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Koronyo Y, Biggs D, Barron E, Boyer DS, Pearlman JA, Au WJ, Kile SJ, Blanco A, Fuchs DT, Ashfaq A, Frautschy S, Cole GM, Miller CA, Hinton DR, Verdooner SR, Black KL, Koronyo-Hamaoui M. Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer's disease. JCI Insight. 2017 Aug 17;2(16) PubMed.
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VU University Medical Center
With great interest, we read Koronyo’s paper on retinal amyloid visualization as a possible non-invasive biomarker in Alzheimer’s disease published in JCI insight and Alzforum’s coverage of it. Because of the huge and imminent interest in easily applicable and affordable biomarkers for AD, we too are studying in vivo and ex vivo retinal imaging in the Amsterdam Dementia Cohort of the VU University Medical Center (VUmc) Alzheimer Center in cooperation with the Dutch Brain Bank, ophthalmology department AMC and VUmc and Laserlab of the VU University. We were impressed by the large and comprehensive body of work described in Koronyo’s paper. In their postmortem work, they present both flat-mount techniques and cross sections to cover a large part of the retina and assess amyloid distribution over retinal layers with immunohistochemistry (amyloid antibodies), fluorescent techniques, and histochemical staining methods, such as Gallyas and Congo red (figure 1). Other labs, however, report absence of retinal amyloid. We therefore would like to discuss some methodological issues while interpreting the current data, before the results of this study can be translated into patients.
Firstly, in Koronyo’s paper, deposits with a range of size and morphologies are observed with different antibodies and stains (4G8, 6E10, 12F4, Gallyas, curcumin, Congo red) and aforementioned techniques and therefore present a complex picture. Flat mounts in figure 2, for example, show plaque-like structures, while cross sections in figure 4 show intracellular staining with the same antibody (12F4). That raises the question how different retinal deposits should be interpreted and how they relate to pathology in the brain. As the retina might physiologically process APP and amyloid differently than does the brain, retinal deposits may be different from those observed in the brain. Deposits shown could be reflective of (ab)normal APP processing in GCL, INL, or RPE cells (Ratnayaka et al., 2015) or could be true pathological deposits. Additional research is warranted to characterize the exact nature of retinal deposits in AD. Finally, it should be noted that all used Aβ antibodies have affinity for APP in higher concentrations (1:150 in this case). Intracellular inclusions, like the ones seen in figure 4, could also be interpreted as intracellular APP upregulation instead of extracellular amyloid deposits.
In conclusion, while we share the enthusiasm for the current findings and agree with the importance of identifying amyloid plaques outside of the brain as a possible biomarker, the postmortem findings of the current study need to be confirmed by other independent groups. We draw attention to the fact that groups from Johns Hopkins (Ho et al., 2014), Harvard (Williams et al., 2017), and the German Center for Neurodegenerative Diseases, Munich (Schön et al., 2012), were unable to do so before. We call for sharing exact protocols on tissue processing (flat-mount techniques and cross sections) and staining methods in order to robustly elucidate the presence of neuropathological hallmarks in retinas of AD patients. By cooperatively applying these protocols in independent labs, we together can eliminate effects of local variations in tissue processing and staining.
On behalf of the multidisciplinary I-READ team, Amsterdam, Tjado Morrema, Aleid van de Kreeke, Oleg Nadyarnykh, Jeroen Hoozemans, Frank Verbraak, Annemieke Rozemuller, Arthur Bergen, Philip Scheltens, Femke Bouwman, and Johannes de Boer.
References:
Ratnayaka JA, Serpell LC, Lotery AJ. Dementia of the eye: the role of amyloid beta in retinal degeneration. Eye (Lond). 2015 Aug;29(8):1013-26. Epub 2015 Jun 19 PubMed.
Ho CY, Troncoso JC, Knox D, Stark W, Eberhart CG. 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. Brain Pathol. 2013 May 29; PubMed.
Williams EA, McGuone D, Frosch MP, Hyman BT, Laver N, Stemmer-Rachamimov A. Absence of Alzheimer Disease Neuropathologic Changes in Eyes of Subjects With Alzheimer Disease. J Neuropathol Exp Neurol. 2017 May 1;76(5):376-383. PubMed.
Schön C, Hoffmann NA, Ochs SM, Burgold S, Filser S, Steinbach S, Seeliger MW, Arzberger T, Goedert M, Kretzschmar HA, Schmidt B, Herms J. Long-term in vivo imaging of fibrillar tau in the retina of P301S transgenic mice. PLoS One. 2012;7(12):e53547. PubMed.
View all comments by Jurre den HaanBanner Sun Health Research Institute
Readers should see comments made earlier this year on the same topic, i.e., my own comment regarding labs at Johns Hopkins and Massachussetts General Hospital that have not seen Aβ or tau pathology in the retina of AD subjects (see references below).
Our own lab failed to see Aβ or tau pathology in unpublished work on whole-mount AD and control retina. Histological evidence needs to be confirmed with biochemical analysis, e.g., western blot of retina.
References:
Ho CY, Troncoso JC, Knox D, Stark W, Eberhart CG. 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. Brain Pathol. 2013 May 29; PubMed.
Williams EA, McGuone D, Frosch MP, Hyman BT, Laver N, Stemmer-Rachamimov A. Absence of Alzheimer Disease Neuropathologic Changes in Eyes of Subjects With Alzheimer Disease. J Neuropathol Exp Neurol. 2017 May 1;76(5):376-383. PubMed.
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