There is increasing interest in the use of edited proton magnetic resonance spectroscopy for the detection of GABA in the human brain. At a recent meeting held at Cardiff University, a number of spectroscopy groups met to discuss the acquisition, analysis and interpretation of GABA-edited MR spectra. This paper aims to set out the issues discussed at this meeting, reporting areas of consensus around parameters and procedures in the field and highlighting those areas where differences remain. It is hoped that this paper can fulfill two needs, providing a summary of the current ‘state-of-the-art’ in the field of GABA-edited MRS at 3 T using MEGA-PRESS and a basic guide to help researchers new to the field to avoid some of the pitfalls inherent in the acquisition and processing of edited MRS for GABA.

Cerebral ischaemia usually results in the rapid death of neurons within the immediate territory of the affected artery. Neuronal loss is accompanied by a sequence of events, including brain oedema, blood-brain barrier (BBB) breakdown, and neuroinflammation, all of which contribute to further neuronal death. Although the role of macrophages and mononuclear phagocytes in the expansion of ischaemic injury has been widely studied, the relative contribution of these cells, either of exogenous or intrinsic central nervous system (CNS) origin is still not entirely clear. The purpose of this study, therefore, was to use different durations of transient middle cerebral artery occlusion (tMCAo) in the mouse to investigate fully post-occlusion BBB permeability and cellular changes in the brain during the 72 h post-MCAo period. This was achieved using in vivo magnetic resonance imaging (MRI) and cell labelling techniques. Our results show that BBB breakdown and formation of the primary ischaemic damage after tMCAo is not associated with significant infiltration of neutrophils, although more are observed with longer periods of MCAo. In addition, we observe very few infiltrating exogenous macrophages over a 72 h period after 30 or 60 mins of occlusion, instead a profound increase in proliferating resident microglia cells was observed. Interestingly, the more severe injury associated with 60 mins of MCAo leads to a markedly reduced proliferation of resident microglial cells, suggesting that these cells may play a protective function, possibly through phagocytosis of infiltrating neutrophils. These data further support possible beneficial actions of microglial cells in the injured brain.

Idiopathic Parkinson's disease (IPD) is the second most common neurodegenerative disease, yet effective disease modifying treatments are still lacking. Neurodegeneration involves multiple interacting pathological pathways. The extent to which neurovascular mechanisms are involved is not well defined in IPD. We aimed to determine whether novel magnetic resonance imaging (MRI) techniques, including arterial spin labelling (ASL) quantification of cerebral perfusion, can reveal altered neurovascular status (NVS) in IPD.Fourteen participants with IPD (mean ± SD age 65.1 ± 5.9 years) and 14 age and cardiovascular risk factor matched control participants (mean ± SD age 64.6 ± 4.2 years) underwent a 3T MRI scan protocol. ASL images were collected before, during and after a 6 minute hypercapnic challenge. FLAIR images were used to determine white matter lesion score. Quantitative images of cerebral blood flow (CBF) and arterial arrival time (AAT) were calculated from the ASL data both at rest and during hypercapnia. Cerebrovascular reactivity (CVR) images were calculated, depicting the change in CBF and AAT relative to the change in end-tidal CO2.A significant (p = 0.005) increase in whole brain averaged baseline AAT was observed in IPD participants (mean ± SD age 1532 ± 138 ms) compared to controls (mean ± SD age 1335 ± 165 ms). Voxel-wise analysis revealed this to be widespread across the brain. However, there were no statistically significant differences in white matter lesion score, CBF, or CVR between patients and controls. Regional CBF, but not AAT, in the IPD group was found to correlate positively with Montreal cognitive assessment (MoCA) scores. These findings provide further evidence of alterations in NVS in IPD.

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Hepatocyte growth factor/scatter factor (HGF/SF) acts via a dual receptor system consisting of the MET tyrosine kinase receptor and heparan sulfate or dermatan sulfate proteoglycans. In optical biosensor binding assays, competition by oligosaccharides for binding of HGF/SF to immobilized heparin showed that disaccharides failed to compete, whereas tetrasaccharides inhibited HGF/SF binding (IC 50 8 g/ml). The inhibitory potency of the oligosaccharides increased as their length increased by successive disaccharide units, to reach a maximum (IC 50 1 g/ml) at degree of polymerization (dp) 10. In binding assays, HGF/SF was found to bind directly to oligosaccharides as small as dp 4, and the binding parameters were similar for oligosaccharides of dp 4 -14 (k a 2.2-45.3 ؋ 10 6 M ؊1 s ؊1 , k d 0.033-0.039 s ؊1 , and K d 9 -16 nM). In human keratinocytes, HGF/SF stimulated DNA synthesis, and this was dependent on a sustained phosphorylation of p42/44 MAPK . In chlorate-treated and hence sulfated glycosaminoglycan-deficient HaCaT cells, the stimulation of DNA synthesis by HGF/SF was almost abolished. Heparin-derived oligosaccharides from dp 2 to dp 24 were added together with HGF/SF to chlorate-treated cells to determine the minimum size of oligosaccharides able to restore HGF/SF activity. At restricted concentrations of oligosaccharides (4 ng/ml), HGF/SF required decasaccharides, whereas at higher concentrations (100 ng/ml) even tetrasaccharides were able to partly restore DNA synthesis. The results suggest that HGF/SF binds to a tetrasaccharide and that although this is sufficient to enable the stimulation of DNA synthesis, longer oligosaccharides are more efficient, perhaps by virtue of their ability to bind more easily other molecules.

Black tea consumption has been shown to improve peripheral vascular function. Its effect on brain vasculature is unknown, though tea contains small amounts of caffeine, a psychoactive substance known to influence cerebral blood flow (CBF). We investigated the effects on CBF due to the intake of tea components in 20 healthy men in a double-blinded, randomized, placebo-controlled study. On separate days, subjects received a single dose of 184 mg caffeine (equivalent to one strong espresso coffee), 2,820 mg black tea solids containing 184 mg caffeine (equivalent to 6 cups of tea), 2,820 mg decaffeinated black tea solids, or placebo. The CBF and cerebrovascular reactivity (CVR) to hypercapnia were measured with arterial spin labeled magnetic resonance imaging (MRI) before and 2 hours after administration. We found a significant global reduction with caffeine (20%) and tea (21%) in gray matter CBF, with no effect of decaffeinated tea, suggesting that only caffeine influences CBF acutely. Voxelwise analysis revealed the effect of caffeine to be regionally specific. None of the interventions had an effect on CVR. Additional research is required to conclude on the physiologic relevance of these findings and the chronic effects of caffeine and tea intake on CBF.

A proinflammatory cytokine response is associated with greater clinical severity, BBB permeability, and neuroimaging damage during encephalitis. IL-1 antagonists should be investigated as adjunctive treatment in encephalitis.

IPD patients showed diffuse regions of significantly prolonged AAT, small regions of lower CBF and greater WML burden by comparison with CN subjects. TD patients showed lower WML volume by comparison with PIGD patients. These imaging data thus show altered NVS in IPD, with some evidence for IPD phenotype specific differences.