Abstract

Current clinical imaging modalities do not reliably identify brain tissue regions with necrosis following radiotherapy. This creates challenges for stereotaxic biopsies and surgical-decision making. Time-resolved fluorescence spectroscopy (TRFS) provides a means to rapidly identify necrotic tissue by its distinct autofluorescence signature resulting from tissue breakdown and altered metabolic profiles in regions with radiation damage. Studies conducted in a live animal model of radiation necrosis demonstrated that necrotic tissue is characterized by respective increases of 27% and 108% in average lifetime and redox ratio, when compared with healthy tissue. Moreover, radiation-damaged tissue not visible by MRI but confirmed by histopathology, was detected by TRFS. Current results demonstrate the ability of TRFS to identify radiation-damaged brain tissue in real-time and indicates its potential to assist with surgical guidance and MRI-guided biopsy procedures.

© 2018 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

Full Article  |  PDF Article
OSA Recommended Articles
Characterization of NAD(P)H and FAD autofluorescence signatures in a Langendorff isolated-perfused rat heart model

João L. Lagarto, Benjamin T. Dyer, Clifford B. Talbot, Nicholas S. Peters, Paul M. W. French, Alexander R. Lyon, and Chris Dunsby
Biomed. Opt. Express 9(10) 4961-4978 (2018)

Spectral and lifetime domain measurements of rat brain tumors

D. Abi Haidar, B. Leh, M. Zanello, and R. Siebert
Biomed. Opt. Express 6(4) 1219-1233 (2015)

Fluorescence lifetime microscopy of NADH distinguishes alterations in cerebral metabolism in vivo

Mohammad A. Yaseen, Jason Sutin, Weicheng Wu, Buyin Fu, Hana Uhlirova, Anna Devor, David A. Boas, and Sava Sakadžić
Biomed. Opt. Express 8(5) 2368-2385 (2017)

References

  • View by:
  • |
  • |
  • |

  1. J. D. Ruben, M. Dally, M. Bailey, R. Smith, C. A. McLean, and P. Fedele, “Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy,” Int. J. Radiat. Oncol. Biol. Phys. 65, 499–508 (2006).
    [Crossref] [PubMed]
  2. P. Y. Wen and S. Kesari, “Malignant gliomas in adults,” N. Engl. J. Med. 359, 492–507 (2008).
    [Crossref] [PubMed]
  3. F. G. Aksoy and M. H. Lev, “Dynamic contrast-enhanced brain perfusion imaging: technique and clinical applications,” Semin. Ultrasound CT MR 21, 462–477 (2000).
    [Crossref]
  4. C. Asao, Y. Korogi, M. Kitajima, T. Hirai, Y. Baba, K. Makino, M. Kochi, S. Morishita, and Y. Yamashita, “Diffusion-weighted imaging of radiation-induced brain injury for differentiation from tumor recurrence,” Am. J. Neuroradiol. 26, 1455–1460 (2005).
    [PubMed]
  5. E. E. Graves, S. J. Nelson, D. B. Vigneron, L. Verhey, M. McDermott, D. Larson, S. Chang, M. D. Prados, and W. P. Dillon, “Serial proton MR spectroscopic imaging of recurrent malignant gliomas after gamma knife radiosurgery,” Am. J. Neuroradiol. 22, 613–624 (2001).
    [PubMed]
  6. F. Benard, J. Romsa, and R. Hustinx, “Imaging gliomas with positron emission tomography and single-photon emission computed tomography,” Semin. Nucl. Med. 33, 148–162 (2003).
    [Crossref] [PubMed]
  7. D. D. Langleben and G. M. Segall, “PET in differentiation of recurrent brain tumor from radiation injury,” J. Nucl. Med. 41, 1861–1867 (2000).
    [PubMed]
  8. T. Tihan, J. Barletta, I. Parney, K. Lamborn, P. K. Sneed, and S. Chang, “Prognostic value of detecting recurrent glioblastoma multiforme in surgical specimens from patients after radiotherapy: should pathology evaluation alter treatment decisions?” Hum. Pathol. 37, 272–282 (2006).
    [Crossref] [PubMed]
  9. P. A. Valdes, D. W. Roberts, F. K. Lu, and A. Golby, “Optical technologies for intraoperative neurosurgical guidance,” Neurosurg. Focus 40, E8 (2016).
    [Crossref] [PubMed]
  10. C. Fang, K. Wang, C. T. Zeng, C. W. Chi, W. T. Shang, J. Z. Ye, Y. M. Mao, Y. F. Fan, J. Yang, N. Xiang, N. Zeng, W. Zhu, C. H. Fang, and J. Tian, “Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green,” Sci. Rep. 6, 21013 (2016).
    [Crossref] [PubMed]
  11. J. Y. S. Lee and P. B. Little, “Studies of Autofluorescence in Experimentally Induced Cerebral Necrosis in Pigs,” Vet. Pathol. 17, 226–233 (1980).
    [Crossref] [PubMed]
  12. E. E. Edwin and R. Jackman, “Nature of the autofluorescent material in cerebrocortical necrosis,” J. Neurochem. 37, 1054–1056 (1981).
    [Crossref] [PubMed]
  13. R. Jackman and E. E. Edwin, “Cerebral Autofluorescence and Thiamine-Deficiency in Cerebrocortical Necrosis,” Vet. Rec. 112, 548–550 (1983).
    [Crossref] [PubMed]
  14. T. Shibahara, R. Horino, T. Taniguchi, and Y. Ando, “Autofluorescent substance and neurocyte necrosis in thiamine deficiency in cattle,” Aust. Vet. J. 77, 329–330 (1999).
    [Crossref] [PubMed]
  15. W. C. Lin, A. Mahadevan-Jansen, M. D. Johnson, R. J. Weil, and S. A. Toms, “In vivo optical spectroscopy detects radiation damage in brain tissue,” Neurosurgery 57, 518–525 (2005).
    [Crossref] [PubMed]
  16. P. V. Butte, Q. Y. Fang, J. A. Jo, W. H. Yong, B. K. Pikul, K. L. Black, and L. Marcu, “Intraoperative delineation of primary brain tumors using time-resolved fluorescence spectroscopy,” J. Biomed. Opt. 15, 027008 (2010).
    [Crossref] [PubMed]
  17. Y. H. Sun, N. Hatami, M. Yee, J. Phipps, D. S. Elson, F. Gorin, R. J. Schrot, and L. Marcu, “Fluorescence lifetime imaging microscopy for brain tumor image-guided surgery,” J. Biomed. Opt. 15, 056022 (2010).
    [Crossref] [PubMed]
  18. P. V. Butte, A. N. Mamelak, M. Nuno, S. I. Bannykh, K. L. Black, and L. Marcu, “Fluorescence lifetime spectroscopy for guided therapy of brain tumors,” Neuroimage 54, S125–S135 (2011).
    [Crossref]
  19. B. A. Hartl, H. S. W. Ma, K. S. Hansen, J. Perks, M. S. Kent, R. C. Fragoso, and L. Marcu, “The effect of radiation dose on the onset and progression of radiation-induced brain necrosis in the rat model,” Int. J. Radiat. Biol. 93, 676–682 (2017).
    [Crossref] [PubMed]
  20. “American National Standard for Safe Use of Lasers in Health Care ANSI Z136.1,” Laser Institute of America (2011).
  21. D. L. Ma, J. Bec, D. Gorpas, D. Yankelevich, and L. Marcu, “Technique for real-time tissue characterization based on scanning multispectral fluorescence lifetime spectroscopy (ms-TRFS),” Biomed. Opt. Express 6, 987–1002 (2015).
    [Crossref] [PubMed]
  22. J. Liu, Y. Sun, J. Y. Qi, and L. Marcu, “A novel method for fast and robust estimation of fluorescence decay dynamics using constrained least-squares deconvolution with Laguerre expansion,” Phys. Med. Biol. 57, 843–865 (2012).
    [Crossref] [PubMed]
  23. J. R. Lakowicz, Principles of Fluorescence Spectroscopy (SpringerUS, 2013).
  24. F. Fereidouni, D. Gorpas, D. Ma, H. Fatakdawala, and L. Marcu, “Rapid fluorescence lifetime estimation with modified phasor approach and Laguerre deconvolution: a comparative study,” Methods Appl. Fluoresc. 5(3), 035003 (2017).
    [Crossref] [PubMed]
  25. M. Morawski, G. Bruckner, T. Arendt, and R. T. Matthews, “Aggrecan: Beyond cartilage and into the brain,” Int. J. Biochem. Cell Biol. 44, 690–693 (2012).
    [Crossref] [PubMed]
  26. J. C. F. Kwok, P. Warren, and J. W. Fawcett, “Chondroitin sulfate: A key molecule in the brain matrix,” Int. J. Biochem. Cell Biol. 44, 582–586 (2012).
    [Crossref] [PubMed]
  27. I. Bjorkhem and S. Meaney, “Brain cholesterol: Long secret life behind a barrier,” Arterioscl. Throm. Vas. 24, 806–815 (2004).
    [Crossref]
  28. J. Cohen, Statistical Power Analysis for the Behavioral Sciences (Taylor & Francis, 2013).
  29. Gail M. Sullivan and Richard Feinn, “Using Effect Size-or Why the P Value Is Not Enough,” J. Grad. Med. Educ. 4, 279–282 (2012).
    [Crossref]
  30. R. G. Brereton, Chemometrics: Data Analysis for the Laboratory and Chemical Plant (Wiley, 2003).
    [Crossref]
  31. X. Y. Jiang, L. Y. Yuan, J. A. Engelbach, J. Cates, C. J. Perez-Torres, F. Gao, D. Thotala, R. E. Drzymala, R. E. Schmidt, K. M. Rich, D. E. Hallahan, J. J. H. Ackerman, and J. R. Garbow, “A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis,” Plos One 10, e0139596 (2015).
    [Crossref]
  32. C. Abram, M. Pougin, and F. Beyrau, “Temperature field measurements in liquids using ZnO thermographic phosphor tracer particles,” Exp. Fluids 57, 115 (2016).
    [Crossref]
  33. D. Greene-Schloesser, M. E. Robbins, A. M. Peiffer, E. G. Shaw, K. T. Wheeler, and M. D. Chan, “Radiation-induced brain injury: A review,” Front. Oncol. 2, 73 (2012).
    [Crossref] [PubMed]
  34. M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” P. rNatl. Acad. Sci. 104, 19494–19499 (2007).
    [Crossref]
  35. T. S. Blacker and M. R. Duchen, “Investigating mitochondrial redox state using NADH and NADPH autofluorescence,” Free Radical Bio. Med. 100, 53–65 (2016).
    [Crossref]
  36. T. S. Blacker, Z. F. Mann, J. E. Gale, M. Ziegler, A. J. Bain, G. Szabadkai, and M. R. Duchen, “Separating NADH and NADPH fluorescence in live cells and tissues using FLIM,” Nat. Commun. 5, 3936 (2014).
    [Crossref] [PubMed]
  37. W. Ying, “NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences,” Antioxid. Redox Signal. 10, 179–206 (2008).
    [Crossref]
  38. M. A. Yaseen, J. Sutin, W. Wu, B. Fu, H. Uhlirova, A. Devor, D. A. Boas, and S. Sakadžić, “Fluorescence lifetime microscopy of NADH distinguishes alterations in cerebral metabolism in vivo,” Biomed. Opt. Express 8, 2368–2385 (2017).
    [Crossref] [PubMed]
  39. K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by Complex I binding,” Biochem. 47, 9636–9645 (2008).
    [Crossref]
  40. B. Valeur and M. N. Berberan-Santos, Molecular Fluorescence: Principles and Applications (Wiley, 2013).
  41. A. Gafni and L. Brand, “Fluorescence Decay Studies of Reduced Nicotinamide Adenine-Dinucleotide in Solution and Bound to Liver Alcohol-Dehydrogenase,” Biochem. 15, 3165–3171 (1976).
    [Crossref]
  42. W. Zheng, Y. Wu, D. Li, and J. Y. Qu, “Autofluorescence of epithelial tissue: single-photon versus two-photon excitation,” J. Biomed. Opt. 13, 054010 (2008).
    [Crossref] [PubMed]
  43. M. A. Yaseen, S. Sakadzic, W. Wu, W. Becker, K. A. Kasischke, and D. A. Boas, “In vivo imaging of cerebral energy metabolism with two-photon fluorescence lifetime microscopy of NADH,” Biomed. Opt. Express 4, 307–321 (2013).
    [Crossref] [PubMed]
  44. J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic Imaging Using Two-Photon Excited NADH Intensity and Fluorescence Lifetime Imaging,” Microsc. Microanal. 18, 761–770 (2012).
    [Crossref] [PubMed]
  45. F. S. Pavone and S. Shoham, “Label-free fluorescence interrogation of brain tumors,” in Handbook of Neurophotonics (CRC Press Taylor & Francis, 2018).

