More than meets the eye
Authors:   , Hart de Ruijter Frederique Jasmine 
Published: October 2024

In the scientific quest for non-invasive biomarkers for neurodegenerative diseases, the retina is suggested as a potential source for use in (pre)clinical settings to aid in diagnosis and/or disease monitoring. The main objective of this thesis is to investigate protein alterations in the post-mortem retina associated with neurodegenerative brain diseases through immunohistochemistry.

In Chapter 2, we aim to evaluate the presence of multiple Tau phospho-epitopes in the retina and the differences between tau-associated neurodegenerative diseases, non-tau neurodegenerative diseases and cognitively normal controls with and without tau pathology in the brain. We show that Tau phosphorylated at sites Ser202/Thr205 (AT8) and Thr217 are elevated, with significant discrimination between groups, and that pTau is not specifically associated with the pathogenesis underlying Alzheimer’s disease. We found a direct link between pTau burden in the retina and the tau load in the hippocampus and cortical areas, except the occipital lobe. pTau is observed as a diffuse signal in the synaptic layers of the retina and shows somatodendritic positivity in the nuclear layer.

In Chapter 3 we set out to explore whether retinal alpha-synuclein pathology is specific for clinicopathological synucleinopathies. We show that alpha-synuclein pathology in the retina and optic nerve accurately "predicts" the presence of a clinicopathological alpha-synucleinopathy. Moreover, there is a significant association with Braak stages IV-VI. The strong association with stage VI and the high proportion of cases with alpha-synuclein pathology in the retina and optic nerve within the neocortical LPC stage strengthens the hypothesis that the retina becomes more involved in the case of neocortical alpha-synuclein pathology. We also show that MSA cases exhibit glial cytoplasmic inclusions in the optic nerve. Interestingly, no Lewy neurites are observed in the retina despite Lewy copathology in the brain. This differentiation between MSA and Lewy body diseases suggests the potential of retinal alpha-synuclein pathology in discriminating between synucleinopathies.

In Chapter 4, pTDP-43 is quantified in a subcohort, including the spectrum of different pathological subtypes of FTLD-TDP. pTDP-43 inclusions are detected in C9orf72, progranulin and sporadic FTLD-TDP cases in the outer plexiform layer. Additionally, dipeptide pathology is present in all C9orf72 mutation carriers in the inner nuclear layer. The most abundant retinal pTDP-43 pathology is seen in cases with the most advanced (sub)cortical TDP-43 pathology. The presence of retinal pTDP-43 in sporadic forms suggests that retinal pTDP-43 is not specific for FTLD-TDP pathogenesis but is more likely associated with the presence of TDP-43 pathology in general.

In Chapter 5 we integrate all immunohistochemical data of retina and brain tissue and analyze the implications of copathology on retinal proteinopathy. First, we summarize the morphological retina-brain differences that appear for pTau, Abeta, and alpha-synuclein pathology and show that pTDP-43 inclusions in the retina seem similar to the brain. Specifically, no neurofibrillary tangles, extra-cellular plaques, or Lewy bodies were detected. This suggests that pathological protein aggregation in retinal neuronal cells does not manifest similarly in the retina as in neurons of the brain. We also show that Abeta (4G8) is present in the retina but not specifically in Alzheimer’s disease. Furthermore, we demonstrate that pTau (AT8) is present in typical Alzheimer’s disease, but not in atypical Alzheimer’s disease, including posterior cortical atrophy, suggesting a hierarchical involvement of the retina in the spreading of tau pathology throughout the neuronal tissue. pTau is significantly associated with higher Braak stages for neurofibrillary tangles and Thal amyloid phase, although cases with lower Braak stages (I-III) also show retinal pTau. We further show that retinal pTDP-43 is associated with frontotemporal lobar degeneration and with more advanced limbic-predominant age-related TDP-43 encephalopathy (LATE).