Research paper Figure 2 Regional and global changes from baseline in glucose metabolism in patients with Alzheimer disease in a 52-week randomised, double-blind, placebo-controlled trial. Numbers below regions indicate the percentage decline in patients receiving memantine vs those receiving placebo. After 52 weeks, memantine-treated subjects had smaller reductions in all brain regions and globally. Differences did not reach statistical significance in this pilot study. consistent with previous reports,31–34 which supports the validity of our study. The greatest problems were posed by CSI. It is important to note here that there was a tremendous difference between single-voxel MRS and CSI regarding motion sensitivity. Obviously, a 20-min acquisition time required per our quanti- tative CSI protocol was too long for many study participants. In patients who remained still in the scanner, CSI was technically feasible, but data quality was often severely degraded by patient-induced motion artefacts. Typically, head motion resulted in line-width broadening and displacement errors leading to a high rate of spectra of unacceptable quality and to highly variable metabolite concentrations. Thus, low patient compliance can clearly be a major limiting factor when using CSI in longitudinal dementia studies. Recent developments such as turbo CSI or the incorporation of the SENSE technique reduces acquisition time and may overcome some of the problems we encountered. Until respective studies are available, single-voxel spectroscopy with substantially shorter acquisition times may be preferable in demented patient populations. We saw no, or at most poor, correlations between metabolic and volumetric cerebral changes over time. Even in the case with almost complete focal loss of metabolic activity in the right temporal-parietal area, sulcul widening was barely present. This suggests long-term latency between functional deteriora- tion and cellular loss in AD, a finding corroborated by studies in presymptomatic familial AD individuals who also showed widespread reductions in glucose metabolism in the relative absence of structural brain changes long before the clinical onset of the disease.35 This is also the first investigation utilising neuroimaging techniques to study treatment effects of memantine. Memantine preferentially blocks excessive N-methyl-D-aspartic acid (NMDA) receptor activity without disrupting normal receptor activity and is thought to be a neuroprotective agent that attenuates excitotoxicity. Various experiments on cellular and tissue level as well as in animal models support this assumption.36 Selection of imaging methods for the current study attempted to cover possible treatment-related effects as comprehensively as possible. Slowing of decline in glucose metabolism and of hippocampal volume loss seen in patients treated with memantine compared to those on placebo is in favour of functional and neuroprotective effects of this substance. However, caution is advised when interpreting these findings, because our study was not powered to detect statistically significant results and we could be dealing with spurious findings. It is important to emphasise that this study was conducted to facilitate planning of larger confirmatory trials. Nevertheless, glucose metabolism in patients treated with memantine was preserved longer in all brain areas, and the effects on PET results and on hippocampal volume were substantial (PET global annual change: 1.8% in patients treated with memantine vs 3% in patients on placebo; hippocampal volume annual percentage change: 2.4% in patients treated with memantine vs 4% in patients on placebo). In relative terms, global cerebral glucose utilisation and hippocampal volume showed a non-significant trend towards a 40% lower annual decline in the memantine than in the placebo group. This result can serve for rough orientation on sample sizes needed. Based on memantine’s 1-year effect on global glucose metabolism and hippocampal volume, the sample sizes required to detect this 40%-reduction in a 1-year trial with a power of 80% (two-sided Student t test at 5% level) are 202 and 70 patients per group, respectively. The use of multimodal imaging in this study suggests that memantine has functional effects in all brain regions affected by AD while the substance exerted morphological effects only on the hippocampus but not on the whole brain. We certainly cannot exclude that global effects on brain volume may be seen with observation times exceeding 1 year. Hypotheses explaining slower hippocampal degeneration in the absence of effects on total brain volume are difficult to formulate as the mechanisms of neuronal loss in AD are largely unknown. Possibly, the hippocampus may be particularly involved in mild to moderate AD stages studied in the current trial. Another explanation is that memantine exerts more pronounced activity on the hippocampus than on other brain regions because the hippo- campus contains a high density of NMDA receptors, particu- larly in the CA1 area. In conclusion, the data of this pilot study show that multimodal neuroimaging is feasible in a patient population with mild to moderate AD, and consistent changes over time J Neurol Neurosurg Psychiatry 2008;79:1312–1317. doi:10.1136/jnnp.2007.141648 Volumetry 1316 Numbers are mean (SD). Differences between treatment groups were non-significant based on analysis of covariance (ANCOVA). Table 2 Changes in MRI volumetric outcome measures from baseline in patients with Alzheimer disease (AD) in a 52-week, randomised, double-blind, placebo-controlled trial of the effects of memantine on brain morphology and metabolism Imaging endpoint Brain volume change (%) Hippocampal volume change (%) Assessment Week 26 Week 52 Week 26 Week 52 n 29 21 29 21 Total group 20.6 (1.69) 22.1 (2.01) 21.9 (2.82) 22.7 (3.64) n 15 12 15 12 Placebo 20.8 (2.04) 22.0 (1.92) 22.4 (2.01) 24.0 (3.99) n 14 9 14 9 Memantine 20.6 (1.23) 22.3 (2.22) 22.0 (2.70) 22.4 (2.81)