Non-invasive in vivo hyperspectral imaging of the retina for potential biomarker use in Alzheimer’s disease

Studies of rodent models of Alzheimer’s disease (AD) and of human tissues suggest that the retinal changes that occur in AD, including the accumulation of amyloid beta (Aβ), may serve as surrogate markers of brain Aβ levels. As Aβ has a wavelength-dependent effect on light scatter, we investigate the potential for in vivo retinal hyperspectral imaging to serve as a biomarker of brain Aβ. Significant differences in the retinal reflectance spectra are found between individuals with high Aβ burden on brain PET imaging and mild cognitive impairment (n = 15), and age-matched PET-negative controls (n = 20). Retinal imaging scores are correlated with brain Aβ loads. The findings are validated in an independent cohort, using a second hyperspectral camera. A similar spectral difference is found between control and 5xFAD transgenic mice that accumulate Aβ in the brain and retina. These findings indicate that retinal hyperspectral imaging may predict brain Aβ load. The use of PET for detection of Aβ in the brain in AD has limitations; studies also indicate that retinal changes, including Aβ deposition, occur in AD. Here the authors demonstrate the potential to use in vivo retinal hyperspectral imaging as a surrogate for brain accumulation of Aβ.

[1]  I. Deary,et al.  Retinal image analysis: Concepts, applications and potential , 2006, Progress in Retinal and Eye Research.

[2]  Zhikuan Yang,et al.  Amyloid-peptide vaccinations reduce {beta}-amyloid plaques but exacerbate vascular deposition and inflammation in the retina of Alzheimer's transgenic mice. , 2009, The American journal of pathology.

[3]  R. C. Macridis A review , 1963 .

[4]  Alexei Verkhratsky,et al.  Retinal macroglia changes in a triple transgenic mouse model of Alzheimer's disease. , 2014, Experimental eye research.

[5]  M. Tso,et al.  Immunoreactivity against tau, amyloid precursor protein, and beta-amyloid in the human retina. , 1995, Investigative ophthalmology & visual science.

[6]  M. Schwartz,et al.  The retina as a window to the brain—from eye research to CNS disorders , 2013, Nature Reviews Neurology.

[7]  M. Ohno,et al.  Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation , 2006, The Journal of Neuroscience.

[8]  R. Vassar,et al.  Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ42 accumulation and Caspase-3 activation , 2013, Molecular Neurodegeneration.

[9]  Aileen I. Pogue,et al.  Retinal amyloid peptides and complement factor H in transgenic models of Alzheimer's disease , 2011, Neuroreport.

[10]  M. Ohno,et al.  Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model , 2009, Neurobiology of Disease.

[11]  Christine T. O. Nguyen,et al.  Retinal biomarkers provide “insight” into cortical pharmacology and disease☆,☆☆ , 2017, Pharmacology & therapeutics.

[12]  D Marr,et al.  Theory of edge detection , 1979, Proceedings of the Royal Society of London. Series B. Biological Sciences.

[13]  Bunyarit Uyyanonvara,et al.  Blood vessel segmentation methodologies in retinal images - A survey , 2012, Comput. Methods Programs Biomed..

[14]  Geraint Rees,et al.  Association of Retinal Nerve Fiber Layer Thinning With Current and Future Cognitive Decline: A Study Using Optical Coherence Tomography , 2018, JAMA neurology.

[15]  Christine T. O. Nguyen,et al.  The Eye As a Biomarker for Alzheimer's Disease , 2016, Frontiers in neuroscience.

[16]  Swati S. More,et al.  Early Detection of Amyloidopathy in Alzheimer's Mice by Hyperspectral Endoscopy. , 2016, Investigative ophthalmology & visual science.

[17]  Jean-Michel Roger,et al.  Comparison of the efficacy of spectral pre-treatments for wheat and weed discrimination in outdoor conditions , 2014 .

[18]  S. Jacques Optical properties of biological tissues: a review , 2013, Physics in medicine and biology.

[19]  A. Savitzky,et al.  Smoothing and Differentiation of Data by Simplified Least Squares Procedures. , 1964 .

[20]  L. Zangwill,et al.  Glaucoma detection using scanning laser polarimetry with variable corneal polarization compensation. , 2003, Archives of ophthalmology.

[21]  Swati S. More,et al.  Hyperspectral imaging signatures detect amyloidopathy in Alzheimer's mouse retina well before onset of cognitive decline. , 2015, ACS chemical neuroscience.

[22]  Keith L Black,et al.  Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer's disease. , 2017, JCI insight.

[23]  P. Visser,et al.  Retinal thickness in Alzheimer's disease: A systematic review and meta-analysis , 2017, Alzheimer's & dementia.