2017 (3)

F. Fereidouni, D. Gorpas, D. Ma, H. Fatakdawala, and L. Marcu, “Rapid fluorescence lifetime estimation with modified phasor approach and Laguerre deconvolution: a comparative study,” Methods Appl. Fluoresc. 5(3), 035003 (2017).
[Crossref] [PubMed]

B. A. Hartl, H. S. W. Ma, K. S. Hansen, J. Perks, M. S. Kent, R. C. Fragoso, and L. Marcu, “The effect of radiation dose on the onset and progression of radiation-induced brain necrosis in the rat model,” Int. J. Radiat. Biol. 93, 676–682 (2017).
[Crossref] [PubMed]

M. A. Yaseen, J. Sutin, W. Wu, B. Fu, H. Uhlirova, A. Devor, D. A. Boas, and S. Sakadžić, “Fluorescence lifetime microscopy of NADH distinguishes alterations in cerebral metabolism in vivo,” Biomed. Opt. Express 8, 2368–2385 (2017).
[Crossref] [PubMed]

2016 (4)

C. Abram, M. Pougin, and F. Beyrau, “Temperature field measurements in liquids using ZnO thermographic phosphor tracer particles,” Exp. Fluids 57, 115 (2016).
[Crossref]

T. S. Blacker and M. R. Duchen, “Investigating mitochondrial redox state using NADH and NADPH autofluorescence,” Free Radical Bio. Med. 100, 53–65 (2016).
[Crossref]

P. A. Valdes, D. W. Roberts, F. K. Lu, and A. Golby, “Optical technologies for intraoperative neurosurgical guidance,” Neurosurg. Focus 40, E8 (2016).
[Crossref] [PubMed]

C. Fang, K. Wang, C. T. Zeng, C. W. Chi, W. T. Shang, J. Z. Ye, Y. M. Mao, Y. F. Fan, J. Yang, N. Xiang, N. Zeng, W. Zhu, C. H. Fang, and J. Tian, “Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green,” Sci. Rep. 6, 21013 (2016).
[Crossref] [PubMed]

2015 (2)

X. Y. Jiang, L. Y. Yuan, J. A. Engelbach, J. Cates, C. J. Perez-Torres, F. Gao, D. Thotala, R. E. Drzymala, R. E. Schmidt, K. M. Rich, D. E. Hallahan, J. J. H. Ackerman, and J. R. Garbow, “A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis,” Plos One 10, e0139596 (2015).
[Crossref]

D. L. Ma, J. Bec, D. Gorpas, D. Yankelevich, and L. Marcu, “Technique for real-time tissue characterization based on scanning multispectral fluorescence lifetime spectroscopy (ms-TRFS),” Biomed. Opt. Express 6, 987–1002 (2015).
[Crossref] [PubMed]

2014 (1)

T. S. Blacker, Z. F. Mann, J. E. Gale, M. Ziegler, A. J. Bain, G. Szabadkai, and M. R. Duchen, “Separating NADH and NADPH fluorescence in live cells and tissues using FLIM,” Nat. Commun. 5, 3936 (2014).
[Crossref] [PubMed]

2013 (1)

2012 (6)

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic Imaging Using Two-Photon Excited NADH Intensity and Fluorescence Lifetime Imaging,” Microsc. Microanal. 18, 761–770 (2012).
[Crossref] [PubMed]

D. Greene-Schloesser, M. E. Robbins, A. M. Peiffer, E. G. Shaw, K. T. Wheeler, and M. D. Chan, “Radiation-induced brain injury: A review,” Front. Oncol. 2, 73 (2012).
[Crossref] [PubMed]

J. Liu, Y. Sun, J. Y. Qi, and L. Marcu, “A novel method for fast and robust estimation of fluorescence decay dynamics using constrained least-squares deconvolution with Laguerre expansion,” Phys. Med. Biol. 57, 843–865 (2012).
[Crossref] [PubMed]

Gail M. Sullivan and Richard Feinn, “Using Effect Size-or Why the P Value Is Not Enough,” J. Grad. Med. Educ. 4, 279–282 (2012).
[Crossref]

M. Morawski, G. Bruckner, T. Arendt, and R. T. Matthews, “Aggrecan: Beyond cartilage and into the brain,” Int. J. Biochem. Cell Biol. 44, 690–693 (2012).
[Crossref] [PubMed]

J. C. F. Kwok, P. Warren, and J. W. Fawcett, “Chondroitin sulfate: A key molecule in the brain matrix,” Int. J. Biochem. Cell Biol. 44, 582–586 (2012).
[Crossref] [PubMed]

2011 (1)

P. V. Butte, A. N. Mamelak, M. Nuno, S. I. Bannykh, K. L. Black, and L. Marcu, “Fluorescence lifetime spectroscopy for guided therapy of brain tumors,” Neuroimage 54, S125–S135 (2011).
[Crossref]

2010 (2)

P. V. Butte, Q. Y. Fang, J. A. Jo, W. H. Yong, B. K. Pikul, K. L. Black, and L. Marcu, “Intraoperative delineation of primary brain tumors using time-resolved fluorescence spectroscopy,” J. Biomed. Opt. 15, 027008 (2010).
[Crossref] [PubMed]

Y. H. Sun, N. Hatami, M. Yee, J. Phipps, D. S. Elson, F. Gorin, R. J. Schrot, and L. Marcu, “Fluorescence lifetime imaging microscopy for brain tumor image-guided surgery,” J. Biomed. Opt. 15, 056022 (2010).
[Crossref] [PubMed]

2008 (4)

P. Y. Wen and S. Kesari, “Malignant gliomas in adults,” N. Engl. J. Med. 359, 492–507 (2008).
[Crossref] [PubMed]

W. Ying, “NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences,” Antioxid. Redox Signal. 10, 179–206 (2008).
[Crossref]

W. Zheng, Y. Wu, D. Li, and J. Y. Qu, “Autofluorescence of epithelial tissue: single-photon versus two-photon excitation,” J. Biomed. Opt. 13, 054010 (2008).
[Crossref] [PubMed]

K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by Complex I binding,” Biochem. 47, 9636–9645 (2008).
[Crossref]

2007 (1)

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” P. rNatl. Acad. Sci. 104, 19494–19499 (2007).
[Crossref]

2006 (2)

J. D. Ruben, M. Dally, M. Bailey, R. Smith, C. A. McLean, and P. Fedele, “Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy,” Int. J. Radiat. Oncol. Biol. Phys. 65, 499–508 (2006).
[Crossref] [PubMed]

T. Tihan, J. Barletta, I. Parney, K. Lamborn, P. K. Sneed, and S. Chang, “Prognostic value of detecting recurrent glioblastoma multiforme in surgical specimens from patients after radiotherapy: should pathology evaluation alter treatment decisions?” Hum. Pathol. 37, 272–282 (2006).
[Crossref] [PubMed]

2005 (2)

C. Asao, Y. Korogi, M. Kitajima, T. Hirai, Y. Baba, K. Makino, M. Kochi, S. Morishita, and Y. Yamashita, “Diffusion-weighted imaging of radiation-induced brain injury for differentiation from tumor recurrence,” Am. J. Neuroradiol. 26, 1455–1460 (2005).
[PubMed]

W. C. Lin, A. Mahadevan-Jansen, M. D. Johnson, R. J. Weil, and S. A. Toms, “In vivo optical spectroscopy detects radiation damage in brain tissue,” Neurosurgery 57, 518–525 (2005).
[Crossref] [PubMed]

2004 (1)

I. Bjorkhem and S. Meaney, “Brain cholesterol: Long secret life behind a barrier,” Arterioscl. Throm. Vas. 24, 806–815 (2004).
[Crossref]

2003 (1)

F. Benard, J. Romsa, and R. Hustinx, “Imaging gliomas with positron emission tomography and single-photon emission computed tomography,” Semin. Nucl. Med. 33, 148–162 (2003).
[Crossref] [PubMed]

2001 (1)

E. E. Graves, S. J. Nelson, D. B. Vigneron, L. Verhey, M. McDermott, D. Larson, S. Chang, M. D. Prados, and W. P. Dillon, “Serial proton MR spectroscopic imaging of recurrent malignant gliomas after gamma knife radiosurgery,” Am. J. Neuroradiol. 22, 613–624 (2001).
[PubMed]

2000 (2)

F. G. Aksoy and M. H. Lev, “Dynamic contrast-enhanced brain perfusion imaging: technique and clinical applications,” Semin. Ultrasound CT MR 21, 462–477 (2000).
[Crossref]

D. D. Langleben and G. M. Segall, “PET in differentiation of recurrent brain tumor from radiation injury,” J. Nucl. Med. 41, 1861–1867 (2000).
[PubMed]

1999 (1)

T. Shibahara, R. Horino, T. Taniguchi, and Y. Ando, “Autofluorescent substance and neurocyte necrosis in thiamine deficiency in cattle,” Aust. Vet. J. 77, 329–330 (1999).
[Crossref] [PubMed]

1983 (1)

R. Jackman and E. E. Edwin, “Cerebral Autofluorescence and Thiamine-Deficiency in Cerebrocortical Necrosis,” Vet. Rec. 112, 548–550 (1983).
[Crossref] [PubMed]

1981 (1)

E. E. Edwin and R. Jackman, “Nature of the autofluorescent material in cerebrocortical necrosis,” J. Neurochem. 37, 1054–1056 (1981).
[Crossref] [PubMed]

1980 (1)

J. Y. S. Lee and P. B. Little, “Studies of Autofluorescence in Experimentally Induced Cerebral Necrosis in Pigs,” Vet. Pathol. 17, 226–233 (1980).
[Crossref] [PubMed]

1976 (1)

A. Gafni and L. Brand, “Fluorescence Decay Studies of Reduced Nicotinamide Adenine-Dinucleotide in Solution and Bound to Liver Alcohol-Dehydrogenase,” Biochem. 15, 3165–3171 (1976).
[Crossref]

Abram, C.

C. Abram, M. Pougin, and F. Beyrau, “Temperature field measurements in liquids using ZnO thermographic phosphor tracer particles,” Exp. Fluids 57, 115 (2016).
[Crossref]

Ackerman, J. J. H.

X. Y. Jiang, L. Y. Yuan, J. A. Engelbach, J. Cates, C. J. Perez-Torres, F. Gao, D. Thotala, R. E. Drzymala, R. E. Schmidt, K. M. Rich, D. E. Hallahan, J. J. H. Ackerman, and J. R. Garbow, “A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis,” Plos One 10, e0139596 (2015).
[Crossref]

Aksoy, F. G.

F. G. Aksoy and M. H. Lev, “Dynamic contrast-enhanced brain perfusion imaging: technique and clinical applications,” Semin. Ultrasound CT MR 21, 462–477 (2000).
[Crossref]

Ando, Y.

T. Shibahara, R. Horino, T. Taniguchi, and Y. Ando, “Autofluorescent substance and neurocyte necrosis in thiamine deficiency in cattle,” Aust. Vet. J. 77, 329–330 (1999).
[Crossref] [PubMed]

Arendt, T.

M. Morawski, G. Bruckner, T. Arendt, and R. T. Matthews, “Aggrecan: Beyond cartilage and into the brain,” Int. J. Biochem. Cell Biol. 44, 690–693 (2012).
[Crossref] [PubMed]

Asao, C.

C. Asao, Y. Korogi, M. Kitajima, T. Hirai, Y. Baba, K. Makino, M. Kochi, S. Morishita, and Y. Yamashita, “Diffusion-weighted imaging of radiation-induced brain injury for differentiation from tumor recurrence,” Am. J. Neuroradiol. 26, 1455–1460 (2005).
[PubMed]

Baba, Y.

