double-blind code and remain in the study. This applied to three cases in the placebo group. None of the patients included could obtain licensed treatment at study entry or would be withheld such treatment during the study, which prompted the local ethics committee to approve a 1-year placebo-controlled trial. Cholinesterase inhibitor treat- ment had to be terminated at least 4 weeks before screening. In addition, patients had to be in generally good health, ambulatory and with sufficient hearing and vision for com- pliance with testing procedures. Only patients able to undergo MRI were enrolled. Patients with a primary diagnosis of psychiatric disorders other than AD, cerebrovascular disease, or any unstable medical condition were excluded. Patients were permitted to continue on stable doses of concomitant medica- tions received at least 3 months before screening. These included low-dose atypical neuroleptics, selective serotonin re- uptake inhibitors, non-centrally active antihypertensives, anti- inflammatory drugs, platelet antiaggregants and anticoagulants, laxatives, diuretics and sedatives/hypnotics. Anticonvulsants, anti-Parkinson agents, barbiturates, Gingko biloba and nootro- pics, systemic corticosteroids and insulin were not permitted. The study was carried out according to the Declaration of Helsinki. Written informed consent was obtained from the patients and their caregivers. Protocol This was a single-centre, 52-week, randomised, double-blind, placebo-controlled, parallel-group pilot study conducted at the Medical University of Graz, Graz, Austria, between March 2003 and August 2005. Patients were randomly assigned by a computerised randomisation schedule to either placebo or memantine. Randomisation used a permuted block design and considered the presence or absence of an apolipoprotein-E-e4 allele as a stratification criterion, because of previous data indicating more rapid decline in apolipoprotein-E-e4 carriers.19 Briefly, two randomisation lists were generated, one for all patients carrying at least one apolipoprotein-E-e4 allele and one for all other apolipoprotein-E genotypes, so that carriers and non-carriers were equally distributed between the two treat- ment groups. Patients assigned to memantine were titrated to a dose of 20 mg/day over a 4-week period. Daily dose consisted of two identical tablets so as not to reveal the titration scheme: two placebo tablets throughout the study for patients treated with placebo and two tablets containing either 5 mg or 10 mg memantine depending on the titration stage for patients treated with memantine. Evaluation of imaging data was performed blinded to the patients’ clinical results. We screened patients by medical history, physical and neuropsychiatric examination, laboratory assessment including apolipoprotein-E genotyping, MMSE,18 Geriatric Depression Scale (GDS),20 and modified Hachinski scale.17 All subjects had an electrocardiogram (ECG) and a brain computed tomography (CT) or MRI scan not older than 1 year. Screening was performed within 31 days before patients began double-blind treatment and verification of AD diagnosis was based on screening results. At baseline, we repeated the physical examination including vital signs, MMSE and laboratory tests. In addition, participants underwent psychometric testing including Alzheimer Disease Assessment Scale – cognitive subscale (ADAS-Cog),21 Clinical Dementia Rating (CDR),22 and Alzheimer Disease Cooperative Study – activities of daily living (ADCS-ADL) inventory ,23 and MRI, quantitative 1H-CSI and 18F-FDG PET. The first dose of study medication was then J Neurol Neurosurg Psychiatry 2008;79:1312–1317. doi:10.1136/jnnp.2007.141648 Research paper administered. Follow-up visits were scheduled at the end of weeks 12, 26 and 52. At each follow-up visit, routine physical examination, laboratory tests, psychometric testing, medication compliance check and adverse events monitoring were per- formed. MRI and 1H-CSI were repeated at weeks 26 and 52; PET scanning was repeated at the end of week 52, only. Patients who withdrew prematurely were requested to return for a final evaluation identical to week 52. Efficacy assessments The outcome variables were changes of total brain and hippocampal volume, regional changes in NAA and MI in relation to baseline at weeks 26 and 52, as well as the global and regional changes of glucose metabolism between baseline and week 52. 18F–FDG Positron Emission Tomography (PET) PET scans were acquired on a Siemens-ECAT scanner (Siemens Medical Systems, Erlangen, Germany) 30 min after intravenous injection of 250 MBq of 18F-FDG. Imaging was performed in a resting condition with eyes open and ears unoccluded in a dark room with minimal ambient noise. Transmission scans were acquired before the emission scan for attenuation correction. The imaging plane was parallel to the canthomeatal line. The spatial inplane resolution was 4.5 mm and axial resolution was 6 mm full width at half maximum. Using a filtered back- projection method, all images were reconstructed in a 1286128663 matrix providing a pixel size of 2.562.562.4 mm. MRI The acquisition of structural scans and CSI was performed in a single session on a 1.5T Philips-Intera scanner (Philips Medical Systems, Best, The Netherlands). The scan protocol included an axial fluid-attenuated inversion recovery (FLAIR) sequence (repetition time (TR) = 6000 ms; echo time (TE) = 130 ms; inversion time (TI) = 1200 ms; field of view (FOV) = 230 mm; matrix = 2566256; slice thickness (THK) = 5 mm), an axial T2- weighted fast spin echo (FSE) sequence (TR = 3900 ms; TE = 80 ms; FOV = 230 mm; matrix = 2566256; THK = 5 mm) and a volumetric magnetisation-prepared rapid acquisition gradient echo (MPRAGE) sequence (flip angle = 15u; TR = 20 ms; TE = 4.5 ms; TI = 400 ms) with whole brain coverage. To allow manual segmentation of the hippocampus, the MPRAGE sequence was acquired perpendicularly to the long axis of the hippocampus with a 1.061.0 mm inplane resolution and with 1.2 mm-thick partitions. Additionally, for the CSF correction of the CSI data and for the regional analysis of the PET data, a T1-weighted true inversion recovery (IR)-FSE sequence (TR = 4400 ms; TE = 15 ms; TI = 350 ms) with a high inplane resolution (0.4560.90 mm) was performed in an axial orientation. Quantitative 1H-CSI CSI was performed in a single axial slice using a point-resolved spectroscopy sequence (PRESS) and a circularly polarised transmit-receive coil. The PRESS sequence was performed with TE = 30 ms, TR = 1500 ms and a 24624 acquisition matrix. The 15 mm-thick slice had an inplane resolution of 10610 mm and was positioned to match exactly the five central slices of the IR-FSE sequence. The PRESS sequence was performed slice- selectively instead of selecting a large volume of interest. This enabled full coverage of the parenchyma in the imaging slice but 1313