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OBJECTIVE: To explore retinal changes in patients with Dementia with Lewy Bodies (DLB) using Spectral Domain-Optical Coherence Tomography (SD-OCT) and Optical Coherence Tomography Angiography (OCTA), aiming to identify potential biomarkers for diagnosis and monitoring. METHODS: A cross-sectional study analyzed 15 DLB patients and 18 matched controls. Participants underwent physical, neurological, neuropsychological, and ophthalmological evaluations, including SD-OCT and OCTA. Logistic regression, adjusted for age, sex, and inter-eye correlation, was employed to identify retinal alterations in patients affected by DLB. RESULTS: OCTA revealed that DLB is associated with reduced superficial and deep vessel densities (SVD and DVD) in the macula (p < 0.01), as well as decreased peripapillary vessel density (ppVD, p < 0.01). SD-OCT parameters showed correlations with DLB, including reduced central macular thickness (CMT, p < 0.001) and thinning of the ganglion cell layer-inner plexiform layer (GCL-IPL, p < 0.01). Logistic regression (R²=0.26) identified reduced ppVD as a significant predictor of DLB (p = 0.030). CONCLUSIONS: Impairments in retinal capillaries, especially lower ppVD, might mirror cerebral hypoperfusion in DLB, potentially due to reduced Vascular Endothelial Growth Factor (VEGF) levels and increased α-synuclein. Further investigations are warranted to confirm the causal relationship between these observations, disease severity, and progression, as well as their potential role as biomarkers for DLB.

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This study investigates various pathological tau isoforms in the retina of individuals with early and advanced Alzheimer's disease (AD), exploring their connection with disease status. Retinal cross-sections from predefined superior-temporal and inferior-temporal subregions and corresponding brains from neuropathologically confirmed AD patients with a clinical diagnosis of either mild cognitive impairment (MCI) or dementia (n = 45) were compared with retinas from age- and sex-matched individuals with normal cognition (n = 30) and non-AD dementia (n = 4). Retinal tau isoforms, including tau tangles, paired helical filament of tau (PHF-tau), oligomeric-tau (Oligo-tau), hyperphosphorylated-tau (p-tau), and citrullinated-tau (Cit-tau), were stereologically analyzed by immunohistochemistry and Nanostring GeoMx digital spatial profiling, and correlated with clinical and neuropathological outcomes. Our data indicated significant increases in various AD-related pretangle tau isoforms, especially p-tau (AT8, 2.9-fold, pS396-tau, 2.6-fold), Cit-tau at arginine residue 209 (CitR209-tau; 4.1-fold), and Oligo-tau (T22+, 9.2-fold), as well as pretangle and mature tau tangle forms like MC-1-positive (1.8-fold) and PHF-tau (2.3-fold), in AD compared to control retinas. MCI retinas also exhibited substantial increases in Oligo-tau (5.2-fold), CitR209-tau (3.5-fold), and pS396-tau (2.2-fold). Nanostring GeoMx analysis confirmed elevated retinal p-tau at epitopes: Ser214 (2.3-fold), Ser396 (2.6-fold), Ser404 (2.4-fold), and Thr231 (1.8-fold), particularly in MCI patients. Strong associations were found between retinal tau isoforms versus brain pathology and cognitive status: a) retinal Oligo-tau vs. Braak stage, neurofibrillary tangles (NFTs), and CDR cognitive scores (ρ = 0.63-0.71), b) retinal PHF-tau vs. neuropil threads (NTs) and ABC scores (ρ = 0.69-0.71), and c) retinal pS396-tau vs. NTs, NFTs, and ABC scores (ρ = 0.67-0.74). Notably, retinal Oligo-tau strongly correlated with retinal Aß42 and arterial Aß40 forms (r = 0.76-0.86). Overall, this study identifies and quantifies diverse retinal tau isoforms in MCI and AD patients, underscoring their link to brain pathology and cognition. These findings advocate for further exploration of retinal tauopathy biomarkers to facilitate AD detection and monitoring via noninvasive retinal imaging.