C. Asao, Y. Korogi, M. Kitajima, T. Hirai, Y. Baba, K. Makino, M. Kochi, S. Morishita, and Y. Yamashita, “Diffusion-weighted imaging of radiation-induced brain injury for differentiation from tumor recurrence,” Am. J. Neuroradiol. 26, 1455–1460 (2005).
[PubMed]

Bailey, M.

J. D. Ruben, M. Dally, M. Bailey, R. Smith, C. A. McLean, and P. Fedele, “Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy,” Int. J. Radiat. Oncol. Biol. Phys. 65, 499–508 (2006).
[Crossref] [PubMed]

Bain, A. J.

T. S. Blacker, Z. F. Mann, J. E. Gale, M. Ziegler, A. J. Bain, G. Szabadkai, and M. R. Duchen, “Separating NADH and NADPH fluorescence in live cells and tissues using FLIM,” Nat. Commun. 5, 3936 (2014).
[Crossref] [PubMed]

Balaban, R. S.

K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by Complex I binding,” Biochem. 47, 9636–9645 (2008).
[Crossref]

Bannykh, S. I.

P. V. Butte, A. N. Mamelak, M. Nuno, S. I. Bannykh, K. L. Black, and L. Marcu, “Fluorescence lifetime spectroscopy for guided therapy of brain tumors,” Neuroimage 54, S125–S135 (2011).
[Crossref]

Barletta, J.

T. Tihan, J. Barletta, I. Parney, K. Lamborn, P. K. Sneed, and S. Chang, “Prognostic value of detecting recurrent glioblastoma multiforme in surgical specimens from patients after radiotherapy: should pathology evaluation alter treatment decisions?” Hum. Pathol. 37, 272–282 (2006).
[Crossref] [PubMed]

Bec, J.

Becker, W.

Benard, F.

F. Benard, J. Romsa, and R. Hustinx, “Imaging gliomas with positron emission tomography and single-photon emission computed tomography,” Semin. Nucl. Med. 33, 148–162 (2003).
[Crossref] [PubMed]

Berberan-Santos, M. N.

B. Valeur and M. N. Berberan-Santos, Molecular Fluorescence: Principles and Applications (Wiley, 2013).

Beyrau, F.

C. Abram, M. Pougin, and F. Beyrau, “Temperature field measurements in liquids using ZnO thermographic phosphor tracer particles,” Exp. Fluids 57, 115 (2016).
[Crossref]

Bjorkhem, I.

I. Bjorkhem and S. Meaney, “Brain cholesterol: Long secret life behind a barrier,” Arterioscl. Throm. Vas. 24, 806–815 (2004).
[Crossref]

Black, K. L.

P. V. Butte, A. N. Mamelak, M. Nuno, S. I. Bannykh, K. L. Black, and L. Marcu, “Fluorescence lifetime spectroscopy for guided therapy of brain tumors,” Neuroimage 54, S125–S135 (2011).
[Crossref]

P. V. Butte, Q. Y. Fang, J. A. Jo, W. H. Yong, B. K. Pikul, K. L. Black, and L. Marcu, “Intraoperative delineation of primary brain tumors using time-resolved fluorescence spectroscopy,” J. Biomed. Opt. 15, 027008 (2010).
[Crossref] [PubMed]

Blacker, T. S.

T. S. Blacker and M. R. Duchen, “Investigating mitochondrial redox state using NADH and NADPH autofluorescence,” Free Radical Bio. Med. 100, 53–65 (2016).
[Crossref]

T. S. Blacker, Z. F. Mann, J. E. Gale, M. Ziegler, A. J. Bain, G. Szabadkai, and M. R. Duchen, “Separating NADH and NADPH fluorescence in live cells and tissues using FLIM,” Nat. Commun. 5, 3936 (2014).
[Crossref] [PubMed]

Blinova, K.

K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by Complex I binding,” Biochem. 47, 9636–9645 (2008).
[Crossref]

Boas, D. A.

Boja, E. S.

K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by Complex I binding,” Biochem. 47, 9636–9645 (2008).
[Crossref]

Brand, L.

A. Gafni and L. Brand, “Fluorescence Decay Studies of Reduced Nicotinamide Adenine-Dinucleotide in Solution and Bound to Liver Alcohol-Dehydrogenase,” Biochem. 15, 3165–3171 (1976).
[Crossref]

Brereton, R. G.

R. G. Brereton, Chemometrics: Data Analysis for the Laboratory and Chemical Plant (Wiley, 2003).
[Crossref]

Bruckner, G.

M. Morawski, G. Bruckner, T. Arendt, and R. T. Matthews, “Aggrecan: Beyond cartilage and into the brain,” Int. J. Biochem. Cell Biol. 44, 690–693 (2012).
[Crossref] [PubMed]

Butte, P. V.

P. V. Butte, A. N. Mamelak, M. Nuno, S. I. Bannykh, K. L. Black, and L. Marcu, “Fluorescence lifetime spectroscopy for guided therapy of brain tumors,” Neuroimage 54, S125–S135 (2011).
[Crossref]

P. V. Butte, Q. Y. Fang, J. A. Jo, W. H. Yong, B. K. Pikul, K. L. Black, and L. Marcu, “Intraoperative delineation of primary brain tumors using time-resolved fluorescence spectroscopy,” J. Biomed. Opt. 15, 027008 (2010).
[Crossref] [PubMed]

Cates, J.

X. Y. Jiang, L. Y. Yuan, J. A. Engelbach, J. Cates, C. J. Perez-Torres, F. Gao, D. Thotala, R. E. Drzymala, R. E. Schmidt, K. M. Rich, D. E. Hallahan, J. J. H. Ackerman, and J. R. Garbow, “A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis,” Plos One 10, e0139596 (2015).
[Crossref]

Chan, M. D.

D. Greene-Schloesser, M. E. Robbins, A. M. Peiffer, E. G. Shaw, K. T. Wheeler, and M. D. Chan, “Radiation-induced brain injury: A review,” Front. Oncol. 2, 73 (2012).
[Crossref] [PubMed]

Chang, S.

T. Tihan, J. Barletta, I. Parney, K. Lamborn, P. K. Sneed, and S. Chang, “Prognostic value of detecting recurrent glioblastoma multiforme in surgical specimens from patients after radiotherapy: should pathology evaluation alter treatment decisions?” Hum. Pathol. 37, 272–282 (2006).
[Crossref] [PubMed]

E. E. Graves, S. J. Nelson, D. B. Vigneron, L. Verhey, M. McDermott, D. Larson, S. Chang, M. D. Prados, and W. P. Dillon, “Serial proton MR spectroscopic imaging of recurrent malignant gliomas after gamma knife radiosurgery,” Am. J. Neuroradiol. 22, 613–624 (2001).
[PubMed]

Chi, C. W.

C. Fang, K. Wang, C. T. Zeng, C. W. Chi, W. T. Shang, J. Z. Ye, Y. M. Mao, Y. F. Fan, J. Yang, N. Xiang, N. Zeng, W. Zhu, C. H. Fang, and J. Tian, “Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green,” Sci. Rep. 6, 21013 (2016).
[Crossref] [PubMed]

Cohen, J.

J. Cohen, Statistical Power Analysis for the Behavioral Sciences (Taylor & Francis, 2013).

Dally, M.

J. D. Ruben, M. Dally, M. Bailey, R. Smith, C. A. McLean, and P. Fedele, “Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy,” Int. J. Radiat. Oncol. Biol. Phys. 65, 499–508 (2006).
[Crossref] [PubMed]

Devor, A.

Dillon, W. P.

E. E. Graves, S. J. Nelson, D. B. Vigneron, L. Verhey, M. McDermott, D. Larson, S. Chang, M. D. Prados, and W. P. Dillon, “Serial proton MR spectroscopic imaging of recurrent malignant gliomas after gamma knife radiosurgery,” Am. J. Neuroradiol. 22, 613–624 (2001).
[PubMed]

Drzymala, R. E.

X. Y. Jiang, L. Y. Yuan, J. A. Engelbach, J. Cates, C. J. Perez-Torres, F. Gao, D. Thotala, R. E. Drzymala, R. E. Schmidt, K. M. Rich, D. E. Hallahan, J. J. H. Ackerman, and J. R. Garbow, “A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis,” Plos One 10, e0139596 (2015).
[Crossref]

Duchen, M. R.

T. S. Blacker and M. R. Duchen, “Investigating mitochondrial redox state using NADH and NADPH autofluorescence,” Free Radical Bio. Med. 100, 53–65 (2016).
[Crossref]

T. S. Blacker, Z. F. Mann, J. E. Gale, M. Ziegler, A. J. Bain, G. Szabadkai, and M. R. Duchen, “Separating NADH and NADPH fluorescence in live cells and tissues using FLIM,” Nat. Commun. 5, 3936 (2014).
[Crossref] [PubMed]

Edwin, E. E.

R. Jackman and E. E. Edwin, “Cerebral Autofluorescence and Thiamine-Deficiency in Cerebrocortical Necrosis,” Vet. Rec. 112, 548–550 (1983).
[Crossref] [PubMed]

E. E. Edwin and R. Jackman, “Nature of the autofluorescent material in cerebrocortical necrosis,” J. Neurochem. 37, 1054–1056 (1981).
[Crossref] [PubMed]

Eickhoff, J.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” P. rNatl. Acad. Sci. 104, 19494–19499 (2007).
[Crossref]

Eliceiri, K. W.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” P. rNatl. Acad. Sci. 104, 19494–19499 (2007).
[Crossref]

Elson, D. S.

Y. H. Sun, N. Hatami, M. Yee, J. Phipps, D. S. Elson, F. Gorin, R. J. Schrot, and L. Marcu, “Fluorescence lifetime imaging microscopy for brain tumor image-guided surgery,” J. Biomed. Opt. 15, 056022 (2010).
[Crossref] [PubMed]

Engelbach, J. A.

X. Y. Jiang, L. Y. Yuan, J. A. Engelbach, J. Cates, C. J. Perez-Torres, F. Gao, D. Thotala, R. E. Drzymala, R. E. Schmidt, K. M. Rich, D. E. Hallahan, J. J. H. Ackerman, and J. R. Garbow, “A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis,” Plos One 10, e0139596 (2015).
[Crossref]

Fan, Y. F.

C. Fang, K. Wang, C. T. Zeng, C. W. Chi, W. T. Shang, J. Z. Ye, Y. M. Mao, Y. F. Fan, J. Yang, N. Xiang, N. Zeng, W. Zhu, C. H. Fang, and J. Tian, “Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green,” Sci. Rep. 6, 21013 (2016).
[Crossref] [PubMed]

Fang, C.

C. Fang, K. Wang, C. T. Zeng, C. W. Chi, W. T. Shang, J. Z. Ye, Y. M. Mao, Y. F. Fan, J. Yang, N. Xiang, N. Zeng, W. Zhu, C. H. Fang, and J. Tian, “Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green,” Sci. Rep. 6, 21013 (2016).
[Crossref] [PubMed]

Fang, C. H.

C. Fang, K. Wang, C. T. Zeng, C. W. Chi, W. T. Shang, J. Z. Ye, Y. M. Mao, Y. F. Fan, J. Yang, N. Xiang, N. Zeng, W. Zhu, C. H. Fang, and J. Tian, “Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green,” Sci. Rep. 6, 21013 (2016).
[Crossref] [PubMed]

Fang, Q. Y.

P. V. Butte, Q. Y. Fang, J. A. Jo, W. H. Yong, B. K. Pikul, K. L. Black, and L. Marcu, “Intraoperative delineation of primary brain tumors using time-resolved fluorescence spectroscopy,” J. Biomed. Opt. 15, 027008 (2010).
[Crossref] [PubMed]

Fatakdawala, H.

F. Fereidouni, D. Gorpas, D. Ma, H. Fatakdawala, and L. Marcu, “Rapid fluorescence lifetime estimation with modified phasor approach and Laguerre deconvolution: a comparative study,” Methods Appl. Fluoresc. 5(3), 035003 (2017).
[Crossref] [PubMed]

Fawcett, J. W.

