The Impact of Vaping on the Ocular Surface: A Systematic Review of the Literature.

Background: The use of electronic cigarettes has become increasingly popular in recent years. However, the impact that electronic cigarettes have on the ocular surface is not well known. Therefore, the aim of this review is to explore the current literature on the acute and chronic sequelae of electronic cigarettes on the ocular surface. Methods: A systematic review of the literature was undertaken by keyword searching on the Embase, Medline, and Web of Science databases. Articles identified through the search underwent title/abstract screening, full-text screening, and data extraction. Results: A total of 18 studies were included in this review. Non-intended ocular surface exposures and intended exposures on the ocular surface were found to be associated with the use of electronic cigarettes. Conclusions: The impact of vaping on the ocular surface is not benign. There are significant risks that vaping can pose to the ocular surface. Hence, it is necessary to develop appropriate risk communication tools given the increasing popularity of this activity. Additionally, future long-term studies are needed to better understand the long-term impacts of vaping on the ocular surface given the lack of current data.

Synthesis and Evaluation of a Novel PET Radioligand for Imaging Glutaminyl Cyclase Activity as a Biomarker for Detecting Alzheimer's Disease.

Several new lines of research have demonstrated that a significant number of amyloid-ß peptides found in Alzheimer's disease (AD) are truncated and undergo post-translational modification by glutaminyl cyclase (QC) at the N-terminal. Notably, QC's products of Abeta-pE3 and Abeta-pE11 have been active targets for investigational drug development. This work describes the design, synthesis, characterization, and in vivo validation of a novel PET radioligand, [18F]PB0822, for targeted imaging of QC. We report herein a simplified and robust chemistry for the synthesis of the standard compound, [19F]PB0822, and the corresponding [18F]PB0822 radioligand. The PET probe was developed with 99.9% radiochemical purity, a molar activity of 965 Ci.mmol-1, and an IC50 of 56.3 nM, comparable to those of the parent PQ912 inhibitor (62.5 nM). Noninvasive PET imaging showed that the probe is distributed in the brain 5 min after intravenous injection. Further, in vivo PET imaging with [18F]PB0822 revealed that AD 5XFAD mice harbor significantly higher QC activity than WT counterparts. The data also suggested that QC activity is found across different brain regions of the tested animals.

TARGETING SOLUBLE AMYLOID-BETA OLIGOMERS WITH A NOVEL NANOBODY.

The classical amyloid cascade hypothesis postulates that the aggregation of amyloid plaques and the accumulation of intracellular hyperphosphorylated Tau tangles, together, lead to profound neuronal death. However, emerging research has demonstrated that soluble amyloid-ß oligomers (SAßOs) accumulate early, prior to amyloid plaque formation. SAßOs induce memory impairment and disrupt cognitive function independent of amyloid-ß plaques, and even in the absence of plaque formation. This work describes the development and characterization of a novel anti-SAßO (E3) nanobody generated from an alpaca immunized with SAßO. In-vitro assays and in-vivo studies using 5XFAD mice indicate that the fluorescein (FAM)-labeled E3 nanobody recognizes both SAßOs and amyloid-ß plaques. The E3 nanobody traverses across the blood-brain barrier and binds to amyloid species in the brain of 5XFAD mice. Imaging of mouse brains reveals that SAßO and amyloid-ß plaques are not only different in size, shape, and morphology, but also have a distinct spatial distribution in the brain. SAßOs are associated with neurons, while amyloid plaques reside in the extracellular matrix. The results of this study demonstrate that the SAßO nanobody can serve as a diagnostic agent with potential theragnostic applications in Alzheimer's disease.

Granzyme B degrades extracellular matrix and promotes inflammation and choroidal neovascularization.

Age-related macular degeneration (AMD) is a common retinal neurodegenerative disease among the elderly. Neovascular AMD (nAMD), a leading cause of AMD-related blindness, involves choroidal neovascularization (CNV), which can be suppressed by anti-angiogenic treatments. However, current CNV treatments do not work in all nAMD patients. Here we investigate a novel target for AMD. Granzyme B (GzmB) is a serine protease that promotes aging, chronic inflammation and vascular permeability through the degradation of the extracellular matrix (ECM) and tight junctions. Extracellular GzmB is increased in retina pigment epithelium (RPE) and mast cells in the choroid of the healthy aging outer retina. It is further increased in donor eyes exhibiting features of nAMD and CNV. Here, we show in RPE-choroidal explant cultures that exogenous GzmB degrades the RPE-choroid ECM, promotes retinal/choroidal inflammation and angiogenesis while diminishing anti-angiogenic factor, thrombospondin-1 (TSP-1). The pharmacological inhibition of either GzmB or mast-cell degranulation significantly reduces choroidal angiogenesis. In line with our in vitro data, GzmB-deficiency reduces the extent of laser-induced CNV lesions and the age-related deterioration of electroretinogram (ERG) responses in mice. These findings suggest that targeting GzmB, a serine protease with no known endogenous inhibitors, may be a potential novel therapeutic approach to suppress CNV in nAMD.

