Abstract

Multicolor fluorescence imaging has been widely used by neuroscientists to simultaneously observe different neuropathological features of the brain. However, these optical modalities rely on exogenous labeling. Here, we demonstrate, for the first time, a label-free additive-color multi-harmonic generation microscopy to elucidate, concurrently with different hues, Alzheimer’s disease (AD) neuropathological hallmarks: amyloid β (Aβ) plaques and neurofibrillary tangles (NFT). By treating third harmonic generation (THG) and second harmonic generation (SHG) as two primary colors, our study can simultaneously label-free differentiate AD hallmarks by providing different additive colors between Aβ plaques, NFT, and neuronal axons, with weaker THG presentation from NFT in most places of the brain. Interestingly our pixel-based quantification and Pearson’s correlation results further corroborated these findings. Our proposed label-free technique fulfills the unmet challenge in the clinical histopathology for stain-free slide-free differential visualization of neurodegenerative disease pathologies, with a sub-femtoliter resolution in a single image field-of-view.

© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

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References

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  1. J. W. Lichtman and W. Denk, “The big and the small: challenges of imaging the brain’s circuits,” Science 334(6056), 618–623 (2011).
    [Crossref]
  2. N. Yamamoto, H. Tsuchiya, and R. M. Hoffman, “Tumor imaging with multicolor fluorescent protein expression,” Int. J. Clin. Oncol. 16(2), 84–91 (2011).
    [Crossref]
  3. J. Licea-Rodriguez, A. Figueroa-Melendez, K. Falaggis, M. P. Sanchez, M. Riquelme, and I. Rocha-Mendoza, “Multicolor fluorescence microscopy using static light sheets and a single channel detection,” J. Biomed. Opt. 24(01), 1 (2019).
    [Crossref]
  4. T. A. Weissman and Y. A. Pan, “Brainbow: new resources and emerging applications for multicolor genetic labeling and analysis,” Genetics 199(2), 293–306 (2015).
    [Crossref]
  5. S. Love, “Neuropathological investigation of dementia: A guide for neurologists,” J. Neurol., Neurosurg. Psychiatry 76(suppl_5), v8–v14 (2005).
    [Crossref]
  6. A. Burns and S. Iliffe, “Alzheimer’s disease,” BMJ 338, b158 (2009).
    [Crossref]
  7. J. H. Dowson, “A sensitive method for demonstration of senile plaques in the dementing brain,” Histopathology 5(3), 305–310 (1981).
    [Crossref]
  8. D. R. Thal, E. Ghebremedhin, C. Haass, and C. Schultz, “UV light-induced autofluorescence of full-length abeta-protein deposits in the human brain,” Clin. Neuropathol. 21(1), 35–40 (2002).
  9. M. Diez, “Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein-initial observations,” Neuroscience 100(2), 259–286 (2000).
    [Crossref]
  10. W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. 100(12), 7075–7080 (2003).
    [Crossref]
  11. R. Micheal, A. Lenferink, G. F. J. M. Vrensen, E. Gelpi, R. I. Barraquer, and C. Otto, “Hyperspectral Raman imaging of neuritic plaques and neurofibrillary tangles in brain tissue from Alzheimer’s disease patients,” Sci. Rep. 7(1), 15603 (2017).
    [Crossref]
  12. J. Kiskis, H. Fink, L. Nyberg, J. Thyr, J.-Y. Li, and A. Enejder, “Plaque-associated lipids in Alzheimer’s diseased brain tissue visualized by nonlinear microscopy,” Sci. Rep. 5(1), 13489 (2015).
    [Crossref]
  13. B. Baumann, A. Woehrer, G. Ricken, M. Augustin, C. Mitter, M. Pircher, G. G. Kovacs, and C. K. Hitzenberger, “Visualization of neuritic plaques in Alzheimer’s disease by polarization-sensitive optical coherence microscopy,” Sci. Rep. 7(1), 43477 (2017).
    [Crossref]
  14. C.-K. Sun, “Higher Harmonic Generation Microscopy,” J. Struct. Biol. 147(1), 19–30 (2004).
    [Crossref]
  15. B. Weiglein, G.-J. Bakker, and P. Friedl, “Third harmonic generation microscopy of cells and tissue organization,” J. Cell Sci. 129(2), 245–255 (2016).
    [Crossref]
  16. S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
    [Crossref]
  17. P. Campagnola, “Second harmonic generation imaging microscopy: applications to disease diagnostics,” Anal. Chem. 83(9), 3224–3231 (2011).
    [Crossref]
  18. G.-F. Chen, “Amyloid beta: structure, biology and structure-based therapeutic development,” Acta Pharmacol. Sin. 38(9), 1205–1235 (2017).
    [Crossref]
  19. V. Daebel, S. Chinnathambi, J. Biernat, M. Schwalbe, B. Habenstein, A. Loquet, E. Akoury, K. Tepper, H. Muller, M. Baldus, C. Griesinger, M. Zweckstetter, E. Mandelkow, V. Vijayan, and A. Lange, “β-sheet core of tau paired helical filaments revealed by solid-state NMR,” J. Am. Chem. Soc. 134(34), 13982–13989 (2012).
    [Crossref]
  20. A. C. Kwan, K. Duff, G. K. Gouras, and W. W. Webb, “Optical visualization of Alzheimer’s pathology via multiphoton excited intrinsic fluorescence and second harmonic generation,” Opt. Express 17(5), 3679–3689 (2009).
    [Crossref]
  21. W. H. Stoothoff, B. J. Bacskai, and B. T. Hyman, “Monitoring tau-tubulin interactions utilizing second harmonic generation in living neurons,” J. Biomed. Opt. 13(6), 064039 (2008).
    [Crossref]
  22. Y.-C. Chen, H.-C. Hsu, C.-M. Lee, and C.-K. Sun, “Third harmonic generation susceptibility spectroscopy in free fatty acids,” J. Biomed. Opt. 20(9), 095013 (2015).
    [Crossref]
  23. T.-H. Tsai, S.-P. Tai, W.-J. Lee, H.-Y. Huang, Y.-H. Liao, and C.-K. Sun, “Optical signal degradation study in fixed human skin using confocal microscopy and higher-harmonic optical microscopy,” Opt. Express 14(2), 749–758 (2006).
    [Crossref]
  24. C.-K. Sun, C.-T. Kao, M.-L. Wei, S.-H. Chia, F. X. Kärtner, A. Ivanov, and Y.-H. Liao, “Slide-free imaging of hematoxylin-eosin stained whole-mount tissues using combined third-harmonic generation and three-photon fluorescence microscopy,” J. Biophotonics 12(5), e201800341 (2019).
    [Crossref]
  25. M.-R. Tsai, S.-Y. Chen, D.-B. Shieh, P.-J. Lou, and C.-K. Sun, “In vivo optical biopsy of human oral mucosa with harmonic generation microscopy,” Biomed. Opt. Express 2(8), 2317–2328 (2011).
    [Crossref]
  26. S. Witte, A. Negrean, J. C. Lodder, C. P. J. de Kock, G. T. Silva, H. D. Mansvelder, and M. L. Groot, “Label-free live brain imaging and targeted patching with third-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 108(15), 5970–5975 (2011).
    [Crossref]
  27. N. V. Kuzmin, P. Wesseling, P. C. de Witt Hamer, D. P. Noske, G. D. galgano, H. D. Mansvelder, J. C. Baayen, and M. L. Groot, “Third harmonic generation imaging for fast, label-free pathology of human brain tumors,” Biomed. Opt. Express 7(5), 1889–1904 (2016).
    [Crossref]
  28. C.-F. Chang, H.-C. Chen, M.-J. Chen, W.-R. Liu, W.-F. Hsieh, C.-H. Hsu, C.-Y. Chen, F.-H. Chang, C.-H. Yu, and C.-K. Sun, “Direct backward third-harmonic generation in nanostructures,” Opt. Express 18(7), 7397–7406 (2010).
    [Crossref]
  29. N. Matuschek, F. X. Kartner, and U. Keller, “Theory of double-chirped mirrors,” IEEE J. Select. Topics Quantum Electron. 4(2), 197–208 (1998).
    [Crossref]
  30. D. E. Hinkel, W. Wiersma, and S. G. Jurs, Applied Statistics for the Behavioral Sciences, 2nd ed., (Houghton Mifflin Co.1988).
  31. R. Sterniczuk, M. C. Antle, R. Laferla, and R. H. Dyck, “Characterization of the 3xTg-AD mouse model of Alzheimer’s disease: Part 2. Behavioral and cognitive changes,” Brain Res. 1348, 149–155 (2010).
    [Crossref]
  32. D. P. Brown, M. A. Walker, A. M. Urbas, A. V. Kildishev, S. Xiao, and V. Drachev, “Direct measurement of group delay dispersion in metamagnetics for ultrafast pulse shaping,” Opt. Express 20(21), 23082–23087 (2012).
    [Crossref]
  33. “Technical note: The effect of dispersion on ultrashort pulses”, https://www.newport.com/n/the-effect-of-dispersion-on-ultrashort-pulses (as accessed on 14th November, 2019).
  34. D. J. Kane and R. Trebino, “Characterization of arbitrary femtosecond pulses using frequency-resolved optical gating,” IEEE J. Quantum Electron. 29(2), 571–579 (1993).
    [Crossref]
  35. B. Liu, E. A. Macdonald, D. L. Stamper, and M. E. Brezinski, “Group velocity dispersion effects with water and lipid in 1.3 µm optical coherence tomography system,” Phys. Med. Biol. 49(6), 923–930 (2004).
    [Crossref]
  36. G. M. Hale and M. R. Querry, “Optical constants of water in the 200-nm to 200-µm wavelength region,” Appl. Opt. 12(3), 555–563 (1973).
    [Crossref]
  37. D. Kobat, D. E. Michael, N. Nishimura, A. W. Wong, C. B. Schaffer, and C. Xu, “Deep tissue multiphoton microscopy using longer wavelength excitation,” Opt. Express 17(16), 13354–13364 (2009).
    [Crossref]
  38. C.-K. Sun, S.-W. Chu, S.-Y. Chen, T.-H. Tsai, T.-M. Liu, C.-Y. Lin, and H.-J. Tsai, “Higher harmonic generation microscopy for developmental biology,” J. Struct. Biol. 147(1), 19–30 (2004).
    [Crossref]
  39. S.-Y. Chen, C.-S. Hsieh, S.-W. Chu, C.-Y. Lin, C.-Y. Ko, Y.-C. Chen, H.-J. Tsai, C.-H. Hu, and C.-K. Sun, “Noninvasive harmonics optical microscopy for long-term observation of embryonic nervous system development in vivo,” J. Biomed. Opt. 11(5), 054022 (2006).
    [Crossref]
  40. S.-P. Tai, W.-J. Lee, D.-B. Shieh, P.-C. Wu, H.-Y. Huang, C.-H. Yu, and C.-K. Sun, “In vivo optical biopsy of hamster oral cavity with epi-third-harmonic-generation microscopy,” Opt. Express 14(13), 6178–6187 (2006).
    [Crossref]
  41. L. Kou, D. Labrie, and P. Chýlek, “Refractive indices of water and ice the 0.65- to 2.5-µm spectral range,” Appl. Opt. 32(19), 3531–3540 (1993).
    [Crossref]
  42. Y.-H. Liao, Y.-H. Su, Y.-T. Shih, W.-S. Chen, S.-H. Jee, and C.-K. Sun, “In vivo third-harmonic generation microscopy study on vitiligo patients,” J. Biomed. Opt. 25(1), 014504 (2019).
    [Crossref]
  43. S.-Y. Chen, S.-U. Chen, H.-Y. Wu, W.-J. Lee, Y.-H. Liao, and C.-K. Sun, “In vivo virtual biopsy of human skin by using noninvasive higher harmonic generation microscopy,” IEEE J. Sel. Top. Quantum Electron. 16(3), 478–492 (2010).
    [Crossref]
  44. S. E. Crowe and G. C. R. Ellis-Davies, “In vivo charactierization of a bigenic fluorescent mouse models of Alzheimer’s disease with neurodegeneration,” J. Comp. Neurol. 521(10), 2181–2194 (2013).
    [Crossref]
  45. E. Drummond and T. Wisniewski, “Alzheimer’s disease: experimental models and reality,” Acta Neuropathol. 133(2), 155–175 (2017).
    [Crossref]
  46. W. E. Klunk, B. J. Bacskal, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, “Imaging Aβ plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered congo red derivative,” J. Neuropathol. Exp. Neurol. 61(9), 797–805 (2002).
    [Crossref]
  47. S.-Y. Chen, H.-Y. Wu, and C.-K. Sun, “In vivo harmonic generation biopsy of human skin,” J. Biomed. Opt. 14(6), 060505 (2009).
    [Crossref]
  48. M. J. Farrar, E. W. Wise, J. R. Fetcho, and C. B. Schaffer, “In vivo imaging of myelin in the vertebrate central nervous system using third harmonic generation microscopy,” Biophys. J. 100(5), 1362–1371 (2011).
    [Crossref]
  49. D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernandez, Y.-T. Cheng, J. Reimer, A. S. Tolias, N. Nishimura, and C. Xu, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
    [Crossref]

