Research paper 1 Department of Neurology, Medical University of Graz, Austria; 2 Divisions of Neuroradiology and Nuclear Medicine, Medical University of Graz, Austria; 3 Department of Radiology, Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria; 4 Institute for Molecular Biology and Biochemistry, Medical University of Graz, Austria; 5 JSW Research, Forschungslabor GmbH, Graz, Austria; 6 Merz Pharma Austria GmbH, Vienna, Austria Correspondence to: R Schmidt, Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, A-8036 Graz, Austria; reinhold. schmidt@meduni-graz.at Received 5 December 2007 Revised 6 June 2008 Accepted 10 June 2008 Published Online First 27 June 2008 This paper is freely available online under the BMJ Journals unlocked scheme, see http:// jnnp.bmj.com/info/unlocked.dtl 1312 Longitudinal multimodal imaging in mild to moderate Alzheimer disease: a pilot study with memantine R Schmidt,1,2 S Ropele,1 B Pendl,1 P Ofner,3 C Enzinger,1 H Schmidt,4 A Berghold,3 M Windisch,5 H Kolassa,6 F Fazekas1 ABSTRACT Objective: To study the feasibility of multimodal neuroimaging in mild to moderate Alzheimer disease (AD) and to estimate the size of possible treatment effects of memantine on potential functional, structural and meta- bolic biomarkers of disease progression. Methods: In this randomised, double-blind, placebo- controlled pilot study, 36 patients with moderate AD received 52 weeks of memantine (20 mg/day) or placebo. Patients were re-evaluated after 26 and 52 weeks to measure the change from baseline in several outcome measures including global and regional glucose metabolism, total brain and hippocampal volumes, as well as chemical shift imaging-derived global and regional N-acetylaspartate and myoinositol concentrations. Results: In the total population, global glucose metabo- lism decreased by 2.3% (p,0.01), total brain volume by 2.1% (p,0.001) and hippocampal volume by 2.7% (p,0.01) after 52 weeks. Chemical shift imaging (CSI) spectra were severely affected by patient-induced artefacts and highly variable. Patients receiving meman- tine showed less decline in glucose metabolism in all brain areas than patients on placebo. Their loss of hippocampal volume was substantially smaller (2.4% vs 4.0%). No between-group differences were seen for changes in total brain volume. Conclusions: The results support the use of multimodal imaging including MRI and positron emission tomography (PET) to monitor the progression of moderate AD. CSI yielded unreliable longitudinal results. The data suggest that memantine has potentially protective effects in AD and they can be used for planning larger confirmatory studies on the cerebral effects of memantine. Current treatments in Alzheimer disease (AD) apparently do not slow the disease.1 Therapies that modify AD by interfering with the underlying neurodegeneration are under investigation.2 Neuroimaging markers that substantiate disease- modifying effects are attractive investigational targets.3 4 The rate of whole brain and hippocampal volume loss, longitudinal changes in N-acetylas- partate (NAA), choline and myoinositol (MI) concentrations, and decline in brain perfusion and metabolism, are potential imaging endpoints for therapeutic trials.4 They reportedly correlate with the severity of histopathology5–8 and cognitive performance.4 Few therapeutic trials have implemented these measures in patients with AD and most of them used a single modality approach.9–14 This provides a restricted view on disease-related changes over time and considers only selected aspects of treat- ment effects although these may be manifold, including brain metabolism, function and struc- ture. These different aspects may now be appre- ciated by specific imaging technologies, but the feasibility and contribution of long-term multi- modal imaging to study therapeutic responses in AD has not yet been sufficiently explored. Knowledge of long-term change in different imaging measures and assessment of the variability of results in patients with AD are a prerequisite for the use of such methods in treatment trials, as is reproducibility assessment. Such data could be obtained from a purely observational study unclouded by possible therapeutic effects. However, it is difficult to conduct long-term studies in patients with AD without offering them any treatment. We therefore performed a 1-year pilot feasibility study on multimodal imaging in mild to moderate AD coupled with specific treatment. We determined the longitudinal changes and their variability on 18F-fluorodeoxy- glucose (FDG) positron emission tomography (PET), chemical shift imaging (CSI) and 3D MRI in patients with AD who had been randomised to receive either memantine or placebo. PATIENTS AND METHODS Patients Patients over 50 years old were eligible if they had a diagnosis of probable AD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV15 and National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS–ADRDA) cri- teria,16 a Hachinski score (4,17 and an Mini- Mental State Examination (MMSE) score between 14 and 22.18 When we started the study, cholines- terase inhibitors were approved in Austria for mild to moderate AD (MMSE 12–24), and memantine for moderately severe and severe AD (MMSE 3–14). We considered a placebo group to be crucial but did not want to exclude study participants from approved treatments. Therefore, we included only those patients who (1) had either failed to respond to cholinesterase inhibitors or experienced severe side effects leading to termination of such treatment and (2) had MMSE scores .14, which, at the time of study conduct, had excluded them from other approved antidementia treatment once cholinesterase inhibitors had been stopped. To avoid withholding licensed therapy from study participants, we a priori defined that, whenever a participant worsened clinically obtaining an MMSE score ,15, he/she would be switched to active treatment without breaking the J Neurol Neurosurg Psychiatry 2008;79:1312–1317. doi:10.1136/jnnp.2007.141648