Purinergic signaling via P2X receptors and mechanisms of unregulated ATP release in the outer retina and age-related macular degeneration.

Age-related macular degeneration (AMD) is a chronic and progressive inflammatory disease of the retina characterized by photoceptor loss and significant central visual impairment due to either choroidal neovascularization or geographic atrophy. The pathophysiology of AMD is complex and multifactorial, driven by a combination of modifiable and non-modifiable risk factors, molecular mechanisms, and cellular processes that contribute to overall disease onset, severity, and progression. Unfortunately, due to the structural, cellular, and pathophysiologic complexity, therapeutic discovery is challenging. While purinergic signaling has been investigated for its role in the development and treatment of ocular pathologies including AMD, the potential crosstalk between known contributors to AMD, such as the complement cascade and inflammasome activation, and other biological systems, such as purinergic signaling, have not been fully characterized. In this review, we explore the interactions between purinergic signaling, ATP release, and known contributors to AMD pathogenesis including complement dysregulation and inflammasome activation. We begin by identifying what is known about purinergic receptors in cell populations of the outer retina and potential sources of extracellular ATP required to trigger purinergic receptor activation. Next, we examine evidence in the literature that the purinergic system accelerates AMD pathogenesis leading to apoptotic and pyroptotic cell death in retinal cells. To fully understand the potential role that purinergic signaling plays in AMD, more research is needed surrounding the expression, distribution, functions, and interactions of purinergic receptors within cells of the outer retina as well as potential crosstalk with other systems. By determining how these processes are affected in the context of purinergic signaling, it will improve our understanding of the mechanisms that drive AMD pathogenesis which is critical in developing treatment strategies that prevent or slow progression of the disease.

MicroRNAs in tear fluids predict underlying molecular changes associated with Alzheimer's disease.

Extracellular circulating microRNAs (miRNAs) have been discussed as potential biomarkers for Alzheimer's disease (AD) diagnosis. As the retina is a part of the CNS, we hypothesize that miRNAs expression levels in the brain, particularly neocortex-hippocampus, eye tissues, and tear fluids are similar at different stages of AD progression. Ten miRNA candidates were systematically investigated in transgenic APP-PS1 mice, noncarrier siblings, and C57BL/6J wild-type controls at young and old ages. Relative expression levels of tested miRNAs revealed a similar pattern in both APP-PS1 mice and noncarrier siblings when compared with age- and sex-matched wild-type controls. However, the differences seen in expression levels between APP-PS1 mice and noncarrier siblings could possibly have resulted from underlying molecular etiology of AD. Importantly, miRNAs associated with amyloid beta (Aß) production (-101a, -15a, and -342) and proinflammation (-125b, -146a, and -34a) showed significant up-regulations in the tear fluids with disease progression, as tracked by cortical Aß load and reactive astrogliosis. Overall, for the first time, the translational potential of up-regulated tear fluid miRNAs associated with AD pathogenesis was comprehensively demonstrated.

Ergothioneine, a dietary antioxidant improves amyloid beta clearance in the neuroretina of a mouse model of Alzheimer's disease.