2019 (3)

J. Licea-Rodriguez, A. Figueroa-Melendez, K. Falaggis, M. P. Sanchez, M. Riquelme, and I. Rocha-Mendoza, “Multicolor fluorescence microscopy using static light sheets and a single channel detection,” J. Biomed. Opt. 24(01), 1 (2019).
[Crossref]

C.-K. Sun, C.-T. Kao, M.-L. Wei, S.-H. Chia, F. X. Kärtner, A. Ivanov, and Y.-H. Liao, “Slide-free imaging of hematoxylin-eosin stained whole-mount tissues using combined third-harmonic generation and three-photon fluorescence microscopy,” J. Biophotonics 12(5), e201800341 (2019).
[Crossref]

Y.-H. Liao, Y.-H. Su, Y.-T. Shih, W.-S. Chen, S.-H. Jee, and C.-K. Sun, “In vivo third-harmonic generation microscopy study on vitiligo patients,” J. Biomed. Opt. 25(1), 014504 (2019).
[Crossref]

2017 (5)

E. Drummond and T. Wisniewski, “Alzheimer’s disease: experimental models and reality,” Acta Neuropathol. 133(2), 155–175 (2017).
[Crossref]

D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernandez, Y.-T. Cheng, J. Reimer, A. S. Tolias, N. Nishimura, and C. Xu, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
[Crossref]

G.-F. Chen, “Amyloid beta: structure, biology and structure-based therapeutic development,” Acta Pharmacol. Sin. 38(9), 1205–1235 (2017).
[Crossref]

R. Micheal, A. Lenferink, G. F. J. M. Vrensen, E. Gelpi, R. I. Barraquer, and C. Otto, “Hyperspectral Raman imaging of neuritic plaques and neurofibrillary tangles in brain tissue from Alzheimer’s disease patients,” Sci. Rep. 7(1), 15603 (2017).
[Crossref]

B. Baumann, A. Woehrer, G. Ricken, M. Augustin, C. Mitter, M. Pircher, G. G. Kovacs, and C. K. Hitzenberger, “Visualization of neuritic plaques in Alzheimer’s disease by polarization-sensitive optical coherence microscopy,” Sci. Rep. 7(1), 43477 (2017).
[Crossref]

2016 (2)

2015 (3)

Y.-C. Chen, H.-C. Hsu, C.-M. Lee, and C.-K. Sun, “Third harmonic generation susceptibility spectroscopy in free fatty acids,” J. Biomed. Opt. 20(9), 095013 (2015).
[Crossref]

J. Kiskis, H. Fink, L. Nyberg, J. Thyr, J.-Y. Li, and A. Enejder, “Plaque-associated lipids in Alzheimer’s diseased brain tissue visualized by nonlinear microscopy,” Sci. Rep. 5(1), 13489 (2015).
[Crossref]

T. A. Weissman and Y. A. Pan, “Brainbow: new resources and emerging applications for multicolor genetic labeling and analysis,” Genetics 199(2), 293–306 (2015).
[Crossref]

2013 (1)

S. E. Crowe and G. C. R. Ellis-Davies, “In vivo charactierization of a bigenic fluorescent mouse models of Alzheimer’s disease with neurodegeneration,” J. Comp. Neurol. 521(10), 2181–2194 (2013).
[Crossref]

2012 (2)

V. Daebel, S. Chinnathambi, J. Biernat, M. Schwalbe, B. Habenstein, A. Loquet, E. Akoury, K. Tepper, H. Muller, M. Baldus, C. Griesinger, M. Zweckstetter, E. Mandelkow, V. Vijayan, and A. Lange, “β-sheet core of tau paired helical filaments revealed by solid-state NMR,” J. Am. Chem. Soc. 134(34), 13982–13989 (2012).
[Crossref]

D. P. Brown, M. A. Walker, A. M. Urbas, A. V. Kildishev, S. Xiao, and V. Drachev, “Direct measurement of group delay dispersion in metamagnetics for ultrafast pulse shaping,” Opt. Express 20(21), 23082–23087 (2012).
[Crossref]

2011 (6)

M.-R. Tsai, S.-Y. Chen, D.-B. Shieh, P.-J. Lou, and C.-K. Sun, “In vivo optical biopsy of human oral mucosa with harmonic generation microscopy,” Biomed. Opt. Express 2(8), 2317–2328 (2011).
[Crossref]

S. Witte, A. Negrean, J. C. Lodder, C. P. J. de Kock, G. T. Silva, H. D. Mansvelder, and M. L. Groot, “Label-free live brain imaging and targeted patching with third-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 108(15), 5970–5975 (2011).
[Crossref]

J. W. Lichtman and W. Denk, “The big and the small: challenges of imaging the brain’s circuits,” Science 334(6056), 618–623 (2011).
[Crossref]

N. Yamamoto, H. Tsuchiya, and R. M. Hoffman, “Tumor imaging with multicolor fluorescent protein expression,” Int. J. Clin. Oncol. 16(2), 84–91 (2011).
[Crossref]

P. Campagnola, “Second harmonic generation imaging microscopy: applications to disease diagnostics,” Anal. Chem. 83(9), 3224–3231 (2011).
[Crossref]

M. J. Farrar, E. W. Wise, J. R. Fetcho, and C. B. Schaffer, “In vivo imaging of myelin in the vertebrate central nervous system using third harmonic generation microscopy,” Biophys. J. 100(5), 1362–1371 (2011).
[Crossref]

2010 (3)

R. Sterniczuk, M. C. Antle, R. Laferla, and R. H. Dyck, “Characterization of the 3xTg-AD mouse model of Alzheimer’s disease: Part 2. Behavioral and cognitive changes,” Brain Res. 1348, 149–155 (2010).
[Crossref]

S.-Y. Chen, S.-U. Chen, H.-Y. Wu, W.-J. Lee, Y.-H. Liao, and C.-K. Sun, “In vivo virtual biopsy of human skin by using noninvasive higher harmonic generation microscopy,” IEEE J. Sel. Top. Quantum Electron. 16(3), 478–492 (2010).
[Crossref]

C.-F. Chang, H.-C. Chen, M.-J. Chen, W.-R. Liu, W.-F. Hsieh, C.-H. Hsu, C.-Y. Chen, F.-H. Chang, C.-H. Yu, and C.-K. Sun, “Direct backward third-harmonic generation in nanostructures,” Opt. Express 18(7), 7397–7406 (2010).
[Crossref]

2009 (4)

2008 (1)

W. H. Stoothoff, B. J. Bacskai, and B. T. Hyman, “Monitoring tau-tubulin interactions utilizing second harmonic generation in living neurons,” J. Biomed. Opt. 13(6), 064039 (2008).
[Crossref]

2006 (3)

2005 (1)

S. Love, “Neuropathological investigation of dementia: A guide for neurologists,” J. Neurol., Neurosurg. Psychiatry 76(suppl_5), v8–v14 (2005).
[Crossref]

2004 (3)

C.-K. Sun, “Higher Harmonic Generation Microscopy,” J. Struct. Biol. 147(1), 19–30 (2004).
[Crossref]

C.-K. Sun, S.-W. Chu, S.-Y. Chen, T.-H. Tsai, T.-M. Liu, C.-Y. Lin, and H.-J. Tsai, “Higher harmonic generation microscopy for developmental biology,” J. Struct. Biol. 147(1), 19–30 (2004).
[Crossref]

B. Liu, E. A. Macdonald, D. L. Stamper, and M. E. Brezinski, “Group velocity dispersion effects with water and lipid in 1.3 µm optical coherence tomography system,” Phys. Med. Biol. 49(6), 923–930 (2004).
[Crossref]

2003 (1)

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. 100(12), 7075–7080 (2003).
[Crossref]

2002 (3)

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[Crossref]

D. R. Thal, E. Ghebremedhin, C. Haass, and C. Schultz, “UV light-induced autofluorescence of full-length abeta-protein deposits in the human brain,” Clin. Neuropathol. 21(1), 35–40 (2002).

W. E. Klunk, B. J. Bacskal, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, “Imaging Aβ plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered congo red derivative,” J. Neuropathol. Exp. Neurol. 61(9), 797–805 (2002).
[Crossref]

2000 (1)

M. Diez, “Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein-initial observations,” Neuroscience 100(2), 259–286 (2000).
[Crossref]

1998 (1)

N. Matuschek, F. X. Kartner, and U. Keller, “Theory of double-chirped mirrors,” IEEE J. Select. Topics Quantum Electron. 4(2), 197–208 (1998).
[Crossref]

1993 (2)

D. J. Kane and R. Trebino, “Characterization of arbitrary femtosecond pulses using frequency-resolved optical gating,” IEEE J. Quantum Electron. 29(2), 571–579 (1993).
[Crossref]

L. Kou, D. Labrie, and P. Chýlek, “Refractive indices of water and ice the 0.65- to 2.5-µm spectral range,” Appl. Opt. 32(19), 3531–3540 (1993).
[Crossref]

1981 (1)

J. H. Dowson, “A sensitive method for demonstration of senile plaques in the dementing brain,” Histopathology 5(3), 305–310 (1981).
[Crossref]

1973 (1)

Akoury, E.

V. Daebel, S. Chinnathambi, J. Biernat, M. Schwalbe, B. Habenstein, A. Loquet, E. Akoury, K. Tepper, H. Muller, M. Baldus, C. Griesinger, M. Zweckstetter, E. Mandelkow, V. Vijayan, and A. Lange, “β-sheet core of tau paired helical filaments revealed by solid-state NMR,” J. Am. Chem. Soc. 134(34), 13982–13989 (2012).
[Crossref]

Antle, M. C.

R. Sterniczuk, M. C. Antle, R. Laferla, and R. H. Dyck, “Characterization of the 3xTg-AD mouse model of Alzheimer’s disease: Part 2. Behavioral and cognitive changes,” Brain Res. 1348, 149–155 (2010).
[Crossref]

Augustin, M.

