Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease.
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 [Abeta] 1 to 42) who were antibody responders (anti-AN1792 IgG titer of > or =1:2,200) compared with placebo patients.


METHODS
This randomized, multicenter, placebo-controlled, double-blind trial of AN1792 225 mug plus QS-21 50 mug 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.
Fox
N C
NC
Dementia Research Centre, Institute of Neurology, London, UK. nfox@dementia.ion.ucl.ac.uk
Black
R S
RS
Gilman
S
S
Rossor
M N
MN
Griffith
S G
SG
Jenkins
L
L
Koller
M
M
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D000906:Antibodies / Q000097:blood / Q000276:immunology; D001284:Atrophy / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D002555:Cerebrospinal Fluid / Q000187:drug effects / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D004311:Double-Blind Method; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006801:Humans; D016233:Immunotherapy, Active / Q000009:adverse effects* / Q000379:methods; D020547:Lateral Ventricles / Q000187:drug effects / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D010919:Placebos; D016896:Treatment Outcome; D014612:Vaccines / Q000009:adverse effects* / Q000276:immunology
D016229:Amyloid beta-Peptides; D000906:Antibodies; D010446:Peptide Fragments; D010919:Placebos; D014612:Vaccines; C075222:amyloid beta-protein (1-42)