Introduction: Ergothioneine (Ergo) is a naturally occurring dietary antioxidant. Ergo uptake is dependent on the transporter, organic cation transporter novel-type 1 (OCTN1) distribution. OCTN1 is highly expressed in blood cells (myeloid lineage cells), brain and ocular tissues that are likely predisposed to oxidative stress. Ergo may protect the brain and eye against oxidative damage and inflammation, however, the underlying mechanism remains unclear. Amyloid beta (Aß) clearance is a complex process mediated by various systems and cell types including vascular transport across the blood-brain barrier, glymphatic drainage, and engulfment and degradation by resident microglia and infiltrating innate immune cells. Impaired Aß clearance is a major cause for Alzheimer's disease (AD). Here we investigated neuroretinas to explore the neuroprotective effect of Ergo in a transgenic AD mouse model. Methods: Age-matched groups of Ergo-treated 5XFAD, non-treated 5XFAD, and C57BL/6J wildtype (WT controls) were used to assess Ergo transporter OCTN1 expression and Aß load along with microglia/macrophage (IBA1) and astrocyte (GFAP) markers in wholemount neuroretinas (n = 26) and eye cross-sections (n = 18). Immunoreactivity was quantified by fluorescence or by semi-quantitative assessments. Results and discussion: OCTN1 immunoreactivity was significantly low in the eye cross-sections of Ergo-treated and non-treated 5XFAD vs. WT controls. Strong Aß labeling, detected in the superficial layers in the wholemounts of Ergo-treated 5XFAD vs. non-treated 5XFAD reflects the existence of an effective Aß clearance system. This was supported by imaging of cross-sections where Aß immunoreactivity was significantly low in the neuroretina of Ergo-treated 5XFAD vs. non-treated 5XFAD. Moreover, semi-quantitative analysis in wholemounts identified a significantly reduced number of large Aß deposits or plaques, and a significantly increased number of IBA1(+)ve blood-derived phagocytic macrophages in Ergo-treated 5XFAD vs. non-treated 5XFAD. In sum, enhanced Aß clearance in Ergo-treated 5XFAD suggests that Ergo uptake may promote Aß clearance possibly by blood-derived phagocytic macrophages and via perivascular drainage.

Granzyme B Contributes to Choroidal Neovascularization and Age-Related Macular Degeneration Through Proteolysis of Thrombospondin-1.

Age-related macular degeneration (AMD) is a leading cause of irreversible central vision loss in the elderly. The pathology of neovascular age-related macular degeneration (nAMD), also known as wet AMD, is associated with an abnormal blood vessel growth in the eye and involves an imbalance of proangiogenic and antiangiogenic factors. Thrombospondin (TSP)-1 and TSP-2 are endogenous matricellular proteins that inhibit angiogenesis. TSP-1 is significantly diminished in eyes with AMD, although the mechanisms involved in its reduction are unknown. Granzyme B (GzmB) is a serine protease with an increased extracellular activity in the outer retina and choroid of human eyes with nAMD-related choroidal neovascularization (CNV). This study investigated whether TSP-1 and TSP-2 are GzmB substrates using in silico and cell-free cleavage assays and explored the relationship between GzmB and TSP-1 in human eyes with nAMD-related CNV and the effect of GzmB on TSP-1 in retinal pigment epithelial culture and an explant choroid sprouting assay (CSA). In this study, TSP-1 and TSP-2 were identified as GzmB substrates. Cell-free cleavage assays substantiated the GzmB proteolysis of TSP-1 and TSP-2 by showing dose-dependent and time-dependent cleavage products. TSP-1 and TSP-2 proteolysis were hindered by the inhibition of GzmB. In the retinal pigment epithelium and choroid of human eyes with CNV, we observed a significant inverse correlation between TSP-1 and GzmB, as indicated by lower TSP-1 and higher GzmB immunoreactivity. In CSA, the vascular sprouting area increased significantly with GzmB treatment and reduced significantly with TSP-1 treatment. Western blot showed significantly reduced expression of TSP-1 in GzmB-treated retinal pigment epithelial cell culture and CSA supernatant compared with that in controls. Together, our findings suggest that the proteolysis of antiangiogenic factors such as TSP-1 by extracellular GzmB might represent a mechanism through which GzmB may contribute to nAMD-related CNV. Future studies are needed to investigate whether pharmacologic inhibition of extracellular GzmB can mitigate nAMD-related CNV by preserving intact TSP-1.

Potential role of extracellular granzyme B in wet age-related macular degeneration and fuchs endothelial corneal dystrophy.

Age-related ocular diseases are the leading cause of blindness in developed countries and constitute a sizable socioeconomic burden worldwide. Age-related macular degeneration (AMD) and Fuchs endothelial corneal dystrophy (FECD) are some of the most common age-related diseases of the retina and cornea, respectively. AMD is characterized by a breakdown of the retinal pigment epithelial monolayer, which maintains retinal homeostasis, leading to retinal degeneration, while FECD is characterized by degeneration of the corneal endothelial monolayer, which maintains corneal hydration status, leading to corneal edema. Both AMD and FECD pathogenesis are characterized by disorganized local extracellular matrix (ECM) and toxic protein deposits, with both processes linked to aberrant protease activity. Granzyme B (GrB) is a serine protease traditionally known for immune-mediated initiation of apoptosis; however, it is now recognized that GrB is expressed by a variety of immune and non-immune cells and aberrant extracellular localization of GrB substantially contributes to various age-related pathologies through dysregulated cleavage of ECM, tight junction, and adherens junction proteins. Despite growing recognition of GrB involvement in multiple age-related pathologies, its role in AMD and FECD remains poorly understood. This review summarizes the pathophysiology of, and similarities between AMD and FECD, outlines the current knowledge of the role of GrB in AMD and FECD, as well as hypothesizes putative contributions of GrB to AMD and FECD pathogenesis and highlights the therapeutic potential of pharmacologically inhibiting GrB as an adjunctive treatment for AMD and FECD.