B. Baumann, A. Woehrer, G. Ricken, M. Augustin, C. Mitter, M. Pircher, G. G. Kovacs, and C. K. Hitzenberger, “Visualization of neuritic plaques in Alzheimer’s disease by polarization-sensitive optical coherence microscopy,” Sci. Rep. 7(1), 43477 (2017).
[Crossref]

Baayen, J. C.

Bacskai, B. J.

W. H. Stoothoff, B. J. Bacskai, and B. T. Hyman, “Monitoring tau-tubulin interactions utilizing second harmonic generation in living neurons,” J. Biomed. Opt. 13(6), 064039 (2008).
[Crossref]

Bacskal, B. J.

W. E. Klunk, B. J. Bacskal, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, “Imaging Aβ plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered congo red derivative,” J. Neuropathol. Exp. Neurol. 61(9), 797–805 (2002).
[Crossref]

Bakker, G.-J.

B. Weiglein, G.-J. Bakker, and P. Friedl, “Third harmonic generation microscopy of cells and tissue organization,” J. Cell Sci. 129(2), 245–255 (2016).
[Crossref]

Baldus, M.

V. Daebel, S. Chinnathambi, J. Biernat, M. Schwalbe, B. Habenstein, A. Loquet, E. Akoury, K. Tepper, H. Muller, M. Baldus, C. Griesinger, M. Zweckstetter, E. Mandelkow, V. Vijayan, and A. Lange, “β-sheet core of tau paired helical filaments revealed by solid-state NMR,” J. Am. Chem. Soc. 134(34), 13982–13989 (2012).
[Crossref]

Barraquer, R. I.

R. Micheal, A. Lenferink, G. F. J. M. Vrensen, E. Gelpi, R. I. Barraquer, and C. Otto, “Hyperspectral Raman imaging of neuritic plaques and neurofibrillary tangles in brain tissue from Alzheimer’s disease patients,” Sci. Rep. 7(1), 15603 (2017).
[Crossref]

Baumann, B.

B. Baumann, A. Woehrer, G. Ricken, M. Augustin, C. Mitter, M. Pircher, G. G. Kovacs, and C. K. Hitzenberger, “Visualization of neuritic plaques in Alzheimer’s disease by polarization-sensitive optical coherence microscopy,” Sci. Rep. 7(1), 43477 (2017).
[Crossref]

Biernat, J.

V. Daebel, S. Chinnathambi, J. Biernat, M. Schwalbe, B. Habenstein, A. Loquet, E. Akoury, K. Tepper, H. Muller, M. Baldus, C. Griesinger, M. Zweckstetter, E. Mandelkow, V. Vijayan, and A. Lange, “β-sheet core of tau paired helical filaments revealed by solid-state NMR,” J. Am. Chem. Soc. 134(34), 13982–13989 (2012).
[Crossref]

Brezinski, M. E.

B. Liu, E. A. Macdonald, D. L. Stamper, and M. E. Brezinski, “Group velocity dispersion effects with water and lipid in 1.3 µm optical coherence tomography system,” Phys. Med. Biol. 49(6), 923–930 (2004).
[Crossref]

Brown, D. P.

Burns, A.

A. Burns and S. Iliffe, “Alzheimer’s disease,” BMJ 338, b158 (2009).
[Crossref]

Campagnola, P.

P. Campagnola, “Second harmonic generation imaging microscopy: applications to disease diagnostics,” Anal. Chem. 83(9), 3224–3231 (2011).
[Crossref]

Chang, C.-F.

Chang, F.-H.

Chen, C.-Y.

Chen, G.-F.

G.-F. Chen, “Amyloid beta: structure, biology and structure-based therapeutic development,” Acta Pharmacol. Sin. 38(9), 1205–1235 (2017).
[Crossref]

Chen, H.-C.

Chen, I.-H.

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[Crossref]

Chen, M.-J.

Chen, S.-U.

S.-Y. Chen, S.-U. Chen, H.-Y. Wu, W.-J. Lee, Y.-H. Liao, and C.-K. Sun, “In vivo virtual biopsy of human skin by using noninvasive higher harmonic generation microscopy,” IEEE J. Sel. Top. Quantum Electron. 16(3), 478–492 (2010).
[Crossref]

Chen, S.-Y.

M.-R. Tsai, S.-Y. Chen, D.-B. Shieh, P.-J. Lou, and C.-K. Sun, “In vivo optical biopsy of human oral mucosa with harmonic generation microscopy,” Biomed. Opt. Express 2(8), 2317–2328 (2011).
[Crossref]

S.-Y. Chen, S.-U. Chen, H.-Y. Wu, W.-J. Lee, Y.-H. Liao, and C.-K. Sun, “In vivo virtual biopsy of human skin by using noninvasive higher harmonic generation microscopy,” IEEE J. Sel. Top. Quantum Electron. 16(3), 478–492 (2010).
[Crossref]

S.-Y. Chen, H.-Y. Wu, and C.-K. Sun, “In vivo harmonic generation biopsy of human skin,” J. Biomed. Opt. 14(6), 060505 (2009).
[Crossref]

S.-Y. Chen, C.-S. Hsieh, S.-W. Chu, C.-Y. Lin, C.-Y. Ko, Y.-C. Chen, H.-J. Tsai, C.-H. Hu, and C.-K. Sun, “Noninvasive harmonics optical microscopy for long-term observation of embryonic nervous system development in vivo,” J. Biomed. Opt. 11(5), 054022 (2006).
[Crossref]

C.-K. Sun, S.-W. Chu, S.-Y. Chen, T.-H. Tsai, T.-M. Liu, C.-Y. Lin, and H.-J. Tsai, “Higher harmonic generation microscopy for developmental biology,” J. Struct. Biol. 147(1), 19–30 (2004).
[Crossref]

Chen, W.-S.

Y.-H. Liao, Y.-H. Su, Y.-T. Shih, W.-S. Chen, S.-H. Jee, and C.-K. Sun, “In vivo third-harmonic generation microscopy study on vitiligo patients,” J. Biomed. Opt. 25(1), 014504 (2019).
[Crossref]

Chen, Y.-C.

Y.-C. Chen, H.-C. Hsu, C.-M. Lee, and C.-K. Sun, “Third harmonic generation susceptibility spectroscopy in free fatty acids,” J. Biomed. Opt. 20(9), 095013 (2015).
[Crossref]

S.-Y. Chen, C.-S. Hsieh, S.-W. Chu, C.-Y. Lin, C.-Y. Ko, Y.-C. Chen, H.-J. Tsai, C.-H. Hu, and C.-K. Sun, “Noninvasive harmonics optical microscopy for long-term observation of embryonic nervous system development in vivo,” J. Biomed. Opt. 11(5), 054022 (2006).
[Crossref]

Cheng, P.-C.

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[Crossref]

Cheng, Y.-T.

D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernandez, Y.-T. Cheng, J. Reimer, A. S. Tolias, N. Nishimura, and C. Xu, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
[Crossref]

Chia, S.-H.

C.-K. Sun, C.-T. Kao, M.-L. Wei, S.-H. Chia, F. X. Kärtner, A. Ivanov, and Y.-H. Liao, “Slide-free imaging of hematoxylin-eosin stained whole-mount tissues using combined third-harmonic generation and three-photon fluorescence microscopy,” J. Biophotonics 12(5), e201800341 (2019).
[Crossref]

Chinnathambi, S.

V. Daebel, S. Chinnathambi, J. Biernat, M. Schwalbe, B. Habenstein, A. Loquet, E. Akoury, K. Tepper, H. Muller, M. Baldus, C. Griesinger, M. Zweckstetter, E. Mandelkow, V. Vijayan, and A. Lange, “β-sheet core of tau paired helical filaments revealed by solid-state NMR,” J. Am. Chem. Soc. 134(34), 13982–13989 (2012).
[Crossref]

Christie, R.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. 100(12), 7075–7080 (2003).
[Crossref]

Chu, S.-W.

S.-Y. Chen, C.-S. Hsieh, S.-W. Chu, C.-Y. Lin, C.-Y. Ko, Y.-C. Chen, H.-J. Tsai, C.-H. Hu, and C.-K. Sun, “Noninvasive harmonics optical microscopy for long-term observation of embryonic nervous system development in vivo,” J. Biomed. Opt. 11(5), 054022 (2006).
[Crossref]

C.-K. Sun, S.-W. Chu, S.-Y. Chen, T.-H. Tsai, T.-M. Liu, C.-Y. Lin, and H.-J. Tsai, “Higher harmonic generation microscopy for developmental biology,” J. Struct. Biol. 147(1), 19–30 (2004).
[Crossref]

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[Crossref]

Chýlek, P.

Crowe, S. E.

S. E. Crowe and G. C. R. Ellis-Davies, “In vivo charactierization of a bigenic fluorescent mouse models of Alzheimer’s disease with neurodegeneration,” J. Comp. Neurol. 521(10), 2181–2194 (2013).
[Crossref]

Cruz-Hernandez, J. C.

D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernandez, Y.-T. Cheng, J. Reimer, A. S. Tolias, N. Nishimura, and C. Xu, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
[Crossref]

Daebel, V.

V. Daebel, S. Chinnathambi, J. Biernat, M. Schwalbe, B. Habenstein, A. Loquet, E. Akoury, K. Tepper, H. Muller, M. Baldus, C. Griesinger, M. Zweckstetter, E. Mandelkow, V. Vijayan, and A. Lange, “β-sheet core of tau paired helical filaments revealed by solid-state NMR,” J. Am. Chem. Soc. 134(34), 13982–13989 (2012).
[Crossref]

de Kock, C. P. J.

S. Witte, A. Negrean, J. C. Lodder, C. P. J. de Kock, G. T. Silva, H. D. Mansvelder, and M. L. Groot, “Label-free live brain imaging and targeted patching with third-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 108(15), 5970–5975 (2011).
[Crossref]

de Witt Hamer, P. C.

Debnath, M. L.

W. E. Klunk, B. J. Bacskal, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, “Imaging Aβ plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered congo red derivative,” J. Neuropathol. Exp. Neurol. 61(9), 797–805 (2002).
[Crossref]

Denk, W.

J. W. Lichtman and W. Denk, “The big and the small: challenges of imaging the brain’s circuits,” Science 334(6056), 618–623 (2011).
[Crossref]

Diez, M.

M. Diez, “Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein-initial observations,” Neuroscience 100(2), 259–286 (2000).
[Crossref]

Dowson, J. H.

J. H. Dowson, “A sensitive method for demonstration of senile plaques in the dementing brain,” Histopathology 5(3), 305–310 (1981).
[Crossref]

Drachev, V.

Drummond, E.

E. Drummond and T. Wisniewski, “Alzheimer’s disease: experimental models and reality,” Acta Neuropathol. 133(2), 155–175 (2017).
[Crossref]

Duff, K.

Dyck, R. H.

R. Sterniczuk, M. C. Antle, R. Laferla, and R. H. Dyck, “Characterization of the 3xTg-AD mouse model of Alzheimer’s disease: Part 2. Behavioral and cognitive changes,” Brain Res. 1348, 149–155 (2010).
[Crossref]

Ellis-Davies, G. C. R.

S. E. Crowe and G. C. R. Ellis-Davies, “In vivo charactierization of a bigenic fluorescent mouse models of Alzheimer’s disease with neurodegeneration,” J. Comp. Neurol. 521(10), 2181–2194 (2013).
[Crossref]

Enejder, A.

