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Published online before print April 7, 2005, doi:10.1212/01.WNL.0000159743.08996.99)
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Received August 12, 2004
Accepted January 31, 2005

Effects of A{beta} immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease

N. C. Fox MD, FRCP*, R. S. Black MD, S. Gilman MD, FRCP, M. N. Rossor MD, FRCP, S. G. Griffith MD, PhD, MRCP, L. Jenkins PhD, M. Koller MD, MPH, for the AN1792(QS-21)-201 Study Team

From the Dementia Research Centre (Drs. Fox and Rossor), Institute of Neurology, London, UK; Wyeth Pharmaceuticals (Drs. Black and Jenkins), Collegeville, PA; Department of Neurology (Dr. Gilman), University of Michigan, Ann Arbor; and Elan Pharmaceuticals, Inc. (Drs. Griffith and Koller), San Diego, CA.


* To whom correspondence should be addressed. E-mail: nfox{at}dementia.ion.ucl.ac.uk.

Abstract-- Background: Alzheimer disease (AD) is characterized by progressive cerebral atrophy that may be measured using MRI. Reported are MRI findings of a Phase IIa immunotherapy trial in AD prematurely terminated owing to meningoencephalitis in a subset of patients. Objective: To assess cerebral volume changes in patients immunized with AN1792 ({beta}-amyloid [A{beta}] 1 to 42) who were antibody responders (anti-AN1792 IgG titer of ≥1:2,200) compared with placebo patients. Methods: This randomized, multicenter, placebo-controlled, double-blind trial of AN1792 225 µg plus QS-21 50 µg included 372 patients with probable AD. Patients received one to three injections of AN1792/QS-21 or saline and were assessed for 12 months. Volumetric MRI was performed pre dose and at month 12 or early termination. Brain, ventricular, and hippocampal volume changes were measured from registered scan pairs. Results: Two hundred eighty-eight patients had paired scans (mean interval 10.9 months). Antibody responders (n = 45) had greater brain volume decrease (3.12 ± 1.98 vs 2.04 ± 1.74%; p = 0.007), greater ventricular enlargement as a percentage of baseline brain volume (1.10 ± 0.75 vs 0.48 ± 0.40%; p < 0.001), and a nonsignificant greater hippocampal volume decrease (3.78 ± 2.63 vs 2.86 ± 3.19%; p = 0.124) than placebo patients (n = 57). Increased losses in brain volume were not reflected in worsening cognitive performance; a composite z score across a Neuropsychological Test Battery showed differences favoring antibody responders over placebo (0.03 ± 0.39 vs -0.24 ± 0.45; p = 0.008). Conclusions: A dissociation between brain volume loss and cognitive function was observed in AN1792/QS-21 antibody responders. The reasons for this remain unclear but include the possibility that volume changes were due to amyloid removal and associated cerebral fluid shifts.




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