Abstract

We report optical-resolution photoacoustic microscopy (OR-PAM) for in vivo imaging of amyloid plaques in an Alzheimer’s disease mouse model. Validation using conventional fluorescence microscopy and multiphoton microscopy shows that OR-PAM has sufficient sensitivity and spatial resolution to identify amyloid plaques in living brains. In addition, with dual-wavelength OR-PAM, the three-dimensional morphology of amyloid plaques and the surrounding microvasculature are imaged simultaneously through a cranial window without angiographic contrast agents. OR-PAM, capable of providing both exogenous molecular contrast and endogenous hemoglobin contrast, has the potential to serve as a new technology for in vivo microscopic observations of cerebral plaque deposits.

© 2009 Optical Society of America

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  1. C. Wu, V. W. Pike, and Y. Wang, Curr. Top Dev. Biol. 70, 171 (2005).
    [CrossRef] [PubMed]
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    [PubMed]
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
  5. S. L. Jacques and S. A. Prahl, http://omlc.ogi.edu/spectra/hemoglobin/index. html, retrieved November 16, 2009.
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]

2009 (3)

S. Hu, K. Maslov, and L. V. Wang, Med. Phys. 36, 2320 (2009).
[CrossRef] [PubMed]

S. Hu, K. Maslov, V. Tsytsarev, and L. V. Wang, J. Biomed. Opt. 14, 040503 (2009).
[CrossRef] [PubMed]

P. Yan, A. W. Bero, J. R. Cirrito, Q. Xiao, X. Hu, Y. Wang, E. Gonzales, D. M. Holtzman, and J. M. Lee, J. Neurosci. 29, 10706 (2009).
[CrossRef] [PubMed]

2007 (2)

H. T. Xu, F. Pan, G. Yang, and W. B. Gan, Nat. Neurosci. 10, 549 (2007).
[CrossRef] [PubMed]

C. L. Nie, X. S. Wang, Y. Liu, S. Perrett, and R. Q. He, BMC Neurosci. 8, 9 (2007).
[CrossRef] [PubMed]

2005 (2)

C. Wu, V. W. Pike, and Y. Wang, Curr. Top Dev. Biol. 70, 171 (2005).
[CrossRef] [PubMed]

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, Nat. Biotechnol. 23, 577 (2005).
[CrossRef] [PubMed]

2002 (1)

W. E. Klunk, B. J. Bacskai, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, J. Neuropathol. Exp. Neurol. 61, 797 (2002).
[PubMed]

Bacskai, B. J.

W. E. Klunk, B. J. Bacskai, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, J. Neuropathol. Exp. Neurol. 61, 797 (2002).
[PubMed]

Bero, A. W.

P. Yan, A. W. Bero, J. R. Cirrito, Q. Xiao, X. Hu, Y. Wang, E. Gonzales, D. M. Holtzman, and J. M. Lee, J. Neurosci. 29, 10706 (2009).
[CrossRef] [PubMed]

Cirrito, J. R.

P. Yan, A. W. Bero, J. R. Cirrito, Q. Xiao, X. Hu, Y. Wang, E. Gonzales, D. M. Holtzman, and J. M. Lee, J. Neurosci. 29, 10706 (2009).
[CrossRef] [PubMed]

Debnath, M. L.

W. E. Klunk, B. J. Bacskai, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, J. Neuropathol. Exp. Neurol. 61, 797 (2002).
[PubMed]

Enz, A.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, Nat. Biotechnol. 23, 577 (2005).
[CrossRef] [PubMed]

Frey, P.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, Nat. Biotechnol. 23, 577 (2005).
[CrossRef] [PubMed]

Frosch, M. P.

W. E. Klunk, B. J. Bacskai, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, J. Neuropathol. Exp. Neurol. 61, 797 (2002).
[PubMed]

Gan, W. B.

H. T. Xu, F. Pan, G. Yang, and W. B. Gan, Nat. Neurosci. 10, 549 (2007).
[CrossRef] [PubMed]

Gonzales, E.

P. Yan, A. W. Bero, J. R. Cirrito, Q. Xiao, X. Hu, Y. Wang, E. Gonzales, D. M. Holtzman, and J. M. Lee, J. Neurosci. 29, 10706 (2009).
[CrossRef] [PubMed]

Gremlich, H. U.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, Nat. Biotechnol. 23, 577 (2005).
[CrossRef] [PubMed]

He, R. Q.

C. L. Nie, X. S. Wang, Y. Liu, S. Perrett, and R. Q. He, BMC Neurosci. 8, 9 (2007).
[CrossRef] [PubMed]

Hintersteiner, M.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, Nat. Biotechnol. 23, 577 (2005).
[CrossRef] [PubMed]

Holt, D. P.

W. E. Klunk, B. J. Bacskai, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, J. Neuropathol. Exp. Neurol. 61, 797 (2002).
[PubMed]

Holtzman, D. M.

P. Yan, A. W. Bero, J. R. Cirrito, Q. Xiao, X. Hu, Y. Wang, E. Gonzales, D. M. Holtzman, and J. M. Lee, J. Neurosci. 29, 10706 (2009).
[CrossRef] [PubMed]

Hu, S.