J. Kiskis, H. Fink, L. Nyberg, J. Thyr, J.-Y. Li, and A. Enejder, “Plaque-associated lipids in Alzheimer’s diseased brain tissue visualized by nonlinear microscopy,” Sci. Rep. 5(1), 13489 (2015).
[Crossref]

Falaggis, K.

J. Licea-Rodriguez, A. Figueroa-Melendez, K. Falaggis, M. P. Sanchez, M. Riquelme, and I. Rocha-Mendoza, “Multicolor fluorescence microscopy using static light sheets and a single channel detection,” J. Biomed. Opt. 24(01), 1 (2019).
[Crossref]

Farrar, M. J.

M. J. Farrar, E. W. Wise, J. R. Fetcho, and C. B. Schaffer, “In vivo imaging of myelin in the vertebrate central nervous system using third harmonic generation microscopy,” Biophys. J. 100(5), 1362–1371 (2011).
[Crossref]

Feng, D. D.

D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernandez, Y.-T. Cheng, J. Reimer, A. S. Tolias, N. Nishimura, and C. Xu, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
[Crossref]

Fetcho, J. R.

M. J. Farrar, E. W. Wise, J. R. Fetcho, and C. B. Schaffer, “In vivo imaging of myelin in the vertebrate central nervous system using third harmonic generation microscopy,” Biophys. J. 100(5), 1362–1371 (2011).
[Crossref]

Figueroa-Melendez, A.

J. Licea-Rodriguez, A. Figueroa-Melendez, K. Falaggis, M. P. Sanchez, M. Riquelme, and I. Rocha-Mendoza, “Multicolor fluorescence microscopy using static light sheets and a single channel detection,” J. Biomed. Opt. 24(01), 1 (2019).
[Crossref]

Fink, H.

J. Kiskis, H. Fink, L. Nyberg, J. Thyr, J.-Y. Li, and A. Enejder, “Plaque-associated lipids in Alzheimer’s diseased brain tissue visualized by nonlinear microscopy,” Sci. Rep. 5(1), 13489 (2015).
[Crossref]

Friedl, P.

B. Weiglein, G.-J. Bakker, and P. Friedl, “Third harmonic generation microscopy of cells and tissue organization,” J. Cell Sci. 129(2), 245–255 (2016).
[Crossref]

Frosch, M. P.

W. E. Klunk, B. J. Bacskal, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, “Imaging Aβ plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered congo red derivative,” J. Neuropathol. Exp. Neurol. 61(9), 797–805 (2002).
[Crossref]

galgano, G. D.

Gelpi, E.

R. Micheal, A. Lenferink, G. F. J. M. Vrensen, E. Gelpi, R. I. Barraquer, and C. Otto, “Hyperspectral Raman imaging of neuritic plaques and neurofibrillary tangles in brain tissue from Alzheimer’s disease patients,” Sci. Rep. 7(1), 15603 (2017).
[Crossref]

Ghebremedhin, E.

D. R. Thal, E. Ghebremedhin, C. Haass, and C. Schultz, “UV light-induced autofluorescence of full-length abeta-protein deposits in the human brain,” Clin. Neuropathol. 21(1), 35–40 (2002).

Gouras, G. K.

Griesinger, C.

V. Daebel, S. Chinnathambi, J. Biernat, M. Schwalbe, B. Habenstein, A. Loquet, E. Akoury, K. Tepper, H. Muller, M. Baldus, C. Griesinger, M. Zweckstetter, E. Mandelkow, V. Vijayan, and A. Lange, “β-sheet core of tau paired helical filaments revealed by solid-state NMR,” J. Am. Chem. Soc. 134(34), 13982–13989 (2012).
[Crossref]

Groot, M. L.

N. V. Kuzmin, P. Wesseling, P. C. de Witt Hamer, D. P. Noske, G. D. galgano, H. D. Mansvelder, J. C. Baayen, and M. L. Groot, “Third harmonic generation imaging for fast, label-free pathology of human brain tumors,” Biomed. Opt. Express 7(5), 1889–1904 (2016).
[Crossref]

S. Witte, A. Negrean, J. C. Lodder, C. P. J. de Kock, G. T. Silva, H. D. Mansvelder, and M. L. Groot, “Label-free live brain imaging and targeted patching with third-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 108(15), 5970–5975 (2011).
[Crossref]

Haass, C.

D. R. Thal, E. Ghebremedhin, C. Haass, and C. Schultz, “UV light-induced autofluorescence of full-length abeta-protein deposits in the human brain,” Clin. Neuropathol. 21(1), 35–40 (2002).

Habenstein, B.

V. Daebel, S. Chinnathambi, J. Biernat, M. Schwalbe, B. Habenstein, A. Loquet, E. Akoury, K. Tepper, H. Muller, M. Baldus, C. Griesinger, M. Zweckstetter, E. Mandelkow, V. Vijayan, and A. Lange, “β-sheet core of tau paired helical filaments revealed by solid-state NMR,” J. Am. Chem. Soc. 134(34), 13982–13989 (2012).
[Crossref]

Hale, G. M.

Hinkel, D. E.

D. E. Hinkel, W. Wiersma, and S. G. Jurs, Applied Statistics for the Behavioral Sciences, 2nd ed., (Houghton Mifflin Co.1988).

Hitzenberger, C. K.

B. Baumann, A. Woehrer, G. Ricken, M. Augustin, C. Mitter, M. Pircher, G. G. Kovacs, and C. K. Hitzenberger, “Visualization of neuritic plaques in Alzheimer’s disease by polarization-sensitive optical coherence microscopy,” Sci. Rep. 7(1), 43477 (2017).
[Crossref]

Hoffman, R. M.

N. Yamamoto, H. Tsuchiya, and R. M. Hoffman, “Tumor imaging with multicolor fluorescent protein expression,” Int. J. Clin. Oncol. 16(2), 84–91 (2011).
[Crossref]

Holt, D. P.

W. E. Klunk, B. J. Bacskal, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, “Imaging Aβ plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered congo red derivative,” J. Neuropathol. Exp. Neurol. 61(9), 797–805 (2002).
[Crossref]

Horton, N. G.

D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernandez, Y.-T. Cheng, J. Reimer, A. S. Tolias, N. Nishimura, and C. Xu, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
[Crossref]

Hsieh, C.-S.

S.-Y. Chen, C.-S. Hsieh, S.-W. Chu, C.-Y. Lin, C.-Y. Ko, Y.-C. Chen, H.-J. Tsai, C.-H. Hu, and C.-K. Sun, “Noninvasive harmonics optical microscopy for long-term observation of embryonic nervous system development in vivo,” J. Biomed. Opt. 11(5), 054022 (2006).
[Crossref]

Hsieh, W.-F.

Hsu, C.-H.

Hsu, H.-C.

Y.-C. Chen, H.-C. Hsu, C.-M. Lee, and C.-K. Sun, “Third harmonic generation susceptibility spectroscopy in free fatty acids,” J. Biomed. Opt. 20(9), 095013 (2015).
[Crossref]

Hu, C.-H.

S.-Y. Chen, C.-S. Hsieh, S.-W. Chu, C.-Y. Lin, C.-Y. Ko, Y.-C. Chen, H.-J. Tsai, C.-H. Hu, and C.-K. Sun, “Noninvasive harmonics optical microscopy for long-term observation of embryonic nervous system development in vivo,” J. Biomed. Opt. 11(5), 054022 (2006).
[Crossref]

Huang, H.-Y.

Hyman, B. T.

W. H. Stoothoff, B. J. Bacskai, and B. T. Hyman, “Monitoring tau-tubulin interactions utilizing second harmonic generation in living neurons,” J. Biomed. Opt. 13(6), 064039 (2008).
[Crossref]

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. 100(12), 7075–7080 (2003).
[Crossref]

W. E. Klunk, B. J. Bacskal, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, “Imaging Aβ plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered congo red derivative,” J. Neuropathol. Exp. Neurol. 61(9), 797–805 (2002).
[Crossref]

Iliffe, S.

A. Burns and S. Iliffe, “Alzheimer’s disease,” BMJ 338, b158 (2009).
[Crossref]

Ivanov, A.

C.-K. Sun, C.-T. Kao, M.-L. Wei, S.-H. Chia, F. X. Kärtner, A. Ivanov, and Y.-H. Liao, “Slide-free imaging of hematoxylin-eosin stained whole-mount tissues using combined third-harmonic generation and three-photon fluorescence microscopy,” J. Biophotonics 12(5), e201800341 (2019).
[Crossref]

Jee, S.-H.

Y.-H. Liao, Y.-H. Su, Y.-T. Shih, W.-S. Chen, S.-H. Jee, and C.-K. Sun, “In vivo third-harmonic generation microscopy study on vitiligo patients,” J. Biomed. Opt. 25(1), 014504 (2019).
[Crossref]

Jurs, S. G.

D. E. Hinkel, W. Wiersma, and S. G. Jurs, Applied Statistics for the Behavioral Sciences, 2nd ed., (Houghton Mifflin Co.1988).

Kajdasz, S. T.

W. E. Klunk, B. J. Bacskal, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, “Imaging Aβ plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered congo red derivative,” J. Neuropathol. Exp. Neurol. 61(9), 797–805 (2002).
[Crossref]

Kane, D. J.

D. J. Kane and R. Trebino, “Characterization of arbitrary femtosecond pulses using frequency-resolved optical gating,” IEEE J. Quantum Electron. 29(2), 571–579 (1993).
[Crossref]

Kao, C.-T.

C.-K. Sun, C.-T. Kao, M.-L. Wei, S.-H. Chia, F. X. Kärtner, A. Ivanov, and Y.-H. Liao, “Slide-free imaging of hematoxylin-eosin stained whole-mount tissues using combined third-harmonic generation and three-photon fluorescence microscopy,” J. Biophotonics 12(5), e201800341 (2019).
[Crossref]

Kartner, F. X.

N. Matuschek, F. X. Kartner, and U. Keller, “Theory of double-chirped mirrors,” IEEE J. Select. Topics Quantum Electron. 4(2), 197–208 (1998).
[Crossref]

Kärtner, F. X.

C.-K. Sun, C.-T. Kao, M.-L. Wei, S.-H. Chia, F. X. Kärtner, A. Ivanov, and Y.-H. Liao, “Slide-free imaging of hematoxylin-eosin stained whole-mount tissues using combined third-harmonic generation and three-photon fluorescence microscopy,” J. Biophotonics 12(5), e201800341 (2019).
[Crossref]

Keller, U.

N. Matuschek, F. X. Kartner, and U. Keller, “Theory of double-chirped mirrors,” IEEE J. Select. Topics Quantum Electron. 4(2), 197–208 (1998).
[Crossref]

Kildishev, A. V.

Kiskis, J.

J. Kiskis, H. Fink, L. Nyberg, J. Thyr, J.-Y. Li, and A. Enejder, “Plaque-associated lipids in Alzheimer’s diseased brain tissue visualized by nonlinear microscopy,” Sci. Rep. 5(1), 13489 (2015).
[Crossref]

Klunk, W. E.

W. E. Klunk, B. J. Bacskal, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, “Imaging Aβ plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered congo red derivative,” J. Neuropathol. Exp. Neurol. 61(9), 797–805 (2002).
[Crossref]

Ko, C.-Y.

S.-Y. Chen, C.-S. Hsieh, S.-W. Chu, C.-Y. Lin, C.-Y. Ko, Y.-C. Chen, H.-J. Tsai, C.-H. Hu, and C.-K. Sun, “Noninvasive harmonics optical microscopy for long-term observation of embryonic nervous system development in vivo,” J. Biomed. Opt. 11(5), 054022 (2006).
[Crossref]

Kobat, D.