J. C. F. Kwok, P. Warren, and J. W. Fawcett, “Chondroitin sulfate: A key molecule in the brain matrix,” Int. J. Biochem. Cell Biol. 44, 582–586 (2012).
[Crossref] [PubMed]

Fedele, P.

J. D. Ruben, M. Dally, M. Bailey, R. Smith, C. A. McLean, and P. Fedele, “Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy,” Int. J. Radiat. Oncol. Biol. Phys. 65, 499–508 (2006).
[Crossref] [PubMed]

Feinn, Richard

Gail M. Sullivan and Richard Feinn, “Using Effect Size-or Why the P Value Is Not Enough,” J. Grad. Med. Educ. 4, 279–282 (2012).
[Crossref]

Fereidouni, F.

F. Fereidouni, D. Gorpas, D. Ma, H. Fatakdawala, and L. Marcu, “Rapid fluorescence lifetime estimation with modified phasor approach and Laguerre deconvolution: a comparative study,” Methods Appl. Fluoresc. 5(3), 035003 (2017).
[Crossref] [PubMed]

Fragoso, R. C.

B. A. Hartl, H. S. W. Ma, K. S. Hansen, J. Perks, M. S. Kent, R. C. Fragoso, and L. Marcu, “The effect of radiation dose on the onset and progression of radiation-induced brain necrosis in the rat model,” Int. J. Radiat. Biol. 93, 676–682 (2017).
[Crossref] [PubMed]

Fu, B.

Gafni, A.

A. Gafni and L. Brand, “Fluorescence Decay Studies of Reduced Nicotinamide Adenine-Dinucleotide in Solution and Bound to Liver Alcohol-Dehydrogenase,” Biochem. 15, 3165–3171 (1976).
[Crossref]

Gale, J. E.

T. S. Blacker, Z. F. Mann, J. E. Gale, M. Ziegler, A. J. Bain, G. Szabadkai, and M. R. Duchen, “Separating NADH and NADPH fluorescence in live cells and tissues using FLIM,” Nat. Commun. 5, 3936 (2014).
[Crossref] [PubMed]

Gao, F.

X. Y. Jiang, L. Y. Yuan, J. A. Engelbach, J. Cates, C. J. Perez-Torres, F. Gao, D. Thotala, R. E. Drzymala, R. E. Schmidt, K. M. Rich, D. E. Hallahan, J. J. H. Ackerman, and J. R. Garbow, “A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis,” Plos One 10, e0139596 (2015).
[Crossref]

Garbow, J. R.

X. Y. Jiang, L. Y. Yuan, J. A. Engelbach, J. Cates, C. J. Perez-Torres, F. Gao, D. Thotala, R. E. Drzymala, R. E. Schmidt, K. M. Rich, D. E. Hallahan, J. J. H. Ackerman, and J. R. Garbow, “A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis,” Plos One 10, e0139596 (2015).
[Crossref]

Gendron-Fitzpatrick, A.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” P. rNatl. Acad. Sci. 104, 19494–19499 (2007).
[Crossref]

Golby, A.

P. A. Valdes, D. W. Roberts, F. K. Lu, and A. Golby, “Optical technologies for intraoperative neurosurgical guidance,” Neurosurg. Focus 40, E8 (2016).
[Crossref] [PubMed]

Gorin, F.

Y. H. Sun, N. Hatami, M. Yee, J. Phipps, D. S. Elson, F. Gorin, R. J. Schrot, and L. Marcu, “Fluorescence lifetime imaging microscopy for brain tumor image-guided surgery,” J. Biomed. Opt. 15, 056022 (2010).
[Crossref] [PubMed]

Gorpas, D.

F. Fereidouni, D. Gorpas, D. Ma, H. Fatakdawala, and L. Marcu, “Rapid fluorescence lifetime estimation with modified phasor approach and Laguerre deconvolution: a comparative study,” Methods Appl. Fluoresc. 5(3), 035003 (2017).
[Crossref] [PubMed]

D. L. Ma, J. Bec, D. Gorpas, D. Yankelevich, and L. Marcu, “Technique for real-time tissue characterization based on scanning multispectral fluorescence lifetime spectroscopy (ms-TRFS),” Biomed. Opt. Express 6, 987–1002 (2015).
[Crossref] [PubMed]

Graves, E. E.

E. E. Graves, S. J. Nelson, D. B. Vigneron, L. Verhey, M. McDermott, D. Larson, S. Chang, M. D. Prados, and W. P. Dillon, “Serial proton MR spectroscopic imaging of recurrent malignant gliomas after gamma knife radiosurgery,” Am. J. Neuroradiol. 22, 613–624 (2001).
[PubMed]

Greene-Schloesser, D.

D. Greene-Schloesser, M. E. Robbins, A. M. Peiffer, E. G. Shaw, K. T. Wheeler, and M. D. Chan, “Radiation-induced brain injury: A review,” Front. Oncol. 2, 73 (2012).
[Crossref] [PubMed]

Griffiths, G. L.

K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by Complex I binding,” Biochem. 47, 9636–9645 (2008).
[Crossref]

Hallahan, D. E.

X. Y. Jiang, L. Y. Yuan, J. A. Engelbach, J. Cates, C. J. Perez-Torres, F. Gao, D. Thotala, R. E. Drzymala, R. E. Schmidt, K. M. Rich, D. E. Hallahan, J. J. H. Ackerman, and J. R. Garbow, “A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis,” Plos One 10, e0139596 (2015).
[Crossref]

Hallworth, R.

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic Imaging Using Two-Photon Excited NADH Intensity and Fluorescence Lifetime Imaging,” Microsc. Microanal. 18, 761–770 (2012).
[Crossref] [PubMed]

Hansen, K. S.

B. A. Hartl, H. S. W. Ma, K. S. Hansen, J. Perks, M. S. Kent, R. C. Fragoso, and L. Marcu, “The effect of radiation dose on the onset and progression of radiation-induced brain necrosis in the rat model,” Int. J. Radiat. Biol. 93, 676–682 (2017).
[Crossref] [PubMed]

Hartl, B. A.

B. A. Hartl, H. S. W. Ma, K. S. Hansen, J. Perks, M. S. Kent, R. C. Fragoso, and L. Marcu, “The effect of radiation dose on the onset and progression of radiation-induced brain necrosis in the rat model,” Int. J. Radiat. Biol. 93, 676–682 (2017).
[Crossref] [PubMed]

Hatami, N.

Y. H. Sun, N. Hatami, M. Yee, J. Phipps, D. S. Elson, F. Gorin, R. J. Schrot, and L. Marcu, “Fluorescence lifetime imaging microscopy for brain tumor image-guided surgery,” J. Biomed. Opt. 15, 056022 (2010).
[Crossref] [PubMed]

Hecht, C.

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic Imaging Using Two-Photon Excited NADH Intensity and Fluorescence Lifetime Imaging,” Microsc. Microanal. 18, 761–770 (2012).
[Crossref] [PubMed]

Hirai, T.

C. Asao, Y. Korogi, M. Kitajima, T. Hirai, Y. Baba, K. Makino, M. Kochi, S. Morishita, and Y. Yamashita, “Diffusion-weighted imaging of radiation-induced brain injury for differentiation from tumor recurrence,” Am. J. Neuroradiol. 26, 1455–1460 (2005).
[PubMed]

Horino, R.

T. Shibahara, R. Horino, T. Taniguchi, and Y. Ando, “Autofluorescent substance and neurocyte necrosis in thiamine deficiency in cattle,” Aust. Vet. J. 77, 329–330 (1999).
[Crossref] [PubMed]

Hustinx, R.

F. Benard, J. Romsa, and R. Hustinx, “Imaging gliomas with positron emission tomography and single-photon emission computed tomography,” Semin. Nucl. Med. 33, 148–162 (2003).
[Crossref] [PubMed]

Jackman, R.

R. Jackman and E. E. Edwin, “Cerebral Autofluorescence and Thiamine-Deficiency in Cerebrocortical Necrosis,” Vet. Rec. 112, 548–550 (1983).
[Crossref] [PubMed]

E. E. Edwin and R. Jackman, “Nature of the autofluorescent material in cerebrocortical necrosis,” J. Neurochem. 37, 1054–1056 (1981).
[Crossref] [PubMed]

Jiang, X. Y.

X. Y. Jiang, L. Y. Yuan, J. A. Engelbach, J. Cates, C. J. Perez-Torres, F. Gao, D. Thotala, R. E. Drzymala, R. E. Schmidt, K. M. Rich, D. E. Hallahan, J. J. H. Ackerman, and J. R. Garbow, “A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis,” Plos One 10, e0139596 (2015).
[Crossref]

Jo, J. A.

P. V. Butte, Q. Y. Fang, J. A. Jo, W. H. Yong, B. K. Pikul, K. L. Black, and L. Marcu, “Intraoperative delineation of primary brain tumors using time-resolved fluorescence spectroscopy,” J. Biomed. Opt. 15, 027008 (2010).
[Crossref] [PubMed]

Johnson, M. D.

W. C. Lin, A. Mahadevan-Jansen, M. D. Johnson, R. J. Weil, and S. A. Toms, “In vivo optical spectroscopy detects radiation damage in brain tissue,” Neurosurgery 57, 518–525 (2005).
[Crossref] [PubMed]

Kasischke, K. A.

Kent, M. S.

B. A. Hartl, H. S. W. Ma, K. S. Hansen, J. Perks, M. S. Kent, R. C. Fragoso, and L. Marcu, “The effect of radiation dose on the onset and progression of radiation-induced brain necrosis in the rat model,” Int. J. Radiat. Biol. 93, 676–682 (2017).
[Crossref] [PubMed]

Kesari, S.

P. Y. Wen and S. Kesari, “Malignant gliomas in adults,” N. Engl. J. Med. 359, 492–507 (2008).
[Crossref] [PubMed]

Kitajima, M.

C. Asao, Y. Korogi, M. Kitajima, T. Hirai, Y. Baba, K. Makino, M. Kochi, S. Morishita, and Y. Yamashita, “Diffusion-weighted imaging of radiation-induced brain injury for differentiation from tumor recurrence,” Am. J. Neuroradiol. 26, 1455–1460 (2005).
[PubMed]

Kochi, M.

C. Asao, Y. Korogi, M. Kitajima, T. Hirai, Y. Baba, K. Makino, M. Kochi, S. Morishita, and Y. Yamashita, “Diffusion-weighted imaging of radiation-induced brain injury for differentiation from tumor recurrence,” Am. J. Neuroradiol. 26, 1455–1460 (2005).
[PubMed]

Korogi, Y.

C. Asao, Y. Korogi, M. Kitajima, T. Hirai, Y. Baba, K. Makino, M. Kochi, S. Morishita, and Y. Yamashita, “Diffusion-weighted imaging of radiation-induced brain injury for differentiation from tumor recurrence,” Am. J. Neuroradiol. 26, 1455–1460 (2005).
[PubMed]

Kwok, J. C. F.

J. C. F. Kwok, P. Warren, and J. W. Fawcett, “Chondroitin sulfate: A key molecule in the brain matrix,” Int. J. Biochem. Cell Biol. 44, 582–586 (2012).
[Crossref] [PubMed]

Lakowicz, J. R.

J. R. Lakowicz, Principles of Fluorescence Spectroscopy (SpringerUS, 2013).

Lamborn, K.

T. Tihan, J. Barletta, I. Parney, K. Lamborn, P. K. Sneed, and S. Chang, “Prognostic value of detecting recurrent glioblastoma multiforme in surgical specimens from patients after radiotherapy: should pathology evaluation alter treatment decisions?” Hum. Pathol. 37, 272–282 (2006).
[Crossref] [PubMed]

Langleben, D. D.

D. D. Langleben and G. M. Segall, “PET in differentiation of recurrent brain tumor from radiation injury,” J. Nucl. Med. 41, 1861–1867 (2000).
[PubMed]

Larson, D.

E. E. Graves, S. J. Nelson, D. B. Vigneron, L. Verhey, M. McDermott, D. Larson, S. Chang, M. D. Prados, and W. P. Dillon, “Serial proton MR spectroscopic imaging of recurrent malignant gliomas after gamma knife radiosurgery,” Am. J. Neuroradiol. 22, 613–624 (2001).
[PubMed]

Lee, J. Y. S.