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Stroke stands as a major global health issue, causing high death and disability rates and significant social and economic burdens. The effectiveness of existing stroke risk assessment methods is questionable due to their use of inconsistent and varying biomarkers, which may lead to unpredictable risk evaluations. This study introduces an automatic deep learning-based system for predicting stroke risk (both ischemic and hemorrhagic) and estimating the time frame of its occurrence, utilizing a comprehensive set of known retinal biomarkers from fundus images. Our system, tested on the UK Biobank and DRSSW datasets, achieved AUROC scores of 0.83 (95% CI: 0.79-0.85) and 0.93 (95% CI: 0.9-0.95), respectively. These results not only highlight our system's advantage over established benchmarks but also underscore the predictive power of retinal biomarkers in assessing stroke risk and the unique effectiveness of each biomarker. Additionally, the correlation between retinal biomarkers and cardiovascular diseases broadens the potential application of our system, making it a versatile tool for predicting a wide range of cardiovascular conditions.

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We examined the relationship between genetic risk for schizophrenia (SZ), using polygenic risk scores (PRSs), and retinal morphological alterations. Retinal structural and vascular indices derived from optical coherence tomography (OCT) and color fundus photography (CFP) and PRSs for SZ were analyzed in N = 35,024 individuals from the prospective cohort study, United Kingdom Biobank (UKB). Results indicated that macular ganglion cell-inner plexiform layer (mGC-IPL) thickness was significantly inversely related to PRS for SZ, and this relationship was strongest within higher PRS quintiles and independent of potential confounders and age. PRS, however, was unrelated to retinal vascular characteristics, with the exception of venular tortuosity, and other retinal structural indices (macular retinal nerve fiber layer [mRNFL], inner nuclear layer [INL], cup-to-disc ratio [CDR]). Additionally, the association between greater PRS and reduced mGC-IPL thickness was only significant for participants in the 40-49 and 50-59 age groups, not those in the 60-69 age group. These findings suggest that mGC-IPL thinning is associated with a genetic predisposition to SZ and may reflect neurodevelopmental and/or neurodegenerative processes inherent to SZ. Retinal microvasculature alterations, however, may be secondary consequences of SZ and do not appear to be associated with a genetic predisposition to SZ.

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BACKGROUND: Recent advancements in imaging technologies, particularly structural optical coherence tomography (OCT), have improved the understanding of diabetic macular edema (DME) pathophysiology and provided valuable biomarkers for disease progression and visual outcomes. This prospective study aimed to investigate the association between specific retinal biomarkers identified through OCT imaging and reading performance metrics in patients with previously treated persistent versus resolved DME and good visual acuity. METHODS: Forty-nine eyes from 35 patients with a history of DME were enrolled. Reading performance was assessed using the Radner reading charts, which include standardized sentences with geometrically progressing print sizes. Structural alterations in the inner and outer retina, as well as the retinal pigment epithelium (RPE), were graded based on OCT images. RESULTS: Reading performance, measured as maximum reading speed, was associated with specific retinal biomarkers. The disruption of the ellipsoid zone (EZ) in the parafoveal region and the presence of disorganization of the inner retinal layers (DRIL) in the parafovea were correlated with reduced reading speed. These associations were independent of the presence of intraretinal or subretinal fluid. CONCLUSIONS: Understanding the relationship between retinal biomarkers and reading performance could contribute to a comprehensive evaluation of visual function and quality of life in patients with DME, leading to better management strategies and treatment outcomes.

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Background: Traditional methods for diagnosing dementia are costly, time-consuming, and somewhat invasive. Since the retina shares significant anatomical similarities with the brain, retinal abnormalities detected via optical coherence tomography (OCT) and OCT angiography (OCTA) have been studied as a potential non-invasive diagnostic tool for neurodegenerative disorders; however, the most effective retinal changes remain a mystery to be unraveled in this review. Objective: This study aims to explore the relationship between retinal abnormalities in OCT/OCTA images and cognitive decline as well as evaluating biomarkers' effectiveness in detecting neurodegenerative diseases. Methods: A systematic search was conducted on PubMed, Web of Science, and Scopus until December 2022, resulted in 64 papers using agreed search keywords, and inclusion/exclusion criteria. Results: The superior peripapillary retinal nerve fiber layer (pRNFL) is a trustworthy biomarker to identify most Alzheimer's disease (AD) cases; however, it is inefficient when dealing with mild AD and mild cognitive impairment (MCI). The global pRNFL (pRNFL-G) is another reliable biomarker to discriminate frontotemporal dementia from mild AD and healthy controls (HCs), moderate AD and MCI from HCs, as well as identifing pathological Aß42/tau in cognitively healthy individuals. Conversely, pRNFL-G fails to realize mild AD and the progression of AD. The average pRNFL thickness variation is considered a viable biomarker to monitor the progression of AD. Finally, the superior and average pRNFL thicknesses are considered consistent for advanced AD but not for early/mild AD. Conclusions: Retinal changes may indicate dementia, but further research is needed to confirm the most effective biomarkers for early and mild AD.