Kou, L.

Kovacs, G. G.

B. Baumann, A. Woehrer, G. Ricken, M. Augustin, C. Mitter, M. Pircher, G. G. Kovacs, and C. K. Hitzenberger, “Visualization of neuritic plaques in Alzheimer’s disease by polarization-sensitive optical coherence microscopy,” Sci. Rep. 7(1), 43477 (2017).
[Crossref]

Kuo, M.-X.

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[Crossref]

Kuzmin, N. V.

Kwan, A. C.

Labrie, D.

Laferla, R.

R. Sterniczuk, M. C. Antle, R. Laferla, and R. H. Dyck, “Characterization of the 3xTg-AD mouse model of Alzheimer’s disease: Part 2. Behavioral and cognitive changes,” Brain Res. 1348, 149–155 (2010).
[Crossref]

Lange, A.

V. Daebel, S. Chinnathambi, J. Biernat, M. Schwalbe, B. Habenstein, A. Loquet, E. Akoury, K. Tepper, H. Muller, M. Baldus, C. Griesinger, M. Zweckstetter, E. Mandelkow, V. Vijayan, and A. Lange, “β-sheet core of tau paired helical filaments revealed by solid-state NMR,” J. Am. Chem. Soc. 134(34), 13982–13989 (2012).
[Crossref]

Lee, C.-M.

Y.-C. Chen, H.-C. Hsu, C.-M. Lee, and C.-K. Sun, “Third harmonic generation susceptibility spectroscopy in free fatty acids,” J. Biomed. Opt. 20(9), 095013 (2015).
[Crossref]

Lee, S.-P.

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[Crossref]

Lee, W.-J.

Lenferink, A.

R. Micheal, A. Lenferink, G. F. J. M. Vrensen, E. Gelpi, R. I. Barraquer, and C. Otto, “Hyperspectral Raman imaging of neuritic plaques and neurofibrillary tangles in brain tissue from Alzheimer’s disease patients,” Sci. Rep. 7(1), 15603 (2017).
[Crossref]

Li, J.-Y.

J. Kiskis, H. Fink, L. Nyberg, J. Thyr, J.-Y. Li, and A. Enejder, “Plaque-associated lipids in Alzheimer’s diseased brain tissue visualized by nonlinear microscopy,” Sci. Rep. 5(1), 13489 (2015).
[Crossref]

Liao, Y.-H.

C.-K. Sun, C.-T. Kao, M.-L. Wei, S.-H. Chia, F. X. Kärtner, A. Ivanov, and Y.-H. Liao, “Slide-free imaging of hematoxylin-eosin stained whole-mount tissues using combined third-harmonic generation and three-photon fluorescence microscopy,” J. Biophotonics 12(5), e201800341 (2019).
[Crossref]

Y.-H. Liao, Y.-H. Su, Y.-T. Shih, W.-S. Chen, S.-H. Jee, and C.-K. Sun, “In vivo third-harmonic generation microscopy study on vitiligo patients,” J. Biomed. Opt. 25(1), 014504 (2019).
[Crossref]

S.-Y. Chen, S.-U. Chen, H.-Y. Wu, W.-J. Lee, Y.-H. Liao, and C.-K. Sun, “In vivo virtual biopsy of human skin by using noninvasive higher harmonic generation microscopy,” IEEE J. Sel. Top. Quantum Electron. 16(3), 478–492 (2010).
[Crossref]

T.-H. Tsai, S.-P. Tai, W.-J. Lee, H.-Y. Huang, Y.-H. Liao, and C.-K. Sun, “Optical signal degradation study in fixed human skin using confocal microscopy and higher-harmonic optical microscopy,” Opt. Express 14(2), 749–758 (2006).
[Crossref]

Licea-Rodriguez, J.

J. Licea-Rodriguez, A. Figueroa-Melendez, K. Falaggis, M. P. Sanchez, M. Riquelme, and I. Rocha-Mendoza, “Multicolor fluorescence microscopy using static light sheets and a single channel detection,” J. Biomed. Opt. 24(01), 1 (2019).
[Crossref]

Lichtman, J. W.

J. W. Lichtman and W. Denk, “The big and the small: challenges of imaging the brain’s circuits,” Science 334(6056), 618–623 (2011).
[Crossref]

Lin, B.-L.

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[Crossref]

Lin, C.-Y.

S.-Y. Chen, C.-S. Hsieh, S.-W. Chu, C.-Y. Lin, C.-Y. Ko, Y.-C. Chen, H.-J. Tsai, C.-H. Hu, and C.-K. Sun, “Noninvasive harmonics optical microscopy for long-term observation of embryonic nervous system development in vivo,” J. Biomed. Opt. 11(5), 054022 (2006).
[Crossref]

C.-K. Sun, S.-W. Chu, S.-Y. Chen, T.-H. Tsai, T.-M. Liu, C.-Y. Lin, and H.-J. Tsai, “Higher harmonic generation microscopy for developmental biology,” J. Struct. Biol. 147(1), 19–30 (2004).
[Crossref]

Lin, D.-J.

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[Crossref]

Liu, B.

B. Liu, E. A. Macdonald, D. L. Stamper, and M. E. Brezinski, “Group velocity dispersion effects with water and lipid in 1.3 µm optical coherence tomography system,” Phys. Med. Biol. 49(6), 923–930 (2004).
[Crossref]

Liu, H.-L.

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[Crossref]

Liu, T.-M.

C.-K. Sun, S.-W. Chu, S.-Y. Chen, T.-H. Tsai, T.-M. Liu, C.-Y. Lin, and H.-J. Tsai, “Higher harmonic generation microscopy for developmental biology,” J. Struct. Biol. 147(1), 19–30 (2004).
[Crossref]

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[Crossref]

Liu, W.-R.

Lodder, J. C.

S. Witte, A. Negrean, J. C. Lodder, C. P. J. de Kock, G. T. Silva, H. D. Mansvelder, and M. L. Groot, “Label-free live brain imaging and targeted patching with third-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 108(15), 5970–5975 (2011).
[Crossref]

Loquet, A.

V. Daebel, S. Chinnathambi, J. Biernat, M. Schwalbe, B. Habenstein, A. Loquet, E. Akoury, K. Tepper, H. Muller, M. Baldus, C. Griesinger, M. Zweckstetter, E. Mandelkow, V. Vijayan, and A. Lange, “β-sheet core of tau paired helical filaments revealed by solid-state NMR,” J. Am. Chem. Soc. 134(34), 13982–13989 (2012).
[Crossref]

Lou, P.-J.

Love, S.

S. Love, “Neuropathological investigation of dementia: A guide for neurologists,” J. Neurol., Neurosurg. Psychiatry 76(suppl_5), v8–v14 (2005).
[Crossref]

Macdonald, E. A.

B. Liu, E. A. Macdonald, D. L. Stamper, and M. E. Brezinski, “Group velocity dispersion effects with water and lipid in 1.3 µm optical coherence tomography system,” Phys. Med. Biol. 49(6), 923–930 (2004).
[Crossref]

Mandelkow, E.

V. Daebel, S. Chinnathambi, J. Biernat, M. Schwalbe, B. Habenstein, A. Loquet, E. Akoury, K. Tepper, H. Muller, M. Baldus, C. Griesinger, M. Zweckstetter, E. Mandelkow, V. Vijayan, and A. Lange, “β-sheet core of tau paired helical filaments revealed by solid-state NMR,” J. Am. Chem. Soc. 134(34), 13982–13989 (2012).
[Crossref]

Mansvelder, H. D.

N. V. Kuzmin, P. Wesseling, P. C. de Witt Hamer, D. P. Noske, G. D. galgano, H. D. Mansvelder, J. C. Baayen, and M. L. Groot, “Third harmonic generation imaging for fast, label-free pathology of human brain tumors,” Biomed. Opt. Express 7(5), 1889–1904 (2016).
[Crossref]

S. Witte, A. Negrean, J. C. Lodder, C. P. J. de Kock, G. T. Silva, H. D. Mansvelder, and M. L. Groot, “Label-free live brain imaging and targeted patching with third-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 108(15), 5970–5975 (2011).
[Crossref]

Mathis, C. A.

W. E. Klunk, B. J. Bacskal, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, “Imaging Aβ plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered congo red derivative,” J. Neuropathol. Exp. Neurol. 61(9), 797–805 (2002).
[Crossref]

Matuschek, N.

N. Matuschek, F. X. Kartner, and U. Keller, “Theory of double-chirped mirrors,” IEEE J. Select. Topics Quantum Electron. 4(2), 197–208 (1998).
[Crossref]

McLellan, M. E.

W. E. Klunk, B. J. Bacskal, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, “Imaging Aβ plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered congo red derivative,” J. Neuropathol. Exp. Neurol. 61(9), 797–805 (2002).
[Crossref]

Michael, D. E.

Micheal, R.

R. Micheal, A. Lenferink, G. F. J. M. Vrensen, E. Gelpi, R. I. Barraquer, and C. Otto, “Hyperspectral Raman imaging of neuritic plaques and neurofibrillary tangles in brain tissue from Alzheimer’s disease patients,” Sci. Rep. 7(1), 15603 (2017).
[Crossref]

Mitter, C.

B. Baumann, A. Woehrer, G. Ricken, M. Augustin, C. Mitter, M. Pircher, G. G. Kovacs, and C. K. Hitzenberger, “Visualization of neuritic plaques in Alzheimer’s disease by polarization-sensitive optical coherence microscopy,” Sci. Rep. 7(1), 43477 (2017).
[Crossref]

Muller, H.

V. Daebel, S. Chinnathambi, J. Biernat, M. Schwalbe, B. Habenstein, A. Loquet, E. Akoury, K. Tepper, H. Muller, M. Baldus, C. Griesinger, M. Zweckstetter, E. Mandelkow, V. Vijayan, and A. Lange, “β-sheet core of tau paired helical filaments revealed by solid-state NMR,” J. Am. Chem. Soc. 134(34), 13982–13989 (2012).
[Crossref]

Negrean, A.

S. Witte, A. Negrean, J. C. Lodder, C. P. J. de Kock, G. T. Silva, H. D. Mansvelder, and M. L. Groot, “Label-free live brain imaging and targeted patching with third-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 108(15), 5970–5975 (2011).
[Crossref]

Nikitin, A. Y.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. 100(12), 7075–7080 (2003).
[Crossref]

Nishimura, N.

D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernandez, Y.-T. Cheng, J. Reimer, A. S. Tolias, N. Nishimura, and C. Xu, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
[Crossref]

D. Kobat, D. E. Michael, N. Nishimura, A. W. Wong, C. B. Schaffer, and C. Xu, “Deep tissue multiphoton microscopy using longer wavelength excitation,” Opt. Express 17(16), 13354–13364 (2009).
[Crossref]

Noske, D. P.

Nyberg, L.

J. Kiskis, H. Fink, L. Nyberg, J. Thyr, J.-Y. Li, and A. Enejder, “Plaque-associated lipids in Alzheimer’s diseased brain tissue visualized by nonlinear microscopy,” Sci. Rep. 5(1), 13489 (2015).
[Crossref]

Otto, C.

R. Micheal, A. Lenferink, G. F. J. M. Vrensen, E. Gelpi, R. I. Barraquer, and C. Otto, “Hyperspectral Raman imaging of neuritic plaques and neurofibrillary tangles in brain tissue from Alzheimer’s disease patients,” Sci. Rep. 7(1), 15603 (2017).
[Crossref]

Ouzounov, D. G.