Müller cell degeneration and microglial dysfunction in the Alzheimer's retina.

Amyloid beta (Aß) deposits in the retina of the Alzheimer's disease (AD) eye may provide a useful diagnostic biomarker for AD. This study focused on the relationship of Aß with macroglia and microglia, as these glial cells are hypothesized to play important roles in homeostasis and clearance of Aß in the AD retina. Significantly higher Aß load was found in AD compared to controls, and specifically in the mid-peripheral region. AD retina showed significantly less immunoreactivity against glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS) compared to control eyes. Immunoreactivity against ionized calcium binding adapter molecule-1 (IBA-1), a microglial marker, demonstrated a higher level of microgliosis in AD compared to control retina. Within AD retina, more IBA-1 immunoreactivity was present in the mid-peripheral retina, which contained more Aß than the central AD retina. GFAP co-localized rarely with Aß, while IBA-1 co-localized with Aß in more layers of control than AD donor retina. These results suggest that dysfunction of the Müller and microglial cells may be key features of the AD retina.

Longitudinal Consumption of Ergothioneine Reduces Oxidative Stress and Amyloid Plaques and Restores Glucose Metabolism in the 5XFAD Mouse Model of Alzheimer's Disease.

Background: Ergothioneine (ERGO) is a unique antioxidant and a rare amino acid available in fungi and various bacteria but not in higher plants or animals. Substantial research data indicate that ERGO is a physiological antioxidant cytoprotectant. Different from other antioxidants that need to breach the blood-brain barrier to enter the brain parenchyma, a specialized transporter called OCTN1 has been identified for transporting ERGO to the brain. Purpose: To assess whether consumption of ERGO can prevent the progress of Alzheimer's disease (AD) on young (4-month-old) 5XFAD mice. Methods and materials: Three cohorts of mice were tested in this study, including ERGO-treated 5XFAD, non-treated 5XFAD, and WT mice. After the therapy, the animals went through various behavioral experiments to assess cognition. Then, mice were scanned with PET imaging to evaluate the biomarkers associated with AD using [11C]PIB, [11C]ERGO, and [18F]FDG radioligands. At the end of imaging, the animals went through cardiac perfusion, and the brains were isolated for immunohistology. Results: Young (4-month-old) 5XFAD mice did not show a cognitive deficit, and thus, we observed modest improvement in the treated counterparts. In contrast, the response to therapy was clearly detected at the molecular level. Treating 5XFAD mice with ERGO resulted in reduced amyloid plaques, oxidative stress, and rescued glucose metabolism. Conclusions: Consumption of high amounts of ERGO benefits the brain. ERGO has the potential to prevent AD. This work also demonstrates the power of imaging technology to assess response during therapy.

Clinical explainable differential diagnosis of polypoidal choroidal vasculopathy and age-related macular degeneration using deep learning.

BACKGROUND: This study aims to achieve an automatic differential diagnosis between two types of retinal pathologies with similar pathological features - Polypoidal choroidal vasculopathy (PCV) and wet age-related macular degeneration (AMD) from volumetric optical coherence tomography (OCT) images, and identify clinically-relevant pathological features, using an explainable deep-learning-based framework. METHODS: This is a retrospective study with data from a cross-sectional cohort. The OCT volume of 73 eyes from 59 patients was included in this study. Disease differentiation was achieved through single-B-scan-based classification followed by a volumetric probability prediction aggregation step. We compared different labeling strategies with and without identifying pathological B-scans within each OCT volume. Clinical interpretability was achieved through normalized aggregation of B-scan-based saliency maps followed by maximum-intensity-projection onto the en face plane. We derived the PCV score from the proposed differential diagnosis framework with different labeling strategies. The en face projection of saliency map was validated with the pathologies identified in Indocyanine green angiography (ICGA). RESULTS: Model trained with both labeling strategies achieved similar level differentiation power (>90%), with good correspondence between pathological features detected from the projected en face saliency map and ICGA. CONCLUSIONS: This study demonstrated the potential clinical application of non-invasive differential diagnosis using AI-driven OCT-based analysis, with minimal requirement of labeling efforts, along with clinical explainability achieved through automatically detected disease-related pathologies.