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We present a structured approach to combine explainability of artificial intelligence (AI) with the scientific method for scientific discovery. We demonstrate the utility of this approach in a proof-of-concept study where we uncover biomarkers from a convolutional neural network (CNN) model trained to classify patient sex in retinal images. This is a trait that is not currently recognized by diagnosticians in retinal images, yet, one successfully classified by CNNs. Our methodology consists of four phases: In Phase 1, CNN development, we train a visual geometry group (VGG) model to recognize patient sex in retinal images. In Phase 2, Inspiration, we review visualizations obtained from post hoc interpretability tools to make observations, and articulate exploratory hypotheses. Here, we listed 14 hypotheses retinal sex differences. In Phase 3, Exploration, we test all exploratory hypotheses on an independent dataset. Out of 14 exploratory hypotheses, nine revealed significant differences. In Phase 4, Verification, we re-tested the nine flagged hypotheses on a new dataset. Five were verified, revealing (i) significantly greater length, (ii) more nodes, and (iii) more branches of retinal vasculature, (iv) greater retinal area covered by the vessels in the superior temporal quadrant, and (v) darker peripapillary region in male eyes. Finally, we trained a group of ophthalmologists (N=26) to recognize the novel retinal features for sex classification. While their pretraining performance was not different from chance level or the performance of a nonexpert group (N=31), after training, their performance increased significantly (p<0.001, d=2.63). These findings showcase the potential for retinal biomarker discovery through CNN applications, with the added utility of empowering medical practitioners with new diagnostic capabilities to enhance their clinical toolkit.

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The retina and brain share similar neurochemistry and neurodevelopmental origins, with the retina, often viewed as a "window to the brain." With retinal measures of structure and function becoming easier to obtain in clinical populations there is a growing interest in using retinal findings as potential biomarkers for disorders affecting the central nervous system. Functional retinal biomarkers, such as the electroretinogram, show promise in neurological disorders, despite having limitations imposed by the existence of overlapping genetic markers, clinical traits or the effects of medications that may reduce their specificity in some conditions. This narrative review summarizes the principal functional retinal findings in central nervous system disorders and related mouse models and provides a background to the main excitatory and inhibitory retinal neurotransmitters that have been implicated to explain the visual electrophysiological findings. These changes in retinal neurochemistry may contribute to our understanding of these conditions based on the findings of retinal electrophysiological tests such as the flash, pattern, multifocal electroretinograms, and electro-oculogram. It is likely that future applications of signal analysis and machine learning algorithms will offer new insights into the pathophysiology, classification, and progression of these clinical disorders including autism, attention deficit/hyperactivity disorder, bipolar disorder, schizophrenia, depression, Parkinson's, and Alzheimer's disease. New clinical applications of visual electrophysiology to this field may lead to earlier, more accurate diagnoses and better targeted therapeutic interventions benefiting individual patients and clinicians managing these individuals and their families.

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AIMS: The aims of this study were to analyze retinal and choroidal changes on optical coherence tomography (OCT) and OCT-Angiography (OCT-A) in Alzheimer's disease (AD) patients and compare them to other forms of major dementia. We also aimed to analyze the correlation between clinical severity of global cognitive deficiency assessed by the mini-mental state exam (MMSE) score and OCT/OCT-A parameters. METHODS: Retrospective cross-sectional evaluative study of AD, and age-and gender-matched patients with other dementias. Fundus examination, OCT and OCT-A were compared. RESULTS: Ninety-one eyes of AD patients and 53 eyes of patients with other dementias were included. Retinal deposits were found in 6.59% of AD cases. OCT highlighted the presence of hyperreflective deposits and localized areas of outer retina and ellipsoid zone disruption, respectively in 20.87% and 15.38% of AD cases. Hyperreflective foci were noted within inner retinal layers in 4.39% of AD cases. Quantitative analysis revealed a thicker nasal retinal nerve fiber layer (p = 0.001) and ganglion cell complex in superior (p = 0.011) and temporal quadrants (p = 0.009) in eyes of AD patients, compared to other dementias. OCT-A showed a significantly higher fractal dimension of both superficial and deep capillary plexus (p = 0.005), with lower choriocapillaris density (p = 0.003) in AD patients. CONCLUSIONS: Structural OCT could highlight the presence of hyperreflective deposits in AD, probably reflecting beta-amyloid deposits, associated to outer retinal disruptions. Quantitative OCT analysis showed structural differences between AD patients and other dementias, and combined OCT-A could identify microvascular changes in AD patients representing new potential differential diagnosis criteria.

