Advances in Imaging: Brain Tumors to Alzheimer’s Disease

Main Article Content

Rameshwar Patil, MD
Yosef Koronyo, MD
Alexander V. Ljubimov, MD
Brenda Salumbides, MD
Adam Mamelak, MD
Pallavi R. Gangalum, MD
Hui Ding, MD
Jose Portilla-Arias, MD
Eggehard Holler, MD
Pramod Butte, MD
Maya Koronyo-Hamaoui, MD
Julia Y. Ljubimova, MD
Keith L. Black, MD


Professor Black and colleagues have been working to improve the quality and sensitivity of imaging in the early detection of conditions from brain tumors to Alzheimer’s disease to enhance treatment protocols and patient management. Professor Black et al introduced nanopar- ticles to improve MRI imaging. These nanoparticles consist of poly (b-L- malic acid (PMLA)) conjugates with monoclonal antibodies ((mAbs)) and Gd-DOTA. These are known as MRI nano-imaging agents (NIA). Most importantly, they can penetrate the endothelial blood-brain barrier (BBB) to reach brain tumors (primary or metas- tasis). This is effective in cases of brain tumors or breast cancer or other cancers such as lung cancer and gastric cancer having HER2 and/or EGFR positive crossing BBB. By the covalent conjugation of MR contrast (NIA), the MRI virtual biopsy can differentiate brain tumors from infections or other brain pathological conditions. The brain’s intrinsic natural fluorescence such as NADH, FAD, lipopig- ments and porphyrin in the brain tissue can be identified by using time resolved fluorescence spectroscopy (TRFS) which is operated through the use of ultra-short laser. TRFS produces various color bands to differentiate the tumor from normal brain tissue in real time and registers the data on a 3D map. This is significant, as this will provide a greatly improved assessment methodology of tissue type. Consequently, this will potentially result in shorter operation times as well as more satisfactory tumor removal. In the detection of Alzheimer disease, amyloid plaque is deposited in retina tissue (including the RGC, RNFL and inner plexiform layer) which can produce a fluorescence effect by using curcumin as a contrast. This is then shown by human retina amyloid imaging device. Immunotherapies with glatiramer acetate (GA) have been shown to reduce amyloid deposits in brain and retinal AB deposits in mice. The study of advanced imaging technology and techniques including NIA, TRFS and the detection of amyloid plaque in Alzheimer disease are very important approaches to create a new era for diagnostic and therapeutic management of brain tumors and other cancers (HER2 and/or EGFR positive). This pioneering work by Professor Black, and colleagues, gives rise to a new hope for cancer patients for targeted therapy and for immunotherapies in Alzheimer’s disease.

Article Details

How to Cite
Patil R, Koronyo Y, Ljubimov AV, Salumbides B, Mamelak A, Gangalum PR, Ding H, Portilla-Arias J, Holler E, Butte P, Koronyo-Hamaoui M, Ljubimova JY, Black KL. Advances in Imaging: Brain Tumors to Alzheimer’s Disease. BKK Med J [Internet]. 2015 Sep. 18 [cited 2024 Apr. 15];10(1):83. Available from:
Medical Images


1. Steeg PS, Camphausen KA, Smith QR. Brain Metastases as Preventive and Therapeutic Targets. Nat Rev Cancer 2011;11:352-63.
2. Khanfir A, Lahiani F, Bouzguenda R, et al. Prognostic Factors and Survival in Metastatic Breast Cancer: A Single Institution Experience. Rep Pract Oncol Radiother 2013;18:127-32.
3. Ranjan T, Abrey LE. Current Management of Metastatic Brain Disease. Neurotherapeutics 2009;6: 598-603.
4. Lu J, Steeg PS, Price JE, et al. Breast Cancer Metastasis: Challenges and Opportunities. Cancer Res 2009;69:4951-3.
5. Vona-Davis L, Rose DP, Gadiyaram V, et al. Breast Cancer Pathology, Receptor Status, and Patterns of Metastasis in a Rural Appalachian Population. J Cancer Epidemiol 2014;2014:170634.
6. Lin NU, Amiri-Kordestani L, Palmieri D, et al. CNS Metastases in Breast Cancer: Old Challenge, New Frontiers. Clin Cancer Res 2013;19:6404-18.
