Table 1 Baseline characteristics of patients with Alzheimer disease (AD) in a 52-week, randomised, double-blind, placebo-controlled trial on the effects of memantine on brain morphology and metabolism Total group (n = 36) Characteristic Age, years 76.2 (5.21) Sex, female 23.0 (63.9) Apolipoprotein-E-e4 allele 16.0 (44.4) Hachinski score 1.1 (1.27) MMSE 19.0 (2.90) GDS 2.4 (0.94) CDR 1.6 (0.56) ADAS-Cog 27.5 (10.59) Normalised brain volume, ml 1298.3 (76.5) Placebo (n = 18) 75.8 (5.70) 10.0 (55.6) 8.0 (44.4) 0.8 (0.99) 19.3 (2.72) 2.2 (1.00) 1.5 (0.51) 27.5 (10.00) 1311.4 (77.5) Memantine (n = 18) 76.5 (4.81) 13.0 (72.2) 8.0 (44.4) 1.4 (1.46) 18.7 (3.12) 2.6 (0.85) 1.6 (0.61) 27.6 (11.45) 1285.9 (75.8) All data are expressed as mean and standard deviation (SD) except for sex and APO-E- e4 allele, which are expressed as frequency and percentage. ADAS-Cog, Alzheimer Disease Assessment Scale – cognitive subscale; CDR, Clinical Dementia Rating; GDS, Geriatric Depression Scale; MMSE, Mini-Mental State Examination. concomitant medication during the study. In the placebo and memantine group, 33% and 28% received low-dose neuroleptics, respectively; antidepressants were used in 39% and sedatives/ hypnotics in 11% of patients in each group. Clinically, the total group was stable until week 26 and declined in all clinical assessments at week 52 (4.2 points on ADAS-Cog, 1.3 on MMSE, 0.4 on CDR and 11 on ADCS-ADL). The 52-week decline in patients on placebo on the ADAS-Cog, MMSE, CDR and ADCS- ADL was 8.2, 2.0, 0.5 and 5.1 points, respectively. With 1.0, 0.7, 0.3 and 5.1 points, the clinical 52-week decline in study participants treated with memantine was slower. After 52 weeks, the mean (SD) global decrease in cerebral glucose metabolism from baseline was 2.3% (4.96%); p,0.01. Significant regional metabolic reductions were seen in the parietal (3.1% (5.20%)), basal ganglionic (2.7% (6.00%)) and temporal (2.3% (4.01%)) brain areas (p,0.01 each). Declines in the frontal (2.1% (5.96%)) and occipital (1.3% (5.50%)) areas were non-significant. Longitudinal coregistration of baseline and 52-week follow-up PET studies on MRI reference scans depicted the distribution of functional loss over time. Most AD cases showed a diffuse glucose metabolism decrease involving all brain areas, but some developed substantial asymmetric and focally confined reductions in brain metabo- lism over time (fig 1 A, B). Memantine-treated subjects showed less annual decline in glucose metabolism in all brain areas compared to placebo (fig 2). The differences were non- significant. In relative terms, the annual decline in global glucose metabolism in patients on memantine was 41% smaller than in those on placebo. Table 2 shows the changes of MRI volumetric endpoints over time. There was a significant loss of total brain (2.1% per year; p,0.001) and hippocampal (2.7% per year; p,0.01) volumes in all patients. The annual reduction in total brain volume was similar between the groups (2.0% placebo vs 2.3% memantine). At study end, patients on memantine showed 40.6% less hippocampal volume reduction than patients on placebo (2.4% vs 4.0%). There existed no significant relationship between global change in glucose metabolism and percentage change in total brain (r = 20.02) and hippocampal (r = 20.28) volume. Even in the case with almost complete regional drop in glucose metabolism, only minimal sulcal widening was seen at the affected site during the 52-week observational period (fig 1C,D). J Neurol Neurosurg Psychiatry 2008;79:1312–1317. doi:10.1136/jnnp.2007.141648 Research paper Figure 1 A–D. Baseline (A) and 52-week (B) positron emission tomography (PET) scans registered on MRI in an 85-year-old female study participant who experienced a focal, almost complete loss of glucose utilisation in the right temporoparietal region. Glucose metabolism in other brain regions remained almost unchanged from baseline. The baseline scan demonstrated the typical symmetric temporo-parietal hypometabolism of patients with Alzheimer disease (AD). The coregistered T1-weighted MRI scans show little, if any, sulcal enlargement in the area of metabolic loss in this patient between baseline (C) and follow-up (D). CSI was severely affected by patient-induced artefacts, mostly due to patient motion during the 20-min acquisition time. Motion resulted in incomplete fat saturation and marked line-width broadening in most cases. Depending on the brain region, many spectra were excluded from analysis due to unacceptable quality; this decision was made before unblinding. The exclusion rate was lowest in the parietal (5 cases) and highest in the occipital (19 cases) brain area. Analysis of the remaining spectra still yielded a high intra and interindividual variability of all metabolites with no clear trends over time for the entire cohort and patient subgroups (data not shown). DISCUSSION We have demonstrated that multimodal functional and morphological neuroimaging is feasible in a treatment trial of patients with moderate AD. This 52-week study yielded significant reductions in glucose metabolism and total brain and hippocampal volumes in a group of patients with AD with significant clinical deterioration. Our patients on placebo showed similar cognitive decline to that reported in large-scale clinical AD trials,30 and their annual 2.0% loss of total brain volume and 4.0% loss of hippocampal volume are also 1315