J. Y. S. Lee and P. B. Little, “Studies of Autofluorescence in Experimentally Induced Cerebral Necrosis in Pigs,” Vet. Pathol. 17, 226–233 (1980).
[Crossref] [PubMed]

Lev, M. H.

F. G. Aksoy and M. H. Lev, “Dynamic contrast-enhanced brain perfusion imaging: technique and clinical applications,” Semin. Ultrasound CT MR 21, 462–477 (2000).
[Crossref]

Levine, R. L.

K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by Complex I binding,” Biochem. 47, 9636–9645 (2008).
[Crossref]

Li, D.

W. Zheng, Y. Wu, D. Li, and J. Y. Qu, “Autofluorescence of epithelial tissue: single-photon versus two-photon excitation,” J. Biomed. Opt. 13, 054010 (2008).
[Crossref] [PubMed]

Lin, W. C.

W. C. Lin, A. Mahadevan-Jansen, M. D. Johnson, R. J. Weil, and S. A. Toms, “In vivo optical spectroscopy detects radiation damage in brain tissue,” Neurosurgery 57, 518–525 (2005).
[Crossref] [PubMed]

Little, P. B.

J. Y. S. Lee and P. B. Little, “Studies of Autofluorescence in Experimentally Induced Cerebral Necrosis in Pigs,” Vet. Pathol. 17, 226–233 (1980).
[Crossref] [PubMed]

Liu, J.

J. Liu, Y. Sun, J. Y. Qi, and L. Marcu, “A novel method for fast and robust estimation of fluorescence decay dynamics using constrained least-squares deconvolution with Laguerre expansion,” Phys. Med. Biol. 57, 843–865 (2012).
[Crossref] [PubMed]

Lu, F. K.

P. A. Valdes, D. W. Roberts, F. K. Lu, and A. Golby, “Optical technologies for intraoperative neurosurgical guidance,” Neurosurg. Focus 40, E8 (2016).
[Crossref] [PubMed]

Ma, D.

F. Fereidouni, D. Gorpas, D. Ma, H. Fatakdawala, and L. Marcu, “Rapid fluorescence lifetime estimation with modified phasor approach and Laguerre deconvolution: a comparative study,” Methods Appl. Fluoresc. 5(3), 035003 (2017).
[Crossref] [PubMed]

Ma, D. L.

Ma, H. S. W.

B. A. Hartl, H. S. W. Ma, K. S. Hansen, J. Perks, M. S. Kent, R. C. Fragoso, and L. Marcu, “The effect of radiation dose on the onset and progression of radiation-induced brain necrosis in the rat model,” Int. J. Radiat. Biol. 93, 676–682 (2017).
[Crossref] [PubMed]

Mahadevan-Jansen, A.

W. C. Lin, A. Mahadevan-Jansen, M. D. Johnson, R. J. Weil, and S. A. Toms, “In vivo optical spectroscopy detects radiation damage in brain tissue,” Neurosurgery 57, 518–525 (2005).
[Crossref] [PubMed]

Makino, K.

C. Asao, Y. Korogi, M. Kitajima, T. Hirai, Y. Baba, K. Makino, M. Kochi, S. Morishita, and Y. Yamashita, “Diffusion-weighted imaging of radiation-induced brain injury for differentiation from tumor recurrence,” Am. J. Neuroradiol. 26, 1455–1460 (2005).
[PubMed]

Mamelak, A. N.

P. V. Butte, A. N. Mamelak, M. Nuno, S. I. Bannykh, K. L. Black, and L. Marcu, “Fluorescence lifetime spectroscopy for guided therapy of brain tumors,” Neuroimage 54, S125–S135 (2011).
[Crossref]

Mann, Z. F.

T. S. Blacker, Z. F. Mann, J. E. Gale, M. Ziegler, A. J. Bain, G. Szabadkai, and M. R. Duchen, “Separating NADH and NADPH fluorescence in live cells and tissues using FLIM,” Nat. Commun. 5, 3936 (2014).
[Crossref] [PubMed]

Mao, Y. M.

C. Fang, K. Wang, C. T. Zeng, C. W. Chi, W. T. Shang, J. Z. Ye, Y. M. Mao, Y. F. Fan, J. Yang, N. Xiang, N. Zeng, W. Zhu, C. H. Fang, and J. Tian, “Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green,” Sci. Rep. 6, 21013 (2016).
[Crossref] [PubMed]

Marcu, L.

B. A. Hartl, H. S. W. Ma, K. S. Hansen, J. Perks, M. S. Kent, R. C. Fragoso, and L. Marcu, “The effect of radiation dose on the onset and progression of radiation-induced brain necrosis in the rat model,” Int. J. Radiat. Biol. 93, 676–682 (2017).
[Crossref] [PubMed]

F. Fereidouni, D. Gorpas, D. Ma, H. Fatakdawala, and L. Marcu, “Rapid fluorescence lifetime estimation with modified phasor approach and Laguerre deconvolution: a comparative study,” Methods Appl. Fluoresc. 5(3), 035003 (2017).
[Crossref] [PubMed]

D. L. Ma, J. Bec, D. Gorpas, D. Yankelevich, and L. Marcu, “Technique for real-time tissue characterization based on scanning multispectral fluorescence lifetime spectroscopy (ms-TRFS),” Biomed. Opt. Express 6, 987–1002 (2015).
[Crossref] [PubMed]

J. Liu, Y. Sun, J. Y. Qi, and L. Marcu, “A novel method for fast and robust estimation of fluorescence decay dynamics using constrained least-squares deconvolution with Laguerre expansion,” Phys. Med. Biol. 57, 843–865 (2012).
[Crossref] [PubMed]

P. V. Butte, A. N. Mamelak, M. Nuno, S. I. Bannykh, K. L. Black, and L. Marcu, “Fluorescence lifetime spectroscopy for guided therapy of brain tumors,” Neuroimage 54, S125–S135 (2011).
[Crossref]

Y. H. Sun, N. Hatami, M. Yee, J. Phipps, D. S. Elson, F. Gorin, R. J. Schrot, and L. Marcu, “Fluorescence lifetime imaging microscopy for brain tumor image-guided surgery,” J. Biomed. Opt. 15, 056022 (2010).
[Crossref] [PubMed]

P. V. Butte, Q. Y. Fang, J. A. Jo, W. H. Yong, B. K. Pikul, K. L. Black, and L. Marcu, “Intraoperative delineation of primary brain tumors using time-resolved fluorescence spectroscopy,” J. Biomed. Opt. 15, 027008 (2010).
[Crossref] [PubMed]

Marquardt, M. M.

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic Imaging Using Two-Photon Excited NADH Intensity and Fluorescence Lifetime Imaging,” Microsc. Microanal. 18, 761–770 (2012).
[Crossref] [PubMed]

Matthews, R. T.

M. Morawski, G. Bruckner, T. Arendt, and R. T. Matthews, “Aggrecan: Beyond cartilage and into the brain,” Int. J. Biochem. Cell Biol. 44, 690–693 (2012).
[Crossref] [PubMed]

McDermott, M.

E. E. Graves, S. J. Nelson, D. B. Vigneron, L. Verhey, M. McDermott, D. Larson, S. Chang, M. D. Prados, and W. P. Dillon, “Serial proton MR spectroscopic imaging of recurrent malignant gliomas after gamma knife radiosurgery,” Am. J. Neuroradiol. 22, 613–624 (2001).
[PubMed]

McLean, C. A.

J. D. Ruben, M. Dally, M. Bailey, R. Smith, C. A. McLean, and P. Fedele, “Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy,” Int. J. Radiat. Oncol. Biol. Phys. 65, 499–508 (2006).
[Crossref] [PubMed]

Meaney, S.

I. Bjorkhem and S. Meaney, “Brain cholesterol: Long secret life behind a barrier,” Arterioscl. Throm. Vas. 24, 806–815 (2004).
[Crossref]

Morawski, M.

M. Morawski, G. Bruckner, T. Arendt, and R. T. Matthews, “Aggrecan: Beyond cartilage and into the brain,” Int. J. Biochem. Cell Biol. 44, 690–693 (2012).
[Crossref] [PubMed]

Morishita, S.

C. Asao, Y. Korogi, M. Kitajima, T. Hirai, Y. Baba, K. Makino, M. Kochi, S. Morishita, and Y. Yamashita, “Diffusion-weighted imaging of radiation-induced brain injury for differentiation from tumor recurrence,” Am. J. Neuroradiol. 26, 1455–1460 (2005).
[PubMed]

Nelson, S. J.

E. E. Graves, S. J. Nelson, D. B. Vigneron, L. Verhey, M. McDermott, D. Larson, S. Chang, M. D. Prados, and W. P. Dillon, “Serial proton MR spectroscopic imaging of recurrent malignant gliomas after gamma knife radiosurgery,” Am. J. Neuroradiol. 22, 613–624 (2001).
[PubMed]

Nichols, M. G.

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic Imaging Using Two-Photon Excited NADH Intensity and Fluorescence Lifetime Imaging,” Microsc. Microanal. 18, 761–770 (2012).
[Crossref] [PubMed]

Nuno, M.

P. V. Butte, A. N. Mamelak, M. Nuno, S. I. Bannykh, K. L. Black, and L. Marcu, “Fluorescence lifetime spectroscopy for guided therapy of brain tumors,” Neuroimage 54, S125–S135 (2011).
[Crossref]

Parney, I.

T. Tihan, J. Barletta, I. Parney, K. Lamborn, P. K. Sneed, and S. Chang, “Prognostic value of detecting recurrent glioblastoma multiforme in surgical specimens from patients after radiotherapy: should pathology evaluation alter treatment decisions?” Hum. Pathol. 37, 272–282 (2006).
[Crossref] [PubMed]

Pavone, F. S.

F. S. Pavone and S. Shoham, “Label-free fluorescence interrogation of brain tumors,” in Handbook of Neurophotonics (CRC Press Taylor & Francis, 2018).

Peiffer, A. M.

D. Greene-Schloesser, M. E. Robbins, A. M. Peiffer, E. G. Shaw, K. T. Wheeler, and M. D. Chan, “Radiation-induced brain injury: A review,” Front. Oncol. 2, 73 (2012).
[Crossref] [PubMed]

Perez-Torres, C. J.

X. Y. Jiang, L. Y. Yuan, J. A. Engelbach, J. Cates, C. J. Perez-Torres, F. Gao, D. Thotala, R. E. Drzymala, R. E. Schmidt, K. M. Rich, D. E. Hallahan, J. J. H. Ackerman, and J. R. Garbow, “A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis,” Plos One 10, e0139596 (2015).
[Crossref]

Perks, J.

B. A. Hartl, H. S. W. Ma, K. S. Hansen, J. Perks, M. S. Kent, R. C. Fragoso, and L. Marcu, “The effect of radiation dose on the onset and progression of radiation-induced brain necrosis in the rat model,” Int. J. Radiat. Biol. 93, 676–682 (2017).
[Crossref] [PubMed]

Phipps, J.

Y. H. Sun, N. Hatami, M. Yee, J. Phipps, D. S. Elson, F. Gorin, R. J. Schrot, and L. Marcu, “Fluorescence lifetime imaging microscopy for brain tumor image-guided surgery,” J. Biomed. Opt. 15, 056022 (2010).
[Crossref] [PubMed]

Pikul, B. K.

P. V. Butte, Q. Y. Fang, J. A. Jo, W. H. Yong, B. K. Pikul, K. L. Black, and L. Marcu, “Intraoperative delineation of primary brain tumors using time-resolved fluorescence spectroscopy,” J. Biomed. Opt. 15, 027008 (2010).
[Crossref] [PubMed]

Pougin, M.

C. Abram, M. Pougin, and F. Beyrau, “Temperature field measurements in liquids using ZnO thermographic phosphor tracer particles,” Exp. Fluids 57, 115 (2016).
[Crossref]

Prados, M. D.

E. E. Graves, S. J. Nelson, D. B. Vigneron, L. Verhey, M. McDermott, D. Larson, S. Chang, M. D. Prados, and W. P. Dillon, “Serial proton MR spectroscopic imaging of recurrent malignant gliomas after gamma knife radiosurgery,” Am. J. Neuroradiol. 22, 613–624 (2001).
[PubMed]

Qi, J. Y.