Improved synthesis of an ergothioneine PET radioligand for imaging oxidative stress in Alzheimer's disease.

L-ergothioneine (ERGO) is a potent antioxidant with cytoprotective effects. To study ERGO biodistribution and detect oxidative stress in vivo, we report an efficient and reproducible preparation of [11 C]-labeled ERGO PET radioligand based on protecting the histidine carboxylic group with a methyl ester. Overall, this new protection approach using methyl ester improved the chemical yield of a 4-step reaction from 14% to 24% compared to the previous report using t-butyl ester. The [11 C]CH3 methylation of the precursor provided the desired product with 55 ± 10% radiochemical purity and a molar activity of 450 ± 200 TBq·mmol-1 . The [11 C]ERGO radioligand was able to detect threshold levels of oxidative stress in a preclinical animal model of Alzheimer's disease.

Dysregulation of the NLRP3 Inflammasome in Diabetic Retinopathy and Potential Therapeutic Targets.

Diabetic Retinopathy (DR) is an insidious neurovascular disorder secondary to chronic glycemic dysregulation in elderly diabetic patients. In the later stages of DR, the disease manifests as fluid infiltrating the macula, culminating in the leading cause of irreversible visual impairment in working age adults. With the current mainstay treatments preoccupied with slowing down the progression of DR, this presents an unsustainable solution from both an economic and quality of life perspective. Although the exact mechanisms by which hyperglycemia leads to retinal tissue insult are unknown, the evidence suggests that chronic low-grade inflammation in diabetic eye is in part driving the constellation of symptoms present in DR. Of the innate immune system within the eye, the NLR Family Pyrin Domain Containing 3 Inflammasome (NLRP3) has been identified in retinal cells as a causal factor in the pathogenesis of DR. Multiple pathways appear to be present in the diabetic eye that instigate prolonged activation of the NLRP3 which subsequently exerts its deleterious effects by upregulating the release of Interleukin-1Beta and Interleukin-18. In this review, we highlight the current understanding of the pathophysiology of DR, the dysregulation of the NLRP3 secondary to hyperglycemic stress in retinal cells, and novel therapeutic targets to alleviate overactivation of the inflammasome.

A complement factor H homolog, heparan sulfation, and syndecan maintain inversin compartment boundaries in C. elegans cilia.

Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly. Canonical disease models suggest that defective interactions between complement factor H (CFH) and cell surface heparan sulfate (HS) result in increased alternative complement pathway activity, cytolytic damage, and tissue inflammation in the retina. Although these factors are thought to contribute to increased disease risk, multiple studies indicate that noncanonical mechanisms that result from defective CFH and HS interaction may contribute to the progression of AMD as well. A total of 60 ciliated sensory neurons in the nematode Caenorhabditis elegans detect chemical, olfactory, mechanical, and thermal cues in the environment. Here, we find that a C. elegans CFH homolog localizes on CEP mechanosensory neuron cilia where it has noncanonical roles in maintaining inversin/NPHP-2 within its namesake proximal compartment and preventing inversin/NPHP-2 accumulation in distal cilia compartments in aging adults. CFH localization and maintenance of inversin/NPHP-2 compartment integrity depend on the HS 3-O sulfotransferase HST-3.1 and the transmembrane proteoglycan syndecan/SDN-1. Defective inversin/NPHP-2 localization in mouse and human photoreceptors with CFH mutations indicates that these functions and interactions may be conserved in vertebrate sensory neurons, suggesting that previously unappreciated defects in cilia structure may contribute to the progressive photoreceptor dysfunction associated with CFH loss-of-function mutations in some AMD patients.

Inhalable Thioflavin S for the Detection of Amyloid Beta Deposits in the Retina.