D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernandez, Y.-T. Cheng, J. Reimer, A. S. Tolias, N. Nishimura, and C. Xu, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
[Crossref]

Pan, Y. A.

T. A. Weissman and Y. A. Pan, “Brainbow: new resources and emerging applications for multicolor genetic labeling and analysis,” Genetics 199(2), 293–306 (2015).
[Crossref]

Pircher, M.

B. Baumann, A. Woehrer, G. Ricken, M. Augustin, C. Mitter, M. Pircher, G. G. Kovacs, and C. K. Hitzenberger, “Visualization of neuritic plaques in Alzheimer’s disease by polarization-sensitive optical coherence microscopy,” Sci. Rep. 7(1), 43477 (2017).
[Crossref]

Querry, M. R.

Reimer, J.

D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernandez, Y.-T. Cheng, J. Reimer, A. S. Tolias, N. Nishimura, and C. Xu, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
[Crossref]

Ricken, G.

B. Baumann, A. Woehrer, G. Ricken, M. Augustin, C. Mitter, M. Pircher, G. G. Kovacs, and C. K. Hitzenberger, “Visualization of neuritic plaques in Alzheimer’s disease by polarization-sensitive optical coherence microscopy,” Sci. Rep. 7(1), 43477 (2017).
[Crossref]

Riquelme, M.

J. Licea-Rodriguez, A. Figueroa-Melendez, K. Falaggis, M. P. Sanchez, M. Riquelme, and I. Rocha-Mendoza, “Multicolor fluorescence microscopy using static light sheets and a single channel detection,” J. Biomed. Opt. 24(01), 1 (2019).
[Crossref]

Rocha-Mendoza, I.

J. Licea-Rodriguez, A. Figueroa-Melendez, K. Falaggis, M. P. Sanchez, M. Riquelme, and I. Rocha-Mendoza, “Multicolor fluorescence microscopy using static light sheets and a single channel detection,” J. Biomed. Opt. 24(01), 1 (2019).
[Crossref]

Sanchez, M. P.

J. Licea-Rodriguez, A. Figueroa-Melendez, K. Falaggis, M. P. Sanchez, M. Riquelme, and I. Rocha-Mendoza, “Multicolor fluorescence microscopy using static light sheets and a single channel detection,” J. Biomed. Opt. 24(01), 1 (2019).
[Crossref]

Schaffer, C. B.

M. J. Farrar, E. W. Wise, J. R. Fetcho, and C. B. Schaffer, “In vivo imaging of myelin in the vertebrate central nervous system using third harmonic generation microscopy,” Biophys. J. 100(5), 1362–1371 (2011).
[Crossref]

D. Kobat, D. E. Michael, N. Nishimura, A. W. Wong, C. B. Schaffer, and C. Xu, “Deep tissue multiphoton microscopy using longer wavelength excitation,” Opt. Express 17(16), 13354–13364 (2009).
[Crossref]

Schultz, C.

D. R. Thal, E. Ghebremedhin, C. Haass, and C. Schultz, “UV light-induced autofluorescence of full-length abeta-protein deposits in the human brain,” Clin. Neuropathol. 21(1), 35–40 (2002).

Schwalbe, M.

V. Daebel, S. Chinnathambi, J. Biernat, M. Schwalbe, B. Habenstein, A. Loquet, E. Akoury, K. Tepper, H. Muller, M. Baldus, C. Griesinger, M. Zweckstetter, E. Mandelkow, V. Vijayan, and A. Lange, “β-sheet core of tau paired helical filaments revealed by solid-state NMR,” J. Am. Chem. Soc. 134(34), 13982–13989 (2012).
[Crossref]

Shieh, D.-B.

Shih, Y.-T.

Y.-H. Liao, Y.-H. Su, Y.-T. Shih, W.-S. Chen, S.-H. Jee, and C.-K. Sun, “In vivo third-harmonic generation microscopy study on vitiligo patients,” J. Biomed. Opt. 25(1), 014504 (2019).
[Crossref]

Silva, G. T.

S. Witte, A. Negrean, J. C. Lodder, C. P. J. de Kock, G. T. Silva, H. D. Mansvelder, and M. L. Groot, “Label-free live brain imaging and targeted patching with third-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 108(15), 5970–5975 (2011).
[Crossref]

Stamper, D. L.

B. Liu, E. A. Macdonald, D. L. Stamper, and M. E. Brezinski, “Group velocity dispersion effects with water and lipid in 1.3 µm optical coherence tomography system,” Phys. Med. Biol. 49(6), 923–930 (2004).
[Crossref]

Sterniczuk, R.

R. Sterniczuk, M. C. Antle, R. Laferla, and R. H. Dyck, “Characterization of the 3xTg-AD mouse model of Alzheimer’s disease: Part 2. Behavioral and cognitive changes,” Brain Res. 1348, 149–155 (2010).
[Crossref]

Stoothoff, W. H.

W. H. Stoothoff, B. J. Bacskai, and B. T. Hyman, “Monitoring tau-tubulin interactions utilizing second harmonic generation in living neurons,” J. Biomed. Opt. 13(6), 064039 (2008).
[Crossref]

Su, Y.-H.

Y.-H. Liao, Y.-H. Su, Y.-T. Shih, W.-S. Chen, S.-H. Jee, and C.-K. Sun, “In vivo third-harmonic generation microscopy study on vitiligo patients,” J. Biomed. Opt. 25(1), 014504 (2019).
[Crossref]

Sun, C.-K.

Y.-H. Liao, Y.-H. Su, Y.-T. Shih, W.-S. Chen, S.-H. Jee, and C.-K. Sun, “In vivo third-harmonic generation microscopy study on vitiligo patients,” J. Biomed. Opt. 25(1), 014504 (2019).
[Crossref]

C.-K. Sun, C.-T. Kao, M.-L. Wei, S.-H. Chia, F. X. Kärtner, A. Ivanov, and Y.-H. Liao, “Slide-free imaging of hematoxylin-eosin stained whole-mount tissues using combined third-harmonic generation and three-photon fluorescence microscopy,” J. Biophotonics 12(5), e201800341 (2019).
[Crossref]

Y.-C. Chen, H.-C. Hsu, C.-M. Lee, and C.-K. Sun, “Third harmonic generation susceptibility spectroscopy in free fatty acids,” J. Biomed. Opt. 20(9), 095013 (2015).
[Crossref]

M.-R. Tsai, S.-Y. Chen, D.-B. Shieh, P.-J. Lou, and C.-K. Sun, “In vivo optical biopsy of human oral mucosa with harmonic generation microscopy,” Biomed. Opt. Express 2(8), 2317–2328 (2011).
[Crossref]

C.-F. Chang, H.-C. Chen, M.-J. Chen, W.-R. Liu, W.-F. Hsieh, C.-H. Hsu, C.-Y. Chen, F.-H. Chang, C.-H. Yu, and C.-K. Sun, “Direct backward third-harmonic generation in nanostructures,” Opt. Express 18(7), 7397–7406 (2010).
[Crossref]

S.-Y. Chen, S.-U. Chen, H.-Y. Wu, W.-J. Lee, Y.-H. Liao, and C.-K. Sun, “In vivo virtual biopsy of human skin by using noninvasive higher harmonic generation microscopy,” IEEE J. Sel. Top. Quantum Electron. 16(3), 478–492 (2010).
[Crossref]

S.-Y. Chen, H.-Y. Wu, and C.-K. Sun, “In vivo harmonic generation biopsy of human skin,” J. Biomed. Opt. 14(6), 060505 (2009).
[Crossref]

S.-P. Tai, W.-J. Lee, D.-B. Shieh, P.-C. Wu, H.-Y. Huang, C.-H. Yu, and C.-K. Sun, “In vivo optical biopsy of hamster oral cavity with epi-third-harmonic-generation microscopy,” Opt. Express 14(13), 6178–6187 (2006).
[Crossref]

S.-Y. Chen, C.-S. Hsieh, S.-W. Chu, C.-Y. Lin, C.-Y. Ko, Y.-C. Chen, H.-J. Tsai, C.-H. Hu, and C.-K. Sun, “Noninvasive harmonics optical microscopy for long-term observation of embryonic nervous system development in vivo,” J. Biomed. Opt. 11(5), 054022 (2006).
[Crossref]

T.-H. Tsai, S.-P. Tai, W.-J. Lee, H.-Y. Huang, Y.-H. Liao, and C.-K. Sun, “Optical signal degradation study in fixed human skin using confocal microscopy and higher-harmonic optical microscopy,” Opt. Express 14(2), 749–758 (2006).
[Crossref]

C.-K. Sun, “Higher Harmonic Generation Microscopy,” J. Struct. Biol. 147(1), 19–30 (2004).
[Crossref]

C.-K. Sun, S.-W. Chu, S.-Y. Chen, T.-H. Tsai, T.-M. Liu, C.-Y. Lin, and H.-J. Tsai, “Higher harmonic generation microscopy for developmental biology,” J. Struct. Biol. 147(1), 19–30 (2004).
[Crossref]

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[Crossref]

Tai, S.-P.

Tepper, K.

V. Daebel, S. Chinnathambi, J. Biernat, M. Schwalbe, B. Habenstein, A. Loquet, E. Akoury, K. Tepper, H. Muller, M. Baldus, C. Griesinger, M. Zweckstetter, E. Mandelkow, V. Vijayan, and A. Lange, “β-sheet core of tau paired helical filaments revealed by solid-state NMR,” J. Am. Chem. Soc. 134(34), 13982–13989 (2012).
[Crossref]

Thal, D. R.

D. R. Thal, E. Ghebremedhin, C. Haass, and C. Schultz, “UV light-induced autofluorescence of full-length abeta-protein deposits in the human brain,” Clin. Neuropathol. 21(1), 35–40 (2002).

Thyr, J.

J. Kiskis, H. Fink, L. Nyberg, J. Thyr, J.-Y. Li, and A. Enejder, “Plaque-associated lipids in Alzheimer’s diseased brain tissue visualized by nonlinear microscopy,” Sci. Rep. 5(1), 13489 (2015).
[Crossref]

Tolias, A. S.

D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernandez, Y.-T. Cheng, J. Reimer, A. S. Tolias, N. Nishimura, and C. Xu, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
[Crossref]

Trebino, R.

D. J. Kane and R. Trebino, “Characterization of arbitrary femtosecond pulses using frequency-resolved optical gating,” IEEE J. Quantum Electron. 29(2), 571–579 (1993).
[Crossref]

Tsai, H.-J.

S.-Y. Chen, C.-S. Hsieh, S.-W. Chu, C.-Y. Lin, C.-Y. Ko, Y.-C. Chen, H.-J. Tsai, C.-H. Hu, and C.-K. Sun, “Noninvasive harmonics optical microscopy for long-term observation of embryonic nervous system development in vivo,” J. Biomed. Opt. 11(5), 054022 (2006).
[Crossref]

C.-K. Sun, S.-W. Chu, S.-Y. Chen, T.-H. Tsai, T.-M. Liu, C.-Y. Lin, and H.-J. Tsai, “Higher harmonic generation microscopy for developmental biology,” J. Struct. Biol. 147(1), 19–30 (2004).
[Crossref]

Tsai, M.-R.

Tsai, T.-H.