J. Liu, Y. Sun, J. Y. Qi, and L. Marcu, “A novel method for fast and robust estimation of fluorescence decay dynamics using constrained least-squares deconvolution with Laguerre expansion,” Phys. Med. Biol. 57, 843–865 (2012).
[Crossref] [PubMed]

Qu, J. Y.

W. Zheng, Y. Wu, D. Li, and J. Y. Qu, “Autofluorescence of epithelial tissue: single-photon versus two-photon excitation,” J. Biomed. Opt. 13, 054010 (2008).
[Crossref] [PubMed]

Ramanujam, N.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” P. rNatl. Acad. Sci. 104, 19494–19499 (2007).
[Crossref]

Rich, K. M.

X. Y. Jiang, L. Y. Yuan, J. A. Engelbach, J. Cates, C. J. Perez-Torres, F. Gao, D. Thotala, R. E. Drzymala, R. E. Schmidt, K. M. Rich, D. E. Hallahan, J. J. H. Ackerman, and J. R. Garbow, “A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis,” Plos One 10, e0139596 (2015).
[Crossref]

Riching, K. M.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” P. rNatl. Acad. Sci. 104, 19494–19499 (2007).
[Crossref]

Robbins, M. E.

D. Greene-Schloesser, M. E. Robbins, A. M. Peiffer, E. G. Shaw, K. T. Wheeler, and M. D. Chan, “Radiation-induced brain injury: A review,” Front. Oncol. 2, 73 (2012).
[Crossref] [PubMed]

Roberts, D. W.

P. A. Valdes, D. W. Roberts, F. K. Lu, and A. Golby, “Optical technologies for intraoperative neurosurgical guidance,” Neurosurg. Focus 40, E8 (2016).
[Crossref] [PubMed]

Romsa, J.

F. Benard, J. Romsa, and R. Hustinx, “Imaging gliomas with positron emission tomography and single-photon emission computed tomography,” Semin. Nucl. Med. 33, 148–162 (2003).
[Crossref] [PubMed]

Ruben, J. D.

J. D. Ruben, M. Dally, M. Bailey, R. Smith, C. A. McLean, and P. Fedele, “Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy,” Int. J. Radiat. Oncol. Biol. Phys. 65, 499–508 (2006).
[Crossref] [PubMed]

Ruddy, B.

K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by Complex I binding,” Biochem. 47, 9636–9645 (2008).
[Crossref]

Sakadzic, S.

Sakadžic, S.

Schmidt, R. E.

X. Y. Jiang, L. Y. Yuan, J. A. Engelbach, J. Cates, C. J. Perez-Torres, F. Gao, D. Thotala, R. E. Drzymala, R. E. Schmidt, K. M. Rich, D. E. Hallahan, J. J. H. Ackerman, and J. R. Garbow, “A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis,” Plos One 10, e0139596 (2015).
[Crossref]

Schrot, R. J.

Y. H. Sun, N. Hatami, M. Yee, J. Phipps, D. S. Elson, F. Gorin, R. J. Schrot, and L. Marcu, “Fluorescence lifetime imaging microscopy for brain tumor image-guided surgery,” J. Biomed. Opt. 15, 056022 (2010).
[Crossref] [PubMed]

Segall, G. M.

D. D. Langleben and G. M. Segall, “PET in differentiation of recurrent brain tumor from radiation injury,” J. Nucl. Med. 41, 1861–1867 (2000).
[PubMed]

Shang, W. T.

C. Fang, K. Wang, C. T. Zeng, C. W. Chi, W. T. Shang, J. Z. Ye, Y. M. Mao, Y. F. Fan, J. Yang, N. Xiang, N. Zeng, W. Zhu, C. H. Fang, and J. Tian, “Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green,” Sci. Rep. 6, 21013 (2016).
[Crossref] [PubMed]

Shaw, E. G.

D. Greene-Schloesser, M. E. Robbins, A. M. Peiffer, E. G. Shaw, K. T. Wheeler, and M. D. Chan, “Radiation-induced brain injury: A review,” Front. Oncol. 2, 73 (2012).
[Crossref] [PubMed]

Shi, Z. D.

K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by Complex I binding,” Biochem. 47, 9636–9645 (2008).
[Crossref]

Shibahara, T.

T. Shibahara, R. Horino, T. Taniguchi, and Y. Ando, “Autofluorescent substance and neurocyte necrosis in thiamine deficiency in cattle,” Aust. Vet. J. 77, 329–330 (1999).
[Crossref] [PubMed]

Shoham, S.

F. S. Pavone and S. Shoham, “Label-free fluorescence interrogation of brain tumors,” in Handbook of Neurophotonics (CRC Press Taylor & Francis, 2018).

Skala, M. C.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” P. rNatl. Acad. Sci. 104, 19494–19499 (2007).
[Crossref]

Smith, R.

J. D. Ruben, M. Dally, M. Bailey, R. Smith, C. A. McLean, and P. Fedele, “Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy,” Int. J. Radiat. Oncol. Biol. Phys. 65, 499–508 (2006).
[Crossref] [PubMed]

Sneed, P. K.

T. Tihan, J. Barletta, I. Parney, K. Lamborn, P. K. Sneed, and S. Chang, “Prognostic value of detecting recurrent glioblastoma multiforme in surgical specimens from patients after radiotherapy: should pathology evaluation alter treatment decisions?” Hum. Pathol. 37, 272–282 (2006).
[Crossref] [PubMed]

Sullivan, Gail M.

Gail M. Sullivan and Richard Feinn, “Using Effect Size-or Why the P Value Is Not Enough,” J. Grad. Med. Educ. 4, 279–282 (2012).
[Crossref]

Sun, Y.

J. Liu, Y. Sun, J. Y. Qi, and L. Marcu, “A novel method for fast and robust estimation of fluorescence decay dynamics using constrained least-squares deconvolution with Laguerre expansion,” Phys. Med. Biol. 57, 843–865 (2012).
[Crossref] [PubMed]

Sun, Y. H.

Y. H. Sun, N. Hatami, M. Yee, J. Phipps, D. S. Elson, F. Gorin, R. J. Schrot, and L. Marcu, “Fluorescence lifetime imaging microscopy for brain tumor image-guided surgery,” J. Biomed. Opt. 15, 056022 (2010).
[Crossref] [PubMed]

Sutin, J.

Szabadkai, G.

T. S. Blacker, Z. F. Mann, J. E. Gale, M. Ziegler, A. J. Bain, G. Szabadkai, and M. R. Duchen, “Separating NADH and NADPH fluorescence in live cells and tissues using FLIM,” Nat. Commun. 5, 3936 (2014).
[Crossref] [PubMed]

Taniguchi, T.

T. Shibahara, R. Horino, T. Taniguchi, and Y. Ando, “Autofluorescent substance and neurocyte necrosis in thiamine deficiency in cattle,” Aust. Vet. J. 77, 329–330 (1999).
[Crossref] [PubMed]

Thotala, D.

X. Y. Jiang, L. Y. Yuan, J. A. Engelbach, J. Cates, C. J. Perez-Torres, F. Gao, D. Thotala, R. E. Drzymala, R. E. Schmidt, K. M. Rich, D. E. Hallahan, J. J. H. Ackerman, and J. R. Garbow, “A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis,” Plos One 10, e0139596 (2015).
[Crossref]

Tian, J.

C. Fang, K. Wang, C. T. Zeng, C. W. Chi, W. T. Shang, J. Z. Ye, Y. M. Mao, Y. F. Fan, J. Yang, N. Xiang, N. Zeng, W. Zhu, C. H. Fang, and J. Tian, “Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green,” Sci. Rep. 6, 21013 (2016).
[Crossref] [PubMed]

Tihan, T.

T. Tihan, J. Barletta, I. Parney, K. Lamborn, P. K. Sneed, and S. Chang, “Prognostic value of detecting recurrent glioblastoma multiforme in surgical specimens from patients after radiotherapy: should pathology evaluation alter treatment decisions?” Hum. Pathol. 37, 272–282 (2006).
[Crossref] [PubMed]

Toms, S. A.

W. C. Lin, A. Mahadevan-Jansen, M. D. Johnson, R. J. Weil, and S. A. Toms, “In vivo optical spectroscopy detects radiation damage in brain tissue,” Neurosurgery 57, 518–525 (2005).
[Crossref] [PubMed]

Uhlirova, H.

Valdes, P. A.

P. A. Valdes, D. W. Roberts, F. K. Lu, and A. Golby, “Optical technologies for intraoperative neurosurgical guidance,” Neurosurg. Focus 40, E8 (2016).
[Crossref] [PubMed]

Valeur, B.

B. Valeur and M. N. Berberan-Santos, Molecular Fluorescence: Principles and Applications (Wiley, 2013).

Vergen, J.

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic Imaging Using Two-Photon Excited NADH Intensity and Fluorescence Lifetime Imaging,” Microsc. Microanal. 18, 761–770 (2012).
[Crossref] [PubMed]

Verhey, L.

E. E. Graves, S. J. Nelson, D. B. Vigneron, L. Verhey, M. McDermott, D. Larson, S. Chang, M. D. Prados, and W. P. Dillon, “Serial proton MR spectroscopic imaging of recurrent malignant gliomas after gamma knife radiosurgery,” Am. J. Neuroradiol. 22, 613–624 (2001).
[PubMed]

Vigneron, D. B.

E. E. Graves, S. J. Nelson, D. B. Vigneron, L. Verhey, M. McDermott, D. Larson, S. Chang, M. D. Prados, and W. P. Dillon, “Serial proton MR spectroscopic imaging of recurrent malignant gliomas after gamma knife radiosurgery,” Am. J. Neuroradiol. 22, 613–624 (2001).
[PubMed]

Wang, K.

C. Fang, K. Wang, C. T. Zeng, C. W. Chi, W. T. Shang, J. Z. Ye, Y. M. Mao, Y. F. Fan, J. Yang, N. Xiang, N. Zeng, W. Zhu, C. H. Fang, and J. Tian, “Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green,” Sci. Rep. 6, 21013 (2016).
[Crossref] [PubMed]

Warren, P.

J. C. F. Kwok, P. Warren, and J. W. Fawcett, “Chondroitin sulfate: A key molecule in the brain matrix,” Int. J. Biochem. Cell Biol. 44, 582–586 (2012).
[Crossref] [PubMed]

Weil, R. J.

W. C. Lin, A. Mahadevan-Jansen, M. D. Johnson, R. J. Weil, and S. A. Toms, “In vivo optical spectroscopy detects radiation damage in brain tissue,” Neurosurgery 57, 518–525 (2005).
[Crossref] [PubMed]

Wen, P. Y.

P. Y. Wen and S. Kesari, “Malignant gliomas in adults,” N. Engl. J. Med. 359, 492–507 (2008).
[Crossref] [PubMed]

Wheeler, K. T.

D. Greene-Schloesser, M. E. Robbins, A. M. Peiffer, E. G. Shaw, K. T. Wheeler, and M. D. Chan, “Radiation-induced brain injury: A review,” Front. Oncol. 2, 73 (2012).
[Crossref] [PubMed]

White, J. G.

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” P. rNatl. Acad. Sci. 104, 19494–19499 (2007).
[Crossref]

Wu, W.

Wu, Y.

W. Zheng, Y. Wu, D. Li, and J. Y. Qu, “Autofluorescence of epithelial tissue: single-photon versus two-photon excitation,” J. Biomed. Opt. 13, 054010 (2008).
[Crossref] [PubMed]

Xiang, N.

C. Fang, K. Wang, C. T. Zeng, C. W. Chi, W. T. Shang, J. Z. Ye, Y. M. Mao, Y. F. Fan, J. Yang, N. Xiang, N. Zeng, W. Zhu, C. H. Fang, and J. Tian, “Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green,” Sci. Rep. 6, 21013 (2016).
[Crossref] [PubMed]

Yamashita, Y.

C. Asao, Y. Korogi, M. Kitajima, T. Hirai, Y. Baba, K. Makino, M. Kochi, S. Morishita, and Y. Yamashita, “Diffusion-weighted imaging of radiation-induced brain injury for differentiation from tumor recurrence,” Am. J. Neuroradiol. 26, 1455–1460 (2005).
[PubMed]

Yang, J.