S. Hu, K. Maslov, and L. V. Wang, Med. Phys. 36, 2320 (2009).
[CrossRef] [PubMed]

S. Hu, K. Maslov, V. Tsytsarev, and L. V. Wang, J. Biomed. Opt. 14, 040503 (2009).
[CrossRef] [PubMed]

Hu, X.

P. Yan, A. W. Bero, J. R. Cirrito, Q. Xiao, X. Hu, Y. Wang, E. Gonzales, D. M. Holtzman, and J. M. Lee, J. Neurosci. 29, 10706 (2009).
[CrossRef] [PubMed]

Hyman, B. T.

W. E. Klunk, B. J. Bacskai, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, J. Neuropathol. Exp. Neurol. 61, 797 (2002).
[PubMed]

Jacques, S. L.

S. L. Jacques and S. A. Prahl, http://omlc.ogi.edu/spectra/hemoglobin/index. html, retrieved November 16, 2009.

Jaton, A. L.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, Nat. Biotechnol. 23, 577 (2005).
[CrossRef] [PubMed]

Kajdasz, S. T.

W. E. Klunk, B. J. Bacskai, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, J. Neuropathol. Exp. Neurol. 61, 797 (2002).
[PubMed]

Kinzy, W.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, Nat. Biotechnol. 23, 577 (2005).
[CrossRef] [PubMed]

Klunk, W. E.

W. E. Klunk, B. J. Bacskai, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, J. Neuropathol. Exp. Neurol. 61, 797 (2002).
[PubMed]

Kneuer, R.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, Nat. Biotechnol. 23, 577 (2005).
[CrossRef] [PubMed]

Lee, J. M.

P. Yan, A. W. Bero, J. R. Cirrito, Q. Xiao, X. Hu, Y. Wang, E. Gonzales, D. M. Holtzman, and J. M. Lee, J. Neurosci. 29, 10706 (2009).
[CrossRef] [PubMed]

Liu, Y.

C. L. Nie, X. S. Wang, Y. Liu, S. Perrett, and R. Q. He, BMC Neurosci. 8, 9 (2007).
[CrossRef] [PubMed]

Maslov, K.

S. Hu, K. Maslov, V. Tsytsarev, and L. V. Wang, J. Biomed. Opt. 14, 040503 (2009).
[CrossRef] [PubMed]

S. Hu, K. Maslov, and L. V. Wang, Med. Phys. 36, 2320 (2009).
[CrossRef] [PubMed]

Mathis, C. A.

W. E. Klunk, B. J. Bacskai, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, J. Neuropathol. Exp. Neurol. 61, 797 (2002).
[PubMed]

McLellan, M. E.

W. E. Klunk, B. J. Bacskai, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, J. Neuropathol. Exp. Neurol. 61, 797 (2002).
[PubMed]

Neumann, U.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, Nat. Biotechnol. 23, 577 (2005).
[CrossRef] [PubMed]

Nie, C. L.

C. L. Nie, X. S. Wang, Y. Liu, S. Perrett, and R. Q. He, BMC Neurosci. 8, 9 (2007).
[CrossRef] [PubMed]

Pan, F.

H. T. Xu, F. Pan, G. Yang, and W. B. Gan, Nat. Neurosci. 10, 549 (2007).
[CrossRef] [PubMed]

Perrett, S.

C. L. Nie, X. S. Wang, Y. Liu, S. Perrett, and R. Q. He, BMC Neurosci. 8, 9 (2007).
[CrossRef] [PubMed]

Pike, V. W.

C. Wu, V. W. Pike, and Y. Wang, Curr. Top Dev. Biol. 70, 171 (2005).
[CrossRef] [PubMed]

Prahl, S. A.

S. L. Jacques and S. A. Prahl, http://omlc.ogi.edu/spectra/hemoglobin/index. html, retrieved November 16, 2009.

Rudin, M.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, Nat. Biotechnol. 23, 577 (2005).
[CrossRef] [PubMed]

Staufenbiel, M.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, Nat. Biotechnol. 23, 577 (2005).
[CrossRef] [PubMed]

Stoeckli, M.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, Nat. Biotechnol. 23, 577 (2005).
[CrossRef] [PubMed]

Tsytsarev, V.

S. Hu, K. Maslov, V. Tsytsarev, and L. V. Wang, J. Biomed. Opt. 14, 040503 (2009).
[CrossRef] [PubMed]

Wang, L. V.

S. Hu, K. Maslov, V. Tsytsarev, and L. V. Wang, J. Biomed. Opt. 14, 040503 (2009).
[CrossRef] [PubMed]

S. Hu, K. Maslov, and L. V. Wang, Med. Phys. 36, 2320 (2009).
[CrossRef] [PubMed]

Wang, X. S.

C. L. Nie, X. S. Wang, Y. Liu, S. Perrett, and R. Q. He, BMC Neurosci. 8, 9 (2007).
[CrossRef] [PubMed]

Wang, Y.