7. Eldredge HB, Denittis A, Duhadaway JB, et al. Concurrent Whole Brain Radiotherapy and Short-Course Chloroquine in Patients with Brain Metastases: a Pilot Trial. J Radiat Oncol 2013;2:315-21.
8. Nayak L, Lee EQ, Wen PY. Epidemiology of Brain Metastases. Curr Oncol Rep 2012;14:48-54.
9. Baselga J. Targeting Tyrosine Kinases in Cancer: the Second Wave. Science 2006;312:1175-8.
10. Renfrow JJ, Lesser GJ. Molecular Subtyping of Brain Metastases and Implications for Therapy. Curr Treat Options Oncol 2013;14:514-27.
11. Lin NU, Claus E, Sohl J, et al. Sites of Distant Recurrence and Clinical Outcomes in Patients with Metastatic Triple-Negative Breast Cancer: High Incidence of Central Nervous System Metastases. Cancer 2008; 113:2638-45.
12. Schouten LJ, Rutten J, Huveneers HA, et al. Incidence of Brain Metastases in a Cohort of Patients with Carcinoma of the Breast, Colon, Kidney, and Lung and Melanoma. Cancer 2002;94:2698-705.
13. Brabletz T, Lyden D, Steeg PS, et al. Roadblocks to Translational Advances on Metastasis Research. Nat Med 2013;19:1104-9.
14. Gallego Perez-Larraya J, Hildebrand J. Brain Metastases. Handb Clin Neurol 2014;121:1143-57.
15. Jia W, Lu R, Martin TA, et al. The Role of Claudin-5 in Blood-Brain Barrier (BBB) and Brain Metastases (Review). Mol Med Repts 2014;9:779-85.
16. Lin NU. Targeted Therapies in Brain Metastases. Curr Treat Options Neurol 2014;16:276.
17. Inoue S, Patil R, Portilla-Arias J, et al. Nanobiopolymer for Direct Targeting and Inhibition of EGFR Expression in Triple Negative Breast Cancer. PLoS One 2012; 7:e31070.
18. Markman JL, Rekechenetskiy A, Holler E, et al. Nanomedicine Therapeutic Approaches to Overcome Cancer Drug Resistance. Adv Drug Deliv Rev 2013;65:1866-79.
19. Pardridge WM. Blood-Brain Barrier Drug Delivery of IgG Fusion Proteins with a Transferrin Receptor Monoclonal Antibody. Expert Opin Drug Deliv 2015;12:207-22.
20. Bickel U, Yoshikawa T, Pardridge WM. Delivery of Peptides and Proteins Through the Blood-Brain Barrier. Adv Drug Deliv Rev 2001;46:247-79.
21. Daniels TR, Bernabeu E, Rodriguez JA, et al. The Transferrin Receptor and the Targeted Delivery of Therapeutic Agents Against Cancer. Biochim Biophys Acta 2012; 1820:291-317.
22. Ljubimova JY, Portilla-Arias J, Patil R, et al. Toxicity and Efficacy Evaluation of Multiple Targeted Polymalic Acid Conjugates for Triple-Negative Breast Cancer Treatment. J Drug Target 2013;21:956-67.
23. Lee BS, Fujita M, Khazenzon NM, et al. Polycefin, a New Prototype of a Multifunctional Nanoconjugate Based on Poly (↕-L-Malic Acid) for Drug Delivery. Bioconjug Chem 2006;17:317-26.
24. Inoue S, Ding H, Portilla-Arias J, et al. Polymalic Acid- Based Nanobiopolymer Provides Efficient Systemic Breast Cancer Treatment by Inhibiting Both HER2/Neu Receptor Synthesis and Activity. Cancer Res 2011; 71:1454-64.
25. Pestalozzi BC, Brignoli S. Trastuzumab in CSF. J Clin Oncol 2000;18:2349-51.
26. Sun M, Behrens C, Feng L, et al. HER Family Receptor Abnormalities in Lung Cancer Brain Metastases and Corresponding Primary Tumors. Clin Cancer Res 2009; 15:4829-37.
27. Hu J, Ljubimova JY, Inoue S, et al. Phosphodiesterase Type 5 Inhibitors Increase Herceptin Transport and Treatment Efficacy in Mouse Metastatic Brain Tumor Models. PLoS One 2010;5:e10108.
