Towards non-invasive diagnostic imaging of early-stage Alzheimer's disease



One way to image the molecular pathology in Alzheimer's disease 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 are composed of Aβ oligomers. Here, we report a sensitive molecular magnetic resonance imaging contrast probe that is specific for Aβ oligomers. We attach oligomer-specific antibodies onto magnetic nanostructures and show that the complex is stable and binds to Aβ oligomers on cells and brain tissues to give a magnetic resonance imaging signal. When intranasally administered to an Alzheimer's disease mouse model, the probe readily reached hippocampal Aβ oligomers. In isolated samples of human brain tissue, we observed a magnetic resonance imaging signal that distinguished Alzheimer's disease from controls. Such nanostructures that target neurotoxic Aβ oligomers are potentially useful for evaluating the efficacy of new drugs and ultimately for early-stage Alzheimer's disease diagnosis and disease management.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Aβ oligomers (AβOs) bind to neuronal surfaces in a saturable, receptor-mediated manner and are distinct from amyloid plaques.
Figure 2: Individual components of the NU4MNS probe.
Figure 3: NU4MNS attachment to hippocampal neurons is specific to AβOs.
Figure 4: NU4 and NU4MNS discriminate Alzheimer's disease human frontal cortex sections from aged controls.
Figure 5: NU4 antibody detects dendrite-bound AβOs in fixed tissue and binds its target within 4 h following intranasal inoculation.
Figure 6: NU4MNS labelling of human and Tg mouse brain slices gives a pronounced, Alzheimer's disease-dependent MRI signal that is confirmed in vivo.


  1. 1

    2014 Alzheimer's disease facts and figures. Alzheimers Dement. 10, e47–e92 (2014).

  2. 2

    Georganopoulou, D. G. et al. Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer's disease. Proc. Natl Acad. Sci. USA 102, 2273–2276 (2005).

  3. 3

    Toledo, J. B., Xie, S. X., Trojanowski, J. Q. & Shaw, L. M. Longitudinal change in CSF τ and Aβ biomarkers for up to 48 months in ADNI. Acta Neuropathol. 126, 659–670 (2013).

  4. 4

    Slemmon, J. R. et al. Measurement of Aβ1–42 in cerebrospinal fluid is influenced by matrix effects. J. Neurochem. 120, 325–333 (2012).

  5. 5

    Klunk, W. E. et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh compound-B. Annals Neurol. 55, 306–319 (2004).

  6. 6

    Johnson, K. A. 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. Alzheimers Dement. 9, e1–e16 (2013).

  7. 7

    Terry, R. D. et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572–580 (1991).

  8. 8

    Nyborg, A. C. et al. In vivo and ex vivo imaging of amyloid-beta cascade aggregates with a pronucleon peptide. J. Alzheimer's Dis. 34, 957–967 (2013).

  9. 9

    Klein, W. L., Krafft, G. A. & Finch, C. E. Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum?. Trends Neurosci. 24, 219–224 (2001).

  10. 10

    Lublin, A. L. & Gandy, S. Amyloid-β oligomers: possible roles as key neurotoxins in Alzheimer's disease. Mount Sinai J. Med. New York 77, 43–49 (2010).

  11. 11

    Ferreira, S. T. & Klein, W. L. The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's disease. Neurobiol. Learn. Mem. 96, 529–543 (2011).

  12. 12

    Schnabel, J. Amyloid little proteins, big clues. Nature 475, S12–S14 (2011).

  13. 13

    Mucke, L. & Selkoe, D. J. Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. Cold Spring Harbor Persp. Med. 2, a006338 (2012).

  14. 14

    Lacor, P. N. et al. Synaptic targeting by Alzheimer's-related amyloid β oligomers. J. Neurosci. 24, 10191–10200 (2004).

  15. 15

    De, M., Chou, S. S., Joshi, H. M. & Dravid, V. P. Hybrid magnetic nanostructures (MNS) for magnetic resonance imaging applications. Adv. Drug Deliv. Rev. 63, 1282–1299 (2011).

