Oddbjørn Sæther

Differences in Neurotransmitter Synthesis and Intermediary Metabolism between Glutamatergic and GABAergic Neurons during 4 Hours of Middle Cerebral Artery Occlusion in the Rat: The Role of Astrocytes in Neuronal Survival

Astrocytes are intimately involved in both glutamate and γ-aminobutric acid (GABA) synthesis, and ischemia-induced disruption of normal neuroastrocytic interactions may have important implications for neuronal survival. The effects of middle cerebral artery occlusion (MCAO) on neuronal and astrocytic intermediary metabolism were studied in rats 30, 60, 120, and 240 minutes after MCAO using in vivo injection of [1-13C]glucose and [1,2-13C]acetate combined with ex vivo13C magnetic resonance spectroscopy and high-performance liquid chromatography analysis of the ischemic core (lateral caudoputamen and lower parietal cortex) and penumbra (upper frontoparietal cortex). In the ischemic core, both neuronal and astrocytic metabolism were impaired from 30 minutes MCAO. There was a continuous loss of glutamate from glutamatergic neurons that was not replaced as neuronal glucose metabolism and use of astrocytic precursors gradually declined. In GABAergic neurons astrocytic precursors were not used in GABA synthesis at any time after MCAO, and neuronal glucose metabolism and GABA-shunt activity declined with time. No flux through the tricarboxylic acid cycle was found in GABAergic neurons at 240 minutes MCAO, indicating neuronal death. In the penumbra, the neurotransmitter pool of glutamate coming from astrocytic glutamine was preserved while neuronal metabolism progressively declined, implying that glutamine contributed significantly to glutamate excitotoxicity. In GABAergic neurons, astrocytic precursors were used to a limited extent during the initial 120 minutes, and tricarboxylic acid cycle activity was continued for 240 minutes. The present study showed the paradoxical role that astrocytes play in neuronal survival in ischemia, and changes in the use of astrocytic precursors appeared to contribute significantly to neuronal death, albeit through different mechanisms in glutamatergic and GABAergic neurons.

Altered neurochemical profile in the McGill-R-Thy1-APP rat model of Alzheimer's disease: a longitudinal in vivo 1H MRS study

We investigated metabolite levels during the progression of pathology in McGill‐R‐Thy1‐APP rats, a transgenic animal model of Alzheimers disease, and in healthy age‐matched controls. Rats were subjected to in vivo 1H magnetic resonance spectroscopy (MRS) of the dorsal hippocampus at age 3, 9 and 12 months and of frontal cortex at 9 and 12 months. At 3 months, a stage in which only Aβ oligomers are present, lower glutamate, myo‐inositol and total choline content were apparent in McGill‐R‐Thy1‐APP rats. At age 9 months, lower levels of glutamate, GABA, N‐acetylaspartate and total choline and elevated myo‐inositol and taurine were found in dorsal hippocampus, whereas lower levels of glutamate, GABA, glutamine and N‐acetylaspartate were found in frontal cortex. At age 12 months, only the taurine level was significantly different in dorsal hippocampus, whereas taurine, myo‐inositol, N‐acetylaspartate and total creatine levels were significantly higher in frontal cortex. McGill‐R‐Thy1‐APP rats did not show the same changes in metabolite levels with age as displayed in the controls, and overall, prominent and complex metabolite differences were evident in this transgenic rat model of Alzheimers disease. The findings also demonstrate that in vivo 1H MRS is a powerful tool to investigate disease‐related metabolite changes in the brain.

High-Resolution MAS 1H NMR Spectroscopic Analysis of Rabbit Cornea After Treatment with Dexamethasone and Exposure to UV-B Radiation

Metabolic changes in rabbit cornea after combined long-term steroid treatment and UV-B exposure were investigated. Corneas were exposed to UV-B radiation (2.05 J/cm2) after 36 days topical pretreatment with either 0.1% dexamethasone or saline. Twenty-four hours after UV-B exposure, corneas were excised and aqueous humour aspirated. Intact corneal tissues were analyzed by magic angle spinning proton NMR spectroscopy and pattern recognition methods. UV-B decreased corneal ascorbate (63% reduction), taurine (62%), and choline (63%), whereas glucose was elevated. Dexamethasone pretreatment further depleted corneal taurine and ascorbate, decreased aqueous ascorbate (85%), and accumulated glucose in cornea and aqueous humour. The results reflect antioxidative mechanisms and osmoregulation.

