Journal of Cerebral Blood Flow & Metabolism

Journal Information
ISSN / EISSN : 0271-678X / 1559-7016
Published by: Springer Nature (10.1038)
Total articles ≅ 32
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Marc A Kropholler, , Bart Nm Van Berckel, Alie Schuitemaker, Reina W Kloet, Mark J Lubberink, Cees Jonker, Philip Scheltens,
Journal of Cerebral Blood Flow & Metabolism, Volume 27, pp 1965-1974;

Inflammation in Alzheimer's disease (AD) may be assessed using ( R)-[11C]PK11195 and positron emission tomography. Data can be analyzed using the simplified reference tissue model, provided a suitable reference region is available. This study evaluates various reference regions for analyzing ( R)-[11C]PK11195 scans in patients with mild cognitive impairment (MCI) and probable AD. Healthy subjects ( n = 10, 30 ± 10 years and n = 10, 70 ± 6 years) and patients with MCI ( n = 10, 74 ± 6 years) and probable AD ( n = 9, 71 ± 6 years) were included. Subjects underwent a dynamic three-dimensional ( R)-[11C]PK11195 scan including arterial sampling. Gray matter, white matter, total cerebellum and cerebrum, and cluster analysis were evaluated as reference regions. Both plasma input binding potentials of these reference regions ( BPPLASMA) and corresponding reference region input binding potentials of a target region ( BPSRTM) were evaluated. Simulations were performed to assess cluster analysis performance at 5% to 15% coefficient of variation noise levels. Reasonable correlations for BPPLASMA ( R2 = 0.52 to 0.94) and BPSRTM ( R2 = 0.59 to 0.76) were observed between results using anatomic regions and cluster analysis. For cerebellum white matter, cerebrum white matter, and total cerebrum a considerable number of unrealistic BPSRTM values were observed. Cluster analysis did not extract a valid reference region in 10% of the scans. Simulations showed that potentially cluster analysis suffers from negative bias in BPPLASMA. Most anatomic regions outperformed cluster analysis in terms of absence of both scan rejection and bias. Total cerebellum is the optimal reference region in this patient category.
Matthias L Schroeter, Markus M Bücheler, Christoph Preul, Rainer Scheid, Ole Schmiedel, Thomas Guthke, D Yves Von Cramon
Journal of Cerebral Blood Flow & Metabolism, Volume 27, pp 1094-1094;

Journal of Cerebral Blood Flow & Metabolism stands at the interface between basic and clinical neurovascular research, and features research on experimental, theoretical, and clinical aspects of brain circulation, metabolism and imaging. The journal is relevant to any physician or scientist with an interest in brain function, cerebrovascular disease, cerebral vascular regulation and brain metabolism, including neurologists, neurochemists, physiologists, pharmacologists, anesthesiologists, neuroradiologists, neurosurgeons, neuropathologists and neuroscientists.
, John W Krakauer, Theresa Matejovsky, , , Ronald M Lazar,
Journal of Cerebral Blood Flow & Metabolism, Volume 26, pp 1256-1262;

We used functional magnetic resonance imaging to investigate whether hemispheral hemodynamic impairment can play an independent role in the functional reorganization of motor-related activity in the brain. Fourteen patients with large vessel occlusion but no infarct performed a simple motor task with the hand contralateral to the occluded vessel. Statistical parametric maps of regional activity were generated to compare the distribution of motor-related activity among patients with that of control subjects. Patients were classified into normal or abnormal cerebral hemodynamics on the basis of intracerebral vasomotor reactivity using transcranial Doppler and carbon dioxide inhalation. Controls and patients with normal vasomotor reactivity showed typical motor activity in contralateral motor areas. When the 9 patients with abnormal vasomotor reactivity were compared with the 14 control subjects in a single analysis, unique motor activation was identified in ipsilateral motor regions in the nonhypoperfused hemisphere. In a confirmatory analysis, blood oxygen level-dependent (BOLD) signal intensity was averaged in prespecified motor regions of interest. A significant group by hemisphere interaction was identified, driven by higher ipsilateral and lower contralateral hemisphere BOLD signal in patients with abnormal vasomotor reactivity compared with controls (F = 12.40, P=0.002). The average ipsilateral motor region signal intensity was also significantly higher in the subgroup of patients with abnormal vasoreactivity and no TIA compared with controls (P =0.04). Our results suggest that hemodynamic impairment in one hemisphere, even in the absence of any focal lesion or any symptoms can be associated with a functional reorganization to the opposite hemisphere.
Liang Zhao,
Journal of Cerebral Blood Flow & Metabolism, Volume 26, pp 1128-1140;