T.-H. Tsai, S.-P. Tai, W.-J. Lee, H.-Y. Huang, Y.-H. Liao, and C.-K. Sun, “Optical signal degradation study in fixed human skin using confocal microscopy and higher-harmonic optical microscopy,” Opt. Express 14(2), 749–758 (2006).
[Crossref]

C.-K. Sun, S.-W. Chu, S.-Y. Chen, T.-H. Tsai, T.-M. Liu, C.-Y. Lin, and H.-J. Tsai, “Higher harmonic generation microscopy for developmental biology,” J. Struct. Biol. 147(1), 19–30 (2004).
[Crossref]

Tsuchiya, H.

N. Yamamoto, H. Tsuchiya, and R. M. Hoffman, “Tumor imaging with multicolor fluorescent protein expression,” Int. J. Clin. Oncol. 16(2), 84–91 (2011).
[Crossref]

Urbas, A. M.

Vijayan, V.

V. Daebel, S. Chinnathambi, J. Biernat, M. Schwalbe, B. Habenstein, A. Loquet, E. Akoury, K. Tepper, H. Muller, M. Baldus, C. Griesinger, M. Zweckstetter, E. Mandelkow, V. Vijayan, and A. Lange, “β-sheet core of tau paired helical filaments revealed by solid-state NMR,” J. Am. Chem. Soc. 134(34), 13982–13989 (2012).
[Crossref]

Vrensen, G. F. J. M.

R. Micheal, A. Lenferink, G. F. J. M. Vrensen, E. Gelpi, R. I. Barraquer, and C. Otto, “Hyperspectral Raman imaging of neuritic plaques and neurofibrillary tangles in brain tissue from Alzheimer’s disease patients,” Sci. Rep. 7(1), 15603 (2017).
[Crossref]

Walker, M. A.

Wang, M.

D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernandez, Y.-T. Cheng, J. Reimer, A. S. Tolias, N. Nishimura, and C. Xu, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
[Crossref]

Wang, T.

D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernandez, Y.-T. Cheng, J. Reimer, A. S. Tolias, N. Nishimura, and C. Xu, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
[Crossref]

Wang, Y.

W. E. Klunk, B. J. Bacskal, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, “Imaging Aβ plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered congo red derivative,” J. Neuropathol. Exp. Neurol. 61(9), 797–805 (2002).
[Crossref]

Webb, W. W.

A. C. Kwan, K. Duff, G. K. Gouras, and W. W. Webb, “Optical visualization of Alzheimer’s pathology via multiphoton excited intrinsic fluorescence and second harmonic generation,” Opt. Express 17(5), 3679–3689 (2009).
[Crossref]

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. 100(12), 7075–7080 (2003).
[Crossref]

Wei, M.-L.

C.-K. Sun, C.-T. Kao, M.-L. Wei, S.-H. Chia, F. X. Kärtner, A. Ivanov, and Y.-H. Liao, “Slide-free imaging of hematoxylin-eosin stained whole-mount tissues using combined third-harmonic generation and three-photon fluorescence microscopy,” J. Biophotonics 12(5), e201800341 (2019).
[Crossref]

Weiglein, B.

B. Weiglein, G.-J. Bakker, and P. Friedl, “Third harmonic generation microscopy of cells and tissue organization,” J. Cell Sci. 129(2), 245–255 (2016).
[Crossref]

Weissman, T. A.

T. A. Weissman and Y. A. Pan, “Brainbow: new resources and emerging applications for multicolor genetic labeling and analysis,” Genetics 199(2), 293–306 (2015).
[Crossref]

Wesseling, P.

Wiersma, W.

D. E. Hinkel, W. Wiersma, and S. G. Jurs, Applied Statistics for the Behavioral Sciences, 2nd ed., (Houghton Mifflin Co.1988).

Williams, R. M.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. 100(12), 7075–7080 (2003).
[Crossref]

Wise, E. W.

M. J. Farrar, E. W. Wise, J. R. Fetcho, and C. B. Schaffer, “In vivo imaging of myelin in the vertebrate central nervous system using third harmonic generation microscopy,” Biophys. J. 100(5), 1362–1371 (2011).
[Crossref]

Wisniewski, T.

E. Drummond and T. Wisniewski, “Alzheimer’s disease: experimental models and reality,” Acta Neuropathol. 133(2), 155–175 (2017).
[Crossref]

Witte, S.

S. Witte, A. Negrean, J. C. Lodder, C. P. J. de Kock, G. T. Silva, H. D. Mansvelder, and M. L. Groot, “Label-free live brain imaging and targeted patching with third-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 108(15), 5970–5975 (2011).
[Crossref]

Woehrer, A.

B. Baumann, A. Woehrer, G. Ricken, M. Augustin, C. Mitter, M. Pircher, G. G. Kovacs, and C. K. Hitzenberger, “Visualization of neuritic plaques in Alzheimer’s disease by polarization-sensitive optical coherence microscopy,” Sci. Rep. 7(1), 43477 (2017).
[Crossref]

Wong, A. W.

Wu, H.-Y.

S.-Y. Chen, S.-U. Chen, H.-Y. Wu, W.-J. Lee, Y.-H. Liao, and C.-K. Sun, “In vivo virtual biopsy of human skin by using noninvasive higher harmonic generation microscopy,” IEEE J. Sel. Top. Quantum Electron. 16(3), 478–492 (2010).
[Crossref]

S.-Y. Chen, H.-Y. Wu, and C.-K. Sun, “In vivo harmonic generation biopsy of human skin,” J. Biomed. Opt. 14(6), 060505 (2009).
[Crossref]

Wu, P.-C.

Xiao, S.

Xu, C.

D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernandez, Y.-T. Cheng, J. Reimer, A. S. Tolias, N. Nishimura, and C. Xu, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
[Crossref]

D. Kobat, D. E. Michael, N. Nishimura, A. W. Wong, C. B. Schaffer, and C. Xu, “Deep tissue multiphoton microscopy using longer wavelength excitation,” Opt. Express 17(16), 13354–13364 (2009).
[Crossref]

Yamamoto, N.

N. Yamamoto, H. Tsuchiya, and R. M. Hoffman, “Tumor imaging with multicolor fluorescent protein expression,” Int. J. Clin. Oncol. 16(2), 84–91 (2011).
[Crossref]

Yu, C.-H.

Zipfel, W. R.

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. 100(12), 7075–7080 (2003).
[Crossref]

Zweckstetter, M.

V. Daebel, S. Chinnathambi, J. Biernat, M. Schwalbe, B. Habenstein, A. Loquet, E. Akoury, K. Tepper, H. Muller, M. Baldus, C. Griesinger, M. Zweckstetter, E. Mandelkow, V. Vijayan, and A. Lange, “β-sheet core of tau paired helical filaments revealed by solid-state NMR,” J. Am. Chem. Soc. 134(34), 13982–13989 (2012).
[Crossref]

Acta Neuropathol. (1)

E. Drummond and T. Wisniewski, “Alzheimer’s disease: experimental models and reality,” Acta Neuropathol. 133(2), 155–175 (2017).
[Crossref]

Acta Pharmacol. Sin. (1)

G.-F. Chen, “Amyloid beta: structure, biology and structure-based therapeutic development,” Acta Pharmacol. Sin. 38(9), 1205–1235 (2017).
[Crossref]

Anal. Chem. (1)

P. Campagnola, “Second harmonic generation imaging microscopy: applications to disease diagnostics,” Anal. Chem. 83(9), 3224–3231 (2011).
[Crossref]

Appl. Opt. (2)

Biomed. Opt. Express (2)

Biophys. J. (1)

M. J. Farrar, E. W. Wise, J. R. Fetcho, and C. B. Schaffer, “In vivo imaging of myelin in the vertebrate central nervous system using third harmonic generation microscopy,” Biophys. J. 100(5), 1362–1371 (2011).
[Crossref]

BMJ (1)

A. Burns and S. Iliffe, “Alzheimer’s disease,” BMJ 338, b158 (2009).
[Crossref]

Brain Res. (1)

R. Sterniczuk, M. C. Antle, R. Laferla, and R. H. Dyck, “Characterization of the 3xTg-AD mouse model of Alzheimer’s disease: Part 2. Behavioral and cognitive changes,” Brain Res. 1348, 149–155 (2010).
[Crossref]

Clin. Neuropathol. (1)

D. R. Thal, E. Ghebremedhin, C. Haass, and C. Schultz, “UV light-induced autofluorescence of full-length abeta-protein deposits in the human brain,” Clin. Neuropathol. 21(1), 35–40 (2002).

Genetics (1)

T. A. Weissman and Y. A. Pan, “Brainbow: new resources and emerging applications for multicolor genetic labeling and analysis,” Genetics 199(2), 293–306 (2015).
[Crossref]

Histopathology (1)

J. H. Dowson, “A sensitive method for demonstration of senile plaques in the dementing brain,” Histopathology 5(3), 305–310 (1981).
[Crossref]

IEEE J. Quantum Electron. (1)

D. J. Kane and R. Trebino, “Characterization of arbitrary femtosecond pulses using frequency-resolved optical gating,” IEEE J. Quantum Electron. 29(2), 571–579 (1993).
[Crossref]

IEEE J. Sel. Top. Quantum Electron. (1)

S.-Y. Chen, S.-U. Chen, H.-Y. Wu, W.-J. Lee, Y.-H. Liao, and C.-K. Sun, “In vivo virtual biopsy of human skin by using noninvasive higher harmonic generation microscopy,” IEEE J. Sel. Top. Quantum Electron. 16(3), 478–492 (2010).
[Crossref]

IEEE J. Select. Topics Quantum Electron. (1)

N. Matuschek, F. X. Kartner, and U. Keller, “Theory of double-chirped mirrors,” IEEE J. Select. Topics Quantum Electron. 4(2), 197–208 (1998).
[Crossref]

Int. J. Clin. Oncol. (1)

N. Yamamoto, H. Tsuchiya, and R. M. Hoffman, “Tumor imaging with multicolor fluorescent protein expression,” Int. J. Clin. Oncol. 16(2), 84–91 (2011).
[Crossref]

J. Am. Chem. Soc. (1)

V. Daebel, S. Chinnathambi, J. Biernat, M. Schwalbe, B. Habenstein, A. Loquet, E. Akoury, K. Tepper, H. Muller, M. Baldus, C. Griesinger, M. Zweckstetter, E. Mandelkow, V. Vijayan, and A. Lange, “β-sheet core of tau paired helical filaments revealed by solid-state NMR,” J. Am. Chem. Soc. 134(34), 13982–13989 (2012).
[Crossref]

J. Biomed. Opt. (6)

J. Licea-Rodriguez, A. Figueroa-Melendez, K. Falaggis, M. P. Sanchez, M. Riquelme, and I. Rocha-Mendoza, “Multicolor fluorescence microscopy using static light sheets and a single channel detection,” J. Biomed. Opt. 24(01), 1 (2019).
[Crossref]

W. H. Stoothoff, B. J. Bacskai, and B. T. Hyman, “Monitoring tau-tubulin interactions utilizing second harmonic generation in living neurons,” J. Biomed. Opt. 13(6), 064039 (2008).
[Crossref]

Y.-C. Chen, H.-C. Hsu, C.-M. Lee, and C.-K. Sun, “Third harmonic generation susceptibility spectroscopy in free fatty acids,” J. Biomed. Opt. 20(9), 095013 (2015).
[Crossref]

Y.-H. Liao, Y.-H. Su, Y.-T. Shih, W.-S. Chen, S.-H. Jee, and C.-K. Sun, “In vivo third-harmonic generation microscopy study on vitiligo patients,” J. Biomed. Opt. 25(1), 014504 (2019).
[Crossref]

