Increased choroidal thickness in adults with Down syndrome.

Introduction: People with Down syndrome (DS) are particularly susceptible to Alzheimer's disease (AD) due to the triplication of the amyloid precursor protein (APP) gene. In this cross-sectional study, we hypothesized that choroidal thinning reported in sporadic AD (sAD) is mirrored in adults with DS. Methods: The posterior pole of the eye for 24 adults with DS and 16 age-matched controls (Ctrl) were imaged with optical coherence tomography. Choroidal thickness (ChT) was measured and analyzed in relation to cognitive status and cerebral amyloid beta (Aβ) load. Results: ChT was increased in people with DS (pwDS) compared to Ctrl. This increase was associated with gender differences and positively correlated with cerebral Aβ load in a small subset. There was no significant correlation detected between ChT and age or cognitive status. Discussion: In contrast to sAD this study found a significantly thicker choroid in pwDS. Whether these changes are related to Aβ pathology in DS needs further investigation

Reduced Cone Density Is Associated with Multiple Sclerosis

PURPOSE: Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system. Recent evidence suggests that degeneration of the inner layers of the retina occurs in MS. This study aimed to examine whether there are outer retinal changes in patients living with MS. DESIGN: This was a single center, cross-sectional study. PARTICIPANTS: Sixteen patients with MS and 25 controls (volunteers without diagnosed MS) were recruited for the study. METHODS: We acquired volumetric spectral domain-OCT scans of the macula and a circular scan around the optic nerve head (ONH). We also captured adaptive optics (AO) images at 0° (centered on the foveola), 2°, 4°, and 6° temporal to the fovea. MAIN OUTCOME MEASURES: We calculated the thickness of the different retinal layers in the macula and around the ONH using the inbuilt software of the OCT. We evaluated changes in cone photoreceptors by calculating cone density and spacing by the inbuilt AO automatic segmentation algorithm with manual correction. We compared patients with and without optic neuritis and controls. RESULTS: We found significant thinning of the inner retina and a thickening of the outer retina in the eye with a history of optic neuritis (eyes of patients with MS with a history of optic neuritis; mean difference [MD]: −11.13 ± 3.61 μm, P = 0.002 and MD: 2.86 ± 0.89 μm, P = 0.001; respectively). We did not observe changes in retinal layers without optic neuritis in eyes of patients with MS without a history of optic neuritis. However, regional differences were detected in the peripapillary retinal nerve fiber layer. Analyzing AO images revealed a significantly lower cone outer-segment density at all eccentricities in all patients compared with control eyes (P < 0.05), independent of optic neuritis history. CONCLUSIONS: Our results showed that all MS cases were associated with decreased cone densities. Future longitudinal studies will help to elucidate whether this is a specific and sensitive method to detect and monitor the development and progression of MS

Peripheral Retinal Imaging Biomarkers for Alzheimer’s Disease: A Pilot Study

Purpose: To examine whether ultra-widefield (UWF) retinal imaging can identify biomarkers for Alzheimer's disease (AD) and its progression. Methods: Images were taken using a UWF scanning laser ophthalmoscope (Optos P200C AF) to determine phenotypic variations in 59 patients with AD and 48 healthy controls at baseline (BL). All living participants were invited for a follow-up (FU) after 2 years and imaged again (if still able to participate). All participants had blood taken for genotyping at BL. Images were graded for the prevalence of age-related macular degeneration-like pathologies and retinal vascular parameters. Comparison between AD patients and controls was made using the Student t test and the χ2 test. Results: Analysis at BL revealed a significantly higher prevalence of a hard drusen phenotype in the periphery of AD patients (14/55; 25.4%) compared to controls (2/48; 4.2%) [χ2 = 9.9, df = 4, p = 0.04]. A markedly increased drusen number was observed at the 2-year FU in patients with AD compared to controls. There was a significant increase in venular width gradient at BL (zone C: 8.425 × 10-3 ± 2.865 × 10-3 vs. 6.375 × 10-3 ± 1.532 × 10-3, p = 0.008; entire image: 8.235 × 10-3 ± 2.839 × 10-3 vs. 6.050 × 10-3 ± 1.414 × 10-3, p = 0.004) and a significant decrease in arterial fractal dimension in AD at BL (entire image: 1.250 ± 0.086 vs. 1.304 ± 0.089, p = 0.049) with a trend for both at FU. Conclusions: UWF retinal imaging revealed a significant association between AD and peripheral hard drusen formation and changes to the vasculature beyond the posterior pole, at BL and after clinical progression over 2 years, suggesting that monitoring pathological changes in the peripheral retina might become a valuable tool in AD monitoring

