Magnetic Resonance Imaging Detection and Time Course of Cerebral Microhemorrhages during Passive Immunotherapy in Living Amyloid Precursor Protein Transgenic Mice

Abstract

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-␤ (A␤) 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-A␤ monoclonal antibody, and 8F5, a more selective antioligomeric A␤ monoclonal antibody, were examined in both longitudinal studies. High-resolution T2*-weighted magnetic resonance microscopy (100 ϫ 100 ϫ 400 m) 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 Ն60 m 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 A␤ is needed to address the question of whether antibodies that do not bind to deposited A␤ have microhemorrhage liability.

Contrast-enhanced MR microscopy of amyloid plaques in five mouse models of amyloidosis and in human Alzheimer’s disease brains

“…As previously reported 33–35 , on non-stained MRI, microhemorrhages were visible as rare hypointense spots (Fig. 7F,G).…”

“…Microhemorrhages are often associated with aging and amyloid pathology in mice and in humans 32 . These lesions are hypointense on MR images 33–35 , and could thus be misinterpreted as amyloid plaques on Gd-stained MR images. We showed that large microbleeds are distinguishable from amyloid plaques based on their superior size.…”

Systemic inflammation, blood-brain barrier vulnerability and cognitive/non-cognitive symptoms in Alzheimer disease: relevance to pathogenesis and therapy

“…Along the same line, Dickstein et al (2006) demonstrated that Aβ immunization therapy could restore BBB integrity in the same AD mouse model (Tg2576), in addition to improvement of typical AD brain pathological features such as plaque burden and microgliosis, suggesting a new strategy for AD treatment focusing on BBB function (Dickstein et al, 2006). However, we need to give careful consideration to the effect of Aβ immunization on BBB function because it has also been demonstrated that passive immunization with Aβ antibodies resulted in a significant increase in both the frequency and severity of CAA-related microhemorrhages in different APP transgenic mouse models (Pfeifer et al, 2002; Racke et al, 2005; Burbach et al, 2007; Luo et al, 2010). …”

Imaging of cerebrovascular pathology in animal models of Alzheimer's disease

“…Histological analyses demonstrated an increased number of CAA vessels and of iron loaded macrophages in the vicinity of CAA vessels, for mice receiving the β 1 antibody. In addition, a study using T * 2 -weighted MRI for the detection of CMBs in Tg2576 mice treated with either a non-selective antibody (6G1) targeting soluble and insoluble Aβ or a more selective antibody (8F5) targeting primarily soluble Aβ (Luo et al, 2010). Both antibodies increased CMB incidence in aged APP transgenic mice compared with baseline or vehicle treatment.…”