28. Emlet DR, Gupta P, Holgado-Madruga M, et al. Targeting a Glioblastoma Cancer Stem-Cell Population Defined by EGF Receptor Variant III. Cancer Res 2014;74:1238-49.
29. Moelling K, Schad K, Bosse M, et al. Regulation of Raf-Akt Cross-Talk. J Biol Chem 2002;277:31099-106.
30. Chautard E, Ouedraogo ZG, Biau J, et al. Role of Akt in Human Malignant Glioma: from Oncogenesis to Tumor Aggressiveness. J Neurooncol 2014;117:205-15.
31. Ding H, Inoue S, Ljubimov AV, et al. Inhibition of Brain Tumor Growth by Intravenous Poly (↕-L-Malic Acid) Nanobioconjugate with Ph-Dependent Drug Release. Proc Natl Acad Sci USA 2010;107:18143-8.
32. Langer R, Weissleder, R. Nanotechnology. JAMA 2015; 313:135-6.
33. Hatake K, Tokudome N, Ito Y. Next Generation Molecular Targeted Agents for Breast Cancer: Focus on EGFR and VEGFR Pathways. Breast Cancer 2007;14:132-49.
34. Peddi PF, Hurvitz SA. PI3K Pathway Inhibitors for the Treatment of Brain Metastases with a Focus on HER2+ Breast Cancer. J Neurooncol 2014;117:7-13.
35. Butte PV, Fang Q, Jo JA, et al. Intra-operative delineation of primary brain tumors using time-resolved fluorescence spectroscopy. μJ Biomed Opt§ 2010;15:027008.
36. Butte PV, Pikul BK, Hever A, et al. Diagnosis of meningioma by time-resolved fluorescence spectroscopy. J Biomed Opt 2005;10:064026.
37. Butte PV, Mamelak AN, Nuno M, et al. Fluorescence lifetime spectroscopy for guided therapy of brain tumors. Neuroimage 2011;54 Suppl 1:S125-35.
38. Lin WC, Toms SA, Johnson M, et al. In Vivo Brain Tumor Demarcation Using Optical Spectroscopy. μPhotochem Photobiol§ 2001;73:396-402.
39. Lin WC, Sandberg DI, Bhatia S, et al. Optical spectroscopy for in-vitro differentiation of pediatric neoplastic and epileptogenic brain lesions. μJ Biomed Opt§ 2009; 14:014028.
40. Liu Q, Grant G, Li J, et al. Compact point-detection fluorescence spectroscopy system for quantifying intrinsic fluorescence redox ratio in brain cancer diagnostics. J Biomed Opt 2011;16:037004.
41. Alzheimer’s Disease International (ADI). Policy Brief for Heads of Government The Global Impact of Dementia 2013-2050:3.(Accessed July 20, 2015 at
42. Alzheimer’s Disease International (ADI). World Alzheimer Report 2010: The Global Economic Impact of Dementia. (Accessed July 20, 2015 at
43. World Health Organization. Dementia: A Public Health Priority. (Accessed July 20, 2015 at mental_health/publications/dementia_report_2012).
44. Hardy J, Selkoe DJ. The amyloid hypothesis of alzheimer’s disease: Progress and problems on the road to therapeutics. Science 2002;297:353-6.
45. Trojanowski JQ, Schmidt ML, Shin RW, et al. Altered tau and neurofilament proteins in neuro-degenerative diseases: Diagnostic implications for alzheimer’s disease and lewy body dementias. Brain Pathol 1993;3:45-5.
46. Lee VM.Regulation of tau phosphorylation in alzheimer’s disease. Ann N Y Acad Sci 1996;777:107-13.
47. Jack CR Jr, Albert MS, Knopman DS, et al. Introduction to the recommendations from the national institute on aging-alzheimer’s association workgroups on diagnostic guidelines for alzheimer’s disease. Alzheimers Dement 2011;7:257-62.
48. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of alzheimer’s disease: Recommendations from the national institute on aging-alzheimer’s association workgroups on diagnostic guidelines for alzheimer’s disease. Alzheimers Dement 2011;7:280-92.
49. Reaume AG, Howland DS, Trusko SP, et al. Enhanced amyloidogenic processing of the beta-amyloid precursor protein in gene-targeted mice bearing the swedish familial alzheimer’s disease mutations and a “Humanized” Abeta sequence. J Biol Chem 1996;271:23380-8.