[24]  C. Masters,et al.  Subcellular localization of the Alzheimer's disease amyloid precursor protein and derived polypeptides expressed in a recombinant yeast system. , 1998, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[25]  F. Delori,et al.  Spectral reflectance of the human ocular fundus. , 1989, Applied optics.

[26]  Alexander J. Rivest,et al.  Characterization of β amyloid assemblies in drusen: The deposits associated with aging and age-related macular degeneration , 2004 .

[27]  S. Keel,et al.  Emerging ocular biomarkers of Alzheimer disease , 2017, Clinical & experimental ophthalmology.

[28]  Walter Stark,et al.  Beta‐Amyloid, Phospho‐Tau and Alpha‐Synuclein Deposits Similar to Those in the Brain Are Not Identified in the Eyes of Alzheimer's and Parkinson's Disease Patients , 2014, Brain pathology.

[29]  M. Delgado-Rodríguez,et al.  Systematic review and meta-analysis. , 2017, Medicina intensiva.

[30]  T. Wong,et al.  Retinal pathology as biomarker for cognitive impairment and Alzheimer's disease , 2012, Journal of Neurology, Neurosurgery & Psychiatry.

[31]  B. Hyman,et al.  Absence of Alzheimer Disease Neuropathologic Changes in Eyes of Subjects With Alzheimer Disease , 2017, Journal of neuropathology and experimental neurology.

[32]  Christopher C Rowe,et al.  Biochemically-defined pools of amyloid-&bgr; in sporadic Alzheimer’s disease: correlation with amyloid PET , 2017, Brain : a journal of neurology.

[33]  P. Avanzini,et al.  Melanopsin retinal ganglion cell loss in Alzheimer disease , 2015, Annals of neurology.

[34]  J. Hardy,et al.  The amyloid hypothesis of Alzheimer's disease at 25 years , 2016, EMBO molecular medicine.

[35]  Daniel L. Farkas,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 , 2011, NeuroImage.

[36]  J. J. Vos,et al.  Spectral transmission of the human ocular media. , 1974, Vision research.

[37]  D M Snodderly,et al.  The macular pigment. I. Absorbance spectra, localization, and discrimination from other yellow pigments in primate retinas. , 1984, Investigative ophthalmology & visual science.

[38]  K. Ashe,et al.  Amyloid-beta deposits lead to retinal degeneration in a mouse model of Alzheimer disease. , 2008, Investigative ophthalmology & visual science.

[39]  Jean-Philippe Sylvestre,et al.  A prototype hyperspectral system with a tunable laser source for retinal vessel imaging. , 2013, Investigative ophthalmology & visual science.

[40]  Clive N Svendsen,et al.  Ocular changes in TgF344-AD rat model of Alzheimer's disease. , 2014, Investigative ophthalmology & visual science.

[41]  I. Deary,et al.  Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures , 2005, Journal of anatomy.

[42]  M. Aschner,et al.  Untangling the Manganese-α-Synuclein Web , 2016, Front. Neurosci..

[43]  C. Masters,et al.  Generation of a recombinant Fab antibody reactive with the Alzheimer's disease‐related Aβ peptide , 2002, Clinical and experimental immunology.

[44]  J. Roger,et al.  DROP-D: Dimension reduction by orthogonal projection for discrimination , 2015 .

[45]  R M Hoar,et al.  Embryology of the eye. , 1982, Environmental health perspectives.

[46]  G. Zonios,et al.  Skin melanin, hemoglobin, and light scattering properties can be quantitatively assessed in vivo using diffuse reflectance spectroscopy. , 2001, The Journal of investigative dermatology.

[47]  Yogesan Kanagasingam,et al.  Ocular biomarkers for early detection of Alzheimer's disease. , 2010, Journal of Alzheimer's disease : JAD.

[48]  Colin L. Masters,et al.  Amyloid precursor protein processing and retinal pathology in mouse models of Alzheimer’s disease , 2009, Graefe's Archive for Clinical and Experimental Ophthalmology.

[49]  E. Mufson,et al.  Beta-amyloid deposition and functional impairment in the retina of the APPswe/PS1DeltaE9 transgenic mouse model of Alzheimer's disease. , 2009, Investigative ophthalmology & visual science.

[50]  T. Wong,et al.  Imaging retina to study dementia and stroke , 2017, Progress in Retinal and Eye Research.

[51]  C. Jack,et al.  Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade , 2010, The Lancet Neurology.

[52]  Rebecca Sinn,et al.  An eye on eye development , 2013, Mechanisms of Development.

[53]  Andrea Pavesi,et al.  A 3D microfluidic model for preclinical evaluation of TCR-engineered T cells against solid tumors. , 2017, JCI insight.

[54]  Y. Benjamini,et al.  Adaptive linear step-up procedures that control the false discovery rate , 2006 .