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From the Dementia Research Centre (A.K.G., A.D.W., J.M.S., C.F., N.C.F., M.N.R.) and NMR Research Unit (D.G.M.), Institute of Neurology, University College of London, London School of Hygiene and Tropical Medicine (C.F.), University of London, Department of Neuropsychology (L.C.), National Hospital for Neurology and Neurosurgery, Division of Neuroscience and Psychological Medicine (M.N.R.), Imperial College, and Charing Cross Hospital (A.D.W.), London, UK.
Address correspondence and reprint requests to Dr Rossor, Dementia Research Centre, Institute of Neurology, Queen Square, London WC1N 3BG, UK; e-mail: m.rossor{at}dementia.ion.ucl.ac.uk
Background: Pathologic change in Alzheimer disease (AD) begins some years before symptoms. MRS has the potential to detect metabolic abnormalities reflecting this early pathologic change. Presenilin 1 (PS1) and amyloid precursor protein (APP) mutation carriers have a nearly 100% risk of developing AD and may be studied prior to symptom onset.
Methods: Short echo time proton MR spectra were acquired from a midline posterior cingulate voxel in presymptomatic carriers of PS1 or APP mutations ("presymptomatic mutation carriers" [PMCs]; n = 7) and age- and sex-matched control subjects (n = 6). Ratios of N-acetyl aspartate (NAA), myo-inositol (MI), and choline-containing compounds (Cho) to creatine (Cr) were measured and NAA/MI calculated. Regression analyses and t tests were performed after log transformation.
Results: PMC and control subjects were matched for age and sex. PMC subjects were 1.7 to 21.6 years (mean 9.8 years) before expected symptom onset, predicted from family-specific mean age at onset. Age did not significantly affect metabolite ratios. Geometric mean ratios in control subjects were as follows: NAA/Cr = 1.75, MI/Cr = 0.59, and NAA/MI = 2.95. NAA/Cr and NAA/MI were significantly reduced in PMC relative to controls (NAA/Cr mean decrease 10% [95% CI 2 to 18%]; NAA/MI mean decrease 25% [95% CI 3 to 44%]). MI/Cr was increased in PMC, but the differences did not achieve significance (19% increase [95% CI 1% decrease to 41% increase]; p = 0.07)). In PMCs, reduction in NAA/MI (p = 0.001) and MI/Cr (p = 0.002) were related to proximity of expected age at onset.
Conclusions: Metabolic changes are detectable in presymptomatic mutation carriers years before expected onset of Alzheimer disease. Their magnitude is related to proximity of expected age at onset.
Supported by MRC program grant G9626876 and a grant from the Alzheimer’s Society (J.M.S.). N.C.F. is a Medical Research Council Senior Clinical Fellow.
Disclosure: The authors report no conflicts of interest.
Received June 24, 2005. Accepted in final form November 4, 2005.
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