S.-Y. Chen, C.-S. Hsieh, S.-W. Chu, C.-Y. Lin, C.-Y. Ko, Y.-C. Chen, H.-J. Tsai, C.-H. Hu, and C.-K. Sun, “Noninvasive harmonics optical microscopy for long-term observation of embryonic nervous system development in vivo,” J. Biomed. Opt. 11(5), 054022 (2006).
[Crossref]

S.-Y. Chen, H.-Y. Wu, and C.-K. Sun, “In vivo harmonic generation biopsy of human skin,” J. Biomed. Opt. 14(6), 060505 (2009).
[Crossref]

J. Biophotonics (1)

C.-K. Sun, C.-T. Kao, M.-L. Wei, S.-H. Chia, F. X. Kärtner, A. Ivanov, and Y.-H. Liao, “Slide-free imaging of hematoxylin-eosin stained whole-mount tissues using combined third-harmonic generation and three-photon fluorescence microscopy,” J. Biophotonics 12(5), e201800341 (2019).
[Crossref]

J. Cell Sci. (1)

B. Weiglein, G.-J. Bakker, and P. Friedl, “Third harmonic generation microscopy of cells and tissue organization,” J. Cell Sci. 129(2), 245–255 (2016).
[Crossref]

J. Comp. Neurol. (1)

S. E. Crowe and G. C. R. Ellis-Davies, “In vivo charactierization of a bigenic fluorescent mouse models of Alzheimer’s disease with neurodegeneration,” J. Comp. Neurol. 521(10), 2181–2194 (2013).
[Crossref]

J. Microsc. (1)

S.-W. Chu, I.-H. Chen, T.-M. Liu, C.-K. Sun, S.-P. Lee, B.-L. Lin, P.-C. Cheng, M.-X. Kuo, D.-J. Lin, and H.-L. Liu, “Nonlinear bio-photonic crystal effects revealed with multimodal nonlinear microscopy,” J. Microsc. 208(3), 190–200 (2002).
[Crossref]

J. Neurol., Neurosurg. Psychiatry (1)

S. Love, “Neuropathological investigation of dementia: A guide for neurologists,” J. Neurol., Neurosurg. Psychiatry 76(suppl_5), v8–v14 (2005).
[Crossref]

J. Neuropathol. Exp. Neurol. (1)

W. E. Klunk, B. J. Bacskal, C. A. Mathis, S. T. Kajdasz, M. E. McLellan, M. P. Frosch, M. L. Debnath, D. P. Holt, Y. Wang, and B. T. Hyman, “Imaging Aβ plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered congo red derivative,” J. Neuropathol. Exp. Neurol. 61(9), 797–805 (2002).
[Crossref]

J. Struct. Biol. (2)

C.-K. Sun, S.-W. Chu, S.-Y. Chen, T.-H. Tsai, T.-M. Liu, C.-Y. Lin, and H.-J. Tsai, “Higher harmonic generation microscopy for developmental biology,” J. Struct. Biol. 147(1), 19–30 (2004).
[Crossref]

C.-K. Sun, “Higher Harmonic Generation Microscopy,” J. Struct. Biol. 147(1), 19–30 (2004).
[Crossref]

Nat. Methods (1)

D. G. Ouzounov, T. Wang, M. Wang, D. D. Feng, N. G. Horton, J. C. Cruz-Hernandez, Y.-T. Cheng, J. Reimer, A. S. Tolias, N. Nishimura, and C. Xu, “In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain,” Nat. Methods 14(4), 388–390 (2017).
[Crossref]

Neuroscience (1)

M. Diez, “Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein-initial observations,” Neuroscience 100(2), 259–286 (2000).
[Crossref]

Opt. Express (6)

Phys. Med. Biol. (1)

B. Liu, E. A. Macdonald, D. L. Stamper, and M. E. Brezinski, “Group velocity dispersion effects with water and lipid in 1.3 µm optical coherence tomography system,” Phys. Med. Biol. 49(6), 923–930 (2004).
[Crossref]

Proc. Natl. Acad. Sci. (2)

S. Witte, A. Negrean, J. C. Lodder, C. P. J. de Kock, G. T. Silva, H. D. Mansvelder, and M. L. Groot, “Label-free live brain imaging and targeted patching with third-harmonic generation microscopy,” Proc. Natl. Acad. Sci. 108(15), 5970–5975 (2011).
[Crossref]

W. R. Zipfel, R. M. Williams, R. Christie, A. Y. Nikitin, B. T. Hyman, and W. W. Webb, “Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation,” Proc. Natl. Acad. Sci. 100(12), 7075–7080 (2003).
[Crossref]

Sci. Rep. (3)

R. Micheal, A. Lenferink, G. F. J. M. Vrensen, E. Gelpi, R. I. Barraquer, and C. Otto, “Hyperspectral Raman imaging of neuritic plaques and neurofibrillary tangles in brain tissue from Alzheimer’s disease patients,” Sci. Rep. 7(1), 15603 (2017).
[Crossref]

J. Kiskis, H. Fink, L. Nyberg, J. Thyr, J.-Y. Li, and A. Enejder, “Plaque-associated lipids in Alzheimer’s diseased brain tissue visualized by nonlinear microscopy,” Sci. Rep. 5(1), 13489 (2015).
[Crossref]

B. Baumann, A. Woehrer, G. Ricken, M. Augustin, C. Mitter, M. Pircher, G. G. Kovacs, and C. K. Hitzenberger, “Visualization of neuritic plaques in Alzheimer’s disease by polarization-sensitive optical coherence microscopy,” Sci. Rep. 7(1), 43477 (2017).
[Crossref]

Science (1)

J. W. Lichtman and W. Denk, “The big and the small: challenges of imaging the brain’s circuits,” Science 334(6056), 618–623 (2011).
[Crossref]

Other (2)

“Technical note: The effect of dispersion on ultrashort pulses”, https://www.newport.com/n/the-effect-of-dispersion-on-ultrashort-pulses (as accessed on 14th November, 2019).

D. E. Hinkel, W. Wiersma, and S. G. Jurs, Applied Statistics for the Behavioral Sciences, 2nd ed., (Houghton Mifflin Co.1988).

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Figures (4)

Fig. 1.
Fig. 1. Illustration of additive-color multi-harmonic generation microscopy. (a) Schematic of a simplified Jablonsky diagram of the SHG and THG processes. Excitation with the same wavelength can provide distinct emission signals. Dashed lines represent the virtual state, So, the ground state with thin lines as vibrational levels. (b) Multi-harmonic generation set up: A 1262 nm Cr:forsterite laser was used as the excitation source. Obj.- microscope objective, DM1 & DM2- dichroic mirrors reflecting the back-scattered signal from the sample to the detectors, F1- bandpass filter to detect the SHG signal, F2-bandpass filter to detect the THG signal, L-focusing lens, PMT-photomultiplier tube. (c) Illustration shows the morphology of plaques and NFT with their beta-sheet structures. Such structures can provide strong SHG signals. (d) THG is sensitive to molecular organization, size, and nature. Myelin with its lipid content can provide strong THG signals. Also, plaque can produce strong THG signals due to very dense and bigger fibrillary organization; while NFT might produce weak THG signals due to its sparse fibril organization. (e) Illustration shows the principle of additive-color multi-harmonic generation microscopy. The SHG and THG images are represented with pseudo-red and green colors respectively. The primary colors, green and red, can combine additively to produce hundreds of hues from green to red, with different shades of yellow. In our scheme, the SHG images will mostly appear in the red end of the green-red combinatorial spectrum; while THG images will appear in the green end. Combining these SHG and THG images will produce different hues for brain structures: axons/dendrites-green, yellow-plaques, and red/apricot-NFT. (Images of the biological structures were created using www.biorender.com)
Fig. 2.
Fig. 2. Additive-color multi-harmonic generation microscopy of 13 months old 3xTg AD mice brain tissues. (a)-(b) Gray-labeled SHG and THG microscopy images of cortex respectively; (c)-(d) Corresponding pseudo-red color SHG microscopy image and green color THG microscopy image. (e) Additive-color SHG and THG microscopy image by merging (c) and (d). (f) Enlarged view of the dotted box region in (e). (g) Confocal fluorescence microscopy image of the same region in (f) after IHC staining for Aβ-plaques. Arrows indicate the identical plaque structures observed in the additive-color multi-harmonic generation microscopy image in (f) and IHC stained confocal image in (g). (h)-(i) Gray-labeled SHG and THG microscopy images of another region of the cortex. (j)-(k) Corresponding pseudo-colored SHG and THG images of (h) and (i). (l) Additive-color SHG and THG microscopy image by merging (j) and (k). (m) Enlarged view of the dotted box in (l). (n) Confocal fluorescence microscopy image of the same region in (m) after IHC staining for NFTs. Arrows show the identical intraneuronal NFTs observed in the additive-color multi-harmonic generation microscopy image in (m) and IHC stained confocal image in (n). (o) Box plots for comparison of Pearson’s correlation coefficient, R, between THG and SHG signals originating from NFT and plaques. Total number of data points (n) for Aβ plaques and NFT are 20 and 22 respectively. Unpaired two-tailed t-test statistical significance: “*” p < 0.001 (p = 5.21×10−15). (p). Box plots showing the summary of the pixel based quantification to determine the number of overlapping THG pixels with SHG pixels for both NFT and plaques. Here, the number of areas (n) representing each datum point for Aβ plaques and NFT are 20 and 17 respectively. Unpaired two-tailed t-test statistical significance: “*” p < 0.001 (p = 1.73×10−14). In the box plots, the horizontal line within the box indicates the median, boundaries of the box indicate the 25th - and 75th –percentile, and the whiskers (the lines extended from both sides of the box) indicate the highest and lowest values of the results. The “□” marked in the box indicates the mean. Data points with normal distribution curves are also shown for each box. Scale bar: 50 µm.
Fig. 3.
Fig. 3. Comparison of AD neuropathology between control and different aged 3xTG mice by using label-free additive-color multi-harmonic generation microscopy. (a)-(c) Microscopy images of normal brain tissues of a C57BL/6 mouse from cortex (a), striatum (b), and hippocampus (c). (d)-(e) Microscopy images of the brain tissues from the similar regions of the brain as in control from a 8-months old 3xTg mouse. (g)-(i) Enlarged view of the regions as indicated by dotted boxes in (d)-(f) respectively. (j)-(l) Microscopy images of the cortex, striatum, and hippocampus from 13 months old 3xTg mice. (m)-(o) Enlarged view of the dotted box regions in (j)-(l). (p)-(r) SHG, THG, and merged images showing flame-like NFT in mouse cortex. Scale bar: 50 µm.
Fig. 4.
Fig. 4. Spectral and temporal characteristics of the Cr:forsterite laser output pulse. (a) The spectrometer measured output spectrum (black curve) and the frequency-dependent phase (red curve) measured by FROG. (b) The temporal pulseshape provided by FROG. The full-width-half-maximum (FWHM) pulse duration is 38 fs. (c) The calculated group delay dispersion (GDD) curve, based on the FROG-measured phase in (a). At the laser central wavelength, the GDD value is 301 fs2. (d) The transform-limited pulseshape based on the measured spectrum in (a). The FWHM pulse duration is 27 fs. FROG: frequency-resolved optical gating.

Equations (2)

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R = i = 1 n ( X T H G X ¯ T H G ) ( Y S H G Y ¯ S H G ) ( n 1 ) S T H G S S H G
t o u t = Δ t 4 + 16 ( l n 2 ) 2 2 Δ t

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