Towards Non-Invasive Diagnostic Imaging of Early-Stage Alzheimer’s Disease

One way to image the molecular pathology in Alzheimer’s disease (AD) is by positron emission tomography using probes that target amyloid fibrils. However, these fibrils are not closely linked to the development of the disease. It is now thought that early stage biomarkers that instigate memory loss comprise of Aβ oligomers (AβOs). Here we report a sensitive molecular magnetic resonance imaging (MRI) contrast probe that is specific for AβOs. We attach oligomer-specific antibodies onto magnetic nanostructures and show the complex is stable and it binds to AβOs on cells and brain tissues to give a MRI signal. When intranasally administered to an AD mouse model, the probe readily reached hippocampal AβOs. In isolated samples of human brain tissue, we observed an MRI signal that distinguished AD from controls. Such nanostructures that target neurotoxic AβOs are potentially useful for evaluating the efficacy of new drugs and ultimately for early-stage AD diagnosis and disease management.

[1]  S. Gandy,et al.  Amyloid-beta oligomers: possible roles as key neurotoxins in Alzheimer's Disease. , 2010, The Mount Sinai journal of medicine, New York.

[2]  C. Mirkin,et al.  Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer's disease. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[3]  M. Ohno,et al.  Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1 , 2006, The European journal of neuroscience.

[4]  W. Klein,et al.  Brain transit and ameliorative effects of intranasally delivered anti-amyloid-β oligomer antibody in 5XFAD mice. , 2013, Journal of Alzheimer's disease : JAD.

[5]  Mrinmoy De,et al.  Hybrid magnetic nanostructures (MNS) for magnetic resonance imaging applications. , 2011, Advanced drug delivery reviews.

[6]  Leslie M. Shaw,et al.  Longitudinal change in CSF Tau and Aβ biomarkers for up to 48 months in ADNI , 2013, Acta Neuropathologica.

[7]  V. Dravid,et al.  Nanoscale assembly of amine functionalized colloidal iron oxide. , 2009, Journal of magnetism and magnetic materials.

[8]  Carl W. Cotman,et al.  Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis , 2003, Science.

[9]  M. Robson,et al.  Molecular MRI enables early and sensitive detection of brain metastases , 2012, Proceedings of the National Academy of Sciences.

[10]  Keith A. Johnson,et al.  Appropriate Use Criteria for Amyloid PET: A Report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association , 2013, The Journal of Nuclear Medicine.

[11]  M. Szyf,et al.  Transgenic mice as a model of pre-clinical Alzheimer's disease. , 2011, Current Alzheimer research.

[12]  Marcus Textor,et al.  Stabilization and functionalization of iron oxide nanoparticles for biomedical applications. , 2011, Nanoscale.

[13]  D. Salmon,et al.  Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment , 1991, Annals of neurology.

[14]  E. Bigio,et al.  Monoclonal antibodies that target pathological assemblies of Aβ , 2007, Journal of neurochemistry.

[15]  C. Finch,et al.  Synaptic targeting by Alzheimer's-related amyloid beta oligomers. , 2004, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[16]  W. Thies,et al.  2013 Alzheimer's disease facts and figures , 2013, Alzheimer's & Dementia.

[17]  M. Gallagher,et al.  A specific amyloid-β protein assembly in the brain impairs memory , 2006, Nature.

[18]  J. Schnabel.  Amyloid: Little proteins, big clues , 2011, Nature.

[19]  Kang Hu,et al.  High-Level Neuronal Expression of Aβ1–42 in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation , 2000, The Journal of Neuroscience.

[20]  Marcus Textor,et al.  Ultrastable iron oxide nanoparticle colloidal suspensions using dispersants with catechol-derived anchor groups. , 2009, Nano letters.

[21]  Jens Wuerfel,et al.  Targeting activated microglia in Alzheimer's pathology by intraventricular delivery of a phagocytosable MRI contrast agent in APP23 transgenic mice , 2009, NeuroImage.

[22]  K. Blennow,et al.  Measurement of Aβ1–42 in cerebrospinal fluid is influenced by matrix effects , 2012, Journal of neurochemistry.

[23]  Gang Bao,et al.  Coating optimization of superparamagnetic iron oxide nanoparticles for high T2 relaxivity. , 2010, Nano letters.

[24]  C. Finch,et al.  Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum? , 2001, Trends in Neurosciences.

[25]  Huiguang Zhu,et al.  Bilayers as phase transfer agents for nanocrystals prepared in nonpolar solvents. , 2009, ACS nano.

[26]  G. Forloni,et al.  Cognitive deficits associated with alteration of synaptic metaplasticity precede plaque deposition in AβPP23 transgenic mice. , 2010, Journal of Alzheimer's disease : JAD.

[27]  W. Klunk,et al.  Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound‐B , 2004, Annals of neurology.

[28]  W. Klein,et al.  The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease , 2011, Neurobiology of Learning and Memory.

[29]  Mingyuan Gao,et al.  A novel type of dual-modality molecular probe for MR and nuclear imaging of tumor: preparation, characterization and in vivo application. , 2009, Molecular pharmaceutics.

[30]  Michela Gallagher,et al.  A specific amyloid-beta protein assembly in the brain impairs memory. , 2006, Nature.

[31]  HighWire Press.  The journal of neuroscience : the official journal of the Society for Neuroscience. , 1981 .

[32]  Marie-Hélène Delville,et al.  Fine tuning of the relaxometry of γ-Fe2O3@SiO2 nanoparticles by tweaking the silica coating thickness. , 2010, ACS nano.

[33]  F. Kiessling.  Molecular and Cellular MR Imaging , 2007 .

[34]  L. Mucke,et al.  Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. , 2012, Cold Spring Harbor perspectives in medicine.

[35]  Taeghwan Hyeon,et al.  Inorganic Nanoparticles for MRI Contrast Agents , 2009 .

[36]  M. Ohno,et al.  Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation , 2006, The Journal of Neuroscience.

[37]  Lei Chang,et al.  Femtomole immunodetection of synthetic and endogenous amyloid-β oligomers and its application to Alzheimer’s disease drug candidate screening , 2007, Journal of Molecular Neuroscience.

[38]  Taeghwan Hyeon,et al.  Ultra-large-scale syntheses of monodisperse nanocrystals , 2004, Nature materials.

[39]  W. Klein,et al.  Targeting generation of antibodies specific to conformational epitopes of amyloid beta-derived neurotoxins. , 2009, CNS & neurological disorders drug targets.

[40]  C. Finch,et al.  Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[41]  C. Finch,et al.  Synaptic Targeting by Alzheimer's-Related Amyloid β Oligomers , 2004, The Journal of Neuroscience.

[42]  P. Barone,et al.  Nitrite- and peroxide-dependent oxidation pathways of dopamine: 6-nitrodopamine and 6-hydroxydopamine formation as potential contributory mechanisms of oxidative stress- and nitric oxide-induced neurotoxicity in neuronal degeneration. , 1999, Chemical research in toxicology.

[43]  T. Nabeshima,et al.  Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse , 2011, Molecular Neurodegeneration.

[44]  Marie C. Heffern,et al.  Synapse-binding subpopulations of Aβ oligomers sensitive to peptide assembly blockers and scFv antibodies. , 2012, ACS chemical neuroscience.

[45]  Z. Khachaturian.  Alzheimer's & Dementia: The Journal of the Alzheimer's Association , 2008, Alzheimer's & Dementia.