Experimental stroke models exhibit robust protection after prior preconditioning (PC) insults. This study comprehensively examined cerebral blood flow (CBF) responses to permanent middle cerebral artery (MCA) occlusion in spontaneously hypertensive rats preconditioned by noninjurious transient focal ischemia, using [14C]iodoantipyrine autoradiography at varied occlusion intervals. Preconditioning was produced by 10-min occlusion of the MCA and ipsilateral common carotid artery under halothane anesthesia. These vessels were permanently coagulated 24 h later in naïve, PC, and sham-operated rats. Infarct volumes were determined from hematoxylin-eosin-stained frozen sections after 1 or 3 days. Edema-corrected infarct volume was reduced from 127±21 in naïve rats to 101 ±31 and 52±28 mm3 in sham and PC groups, respectively, at 1 day, with similar results at 3 days. All animals exhibited a consistent CBF threshold for infarction (approximately 30mL/100g/ min). Tissue volumes below this threshold were identical in naïve and PC groups after 15-min occlusion. However, by 3 h the volume of ischemic cortex decreased in the PC group but remained unchanged in naïve rats, predicting final infarct volumes. Cerebral blood flow recovery was confirmed in brains of individual rats evaluated by repeated laser Doppler perfusion imaging during the same 3-h interval. Modest sham protection correlated with better-maintained global perfusion, detectable also in the contralateral cortex, apparently reflecting the PC effects of prior anesthesia. These results establish that timely reperfusion of penumbra, achieved by synergistic mechanisms, is a primary determinant of PC-induced protection in experimental stroke.
, Jianhua S Yao, Wenwu Zhai, B Joseph Guglielmo, Emil Lin, William L Young, Weizhong Liu, Yong Huang,
Journal of Cerebral Blood Flow & Metabolism, Volume 26, pp 1157-1164;

Brain arteriovenous malformations (BAVMs) are a potentially life-threatening disorder. Matrix metalloproteinase (MMP)-9 activity was greatly increased in BAVM tissue specimens. Doxycycline was shown to decrease cerebral MMP-9 activities and angiogenesis induced by vascular endothelial growth factor (VEGF). In the present study, we determined the dose-response effects of doxycycline and minocycline on cerebral MMP-9 using our mouse model with VEGF focal hyperstimulation delivered with adenoviral vector (AdVEGF) in the brain. Mice were treated with doxycycline or minocycline, respectively, at 1, 5, 10, 30, 50, or 100 mg/kg/day through drinking water for 1 week. Our results have shown that MMP-9 messenger ribonucleic acid (mRNA) expression was inhibited by doxycycline starting at 10 mg/kg/day ( P < 0.02). Minocycline showed more potent inhibition on MMP-9 mRNA expression, starting at 1 ( P < 0.005) and further at more than 30 ( P < 0.001) mg/kg/day. At the enzymatic activity level, doxycycline started to suppress MMP-9 activity at 5 mg/kg/day ( P < 0.001), while minocycline had an effect at a lower dose, 1 mg/kg/day ( P < 0.02). The inhibition of cerebral MMP-9 mRNA and activity were highly correlated with drug levels in the brain tissue. We also assessed the potential relevant signaling pathway in vitro to elucidate the mechanisms underlying the MMP-9 inhibition by tetracyclines. In vitro, minocycline, but not doxycycline, inhibits MMP-9, at least in part, via the extracellular signaling-related kinase 1/2 (ERK1/2)-mediated pathway. This study provided the evidence that the tetracyclines inhibit stimulated cerebral MMP-9 at multiple levels and are effective at very low doses, offering great potential for therapeutic use.
, Frank E Hospod, Clifford S Patlak, , Kari A Pulfer, Thomas D Cook, Finbarr O'sullivan
Journal of Cerebral Blood Flow & Metabolism, Volume 26, pp 760-770;

Estimates of cerebral blood volume (CBV) obtained from dynamic contrast T2* -weighted magnetic resonance imaging (MRI) tend to be significantly higher than values obtained by other methods. This may relate to the common assumption that the proportionality constants relating signal change to contrast concentration are equal in tissue and artery. To test this hypothesis and provide estimates for the ratio of those proportionality constants, the authors compared measurements of CBV by both MRI and computed tomography (CT) scans in nine healthy volunteers obtained using identical kinetic paradigms for the two imaging modalities. Both boluses and infusions of contrast were studied. Measurements were made in nine anatomic regions of interest of the cerebral hemispheres bilaterally. Cerebral blood volume values obtained by CT were generally lower than those obtained by MRI, especially in the cerebral cortex. As a result, the calculated values of the ratios of proportionality constants relating signal change to concentration in tissue and artery after bolus injections were significantly less than 1 in cortex (0.69) and white matter (0.76), although not in deep gray matter structures (0.87). Values of the ratios based on infusion measurements were closer to 1. In addition, CBV measurement errors with bolus MRI were significantly larger than those observed with infusion MRI or by CT. The reasons that the constants differ from 1 and for the larger variance of bolus MRI are discussed in terms of the T2* signal mechanisms. These studies help define the magnitude by which CBV is overestimated with typical T2*-weighted perfusion imaging. Infusion measurements of CBV can reduce the variance intrinsic to T2* MRI and lessen the likelihood of type II error.
, Mark Slifstein, , Wolfgang Mueller-Schauenburg, Roland Bares
Journal of Cerebral Blood Flow & Metabolism, Volume 26, pp 751-759;

