Magnetic resonance imaging detection and time course of cerebral microhemorrhages during passive immunotherapy in living amyloid precursor protein transgenic mice.
In recent years immunotherapy-based approaches for treating Alzheimer's disease have become the subject of intensive research. However, an important mechanistic-related safety concern is exacerbation of the risk of microhemorrhage that may be associated with fast removal of amyloid-β (Aβ) deposits found in blood vessels or brain parenchyma. Rapid in vivo detection of microhemorrhages in living amyloid precursor protein transgenic mice has not been described, and histological analysis can take several months before this risk is assessed. Aged transgenic mice were divided into two groups that would undergo longitudinal passive immunotherapy for 12 or 18 weeks. 6G1, a nonselective anti-Aβ monoclonal antibody, and 8F5, a more selective antioligomeric Aβ monoclonal antibody, were examined in both longitudinal studies. High-resolution T2*-weighted magnetic resonance microscopy (100 × 100 × 400 μm) was used for microhemorrhage detection in vivo. Cerebral microhemorrhages by magnetic resonance imaging were compared with histological hemosiderin staining in each animal; results showed that T2*-weighted magnetic resonance microscopy can reliably detect microhemorrhages of ≥60 μm in diameter at baseline and after 12 to 18 weeks of treatment in the same animals in vivo. This correlated significantly with histological readings. This new imaging safety biomarker can be readily applied to preclinical antibody screening in a longitudinal manner. 6G1 and 8F5, however, both increased microhemorrhage incidence in aged amyloid precursor protein transgenic mice compared with their baseline and vehicle treatment. A highly selective antibody for soluble Aβ is needed to address the question of whether antibodies that do not bind to deposited Aβ have microhemorrhage liability.
Luo
Feng
F
Translational Imaging and Biochemical Biomarkers, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. feng.luo@abbott.com
Rustay
Nathan R
NR
Seifert
Terese
T
Roesner
Beate
B
Hradil
Vincent
V
Hillen
Heinz
H
Ebert
Ulrich
U
Severin
Jean M
JM
Cox
Bryan F
BF
Llano
Daniel A
DA
Day
Mark
M
Fox
Gerard B
GB
D000544:Alzheimer Disease / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000276:immunology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use; D002540:Cerebral Cortex / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000175:diagnosis* / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007116:Immunization, Passive / Q000009:adverse effects*; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013997:Time Factors
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal