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Neurological Disorders - Neuroscience - Radiology and Medical Imaging

In Vivo Detection of Amyloid-ß Deposits Using Heavy Chain Antibody Fragments in a Transgenic Mouse Model for Alzheimer's Disease
Published: Monday, June 04, 2012
Author: Rob J. A. Nabuurs et al.

by Rob J. A. Nabuurs, Kim S. Rutgers, Mick M. Welling, Athanasios Metaxas, Maaike E. de Backer, Maarten Rotman, Brian J. Bacskai, Mark A. van Buchem, Silvère M. van der Maarel, Louise van der Weerd

This study investigated the in vivo properties of two heavy chain antibody fragments (VHH), ni3A and pa2H, to differentially detect vascular or parenchymal amyloid-ß deposits characteristic for Alzheimer's disease and cerebral amyloid angiopathy. Blood clearance and biodistribution including brain uptake were assessed by bolus injection of radiolabeled VHH in APP/PS1 mice or wildtype littermates. In addition, in vivo specificity for Aß was examined in more detail with fluorescently labeled VHH by circumventing the blood-brain barrier via direct application or intracarotid co-injection with mannitol. All VHH showed rapid renal clearance (10–20 min). Twenty-four hours post-injection 99mTc-pa2H resulted in a small yet significant higher cerebral uptake in the APP/PS1 animals. No difference in brain uptake were observed for 99mTc-ni3A or DTPA(111In)-pa2H, which lacked additional peptide tags to investigate further clinical applicability. In vivo specificity for Aß was confirmed for both fluorescently labeled VHH, where pa2H remained readily detectable for 24 hours or more after injection. Furthermore, both VHH showed affinity for parenchymal and vascular deposits, this in contrast to human tissue, where ni3A specifically targeted only vascular Aß. Despite a brain uptake that is as yet too low for in vivo imaging, this study provides evidence that VHH detect Aß deposits in vivo, with high selectivity and favorable in vivo characteristics, making them promising tools for further development as diagnostic agents for the distinctive detection of different Aß deposits.