E De Vita

Memory in multiple sclerosis is linked to glutamate concentration in grey matter regions

Objective Glutamate is the principal excitatory neurotransmitter and is involved in normal brain function. Cognitive impairment is common in multiple sclerosis (MS), and understanding its mechanisms is crucial for developing effective treatments. We used structural and metabolic brain imaging to test two hypotheses: (i) glutamate levels in grey matter regions are abnormal in MS, and (ii) patients show a relationship between glutamate concentration and memory performance. Methods Eighteen patients with relapsing-remitting MS and 17 healthy controls were cognitively assessed and underwent 1H-magnetic resonance spectroscopy at 3 T to assess glutamate levels in the hippocampus, thalamus, cingulate and parietal cortices. Regression models investigated the association between glutamate concentration and memory performance independently of magnetisation transfer ratio values and grey matter lesions withint he same regions, and whole-brain grey matter volume. Results Patients had worse visual and verbal memory than controls. A positive relationship between glutamate levels in the hippocampal, thalamic and cingulate regions and visuospatial memory was detected in patients, but not in healthy controls. Conclusions The relationship between memory and glutamate concentration, which is unique to MS patients, suggests the reliance of memory on glutamatergic systems in MS.

Magnetic Resonance Imaging of Neonatal Encephalopathy at 4.7 Tesla: Initial Experiences

OBJECTIVES. The goals were to develop safe 4.7-T MRI examination protocols for newborn infants and to explore the advantages of this field strength in neonatal encephalopathy. METHODS. Nine ventilated newborn infants with moderate or severe encephalopathy were studied at 4.7 T, with ethical approval and informed parental consent. The custom-made, 4.7-T-compatible, neonatal patient management system included acoustic noise protection and physiologic monitoring. An adult head coil was used. Acquisition parameters for T2-weighted fast spin echo MRI and a variety of T1-weighted methods were adapted for MRI of neonatal brain at 4.7 T. The pulse sequences used had a radiofrequency specific absorption rate of <2 W/kg. RESULTS. Physiologic measures were normal throughout each scan. T2-weighted fast spin echo imaging provided better anatomic resolution and gray/white matter contrast than typically obtained at 1.5 T; T1-weighted images were less impressive. CONCLUSIONS. With appropriate safety precautions, MRI of newborn infants undergoing intensive care is as feasible at 4.7 T as it is at 1.5 T; our initial studies produced T2-weighted fast spin echo images with more detail than commonly obtained at 1.5 T. Although T1-weighted images were not adequately informative, additional pulse sequence optimization may be advantageous. A smaller neonatal head coil should also permit greater flexibility in acquisition parameters and even more anatomic resolution and tissue contrast. In neonatal encephalopathy, interpretation of the T2-weighted pathologic detail in combination with comprehensive neurodevelopmental follow-up should improve prognostic accuracy and enable more patient-specific therapeutic interventions. In addition, more precise relationships between structural changes and functional impairment may be defined.

Multiparameter MR Imaging in the 6-OPRI Variant of Inherited Prion Disease

BACKGROUND AND PURPOSE: Inherited prion diseases represent over 15% of human prion cases and are a frequent cause of early onset dementia. The purpose of this study was to define the distribution of changes in cerebral volumetric and microstructural parenchymal tissues in a specific inherited human prion disease mutation combining VBM with VBA of cerebral MTR and MD. MATERIALS AND METHODS: VBM and VBA of cerebral MTR and MD were performed in 16 healthy control participants and 9 patients with the 6-OPRI mutation. An analysis of covariance consisting of diagnostic grouping with age and total intracranial volume as covariates was performed. RESULTS: On VBM, there was a significant reduction in gray matter volume in patients compared with control participants in the basal ganglia, perisylvian cortex, lingual gyrus, and precuneus. Significant MTR reduction and MD increases were more anatomically extensive than volume differences on VBM in the same cortical areas, but MTR and MD changes were not seen in the basal ganglia. CONCLUSIONS: Gray matter and WM changes were seen in brain areas associated with motor and cognitive functions known to be impaired in patients with the 6-OPRI mutation. There were some differences in the anatomic distribution of MTR-VBA and MD-VBA changes compared with VBM, likely to reflect regional variations in the type and degree of the respective pathophysiologic substrates. Combined analysis of complementary multiparameter MR imaging data furthers our understanding of prion disease pathophysiology.

