03), internal capsule ( p = 0.002) and corpus callosum ( p = 0.021); there was reduced microglial activation in corpus callosum ( p = 0.001) and more surviving oligodendrocytes in corpus callosum ( p = 0.029) and periventricular white matter ( p = 0.001). Changes in gene expression were detected in the white matter at 48 h, including KATP channel and endothelin A receptor. Immediate RIPostC is a potentially safe and promising brain protective therapy for babies with NE with protection in white but not grey matter.
Brain interstitial fluid glutamine homeostasis is controlled by blood–brain barrier SLC7A5/LAT1 amino acid transporter
Authors: Dolgodilina Elena , Imobersteg Stefan , Laczko Endre , Welt Tobias , Verrey Francois , Makrides Victoria
Published: December 2015

L-glutamine (Gln) is the most abundant amino acid in plasma and cerebrospinal fluid and a precursor for the main central nervous system excitatory (L-glutamate) and inhibitory (γ-aminobutyric acid (GABA)) neurotransmitters. Concentrations of Gln and 13 other brain interstitial fluid amino acids were measured in awake, freely moving mice by hippocampal microdialysis using an extrapolation to zero flow rate method. Interstitial fluid levels for all amino acids including Gln were ∼5–10 times lower than in cerebrospinal fluid. Although the large increase in plasma Gln by intraperitoneal (IP) injection of 15N2-labeled Gln (hGln) did not increase total interstitial fluid Gln, low levels of hGln were detected in microdialysis samples. Competitive inhibition of system A (SLC38A1&2; SNAT1&2) or system L (SLC7A5&8; LAT1&2) transporters in brain by perfusion with α-(methylamino)-isobutyric acid (MeAIB) or 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) respectively, was tested. The data showed a significantly greater increase in interstitial fluid Gln upon BCH than MeAIB treatment. Furthermore, brain BCH perfusion also strongly increased the influx of hGln into interstitial fluid following IP injection consistent with transstimulation of LAT1-mediated transendothelial transport. Taken together, the data support the independent homeostatic regulation of amino acids in interstitial fluid vs. cerebrospinal fluid and the role of the blood–brain barrier expressed SLC7A5/LAT1 as a key interstitial fluid gatekeeper.
A novel quantitative high-throughput screen identifies drugs that both activate SUMO conjugation via the inhibition of microRNAs 182 and 183 and facilitate neuroprotection in a model of oxygen and glucose deprivation
Authors: Bernstock Joshua D , Lee Yang-ja , Peruzzotti-Jametti Luca , Southall Noel , Johnson Kory R , Maric Dragan , Volpe Giulio , Kouznetsova Jennifer , Zheng Wei , Pluchino Stefano , Hallenbeck John M
Published: December 2015

The conjugation/de-conjugation of Small Ubiquitin-like Modifier (SUMO) has been shown to be associated with a diverse set of physiologic/pathologic conditions. The clinical significance and ostensible therapeutic utility offered via the selective control of the global SUMOylation process has become readily apparent in ischemic pathophysiology. Herein, we describe the development of a novel quantitative high-throughput screening (qHTS) system designed to identify small molecules capable of increasing SUMOylation via the regulation/inhibition of members of the microRNA (miRNA)-182 family. This assay employs a SHSY5Y human neuroblastoma cell line stably transfected with a dual firefly-Renilla luciferase reporter system for identification of specific inhibitors of either miR-182 or miR-183. In this study, we have identified small molecules capable of inducing increased global conjugation of SUMO in both SHSY5Y cells and rat E18-derived primary cortical neurons. The protective effects of a number of the identified compounds were confirmed via an in vitro ischemic model (oxygen/glucose deprivation). Of note, this assay can be easily repurposed to allow high-throughput analyses of the potential drugability of other relevant miRNA(s) in ischemic pathobiology.
Progesterone reduces brain mitochondrial dysfunction after transient focal ischemia in male and female mice
Authors: Gaignard Pauline , Fréchou Magalie , Schumacher Michael , Thérond Patrice , Mattern Claudia , Slama Abdelhamid , Guennoun Rachida
Published: December 2015

This study investigated the effect of intranasal administration of progesterone on the early brain mitochondrial respiratory chain dysfunction and oxidative damage after transient middle cerebral occlusion in male and female mice. We showed that progesterone (8 mg/kg at 1 h post-middle cerebral occlusion) restored the mitochondrial reduced glutathione pool and the nicotinamide adenine dinucleotide-linked respiration in both sexes. Progesterone also reversed the decrease of the flavin adenine dinucleotide-linked respiration, which was only observed in females. Our findings point to a sex difference in stroke effects on the brain respiratory chain and suggest that the actions of progesterone on mitochondrial function may participate in its neuroprotective properties.