  16. 16

    Corot, C. et al. in Molecular and Cellular MR Imaging (eds Modo, M. M. J. & Bulte, J. W. M.) Ch. 4, 59–84 (CRC Press, 2007).

  17. 17

    Liu, S. et al. A novel type of dual-modality molecular probe for MR and nuclear imaging of tumor: preparation, characterization and in vivo application. Mol. Pharmaceut. 6, 1074–1082 (2009).

  18. 18

    Serres, S. et al. Molecular MRI enables early and sensitive detection of brain metastases. Proc. Natl Acad. Sci. USA 109, 6674–6679 (2012).

  19. 19

    Lambert, M. P. et al. Monoclonal antibodies that target pathological assemblies of Aβ. J. Neurochem. 100, 23–35 (2007).

  20. 20

    Lambert, M. P., Velasco, P. T., Viola, K. L. & Klein, W. L. Targeting generation of antibodies specific to conformational epitopes of amyloid β-derived neurotoxins. CNS Neurol. Disord. Drug Targets 8, 65–81 (2009).

  21. 21

    Acton, P. et al. Anti-ADDL antibodies and uses thereof. US patent 7,811,563 (2010).

  22. 22

    Xiao, C. et al. Brain transit and ameliorative effects of intranasally delivered anti-amyloid-β oligomer antibody in 5xFAD mice. J. Alzheimer's Dis. 35, 777–788 (2013).

  23. 23

    Gong, Y. et al. Alzheimer's disease-affected brain: presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc. Natl Acad. Sci. USA 100, 10417–10422 (2003).

  24. 24

    Kayed, R. et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300, 486–489 (2003).

  25. 25

    Chang, L. et al. Femtomole immunodetection of synthetic and endogenous amyloid-β oligomers and its application to Alzheimer's disease drug candidate screening. J. Mol. Neurosci. 20, 305–313 (2003).

  26. 26

    Lesne, S. et al. A specific amyloid-β protein assembly in the brain impairs memory. Nature 440, 352–357 (2006).

  27. 27

    Ohno, M. et al. Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1. Eur. J. Neurosci. 23, 251–260 (2006).

  28. 28

    Mucke, L. et al. High-level neuronal expression of Aβ1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J. Neurosci. 20, 4050–4058 (2000).

  29. 29

    Balducci, C. et al. Cognitive deficits associated with alteration of synaptic metaplasticity precede plaque deposition in AβPP23 transgenic mice. J. Alzheimer's Dis. 21, 1367–1381 (2010).

  30. 30

    Ferretti, M. T. et al. Transgenic mice as a model of pre-clinical Alzheimer's disease. Curr. Alzheimer Res. 8, 4–23 (2011).

  31. 31

    Takamura, A. et al. Extracellular and intraneuronal HMW-AβOs represent a molecular basis of memory loss in Alzheimer's disease model mouse. Mol. Neurodegen. 6, 20 (2011).

  32. 32

    Velasco, P. T. et al. Synapse-binding subpopulations of Aβ oligomers sensitive to peptide assembly blockers and scFv antibodies. ACS Chem. Neurosci. 3, 972–981 (2012).

  33. 33

    Oakley, H. 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. J. Neurosci. 26, 10129–10140 (2006).

  34. 34

    Barick, K. C. et al. Nanoscale assembly of amine-functionalized colloidal iron oxide. J. Magn. Magn. Mater. 321, 1529–1532 (2009).

  35. 35

    Na, H. B., Song, I. C. & Hyeon, T. Inorganic nanoparticles for MRI contrast agents. Adv. Mater. 21, 2133–2148 (2009).

  36. 36

    Pinho, S. L. C. et al. Fine tuning of the relaxometry of γ-Fe2O3@SiO2 nanoparticles by tweaking the silica coating thickness. ACS Nano. 4, 5339–5349 (2010).