50. Holmes C, Boche D, Wilkinson D, et al. Long-term effects of abeta42 immunisation in alzheimer’s disease: Follow-up of a randomised, placebo-controlled phase i trial. Lancet 2008;372:216-223.
51. Nordberg A: Amyloid imaging in early detection of alzheimer’s disease. Neurodegener Dis 2010;7:136-8.
52. Klunk WE, Lopresti BJ, Ikonomovic MD, et al. Binding of the positron emission tomography tracer pittsburgh compound-b reflects the amount of amyloid-beta in alzheimer’s disease brain but not in transgenic mouse brain. J Neurosci 2005;25:10598-606.
53. Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in alzheimer’s disease with pittsburgh compound -b. Ann Neurol 2004;55:306-19.
54. Nakada T, Matsuzawa H, Igarashi H, et al. In vivo visualization of senile-plaque-like pathology in alzheimer’s disease patients by mr microscopy on a 7t system. J Neuroimaging 2008;18:125-9.
55. Wang Y, Klunk WE, Debnath ML, et al. Development of a pet/spect agent for amyloid imaging in alzheimer’s disease. J Mol Neurosci 2004;24:55-62.
56. Lockhart A, Lamb JR, Osredkar T, et al. Pib is a nonspecific imaging marker of amyloid-beta (abeta) peptiderelated cerebral amyloidosis. Brain 2007;130:2607-15.
57. Ng S, Villemagne VL, Berlangieri S, et al. Visual assessment versus quantitative assessment of 11c-pib pet and 18f-fdg pet for detection of alzheimer’s disease. J Nucl Med 2007;48:547-52.
58. Hintersteiner M, Enz A, Frey P, et al. In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe. Nat Biotechnol 2005;23:577-83.
59. Koronyo Y, Salumbides BC, Black KL, et al. Alzheimer’s disease in the retina: imaging retinal aβ plaques for early diagnosis and therapy assessment. Neurodegener Dis 2012;10:285-93.
60. Koronyo-Hamaoui M, Koronyo Y, Ljubimov AV, et al. Identification of amyloid plaques in retinas from Alzheimer’s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model. Neuroimage 2011;54 Suppl 1:S204-17.
61. Chiu K, Chan TF, Wu A, et al. Neurodegeneration of the retina in mouse models of alzheimer’s disease: What can we learn from the retina? μAge (Dordr)§ 2012;34:633-49.
62. Dhillon N, Aggarwal BB, Newman RA, et al. Phase ii trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res 2008;14:4491-9.
63. Alzheimer’s and Dementia. “2015 Alzheimer’s disease facts and figures”. Washington, DC: Alzheimer’s Association Public Policy Office. (Accessed July 20, 2015 at gures_2015.pdf).
64. Ning A, Cui J, To E, et al. Amyloid-beta deposits lead to retinal degeneration in a mouse model of Alzheimer disease. Invest Ophthalmol Vis Sci 2008;49:5136-43.
65. Perez SE, Lumayag S, Kovacs B, et al. Beta-amyloid deposition and functional impairment in the retina of the APP swe/ps1DeltaE9 transgenic mouse model of Alzheimer’s disease. Invest Ophthalmol Vis Sci 2009; 50:793-800.
66. Liu B, Rasool S, Yang Z, et al. Amyloid-peptide vaccinations reduce beta-amyloid plaques but exacerbate vascular deposition and inflammation in the retina of Alzheimer’s transgenic mice. Am J Pathol 2009;175:2099-110.
67. Alexandrov PN, Pogue A, Bhattacharjee S, et al. Retinal amyloid peptides and complement factor H in transgenic models of Alzheimer’s disease. Neuroreport 2011;22: 623-7.
68. Tsai YC, Lu B, Ljubimov AV, et al. Ocular Changes in TgF344-AD Rat Model of Alzheimer’s Disease. Invest Ophthalmol Vis Sci 2014;55:523-34.
69. Guo L, Salt TE, Luong V, et al. Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci USA 2007; 104:13444-9.
70. Liu B, Rasool S, Yang Z, et al. Amyloid-peptide vaccinations reduce beta-amyloid plaques but exacerbate vascular deposition and inflammation in the retina of Alzheimer’s transgenic mice. Am J Pathol 2009;175: 2099-110.