Gray matter metabolism in acute and chronic hydrocephalus

Although hydrocephalus is usually considered a disorder of periventricular white matter, disturbance of gray matter is probably also involved. However, so far gray matter metabolism has not been studied in experimental hydrocephalus using high resolution in vivo magnetic resonance spectroscopy (MRS). Therefore 15 rats were made hydrocephalic by injection of 0.1 ml kaolin into the cisterna magna, whereas 10 sham-operated rats served as controls. (1)H MRS and magnetic resonance imaging were performed longitudinally in acute hydrocephalus 2 and 4 weeks after kaolin treatment and in chronic hydrocephalus after 6 weeks. Volumes of interest included the gray matter regions cortex, thalamus and hippocampus. In hydrocephalic animals, (1)H MRS revealed decreased glutamate levels in all examined areas at all time points. Moreover, in acute hydrocephalus disturbances were noted in the hippocampus with decreased concentrations of N-acetyl aspartate, creatine, inositol and taurine, and in the cortex with decreased taurine levels. A clear lactate peak was detected in CSF spectra from hydrocephalic rats. In addition, T2-weighted images showed increase of free water in the hippocampus. It can be concluded that glutamate metabolism is deranged in gray matter in acute and chronic hydrocephalus in rats. If confirmed in humans, early detection of glutamatergic disturbances and lactate accumulation using in vivo(1)H MRS might serve as an indication for surgical treatment of hydrocephalus before irreversible neuronal damage develops.

A Review of Imaging in Psychiatry

The past decade has seen significant advances in imaging techniques used to measure structure and function in the human brain and many of these have direct relevance to psychiatry. Psychiatric disorders clearly pertain to brain function, however the underlying biology of these putative dysfunctions remains obscure. From a research perspective integrated use of novel imaging techniques in conjunction with clinical assessments now affords an opportunity to advance our understanding of the pathophysiology of psychiatric conditions by allowing the in vivo investigation of abnormalities of brain function as they relate to changes in cognition, mood and behaviour. Whilst most of these imaging techniques are still very much entrenched in the research domain, it is important that clinicians understand the benefits of these new technologies while also appreciating their limitations. These imaging techniques are constantly evolving and hold significant potential to one day provide clinical insights that inform diagnosis and management.

Spectroscopy: technical perspectives

In a previous issue of Brain Bytes (1), the fundamentals of proton magnetic resonance spectroscopy (H MRS) was discussed in the context of neuropsychiatry. The earlier article provided an overview of the MRS technique as well as an introduction into the hardware that was used. This issue of Brain Bytes will extend the MRS discussion and focus on more technical aspects of the technique with particular emphasis on some of the pitfalls to avoid when using this modality. In MRS, data can be acquired either from a single voxel (SVS) or frommultiple voxels, so-called magnetic resonance spectroscopic imaging (MRSI) or chemical shift imaging (CSI). Single voxelMRS produces a spectrum from a predefined volume of interest (VOI), typically with a size of 1–8 cm. The resulting spectrum has no inherent spatial information. Applying MRSI however, which can be carried out in either two or three dimensions, can give a matrix of up to typically 32 3 32 voxels within a two-dimensional slice. The single voxel technique allows for a relative straightforward post-processing, but MRSI requires more steps. Userfriendly H MRS packages, for both SVS and MRSI, are available with state-of-art clinical magnetic resonance scanners, but SVS might be the choice starting up with spectroscopy. The main SVS techniques are Stimulated Echo Acquisition Mode (STEAM) and Point Resolved Spectroscopy (PRESS), both consisting of three mutually orthogonal slice selective radiofrequency pulses and designed to collect signal from the intersection of the three slices (defining the VOI). The sequences are similar, but PRESS gives approximately a factor of 2 better signal-to-noise ratio (SNR) than STEAM. In the following aspects of the SVS method will be discussed, perhaps useful in the initiation of MRS.

Proton Decoupled 19F NMR Spectroscopy of Drugs Used in Eye Treatment

Abstract The potential for detecting fluorinated compounds in a 2.35 T nuclear magnetic resonance system was assessed to evaluate the possibility for in vivo monitoring of fluorinated drugs applied to the eye. Time‐share proton decoupled 19F NMR spectroscopy was implemented for signal enhancement in an experimental eye model. Signal‐to‐noise in 19F NMR spectra of dexamethasone phosphate was enhanced by 56%. However, decoupling did not enhance S/N for ciprofloxacin. The obtained detection limit of 0.1–0.2 µmol did not enable detection of drugs at therapeutic concentrations in the eye. Higher magnetic field and improved coil and detection technology might enable future in vivo monitoring of drugs in the eye.

Is computed tomography still useful as a neuroimaging tool in psychiatry

BACKGROUND Computed tomography (CT) has played a pivotal role in psychiatry from its inception; however with the advent of other high-resolution noninvasive neuroimaging techniques such as MRI, the field has gone through a dramatic transformation. OBJECTIVE This article will explore the current role of CT in psychiatry. METHODS An extensive search of the published literature (1970 - 2008) was conducted, employing a number of databases and terms relevant to CT and imaging. RESULTS/CONCLUSION At present CT is primarily used as a screening tool to exclude intracranial pathology. This is partly because it is widely available and less expensive than other imaging modalities. CT is unable to provide region-specific information like MRI and this has restricted its use in disorders in which functional disturbances are suspected, however it remains the preferred mode of investigation where gross structural abnormalities are suspected.