C. Fang, K. Wang, C. T. Zeng, C. W. Chi, W. T. Shang, J. Z. Ye, Y. M. Mao, Y. F. Fan, J. Yang, N. Xiang, N. Zeng, W. Zhu, C. H. Fang, and J. Tian, “Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green,” Sci. Rep. 6, 21013 (2016).
[Crossref] [PubMed]

Yankelevich, D.

Yaseen, M. A.

Ye, J. Z.

C. Fang, K. Wang, C. T. Zeng, C. W. Chi, W. T. Shang, J. Z. Ye, Y. M. Mao, Y. F. Fan, J. Yang, N. Xiang, N. Zeng, W. Zhu, C. H. Fang, and J. Tian, “Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green,” Sci. Rep. 6, 21013 (2016).
[Crossref] [PubMed]

Yee, M.

Y. H. Sun, N. Hatami, M. Yee, J. Phipps, D. S. Elson, F. Gorin, R. J. Schrot, and L. Marcu, “Fluorescence lifetime imaging microscopy for brain tumor image-guided surgery,” J. Biomed. Opt. 15, 056022 (2010).
[Crossref] [PubMed]

Ying, W.

W. Ying, “NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences,” Antioxid. Redox Signal. 10, 179–206 (2008).
[Crossref]

Yong, W. H.

P. V. Butte, Q. Y. Fang, J. A. Jo, W. H. Yong, B. K. Pikul, K. L. Black, and L. Marcu, “Intraoperative delineation of primary brain tumors using time-resolved fluorescence spectroscopy,” J. Biomed. Opt. 15, 027008 (2010).
[Crossref] [PubMed]

Yuan, L. Y.

X. Y. Jiang, L. Y. Yuan, J. A. Engelbach, J. Cates, C. J. Perez-Torres, F. Gao, D. Thotala, R. E. Drzymala, R. E. Schmidt, K. M. Rich, D. E. Hallahan, J. J. H. Ackerman, and J. R. Garbow, “A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis,” Plos One 10, e0139596 (2015).
[Crossref]

Zeng, C. T.

C. Fang, K. Wang, C. T. Zeng, C. W. Chi, W. T. Shang, J. Z. Ye, Y. M. Mao, Y. F. Fan, J. Yang, N. Xiang, N. Zeng, W. Zhu, C. H. Fang, and J. Tian, “Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green,” Sci. Rep. 6, 21013 (2016).
[Crossref] [PubMed]

Zeng, N.

C. Fang, K. Wang, C. T. Zeng, C. W. Chi, W. T. Shang, J. Z. Ye, Y. M. Mao, Y. F. Fan, J. Yang, N. Xiang, N. Zeng, W. Zhu, C. H. Fang, and J. Tian, “Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green,” Sci. Rep. 6, 21013 (2016).
[Crossref] [PubMed]

Zheng, W.

W. Zheng, Y. Wu, D. Li, and J. Y. Qu, “Autofluorescence of epithelial tissue: single-photon versus two-photon excitation,” J. Biomed. Opt. 13, 054010 (2008).
[Crossref] [PubMed]

Zholudeva, L. V.

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic Imaging Using Two-Photon Excited NADH Intensity and Fluorescence Lifetime Imaging,” Microsc. Microanal. 18, 761–770 (2012).
[Crossref] [PubMed]

Zhu, W.

C. Fang, K. Wang, C. T. Zeng, C. W. Chi, W. T. Shang, J. Z. Ye, Y. M. Mao, Y. F. Fan, J. Yang, N. Xiang, N. Zeng, W. Zhu, C. H. Fang, and J. Tian, “Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green,” Sci. Rep. 6, 21013 (2016).
[Crossref] [PubMed]

Ziegler, M.

T. S. Blacker, Z. F. Mann, J. E. Gale, M. Ziegler, A. J. Bain, G. Szabadkai, and M. R. Duchen, “Separating NADH and NADPH fluorescence in live cells and tissues using FLIM,” Nat. Commun. 5, 3936 (2014).
[Crossref] [PubMed]

Am. J. Neuroradiol. (2)

C. Asao, Y. Korogi, M. Kitajima, T. Hirai, Y. Baba, K. Makino, M. Kochi, S. Morishita, and Y. Yamashita, “Diffusion-weighted imaging of radiation-induced brain injury for differentiation from tumor recurrence,” Am. J. Neuroradiol. 26, 1455–1460 (2005).
[PubMed]

E. E. Graves, S. J. Nelson, D. B. Vigneron, L. Verhey, M. McDermott, D. Larson, S. Chang, M. D. Prados, and W. P. Dillon, “Serial proton MR spectroscopic imaging of recurrent malignant gliomas after gamma knife radiosurgery,” Am. J. Neuroradiol. 22, 613–624 (2001).
[PubMed]

Antioxid. Redox Signal. (1)

W. Ying, “NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences,” Antioxid. Redox Signal. 10, 179–206 (2008).
[Crossref]

Arterioscl. Throm. Vas. (1)

I. Bjorkhem and S. Meaney, “Brain cholesterol: Long secret life behind a barrier,” Arterioscl. Throm. Vas. 24, 806–815 (2004).
[Crossref]

Aust. Vet. J. (1)

T. Shibahara, R. Horino, T. Taniguchi, and Y. Ando, “Autofluorescent substance and neurocyte necrosis in thiamine deficiency in cattle,” Aust. Vet. J. 77, 329–330 (1999).
[Crossref] [PubMed]

Biochem. (2)

K. Blinova, R. L. Levine, E. S. Boja, G. L. Griffiths, Z. D. Shi, B. Ruddy, and R. S. Balaban, “Mitochondrial NADH fluorescence is enhanced by Complex I binding,” Biochem. 47, 9636–9645 (2008).
[Crossref]

A. Gafni and L. Brand, “Fluorescence Decay Studies of Reduced Nicotinamide Adenine-Dinucleotide in Solution and Bound to Liver Alcohol-Dehydrogenase,” Biochem. 15, 3165–3171 (1976).
[Crossref]

Biomed. Opt. Express (3)

Exp. Fluids (1)

C. Abram, M. Pougin, and F. Beyrau, “Temperature field measurements in liquids using ZnO thermographic phosphor tracer particles,” Exp. Fluids 57, 115 (2016).
[Crossref]

Free Radical Bio. Med. (1)

T. S. Blacker and M. R. Duchen, “Investigating mitochondrial redox state using NADH and NADPH autofluorescence,” Free Radical Bio. Med. 100, 53–65 (2016).
[Crossref]

Front. Oncol. (1)

D. Greene-Schloesser, M. E. Robbins, A. M. Peiffer, E. G. Shaw, K. T. Wheeler, and M. D. Chan, “Radiation-induced brain injury: A review,” Front. Oncol. 2, 73 (2012).
[Crossref] [PubMed]

Hum. Pathol. (1)

T. Tihan, J. Barletta, I. Parney, K. Lamborn, P. K. Sneed, and S. Chang, “Prognostic value of detecting recurrent glioblastoma multiforme in surgical specimens from patients after radiotherapy: should pathology evaluation alter treatment decisions?” Hum. Pathol. 37, 272–282 (2006).
[Crossref] [PubMed]

Int. J. Biochem. Cell Biol. (2)

M. Morawski, G. Bruckner, T. Arendt, and R. T. Matthews, “Aggrecan: Beyond cartilage and into the brain,” Int. J. Biochem. Cell Biol. 44, 690–693 (2012).
[Crossref] [PubMed]

J. C. F. Kwok, P. Warren, and J. W. Fawcett, “Chondroitin sulfate: A key molecule in the brain matrix,” Int. J. Biochem. Cell Biol. 44, 582–586 (2012).
[Crossref] [PubMed]

Int. J. Radiat. Biol. (1)

B. A. Hartl, H. S. W. Ma, K. S. Hansen, J. Perks, M. S. Kent, R. C. Fragoso, and L. Marcu, “The effect of radiation dose on the onset and progression of radiation-induced brain necrosis in the rat model,” Int. J. Radiat. Biol. 93, 676–682 (2017).
[Crossref] [PubMed]

Int. J. Radiat. Oncol. Biol. Phys. (1)

J. D. Ruben, M. Dally, M. Bailey, R. Smith, C. A. McLean, and P. Fedele, “Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy,” Int. J. Radiat. Oncol. Biol. Phys. 65, 499–508 (2006).
[Crossref] [PubMed]

J. Biomed. Opt. (3)

P. V. Butte, Q. Y. Fang, J. A. Jo, W. H. Yong, B. K. Pikul, K. L. Black, and L. Marcu, “Intraoperative delineation of primary brain tumors using time-resolved fluorescence spectroscopy,” J. Biomed. Opt. 15, 027008 (2010).
[Crossref] [PubMed]

Y. H. Sun, N. Hatami, M. Yee, J. Phipps, D. S. Elson, F. Gorin, R. J. Schrot, and L. Marcu, “Fluorescence lifetime imaging microscopy for brain tumor image-guided surgery,” J. Biomed. Opt. 15, 056022 (2010).
[Crossref] [PubMed]

W. Zheng, Y. Wu, D. Li, and J. Y. Qu, “Autofluorescence of epithelial tissue: single-photon versus two-photon excitation,” J. Biomed. Opt. 13, 054010 (2008).
[Crossref] [PubMed]

J. Grad. Med. Educ. (1)

Gail M. Sullivan and Richard Feinn, “Using Effect Size-or Why the P Value Is Not Enough,” J. Grad. Med. Educ. 4, 279–282 (2012).
[Crossref]

J. Neurochem. (1)

E. E. Edwin and R. Jackman, “Nature of the autofluorescent material in cerebrocortical necrosis,” J. Neurochem. 37, 1054–1056 (1981).
[Crossref] [PubMed]

J. Nucl. Med. (1)

D. D. Langleben and G. M. Segall, “PET in differentiation of recurrent brain tumor from radiation injury,” J. Nucl. Med. 41, 1861–1867 (2000).
[PubMed]

Methods Appl. Fluoresc. (1)

F. Fereidouni, D. Gorpas, D. Ma, H. Fatakdawala, and L. Marcu, “Rapid fluorescence lifetime estimation with modified phasor approach and Laguerre deconvolution: a comparative study,” Methods Appl. Fluoresc. 5(3), 035003 (2017).
[Crossref] [PubMed]

Microsc. Microanal. (1)

J. Vergen, C. Hecht, L. V. Zholudeva, M. M. Marquardt, R. Hallworth, and M. G. Nichols, “Metabolic Imaging Using Two-Photon Excited NADH Intensity and Fluorescence Lifetime Imaging,” Microsc. Microanal. 18, 761–770 (2012).
[Crossref] [PubMed]

N. Engl. J. Med. (1)

P. Y. Wen and S. Kesari, “Malignant gliomas in adults,” N. Engl. J. Med. 359, 492–507 (2008).
[Crossref] [PubMed]

Nat. Commun. (1)

T. S. Blacker, Z. F. Mann, J. E. Gale, M. Ziegler, A. J. Bain, G. Szabadkai, and M. R. Duchen, “Separating NADH and NADPH fluorescence in live cells and tissues using FLIM,” Nat. Commun. 5, 3936 (2014).
[Crossref] [PubMed]

Neuroimage (1)

P. V. Butte, A. N. Mamelak, M. Nuno, S. I. Bannykh, K. L. Black, and L. Marcu, “Fluorescence lifetime spectroscopy for guided therapy of brain tumors,” Neuroimage 54, S125–S135 (2011).
[Crossref]

Neurosurg. Focus (1)

P. A. Valdes, D. W. Roberts, F. K. Lu, and A. Golby, “Optical technologies for intraoperative neurosurgical guidance,” Neurosurg. Focus 40, E8 (2016).
[Crossref] [PubMed]

Neurosurgery (1)

W. C. Lin, A. Mahadevan-Jansen, M. D. Johnson, R. J. Weil, and S. A. Toms, “In vivo optical spectroscopy detects radiation damage in brain tissue,” Neurosurgery 57, 518–525 (2005).
[Crossref] [PubMed]

P. rNatl. Acad. Sci. (1)

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” P. rNatl. Acad. Sci. 104, 19494–19499 (2007).
[Crossref]

Phys. Med. Biol. (1)