  37. 37

    Prakash, A. et al. Bilayers as phase transfer agents for nanocrystals prepared in nonpolar solvents. ACS Nano. 3, 2139–2146 (2009).

  38. 38

    Amstad, E., Textor, M. & Reimhult, E. Stabilization and functionalization of iron oxide nanoparticles for biomedical applications. Nanoscale 3, 2819–2843 (2011).

  39. 39

    Tong, S. et al. Coating optimization of superparamagnetic iron oxide nanoparticles for high T2 relaxivity. Nano Lett. 10, 4607–4613 (2010).

  40. 40

    Amstad, E. et al. Ultrastable iron oxide nanoparticle colloidal suspensions using dispersants with catechol-derived anchor groups. Nano Lett. 9, 4042–4048 (2009).

  41. 41

    Palumbo, A., Napolitano, A., Barone, P. & d'Ischia, M. 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. Chem. Res. Toxicol. 12, 1213–1222 (1999).

  42. 42

    Robinson, R. MRI probe for amyloid-β oligomers offers potential advantages for detecting Alzheimer's disease. Neurol. Today 12, 20–22 (2012).

  43. 43

    Park, J. et al. Ultra-large-scale syntheses of monodisperse nanocrystals. Nature Mater. 3, 891–895 (2004).

  44. 44

    Mundt, A. P. et al. Targeting activated microglia in Alzheimer's pathology by intraventricular delivery of a phagocytosable MRI contrast agent in APP23 transgenic mice. NeuroImage 46, 367–372 (2009).

Download references


The authors thank the staff of the Biological Imaging Facility (BIF), the Center for Advanced Molecular Imaging (CAMI) and Northwestern University's Atomic and Nanoscale Characterization Experimental Center (NUANCE) at Northwestern University, and the Department of Radiology at NorthShore University HealthSystems. The authors also thank the Northwestern Brain Bank at the Cognitive Neurology and Alzheimer's Disease Center (CNADC) for providing the human Alzheimer's disease and control brain tissue. The authors acknowledge support from their funding agencies and grants. This work was funded by the National Institutes of Health (AG022547, AG029460 and AG045637 to W.L.K.), by Baxter Healthcare (to W.L.K.) and partially by the National Institutes of Health–Centers of Cancer Nanotechnology Excellence through the Nanoconstruct Core (award U54CA119341 to V.P.D., H.J. and M.D.)

Author information

The study concept and design was provided by K.L.V., J.S., R.S., M.D., V.P.D. and W.L.K. The acquisition of data was performed by M.D., H.J., J.S. and S.V. (MNS development, production, and characterization), K.L.V., J.S., R.S., M.A.B., J.W., S.V., S.S., S.W., C.L. and J.P. (antibody conjugation, cell experiments, tissue experiments and immunoprecipitation experiments), K.L.V. and M.A.B. (animal experiments), K.M. (inductively coupled plasma mass spectrometry experiments) and E.A.W. and P.P (magnetic resonance image acquisition). All authors discussed the results and contributed to the analysis of the data. Critical revision of the article for intellectual content was conducted by K.L.V., J.S., R.S., M.D., P.T.V., V.P.D. and W.L.K. Funding was obtained and studies supervised by W.L.K. and V.P.D.

Correspondence to Vinayak P. Dravid or William L. Klein.

Ethics declarations

Competing interests

This work was funded, in part, by Baxter Healthcare. Northwestern University holds the rights to two US and several international patents concerning antibodies that target Aβ oligomer assemblies. Acumen Pharmaceuticals holds the licensing rights to develop anti-Aβ oligomer antibodies for therapeutic use.

Supplementary information

Supplementary information

Supplementary Information (PDF 6608 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Viola, K., Sbarboro, J., Sureka, R. et al. Towards non-invasive diagnostic imaging of early-stage Alzheimer's disease. Nature Nanotech 10, 91–98 (2015).

Download citation

Further reading