Research paper required multiple rest slabs to suppress unwanted fat signal from bone and skull. Water suppression was performed with an adiabatic saturation pulse. Shimming and power optimisation was performed fully automated. To allow for eddy current correction and improved phasing of the spectra, a water- unsuppressed reference scan with a reduced acquisition matrix (12612) but otherwise identical parameters was performed prior to the water-suppressed scan. To obtain absolute metabolite concentrations, a calibration measurement with a spherical phantom containing 50 mmol/litre NAA and 100 mmol/litre phosphate was performed after each session. To correct for variation of the coil load between patients and the calibration phantom, the coil load for each measurement was determined during the power optimisation process and recorded. The acquisition time for MRI and CSI without calibration was approximately 45 min. Analysis of imaging data Glucose metabolism Regional glucose metabolism was measured manually in pre- defined regions of interest in the PET images including the frontal, parietal, occipital and temporal lobe, and the basal ganglia. The relative counts obtained from these regions were normalised by the pons activity. Region outlining was performed on the baseline IR-FSE scan, after the baseline and follow-up PET scan had been registered with it. Registration was performed with an affine nine-parameter model following skull stripping of the IR-FSE scan.24 The region masks produced at baseline were also used for the analysis of the follow-up PET scans. Brain volumes Whole brain atrophy and normalised brain volume (NBV) were calculated from the MPRAGE scan using the fully automated structural image evaluation, using normalisation, of atrophy (SIENA) and structural image evaluation, using normalisation, of atrophy (cross sectional) (SIENAX) methods, respectively, which are part of the University of Oxford Functional MRI of the Brain (FMRIB) group’s Software Library (FSL) (http:// www.fmrib.ox.ac.uk/fsl).25 In addition to its robustness, SIENA provides an error in brain volume change of about 0.2%.26 SIENAX determines NBV by extraction of brain tissue, calculation of brain volume and normalisation for subject head size using a volumetric scaling factor. The scaling factor is obtained by an affine registration of the brain image to MNI152 space. The NBV was assessed at baseline only, while the measurement of brain volume change was performed for all subsequent time points. Hippocampal volumes were measured from the T1-weighted MPRAGE scans. After image intensity normalisation and registration with the baseline examination, manual tracing of the hippocampal formation was performed on magnified and interpolated coronal sections. Manual tracing was performed blinded to clinical information and time point of examination, in consultation with neuroanatomic atlases.26 27 The outlined volume included the hippocampus proper (cornu ammonis CA1 through CA4), gyrus dentatus, subiculum, uncal apex, fimbria and alveus, and excluded the entorhinal cortex (ambient gyrus, parahippocampal gyrus).7 28 The hippocampal volume was obtained by averaging the volume of the left and the right hippocampus. Brain metabolites CSI data were processed voxel by voxel by the fully automated method LCModel.29 LCModel analyses an in vivo spectrum as a 1314 linear combination of model spectra of metabolite solutions in vitro and provides absolute quantification by reference to an external calibration standard. To account for differences in scanner characteristics between the acquisition of the metabo- lite solutions in vitro and the in vivo spectra, LCModel uses a calibration factor to scale the in vivo spectra. According to the methodological requirements, the calibration factor was obtained by using LCModel to estimate the known NAA concentration in the calibration phantom and by regarding differences in the coil load factor. Additionally, the low- resolution, unsuppressed CSI data were incorporated in the algorithm to facilitate phasing and eddy-current correction. NAA and MI maps showing the absolute metabolite concentra- tions were generated from the voxel-wise analysis. These maps were then overlaid on the central slices of the IR-FSE scan, which were virtually aligned with the CSI data. No active registration of the IR-FSE scan and metabolite maps was performed. Regional measurement of metabolite concentration was performed by clustering individual voxels using bespoke in- house tools. Due to the high resolution and excellent T1 contrast, the IR-FSE scan also allowed to separate grey matter, white matter and CSF in each spectroscopic voxel to correct for CSF occupancy. The relative CSF occupancy was calculated by fitting three Gaussian functions into the signal intensity distribution function in each voxel. Statistical analyses This study was a first attempt to provide morphological and functional imaging data on the action of memantine in AD in a complex multimodal manner, and was thus designed as a pilot study. All efficacy variables were analysed in a descriptive and exploratory manner. p Values have to be interpreted accord- ingly, with no adjustments made for multiplicity. The analyses were performed by intention-to-treat. Differences in percentage brain volume change and annual change of normalised glucose metabolism for the whole brain and predefined brain regions between the two groups were assessed using the unpaired Student t test or Mann–Whitney U test, as appropriate. Analysis was performed for changes from baseline to 6 and 12 months. A paired Student t test or the Wilcoxon signed rank test was used for the difference between baseline and final examination overall and within groups. For NAA or MI levels within regions of interest, analysis of covariance including treatment group as the main factor in the model and baseline as covariate was performed. The correlation between glucose metabolism and volumetric measures was determined with the Spearman rank correlation coefficient. RESULTS A total of 37 patients were randomised, of which 36 (1 had claustrophobia in the MRI scanner) received study medication (18 memantine and 18 placebo). Baseline characteristics of the study group are shown in Table 1. The two groups were comparable regarding age, gender, depression score, severity of cognitive symptoms and normalised brain volume. The 26-week follow-up was completed by 32 (89%) patients (16 in each group); 24 (67%) participants (11 on placebo and 13 on memantine) finished the 52-week examination. Overall, 12 (7 placebo and 5 memantine) patients (33.3%) discontinued the study due to adverse events in 4, implantation of pacemaker in 3, technical MRI problems in 2 and non-compliance in 2 subjects. One patient died prior to the 52-week examination. All patients on memantine and 94% of patients on placebo received J Neurol Neurosurg Psychiatry 2008;79:1312–1317. doi:10.1136/jnnp.2007.141648