J. Liu, Y. Sun, J. Y. Qi, and L. Marcu, “A novel method for fast and robust estimation of fluorescence decay dynamics using constrained least-squares deconvolution with Laguerre expansion,” Phys. Med. Biol. 57, 843–865 (2012).
[Crossref] [PubMed]

Plos One (1)

X. Y. Jiang, L. Y. Yuan, J. A. Engelbach, J. Cates, C. J. Perez-Torres, F. Gao, D. Thotala, R. E. Drzymala, R. E. Schmidt, K. M. Rich, D. E. Hallahan, J. J. H. Ackerman, and J. R. Garbow, “A Gamma-Knife-Enabled Mouse Model of Cerebral Single-Hemisphere Delayed Radiation Necrosis,” Plos One 10, e0139596 (2015).
[Crossref]

Sci. Rep. (1)

C. Fang, K. Wang, C. T. Zeng, C. W. Chi, W. T. Shang, J. Z. Ye, Y. M. Mao, Y. F. Fan, J. Yang, N. Xiang, N. Zeng, W. Zhu, C. H. Fang, and J. Tian, “Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green,” Sci. Rep. 6, 21013 (2016).
[Crossref] [PubMed]

Semin. Nucl. Med. (1)

F. Benard, J. Romsa, and R. Hustinx, “Imaging gliomas with positron emission tomography and single-photon emission computed tomography,” Semin. Nucl. Med. 33, 148–162 (2003).
[Crossref] [PubMed]

Semin. Ultrasound CT MR (1)

F. G. Aksoy and M. H. Lev, “Dynamic contrast-enhanced brain perfusion imaging: technique and clinical applications,” Semin. Ultrasound CT MR 21, 462–477 (2000).
[Crossref]

Vet. Pathol. (1)

J. Y. S. Lee and P. B. Little, “Studies of Autofluorescence in Experimentally Induced Cerebral Necrosis in Pigs,” Vet. Pathol. 17, 226–233 (1980).
[Crossref] [PubMed]

Vet. Rec. (1)

R. Jackman and E. E. Edwin, “Cerebral Autofluorescence and Thiamine-Deficiency in Cerebrocortical Necrosis,” Vet. Rec. 112, 548–550 (1983).
[Crossref] [PubMed]

Other (6)

“American National Standard for Safe Use of Lasers in Health Care ANSI Z136.1,” Laser Institute of America (2011).

J. R. Lakowicz, Principles of Fluorescence Spectroscopy (SpringerUS, 2013).

J. Cohen, Statistical Power Analysis for the Behavioral Sciences (Taylor & Francis, 2013).

R. G. Brereton, Chemometrics: Data Analysis for the Laboratory and Chemical Plant (Wiley, 2003).
[Crossref]

F. S. Pavone and S. Shoham, “Label-free fluorescence interrogation of brain tumors,” in Handbook of Neurophotonics (CRC Press Taylor & Francis, 2018).

B. Valeur and M. N. Berberan-Santos, Molecular Fluorescence: Principles and Applications (Wiley, 2013).

Cited By

OSA participates in Crossref's Cited-By Linking service. Citing articles from OSA journals and other participating publishers are listed here.

Alert me when this article is cited.


Figures (9)

Fig. 1
Fig. 1 Timeline and overview of in vivo experimental methods; n indicates number of animals per group. (A) Radiation dose plan overlaid onto axial CT scan with the animal placed in prone position; 20-, 30-, 40-, 50-, 60-Gy isodose lines are shown. A 1-cm-bolus (not shown) was placed on the rat’s head to maximize isodose coverage in the brain. (B) Preoperative axial T2-weighted MRI used for surgical planning. (C) Overhead image of the burr hole pattern on top of rat skull corresponding to where vertical depth scans with TRFS were performed. The central hole on each hemisphere, indicated by solid-lined black circles, is where p-TRFS scans were performed (dash-lined circles for ms-TRFS) and the dashed black horizontal line denotes the scan plane location of B, E, and F. (D) Assessment of brain tissue during live surgery where the fiber was stereotaxically inserted and progressed with a custom-built motorized fiber holder. (E) Postoperative axial T2-weighted MRI showing the needle track locations. (F) Corresponding H&E stained histology section of the same region as B and E, also showing the presence of needle tracks. (G) Histology at 5 mm below the dorsal surface of the brain with ms-TRFS and p-TRFS needle tracks denoted with white and black arrows, respectively. Inset shows zoomed in image for a single ms-TRFS needle track (scale bars are 2.0 and 0.2 mm). The lateral bounds of tissue damage, observed as reduced pigmentation around each needle track, is well contained and not extending to adjacent tracks.
Fig. 2
Fig. 2 Fluorescence lifetimes from both the p-TRFS and ms-TRFS measurements are in good agreement. Channel 2 (A) and channel 3 (B) average lifetimes from the p-TRFS (grayed boxes) and ms-TRFS (white boxes) measurements are shown. The values for p-TRFS points were calculated using intensity weighted averages of the average lifetimes at individual wavelengths corresponding to the ms-TRFS channel windows (see Fig. 4(A)–(B)). Values shown are mean ± SD; * ES > 0.5 and ** ES > 0.8.
Fig. 3
Fig. 3 Fluorescence intensities and average lifetimes from ms-TRFS measurements correspond to features observed in T2-weighted MRI scans and H&E stained histology. Representative preoperative MRI scans with ms-TRFS channel 2 fluorescence intensity (A) and average lifetime (B) measurements overlaid; corresponding H&E stained histology are shown below (C). The left ventricle has been marked with a white arrow on the necrosis MRI image and the approximate regions of necrosis have been indicated with a dashed line.
Fig. 4
Fig. 4 p-TRFS measurements from pre-necrosis and necrosis rat brain tissue. Necrotic tissue demonstrates significantly longer lifetimes and increased redox state relative to control healthy tissues with p-TRFS measurements. (A–B) Normalized integrated intensity and average fluorescence lifetime; solid lines indicate the mean, with the shaded region showing mean ± SEM. The spectral integration windows for each of the three channels of the real-time ms-TRFS system are shown in gray. * P < 0.05, ** P < 0.01, *** P < 0.001 compared to corresponding control healthy tissue. (C) Representative H&E histology images at 10× magnification of the pre-necrotic and necrotic tissues along with their corresponding controls are presented. The scale bar is 100 μm. (D) Representative MRI images from each of the four tissue types; the approximate location of the corresponding histology shown in C is indicated with an arrow. (E) Full width at 70% of maximum values of the fluorescence intensity spectrum. (F) The redox ratio (fluorescence intensity of FAD to that of NAD(P)H) for the four tissue types. For E and F, *** ES < 0.001 compared to corresponding control healthy tissue. The number of samples indicated in the legends is the total number of spectra acquired for each tissue type.
Fig. 5
Fig. 5 Biexponential and spectral summation fitting analysis of p-TRFS data. Changes in the bound populations of NAD(P)H are the primary source of the increases in lifetimes observed. Biexponential fitting of the p-TRFS measurements for each of the tissue types; protein-bound fraction β2 (A), fluorescence lifetime of unbound fraction τ1 (B), and fluorescence lifetime of protein-bound fraction τ2 (C). Spectral summation fitting analysis of the p-TRFS measurements. (D) The average measurements from healthy control and necrosis measurements, as well as NAD(P)H (combined as a single plot here), ECM/Cholesterol, and FAD intensity spectra normalized to peak value. (E) The control and necrosis spectra plotted along with their fit, normalized to the area under the curve (AUC). The coefficient of determination (R2) for the fit of control and necrosis were 0.96 and 0.99, respectively.
Fig. 6
Fig. 6 In vitro cell culture studies using p-TRFS demonstrate similar trends to those found in vivo. The effects of the cellular membrane disrupter, saponin, and the cytochrome oxidase inhibitor, sodium azide (NaN3), on normalized fluorescence intensity (A) and average lifetime (B) of F98 cells suspended in PBS. Solid lines indicate the mean and shaded regions showing mean ± SEM. To demonstrate the relative spectral contributions from NAD(P)H and the cells themselves, these spectra are plotted along with the two primary tissue types; normalized fluorescence intensity (C) and average lifetime (D). Note the spectrally flat lifetime of the pure fluorophore NAD(P)H solution relative to the spectrally changing cell and tissue lifetimes.
Fig. 7
Fig. 7 Real-time tissue assessment from ms-TRFS system demonstrate similar tends as p-TRFS for pre-necrotic and necrotic tissues. (A–B) Normalized fluorescence intensity and average lifetime from the ms-TRFS channels (channel 1: 370–410 nm, channel 2: 456–484 nm, channel 3: 515–565 nm) comparing the four tissue types. (C–D) Three-dimensional visualization of the three most discriminating ms-TRFS parameters. Representative needle track in interrogated brain region with necrosis (4.0×0.9 mm2 field of view) shows heterogeneity in regions with necrosis. T2-weighted MRI scan (E), corresponding H&E stained histology at 2× magnification (F), corresponding channel 2 fluorescence normalized intensity (G) and average lifetime (H). * ES > 0.5, ** ES > 0.8, and *** ES > 1.2 compared to corresponding control healthy tissue.
Fig. 8
Fig. 8 Real-time ms-TRFS measurements detect subtle changes in the age of healthy non-irradiated control animals, as well as healthy tissues in irradiated animals. (A) Comparing the healthy tissues from both hemispheres between the two non-irradiated control groups (pre-necrosis controls at ∼24 weeks old, necrosis controls at ∼31 weeks old). (B–C) Differences between the left and right hemispheres for the pre-necrosis controls and necrosis controls. (D) The tissue which received a radiation dose but did not form into necrosis (Adjacent to Necrosis) were also compared to the healthy tissue from the contralateral hemisphere (Contralateral) of irradiated necrosis animals as well as the healthy tissue of the necrosis control animals (Control). Most significant ms-TRFS parameters are plotted for each case; channel 2 normalized fluorescence intensity (top) and average lifetime (middle), and redox ratio (bottom). Color coded diagrams of each animal group’s brain at the top inset indicate where the different compared tissues were from; note that all left hemispheres were not irradiated. * ES > 0.5 and ** ES > 0.8.
Fig. 9
Fig. 9 Real-time ms-TRFS discriminates between healthy and stratified histological grades of necrosis. Representative histology images of the different grades of brain necrosis; all tissue is shown at 10× magnification and stained with H&E. Grade 0: normal healthy (A); Grade I: micro-hemorrhages present (B); Grade II: inflammation and minor tissue loss (C); Grade III: edema, extensive tissue loss, and calcifications (D). Histological images taken from the lateral thalamus region of the brain, roughly corresponding to the peak radiation dose and focalization of necrosis formation. Scale bar shown is 100 μm. Comparison between control healthy, Grade I, Grade II, and Grade III necrotic tissue types for integrated intensities (E), average lifetimes (F), and redox ratio (G). * ES > 0.5, ** ES > 0.8, and *** ES > 1.2 compared to control healthy tissue.

Tables (2)

Tables Icon

Table 1 An SVM classifier was constructed to separate necrotic from healthy control tissue using fluorescence lifetime parameters and was validated using a LOOCV protocol. Sensitivity (SN) of necrosis identification, specificity (SP) of identification of healthy tissue, positive predictive value (PPV), and negative predictive value (NPV) for the two instrumentation systems, ms-TRFS and p-TRFS, are shown. As a methodological validation, the classification performance was also evaluated for the p-TRFS data converted to the three channels of the ms-TRFS system.

Tables Icon

Table 2 Summary of the ms-TRFS measurements comparing the different tissues types from all studied groups; mean ± SD are shown.

Equations (7)

Equations on this page are rendered with MathJax. Learn more.

τ ^ avg = δ t i = 0 N 1 i h ^ ( i ) i = 0 N 1 h ^ ( i ) .
I ( t ) = α 1 e ( t / τ 1 ) + α 2 e ( t / τ 2 ) ,
β l = α l τ l α 1 τ 1 + α 2 τ 2 ,
τ avg = β 1 τ 1 + β 2 τ 2 .
redox ratio Int 600 Int 465 Int Ch . 3 Int Ch . 2 ,
Int Ch . j = k = λ 1 λ 2 Int k
τ Ch . j = k = λ 1 λ 2 τ k Int k k = λ 1 λ 2 Int k

Metrics