Fatal newborn head enlargement: high resolution magnetic resonance imaging at 4.7 T

A male term infant (41+2 weeks gestational age), born in excellent condition after ventouse delivery, presented at 2 hours with pallor and metabolic acidosis (capillary blood sample pH 6.45, base excess −34). He rapidly became encephalopathic, developed disseminated intravascular coagulopathy, multiorgan failure, and an increasing head circumference (41 cm at presentation compared with 35 cm at birth). Despite aggressive blood product replacement and an attempt at draining the scalp haematoma, his condition deteriorated. Neurosurgical intervention was considered but felt inappropriate. Magnetic resonance imaging was performed at 4.7 T …

416 Cerebral Alanine Increases During the Evolution of Secondary Energy Failure Following Transient Hypoxia-Ischaemia in Newborn Brain

Background: Alanine (Ala), a nonessential amino acid, is present in normal brain at a concentration of ∼0.5 mmol/kg. During acute hypoxia-ischaemia (HI) Ala increases due to decreased flux of pyruvate through the Krebs cycle and the activity of alanine transaminase (AAT). Brain Ala increases in proportion to the severity of HI and may be detected using proton (1H) magnetic resonance spectroscopy (MRS).Aim: To investigate relationships between the severity of secondary (delayed) energy failure (SEF) and late brain Ala metabolite ratios following transient cerebral HI in the newborn piglet.Design/Methods: Seven newborn piglets (<24 hrs old) were studied under general anaesthesia (isoflurane & morphine) before, during and for up to 48 hours following transient HI (reversible bilateral carotid occlusion and 12% FiO2 for 45 min). Whole-brain pulse-acquire phosphorus (31P; repetition time (TR) 10 s) and localised 1H (PRESS, thalamic, echo time 270 ms, TR 5 s) MRS data were acquired serially before, during (31P only), and following HI. Spectra were analysed using AMARES (31P) and LCModel (1H).Results: In two piglets SEF was not observed. In the remaining 5 SEF ranged between mild and severe as quantified by delayed reductions in [phosphocreatine]/[inorganic phosphate] ([PCr]/[Pi]) and [nucleotide triphosphate]/[exchangeable high-energy phosphate pool] ([NTP]/[EPP]) and increases in lactate/total creatine (Lac/Cr).Ala was only detected in the 5 SEF piglets. During SEF evolution we observed progressively increasing thalamic Ala/Cr and Lac/Cr. When the final measurements were compared both Lac/Cr and Ala/Cr separately showed inverse linear correlations with [NTP]/[EPP] and [PCr]/[Pi] (all p<0.05) (Figure 1).Figure 1No Caption Available.Conclusions: Both Ala/Cr and Lac/Cr increased concomitant with the development and proportional to the severity of SEF. These observations are consistent with decreased pyruvate flux through the Krebs cycle and increased flux through lactate-dehydrogenase and AAT during the evolution of SEF leading to concomitant accumulation of Lac and Ala respectively.

118 Delayed Hypoyhermia is Neuroprotective in Moderate, but not Severe, Perinatal Hypoxic-Ischaemic Brain Injury

118 Delayed Hypoyhermia is Neuroprotective in Moderate, but not Severe, Perinatal Hypoxic-Ischaemic Brain Injury

128 Quantification of glutamate in the grey matter and its relationship with cognitive performance in multiple sclerosis

We aim to assess whether the concentration of glutamate, an excitatory neurotransmitter, changes in the grey matter (GM) of patients with Multiple Sclerosis (MS), and whether it relates to cognitive dysfunction and disability. Single-voxel MRS was performed at 3T in 18 patients with relapsing-remitting MS [12 women, age 43.5 years, median EDSS 2.8] and 17 healthy subjects [11 women, age 39.7] in the right cingulate and parietal cortices, right hippocampus and thalamus. (Abstract 128 figure 1) Visual and verbal memory and speed of information processing were assessed. Patients showed significantly worse performance on the visual memory test, verbal learning, delayed verbal recall, and speed of information processing, compared to controls. Patients showed lower glutamate concentration in the cingulate and parietal cortices and in the hippocampus compared to controls. Patients showed significantly lower N-Acetyl-Aspartate levels in the thalamus and cortical GM, and reduced glutamate-glutamine, choline-containing compounds and creatine plus phosphocreatine levels in the cortical GM, compared to controls. Lower hippocampal glutamate levels correlated with worse visual memory. Reduced glutamate levels in the cingulate cortex and thalamus correlated with worse speed of processing and visual memory, respectively. We found reduced glutamate neurotransmission in the cortical and hippocampal regions, which was linked to cognitive impairment. Reduced levels of most of the metabolites in the cortical GM, together with normal Inositol, are in agreement with post-mortem findings of GM neuronal loss, modest glial proliferation, low degree of inflammation and energy metabolism.Abstract 128 Figure 1

128 Quantification of glutamate in the grey matter and its relationship with cognitive performance in multiple sclerosis: Abstract 128 Figure 1

