can be detected by all methods except CSI. Our data suggest that memantine slows the decline in glucose metabolism and slows the progression of hippocampal atrophy supporting its potential disease-modifying effect in AD. Larger trials including PET scanning and hippocampal measurements are warranted to confirm these results. Funding: The study was sponsored by Merz Pharma Austria GmbH. Competing interests: RS has received compensation for lectures, consulting fees and research funding from the sponsor of the reported study. MW has received consulting fees and research funding, and acted on behalf of the sponsor of the reported study. HK was a general manager at Merz Pharma Austria GmbH acting as sponsor of the reported study. FF has received consulting fees, reimbursement and research funding (including funds for a staff member) from the sponsor of the reported study. Ethics approval: None of the patients included in the trial could obtain licensed treatment at study entry or would be withheld such treatment during the study, hence the local ethics committee approved a 1-year placebo-controlled trial. Written informed consent was obtained from the patients and their caregivers. REFERENCES 1. Cummings J. Alzheimer’s disease. N Engl J Med 2004;351:56–67. 2. Desai A, Grossberg G. Diagnosis and treatment of Alzheimer’s disease. Neurology 2005;64:S34–9. 3. Schmidt R, Scheltens P, Erkinjuntti T, et al. White matter lesion progression: A surrogate endpoint for trials in cerebral small vessel disease. Neurology 2004;63:139–44. 4. Dickerson B, Sperling R. Neuroimaging biomarkers for clinical trials of disease- modifying therapies in Alzheimer’s disease. NeuroRx 2005;2:348–60. 5. Chen J, Charles H, Barboriak D, et al. Magnetic resonance spectroscopy in Alzheimer’s disease: focus on N-acetylaspartate. Acta Neurol Scand 2000;176(Suppl):20–6. 6. Gosche K, Mortimer J, Smith C, et al. Hippocampal volume as an index of Alzheimer neuropathology: findings from the Nun Study. Neurology 2002;58:1476–82. 7. Jack CJ, Dickson D, Parisi J, et al. Antemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia. Neurology 2002;58:750–7. 8. Mega M, Chen S, Thompson P, et al. Mapping histology to metabolism: coregistration of stained whole-brain sections to premortem PET in Alzheimer’s disease. Neuroimage 1997;5:147–53. 9. Jack CJ, Slomkowski M, Gracon S, et al. MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD. Neurology 2003;60:253–60. 10. Krishnan K, Charles H, Doraiswamy P, et al. Randomized, placebo-controlled trial of the effects of donepezil on neuronal markers and hippocampal volumes in Alzheimer’s disease. Am J Psychiatry 2003;160:2003–11. 11. Mega M, Cummings J, O’Connor S, et al. Cognitive and metabolic responses to metrifonate therapy in Alzheimer disease. Neuropsychiatry Neuropsychol Behav Neurol 2001;14:63–8. 12. Mega M, Dinov I, Porter V, et al. Metabolic patterns associated with the clinical response to galantamine therapy: a fludeoxyglucose f 18 positron emission tomographic study. Arch Neurol 2005;62:721–8. R e s e a r c h p a p e r 13. Satlin A, Bodick N, Offen W, et al. Brain proton magnetic resonance spectroscopy (1H-MRS) in Alzheimer’s disease: changes after treatment with xanomeline, an M1 selective cholinergic agonist. Am J Psychiatry 1997;154:1459–61. 14. Tune L, Tiseo P, Ieni J, et al. Donepezil HCl (E2020) maintains functional brain activity in patients with Alzheimer disease: results of a 24-week, double-blind, placebo- controlled study. Am J Geriatr Psychiatry 2003;11:169–77. 15. American Psychiatric Association. Diagnostic and statistical manual of mental disorders DSM-IV. Washington, DC, USA: American Psychiatric Association, 1994. 16. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS–ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34:939–44. 17. Hachinski V, Iliff L, Zilhka E, et al. Cerebral blood flow in dementia. Arch Neurol 1975;32:632–7. 18. Folstein M, Folstein S, McHugh P. Mini Mental State: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–98. 19. Martins C, Oulhaj A, de Jager C, et al. APOE alleles predict the rate of cognitive decline in Alzheimer disease: a nonlinear model. Neurology 2005;65:1888–93. 20. Brink T, Yesavage J, Lum O, et al. Screening tests for geriatric depression. Clin Gerontol 1982;1:37–43. 21. Mohs R. The Alzheimer’s Disease Assessment Scale. Int Psychogeriatr 1996;8:195–203. 22. Morris J. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993;43:2412–14. 23. Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living for clinical trials in Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997;11:S33–9. 24. Smith S. Fast robust automated brain extraction. Hum Brain Mapp 2002;17:143–55. 25. Smith S, Zhang Y, Jenkinson M, et al. Accurate, robust, and automated longitudinal and cross-sectional brain change analysis. Neuroimage 2002;17:479–89. 26. Duvernoy H. The human hippocampus: functional anatomy, vascularization and serial sections with MRI. New York, NY, USA: Springer, 1998. 27. Insausti R, Juottonen K, Soininen H, et al. MR volumetric analysis of the human entorhinal, perirhinal, and temporopolar cortices. AJNR Am J Neuroradiol 1998;19:659–71. 28. Moffat S, Szekely C, Zonderman A, et al. Longitudinal change in hippocampal volume as a function of apolipoprotein E genotype. Neurology 2000;55:134–6. 29. Provencher S. Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 1993;30:672–9. 30. Behl P, Stefurak T, Black S. Progress in clinical neurosciences: cognitive markers of progression in Alzheimer’s disease. Can J Neurol Sci 2005;32:140–51. 31. Chan D, Fox N, Jenkins R, et al. Rates of global and regional cerebral atrophy in AD and frontotemporal dementia. Neurology 2001;57:1756–63. 32. Fox N, Crum W, Scahill R, et al. Imaging of onset and progression of Alzheimer’s disease with voxel-compression mapping of serial magnetic resonance images. Lancet 2001;358:201–5. 33. Jack CJ, Petersen R, Xu Y, et al. Rates of hippocampal atrophy correlate with change in clinical status in aging and AD. Neurology 2000;55:484–9. 34. Schott J, Fox N, Frost C, et al. Assessing the onset of structural change in familial Alzheimer’s disease. Ann Neurol 2003;53:181–8. 35. Mosconi L, Sorbi S, de Leon M, et al. Hypometabolism exceeds atrophy in presymptomatic early-onset familial Alzheimer’s disease. J Nucl Med 2006;47:1778–86. 36. Danysz W, Parsons C. The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer’s disease: preclinical evidence. Int J Geriatr Psychiatry 2003;18:S23–32. J Neurol Neurosurg Psychiatry 2008;79:1312–1317. doi:10.1136/jnnp.2007.141648 1317