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Geographic atrophy (GA) is an advanced stage of age-related macular degeneration (AMD) that leads to gradual and permanent vision loss. GA is characterized by the loss of photoreceptor cells and retinal pigment epithelium (RPE), leading to distinct atrophic patches in the macula, which tends to increase with time. Patients with geographic atrophy often experience a gradual and painless loss of central vision, resulting in difficulty reading, recognizing faces, or performing activities that require detailed vision. The primary risk factor for the development of geographic atrophy is advanced age; however, other risk factors, such as family history, smoking, and certain genetic variations, are also associated with AMD. Diagnosis is usually based on a comprehensive eye examination, including imaging tests such as fundus photography, optical coherence tomography (OCT), and fluorescein angiography. Numerous clinical trials are underway, targeting identified molecular pathways associated with GA that are promising. Recent approvals of Syfovre and Izervay by the FDA for the treatment of GA provide hope to affected patients. Administration of these drugs resulted in slowing the rate of progression of the disease. Though these products provide treatment benefits to the patients, they do not offer a cure for geographic atrophy and are limited in efficacy. Considering these safety concerns and limited treatment benefits, there is still a significant need for therapeutics with improved efficacy, safety profiles, and better patient compliance. This comprehensive review discusses pathophysiology, currently approved products, their limitations, and potential future treatment strategies for GA.

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Objective: Patients with diabetes have an increased risk of dementia. Improved prediction of dementia is an important goal in developing future prevention strategies. Diabetic retinopathy screening (DRS) photographs may be a convenient source of imaging biomarkers of brain health. We therefore investigated the association of retinal vascular measures (RVMs) from DRS photographs in patients with type 2 diabetes with dementia risk. Research Design and Methods: RVMs were obtained from 6,111 patients in the GoDARTS bioresource (635 incident cases) using VAMPIRE software. Their association, independent of Apo E4 genotype and clinical parameters, was determined for incident all cause dementia (ACD) and separately Alzheimer's disease (AD) and vascular dementia (VD). We used Cox's proportional hazards with competing risk of death without dementia. The potential value of RVMs to increase the accuracy of risk prediction was evaluated. Results: Increased retinal arteriolar fractal dimension associated with increased risk of ACD (csHR 1.17; 1.08-1.26) and AD (HR 1.33; 1.16-1.52), whereas increased venular fractal dimension (FDV) was associated with reduced risk of AD (csHR 0.85; 0.74-0.96). Conversely, FDV was associated with increased risk of VD (csHR 1.22; 1.07-1.40). Wider arteriolar calibre was associated with a reduced risk of ACD (csHR 0.9; 0.83-0.98) and wider venular calibre was associated with a reduced risk of AD (csHR 0.87; 0.78-0.97). Accounting for competing risk did not substantially alter these findings. RVMs significantly increased the accuracy of prediction. Conclusions: Conventional DRS photographs could enhance stratifying patients with diabetes at increased risk of dementia facilitating the development of future prevention strategies.

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The Vienna fluid monitor is an artificial intelligence (AI) algorithm for the precise localization and quantification of retinal fluid. The algorithm is designed to help clinicians to make objective and accurate decisions in the anti-vascular endothelial growth factor (anti-VEGF) therapy of patients with neovascular age-related macular degeneration. The goal of the implementation is to optimize patient safety, preserve visual function and simultaneously to reduce the treatment burden on the healthcare system and patients.