We aim to assess whether the concentration of glutamate, an excitatory neurotransmitter, changes in the grey matter (GM) of patients with Multiple Sclerosis (MS), and whether it relates to cognitive dysfunction and disability. Single-voxel MRS was performed at 3T in 18 patients with relapsing-remitting MS [12 women, age 43.5 years, median EDSS 2.8] and 17 healthy subjects [11 women, age 39.7] in the right cingulate and parietal cortices, right hippocampus and thalamus. (Abstract 128 figure 1) Visual and verbal memory and speed of information processing were assessed. Patients showed significantly worse performance on the visual memory test, verbal learning, delayed verbal recall, and speed of information processing, compared to controls. Patients showed lower glutamate concentration in the cingulate and parietal cortices and in the hippocampus compared to controls. Patients showed significantly lower N-Acetyl-Aspartate levels in the thalamus and cortical GM, and reduced glutamate-glutamine, choline-containing compounds and creatine plus phosphocreatine levels in the cortical GM, compared to controls. Lower hippocampal glutamate levels correlated with worse visual memory. Reduced glutamate levels in the cingulate cortex and thalamus correlated with worse speed of processing and visual memory, respectively. We found reduced glutamate neurotransmission in the cortical and hippocampal regions, which was linked to cognitive impairment. Reduced levels of most of the metabolites in the cortical GM, together with normal Inositol, are in agreement with post-mortem findings of GM neuronal loss, modest glial proliferation, low degree of inflammation and energy metabolism.Abstract 128 Figure 1

022 Voxelwise analysis of cerebral diffusion tensor imaging in prion diseases

The need to find a prion disease neuroimaging biomarker is important with the development of therapeutic agents. Diffusion tensor imaging (DTI) is an MRI sequence that can visualise white matter changes in the brain. Voxel-based analysis of DTI and voxel based morphometry (VBM) was performed on 17 asymptomatic prion protein gene mutation carriers, 14 symptomatic inherited prion disease patients, seven sporadic CJD patients (sCJD) and 24 healthy controls. There were significant differences found in grey matter voxels between the symptomatic and the control patients in the cortex bilaterally. In addition there was reduced fractional anisotropy in the corpus callosum, frontal white matter, internal capsule, optic radiation and cerebellum; these regions did not overlap with areas of brain atrophy. In the asymptomatic patients there were directional changes seen in keeping with the symptomatic patients, but due to the small patient number no statistically significant differences were found with VBM and voxel based analysis of DTI. In sCJD grey matter changes were found in the thalamus on VBM but voxel based analysis of DTI demonstrated change in the corpus callosum, thalamus and cerebellar white matter. These data show that voxel based analysis of DTI can detect significant microstructural white matter changes in the absence of its loss. DTI may prove to be a useful biomarker in prion disease.

P14 Quantification of glutamate in the cortex, hippocampus and thalamus and its relationship with cognitive performance in multiple sclerosis

Objective A previous 1H-MR spectroscopy (MRS) study reported elevated levels of glutamate, an excitatory neurotransmitter, in acute lesions and normal-appearing white matter, which may relate to the presence of inflammatory cells and astrocytosis. We aim to assess whether glutamate levels (1) change in the grey matter (GM), and (2) relate to cognitive dysfunction. Methods Single-voxel MRS was performed at 3 T in 18 patients with relapsing-remitting MS [12 women, age 43.5 years, median EDSS 2.8] and 17 healthy subjects [11 women, age 39.7], using PRESS [TR6000, TE30, water suppression]. Voxels were located in the right cingulate and parietal cortices, right hippocampus and thalamus. Concentrations of metabolites were obtained using LCModel, scaled using the water signal amplitude, and corrected for fractions of different tissue compartments and their T1 and T2 relaxation times. Visual and verbal memory and speed of information processing were assessed. Results Patients showed significantly worse performance on the visual memory test (total errors p<0.01, trials completed at the 1st attempt p<0.05, and total no. of trials p<0.01), on verbal learning (p<0.01), delayed verbal recall (p<0.05), and on processing speed (SDMT, p<0.001), compared to controls. Patients showed lower glutamate concentration in the cingulate (6.3 institutional unit (iu) vs 7.7, p<0.001) and parietal cortices (6.4 iu vs 7.5, p=0.001), and in the hippocampus (3.2 iu vs 4.4, p=0.05), compared to controls. Patients also showed significantly lower N-Acetyl-Aspartate (NAA) levels in the thalamus and cortical GM, compared to controls. Lower hippocampal glutamate levels correlated with worse visual memory (trials at 1st attempt: r=0.5, p<0.05; total trials: r=0.5, p<0.05). Discussion Glutamate neurotransmission is reduced in the cortical and hippocampal regions of people with MS and is linked to cognitive impairment. Reduced levels of glutamate and NAA in cortical GM agree with post-mortem findings of GM neuronal loss in MS. MR spectroscopy of cortical glutamate may provide a surrogate marker for assessing the efficacy of future therapies in reducing memory decline in people with MS.