P. Yan, A. W. Bero, J. R. Cirrito, Q. Xiao, X. Hu, Y. Wang, E. Gonzales, D. M. Holtzman, and J. M. Lee, J. Neurosci. 29, 10706 (2009).
[CrossRef] [PubMed]

C. Wu, V. W. Pike, and Y. Wang, Curr. Top Dev. Biol. 70, 171 (2005).
[CrossRef] [PubMed]

W. E. Klunk, B. J. Bacskai, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, J. Neuropathol. Exp. Neurol. 61, 797 (2002).
[PubMed]

Wiederhold, K. H.

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, Nat. Biotechnol. 23, 577 (2005).
[CrossRef] [PubMed]

Wu, C.

C. Wu, V. W. Pike, and Y. Wang, Curr. Top Dev. Biol. 70, 171 (2005).
[CrossRef] [PubMed]

Xiao, Q.

P. Yan, A. W. Bero, J. R. Cirrito, Q. Xiao, X. Hu, Y. Wang, E. Gonzales, D. M. Holtzman, and J. M. Lee, J. Neurosci. 29, 10706 (2009).
[CrossRef] [PubMed]

Xu, H. T.

H. T. Xu, F. Pan, G. Yang, and W. B. Gan, Nat. Neurosci. 10, 549 (2007).
[CrossRef] [PubMed]

Yan, P.

P. Yan, A. W. Bero, J. R. Cirrito, Q. Xiao, X. Hu, Y. Wang, E. Gonzales, D. M. Holtzman, and J. M. Lee, J. Neurosci. 29, 10706 (2009).
[CrossRef] [PubMed]

Yang, G.

H. T. Xu, F. Pan, G. Yang, and W. B. Gan, Nat. Neurosci. 10, 549 (2007).
[CrossRef] [PubMed]

BMC Neurosci. (1)

C. L. Nie, X. S. Wang, Y. Liu, S. Perrett, and R. Q. He, BMC Neurosci. 8, 9 (2007).
[CrossRef] [PubMed]

Curr. Top Dev. Biol. (1)

C. Wu, V. W. Pike, and Y. Wang, Curr. Top Dev. Biol. 70, 171 (2005).
[CrossRef] [PubMed]

J. Biomed. Opt. (1)

S. Hu, K. Maslov, V. Tsytsarev, and L. V. Wang, J. Biomed. Opt. 14, 040503 (2009).
[CrossRef] [PubMed]

J. Neuropathol. Exp. Neurol. (1)

W. E. Klunk, B. J. Bacskai, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, J. Neuropathol. Exp. Neurol. 61, 797 (2002).
[PubMed]

J. Neurosci. (1)

P. Yan, A. W. Bero, J. R. Cirrito, Q. Xiao, X. Hu, Y. Wang, E. Gonzales, D. M. Holtzman, and J. M. Lee, J. Neurosci. 29, 10706 (2009).
[CrossRef] [PubMed]

Med. Phys. (1)

S. Hu, K. Maslov, and L. V. Wang, Med. Phys. 36, 2320 (2009).
[CrossRef] [PubMed]

Nat. Biotechnol. (1)

M. Hintersteiner, A. Enz, P. Frey, A. L. Jaton, W. Kinzy, R. Kneuer, U. Neumann, M. Rudin, M. Staufenbiel, M. Stoeckli, K. H. Wiederhold, and H. U. Gremlich, Nat. Biotechnol. 23, 577 (2005).
[CrossRef] [PubMed]

Nat. Neurosci. (1)

H. T. Xu, F. Pan, G. Yang, and W. B. Gan, Nat. Neurosci. 10, 549 (2007).
[CrossRef] [PubMed]

Other (1)

S. L. Jacques and S. A. Prahl, http://omlc.ogi.edu/spectra/hemoglobin/index. html, retrieved November 16, 2009.

Supplementary Material (1)

» Media 1: AVI (4634 KB)     

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Figures (3)

Fig. 1
Fig. 1

Schematic of the optical-resolution photoacoustic microscope for amyloid plaque imaging. OR-PAM imaging and multiphoton imaging were performed through a cranial window preparation (inset).

Fig. 2
Fig. 2

In vitro imaging of a Congo-red-stained brain section from a 10 -month -old APP/PS1 mouse; (A) entire hippocampus imaged using conventional fluorescence microscopy; (B) region of interest selected from the boxed area in (A); (C) same region of interest imaged by OR-PAM for comparison. Arrows, plaques. Scale bar in (A) applies to all three parts.

Fig. 3
Fig. 3

In vivo brain imaging of a Congo-red-injected 10 -month -old APP/PS1 mouse through a cranial window. (A) Exposed cortical brain region imaged using conventional fluorescence microscopy through the cranial window. The region of interest marked by a red dashed box was imaged by multiphoton microscopy in (B), and OR-PAM at 570 nm in (C) and 523 nm in (D). (E) The processed dual-contrast OR-PAM image, where amyloid plaques are colored green (online) and blood vessels are colored red (online) [volumetric visualization is available online as (Media 1)]. Arrows, plaques. Scale bar in (B) applies to parts (B)–(E).

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