We present an integrated delivery technology herein employing the aerosolized method to repurpose thioflavin S for imaging amyloid beta (Abeta) deposits in the retina as a surrogate of Abeta in the brain for early detection of Alzheimer's disease. The data showed that wild type (WT) mice also have Abeta deposits in the retinae, albeit much less than 5XFAD mice. Further, only in 5XFAD mice, significant Abeta deposits were found associated with retinal ganglion cells (RGCs) in whole-mount and cross-section data. Furthermore, the fluorescent signal depicted from thioflavin S corroborates with Abeta immunohistochemistry staining information. Overall, this probe delivery via inhalation method is also applicable to other Abeta-binding molecules, such as Congo red, curcumin, and thioflavin T. The advantage of imaging retinal amyloid deposits compared to the brain counterparts is that the eye is easily accessible by in vivo imaging and it reduces the effort to design a probe that must cross the formidable blood-brain barrier.

Targeting Pyroptotic Cell Death Pathways in Retinal Disease.

Pyroptosis is a gasdermin-mediated, pro-inflammatory form of cell death distinct from apoptosis. In recent years, increasing attention has shifted toward pyroptosis as more studies demonstrate its involvement in diverse inflammatory disease states, including retinal diseases. This review discusses how currently known pyroptotic cell death pathways have been implicated in models of age-related macular degeneration, diabetic retinopathy, and glaucoma. We also identify potential future therapeutic strategies for these retinopathies that target drivers of pyroptotic cell death. Presently, the drivers of pyroptosis that have been studied the most in retinal cells are the nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, caspase-1, and gasdermin D (GSDMD). Targeting these proteins may help us develop new drug therapies, or supplement existing therapies, in the treatment of retinal diseases. As novel mechanisms of pyroptosis come to light, including those involving other inflammatory caspases and members of the gasdermin protein family, more targets for pyroptosis-mediated therapies in retinal disease can be explored.

Amyloid Beta Immunoreactivity in the Retinal Ganglion Cell Layer of the Alzheimer's Eye.

Alzheimer's disease (AD) is the most prevalent form of dementia, accounting for 60-70% of all dementias. AD is often under-diagnosed and recognized only at a later, more advanced stage, and this delay in diagnosis has been suggested as a contributing factor in the numerous unsuccessful AD treatment trials. Although there is no known cure for AD, early diagnosis is important for disease management and care. A hallmark of AD is the deposition of amyloid-ß (Aß)-containing senile neuritic plaques and neurofibrillary tangles composed of hyperphosporylated tau in the brain. However, current in vivo methods to quantify Aß in the brain are invasive, requiring radioactive tracers and positron emission tomography. Toward development of alternative methods to assess AD progression, we focus on the retinal manifestation of AD pathology. The retina is an extension of the central nervous system uniquely accessible to light-based, non-invasive ophthalmic imaging. However, earlier studies in human retina indicate that the literature is divided on the presence of Aß in the AD retina. To help resolve this disparity, this study assessed retinal tissues from neuropathologically confirmed AD cases to determine the regional distribution of Aß in retinal wholemounts and to inform on future retinal image studies targeting Aß. Concurrent post-mortem brain tissues were also collected. Neuropathological cortical assessments including neuritic plaque (NP) scores and cerebral amyloid angiopathy (CAA) were correlated with retinal Aß using immunohistochemistry, confocal microscopy, and quantitative image analysis. Aß load was compared between AD and control (non-AD) eyes. Our results indicate that levels of intracellular and extracellular Aß retinal deposits were significantly higher in AD than controls. Mid-peripheral Aß levels were greater than central retina in both AD and control eyes. In AD retina, higher intracellular Aß was associated with lower NP score, while higher extracellular Aß was associated with higher CAA score. Our data support the feasibility of using the retinal tissue to assess ocular Aß as a surrogate measure of Aß in the brain of individuals with AD. Specifically, mid-peripheral retina possesses more Aß deposition than central retina, and thus may be the optimal location for future in vivo ocular imaging.

Substantially thinner internal granular layer and reduced molecular layer surface in the cerebellar cortex of the Tc1 mouse model of down syndrome - a comprehensive morphometric analysis with active staining contrast-enhanced MRI.

Down Syndrome is a chromosomal disorder that affects the development of cerebellar cortical lobules. Impaired neurogenesis in the cerebellum varies among different types of neuronal cells and neuronal layers. In this study, we developed an imaging analysis framework that utilizes gadolinium-enhanced ex vivo mouse brain MRI. We extracted the middle Purkinje layer of the mouse cerebellar cortex, enabling the estimation of the volume, thickness, and surface area of the entire cerebellar cortex, the internal granular layer, and the molecular layer in the Tc1 mouse model of Down Syndrome. The morphometric analysis of our method revealed that a larger proportion of the cerebellar thinning in this model of Down Syndrome resided in the inner granule cell layer, while a larger proportion of the surface area shrinkage was in the molecular layer.