Voxelwise statistical analysis has become popular in explorative functional brain mapping with fMRI or PET. Usually, results are presented as voxelwise levels of significance ( t-maps), and for clusters that survive correction for multiple testing the coordinates of the maximum t-value are reported. Before calculating a voxelwise statistical test, spatial smoothing is required to achieve a reasonable statistical power. Little attention is being given to the fact that smoothing has a nonlinear effect on the voxel variances and thus the local characteristics of a t-map, which becomes most evident after smoothing over different types of tissue. We investigated the related artifacts, for example, white matter peaks whose position depend on the relative variance (variance over contrast) of the surrounding regions, and suggest improving spatial precision with ‘masked contrast images’: color-codes are attributed to the voxelwise contrast, and significant clusters (e.g., detected with statistical parametric mapping, SPM) are enlarged by including contiguous pixels with a contrast above the mean contrast in the original cluster, provided they satisfy P < 0.05. The potential benefit is demonstrated with simulations and data from a [11C]Carfentanil PET study. We conclude that spatial smoothing may lead to critical, sometimes-counterintuitive artifacts in t-maps, especially in subcortical brain regions. If significant clusters are detected, for example, with SPM, the suggested method is one way to improve spatial precision and may give the investigator a more direct sense of the underlying data. Its simplicity and the fact that no further assumptions are needed make it a useful complement for standard methods of statistical mapping.
, Jennifer A Hadway, Ting-Yim Lee, Keith S Lawrence
Journal of Cerebral Blood Flow & Metabolism, Volume 26, pp 722-730;

Predicting the onset of secondary energy failure after a hypoxic–ischemic insult in newborns is critical for providing effective treatment. Measuring reductions in the cerebral metabolic rate of oxygen (CMRO2) may be one method for early detection, as hypoxia–ischemia is believed to impair oxidative metabolism. We have developed a near-infrared spectroscopy (NIRS) technique based on the Fick Principle for measuring CMRO2. This technique combines cerebral blood flow (CBF) measurements obtained using the tracer indocyanine green with measurements of the cerebral deoxy-hemoglobin (Hb) concentration. In this study, NIRS measurements of CMRO2 were compared with CMRO2 determined from the product of CBF and the cerebral arteriovenous difference in oxygen measured from blood samples. The blood samples were collected from a peripheral artery and the sagittal sinus. Eight piglets were subjected to five cerebral metabolic states created by varying the plane of anesthesia. No significant difference was found between CMRO2 measurements obtained with the two techniques at any anesthetic level ( P > 0.5). Furthermore, there was a strong correlation when concomitant CMRO2 values from the two techniques were compared ( R2 = 0.88, P< 0.001). This work showed that CMRO2 can be determined accurately by combining NIRS measurements of CBF and Hb. Since NIRS is safe and measurements can be obtained at the bedside, it is believed that this technique could assist in the early diagnosis of cerebral energy dysfunction after hypoxia–ischemia.
Andrea Cozzi, Giulia Cipriani, , Giuseppe Faraco, , Wookee Min, Ulrich Cortes, , Flavio Moroni,
Journal of Cerebral Blood Flow & Metabolism, Volume 26, pp 684-695;

Poly(ADP-ribose) (PAR) is a polymer synthesized by poly(ADP-ribose) polymerases (PARPs) and metabolized into free adenosine diphosphate (ADP)-ribose units by poly(ADP-ribose) glycohydrolase (PARG). Perturbations in PAR synthesis have been shown to play a key role in brain disorders including postischemic brain damage. A single parg gene but two PARG isoforms (110 and 60 kDa) have been detected in mouse cells. Complete suppression of parg gene causes early embryonic lethality, whereas mice selectively lacking the 110 kDa PARG isoform (PARG−/− 110) develop normally. We used PARG−/− 110 mice to evaluate the importance of PAR catabolism to postischemic brain damage. Poly(ADP-ribose) contents were higher in the brain tissue of PARG−/− 110 than PARG+/+ 110 mice, both under basal conditions and after PARP activation. Distal middle cerebral artery occlusion caused higher increase of brain PAR levels and larger infarct volumes in PARG−/− 110 mice than in wild-type counterparts. Of note, the brain of PARG−/− 110 mice showed reduced heat-shock protein (HSP)-70 and increased cyclooxygenase-2 expression under both control and ischemic conditions. No differences were detected in brain expression/activation of procaspase-3, PARP-1, Akt, HSP-25 and interleukin-1β. Our findings show that PAR accumulation worsens ischemic brain injury, and highlight the therapeutic potential of strategies capable of maintaining PAR homeostasis.
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