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Brain Advance Access originally published online on September 29, 2006
Brain 2006 129(11):2908-2922; doi:10.1093/brain/awl266
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© The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Enhanced brain activity may precede the diagnosis of Alzheimer's disease by 30 years

Christian R. A. Mondadori1, Andreas Buchmann1, Henrietta Mustovic1, Conny F. Schmidt2, Peter Boesiger2, Roger M. Nitsch1, Christoph Hock1, Johannes Streffer1 and Katharina Henke3

1 Division of Psychiatry Research University of Zurich 2 Institute for Biomedical Engineering University and ETH Zurich, Zurich 3 Department of Psychology University of Bern, Bern, Switzerland

Correspondence to: Katharina Henke, Department of Psychology, University of Bern, Muesmattstrasse 45, 3000 Bern 9, Switzerland E-mail: henke{at}psy.unibe.ch

Presenilin 1 (PSEN1) mutations cause autosomal dominant familial Alzheimer's disease (FAD). PSEN1 mutation carriers undergo the course of cognitive deterioration, which is typical for sporadic Alzheimer's disease but disease onset is earlier and disease progression is faster. Here, we sought to detect signs of FAD in presymptomatic carriers of the PSEN1 mutation (C410Y) by use of a neuropsychological examination, functional MRI during learning and memory tasks and MRI volumetry. We examined five non-demented members of a FAD family and 21 non-related controls. Two of the five family members were carrying the mutation; one was 20 years old and the other 45 years old. The age of clinical manifestation of FAD in the family studied here is ~48 years. Neuropsychological assessments suggested subtle problems with episodic memory in the 20-year-old mutation carrier. The middle-aged mutation carrier fulfilled criteria for amnestic mild cognitive impairment. The 20-year-old mutation carrier exhibited increased, while the middle-aged mutation carrier exhibited decreased brain activity compared to controls within memory-related neural networks during episodic learning and retrieval, but not during a working-memory task. The increased memory-related brain activity in the young mutation carrier might reflect a compensatory effort to overcome preclinical neural dysfunction caused by first pathological changes. The activity reductions in the middle-aged mutation carrier might reflect gross neural dysfunction in a more advanced stage of neuropathology. These data suggest that functional neuroimaging along with tasks that challenge specifically those brain areas which are initial targets of Alzheimer's disease pathology may reveal activity alterations on a single-subject level decades before the clinical manifestation of Alzheimer's disease.

Key Words: presenilin 1; fMRI; hippocampus; learning; preclinical

Abbreviations: APOE4, apolipoprotein E {varepsilon}4; CERAD-NAB, Consortium to Establish a Registry for Alzheimer's Disease—Neuropsychological Assessment Battery; FAD, familial Alzheimer's disease; fMRI, functional MRI; HAWIE-R, Hamburg Wechsler Intelligence Scale Revised; MTL, medial temporal lobe; PSEN1, presenilin 1; ROI, region of interest; SAD, sporadic Alzheimer's disease; WMS-R, Wechsler Memory Scale—Revised

Received May 25, 2006. Revised August 25, 2006. Accepted August 29, 2006.


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