Bruch's Membrane Calcification in Pseudoxanthoma Elasticum: Comparing Histopathology and Clinical Imaging

Purpose: To investigate the histology of Bruch's membrane (BM) calcification in pseudoxanthoma elasticum (PXE) and correlate this to clinical retinal imaging. Design: Experimental study with clinicopathological correlation. Subjects and Controls: Six postmortem eyes from 4 PXE patients and 1 comparison eye from an anonymous donor without PXE. One of the eyes had a multimodal clinical image set for comparison. Methods: Calcification was labeled with OsteSense 680RD, a fluorescent dye specific for hydroxyapatite, and visualized with confocal microscopy. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy (SEM-EDX) and time-of-flight secondary ion mass spectrometry (TOF-SIMs) were used to analyze the elemental and ionic composition of different anatomical locations. Findings on cadaver tissues were compared with clinical imaging of 1 PXE patient. Main Outcome Measures: The characteristics and topographical distribution of hydroxyapatite in BM in eyes with PXE were compared with the clinical manifestations of the disease. Results: Analyses of whole-mount and sectioned PXE eyes revealed an extensive, confluent OsteoSense labeling in the central and midperipheral BM, transitioning to a speckled labeling in the midperiphery. These areas corresponded to hyperreflective and isoreflective zones on clinical imaging. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy and TOF-SIMs analyses identified these calcifications as hydroxyapatite in BM of PXE eyes. The confluent fluorescent appearance originates from heavily calcified fibrous structures of both the collagen and the elastic layers of BM. Calcification was also detected in an aged comparison eye, but this was markedly different from PXE eyes and presented as small snowflake-like deposits in the posterior pole. Conclusions: Pseudoxanthoma elasticum eyes show extensive hydroxyapatite deposition in the inner and outer collagenous and elastic BM layers in the macula with a gradual change toward the midperiphery, which seems to correlate with the clinical phenotype. The snowflake-like calcification in BM of an aged comparison eye differed markedly from the extensive calcification in PXE. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article

Nuclear and cellular, micro and nano calcification in Alzheimer's disease patients and correlation to phosphorylated Tau

Brain calcification (calcium phosphate mineral formation) has been reported in the past 100 years in the brains of Alzheimer's disease (AD) patients. However, the association between calcification and AD, the triggers for calcification, and its role within the disease are not clear. On the other hand, hyperphosphorylated tau protein (pTau) tangles have been widely studied and recognized as an essential factor in developing AD. In this work, calcification in the brains of AD patients is characterized by advanced electron microscopy and fluorescence microscopy. Results are then compared to samples from cognitively healthy, age-matched donors, and the colocalization of calcification and pTau is investigated. Here, we show that AD patients' brains present microcalcification associated with the neural cell nuclei and cell projections, and that these are strongly related to the presence of pTau. The link between microcalcification and pTau suggests a potential mechanism of brain cell damage. Together with the formation of amyloid plaques and neurofibrillary tangles, microcalcification in neuronal cells adds to a better understanding of the pathology of AD. Finally, the presence of microcalcification in the neuronal cells of AD patients may assist in AD diagnosis, and may open avenues for developing intervention strategies based on inhibition of calcification. STATEMENT OF SIGNIFICANCE: Brain calcification has been reported in the past 100 years in the brains of Alzheimer's disease (AD) patients. However, the association between calcification and AD is not clear. Hyperphosphorylated tau protein (pTau) have been studied and recognized as a key factor in developing AD. We show here that AD patients' brains present microcalcification associated with the neuronal cell nuclei and cell projections, and that these are related to the presence of pTau. The study of calcification in brain cells can contribute to a better understanding of the biochemical mechanisms associated with AD and might also reveal that calcification is part of the full disease mechanism. Moreover, this work opens the possibility for using calcification as a biomarker to identify AD.</p