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INTRODUCTION: We compared retinal layers' thickness between apolipoprotein E (APOE) Ɛ4 carriers and non-carriers in a cohort of cognitively normal middle-aged adults enriched for Alzheimer's disease (AD) risk. METHODS: Participants (N = 245) underwent spectral domain optical coherence tomography. Multivariate analyses of covariance adjusting for age, sex, education, and best corrected vision acuity was used to compare retinal thickness between APOE groups. RESULTS: Participants' mean age was 59.60 (standard deviation = 6.42) with 66.4% women and 32.2% APOE Ɛ4 carriers. Greater macular full thickness was observed in APOE Ɛ4 carriers compared to non-carriers (P = .017), reaching statistical significance for the inner and outer nasal (P = .009 and P = .005, respectively), inner superior (P = .041), and inner and outer inferior (P = .013 and P = .033, respectively) sectors. The differences between APOE groups were mainly driven by the ganglion cell layer (P < .05) and the inner plexiform layer (P < .05). DISCUSSION: A thicker macula is observed already in midlife asymptomatic APOE Ɛ4 carriers at high AD risk.

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Background: Despite the diagnostic accuracy of advanced neurodiagnostic procedures, the detection of Alzheimer's disease (AD) remains poor in primary care. There is an urgent need for screening tools to aid in the detection of early AD. Objective: This study examines the predictive ability of structural retinal biomarkers in detecting cognitive impairment in a primary care setting. Methods: Participants were recruited from Alzheimer's Disease in Primary Care (ADPC) study. As part of the ADPC Retinal Biomarker Study (ADPC RBS), visual acuity, an ocular history questionnaire, eye pressure, optical coherence tomography (OCT) imaging, and fundus imaging was performed. Results: Data were examined on n = 91 participants. The top biomarkers for predicting cognitive impairment included the inferior quadrant of the outer retinal layers, all four quadrants of the peripapillary retinal nerve fiber layer, and the inferior quadrant of the macular retinal nerve fiber layer. Conclusion: The current data provides strong support for continued investigation into structural retinal biomarkers, particularly the retinal nerve fiber layer, as screening tools for AD.

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Carotid artery stenosis (CAS) is among the leading causes of mortality and permanent disabilities in the Western world. CAS is a consequence of systemic atherosclerotic disease affecting the majority of the aging population. Optical coherence tomography angiography (OCTA) is a novel imaging technique for visualizing retinal blood flow. It is a noninvasive, fast method for qualitative and quantitative assessment of the microcirculation. Cerebral and retinal circulation share similar anatomy, physiology, and embryology; thus, retinal microvasculature provides a unique opportunity to study the pathogenesis of cerebral small vessel disease in vivo. In this study, we aimed to analyze the effect of systemic risk factors on retinal blood flow in the eyes of patients with significant carotid artery stenosis using OCT angiography. A total of 112 eyes of 56 patients with significant carotid stenosis were included in the study. We found that several systemic factors, such as decreased estimated glomerular filtration rate (eGFR), hypertension, and carotid occlusion have a significant negative effect on retinal blood flow, while statin use and carotid surgery substantially improve ocular microcirculation. Neither diabetes, clopidogrel or acetylsalicylic acid use, BMI, serum lipid level, nor thrombocyte count showed a significant effect on ocular blood flow. Our results demonstrate that a systematic connection does exist between certain systemic risk factors and retinal blood flow in this patient population. OCTA could help in the assessment of cerebral circulation of patients with CAS due to its ability to detect subtle changes in retinal microcirculation that is considered to represent changes in intracranial blood flow.

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Carotid artery stenosis (CAS) is a consequence of systemic atherosclerotic disease affecting the aging populations of the Western world. CAS is frequently associated with cognitive impairment. However, the mechanisms contributing to the development of vascular cognitive impairment (VCI) associated with CAS are multifaceted and not fully understood. In addition to embolization and decreased blood flow due to the atherosclerotic lesion in the carotid artery, microcirculatory dysfunction in the cerebral circulation also plays a critical role in CAS-related VCI. To better understand the microvascular contributions to cognitive decline associated with CAS and evaluate microvascular protective effects of therapeutic interventions, it is essential to examine the structural and functional changes of the microvessels in the central nervous system (CNS). However, there are some limitations of in vivo brain vascular imaging modalities. The retinal microvasculature provides a unique opportunity to study pathogenesis of cerebral small vessel disease and VCI, because the cerebral circulation and the retinal circulation share similar anatomy, physiology and embryology. Similar microvascular pathologies may manifest in the brain and the retina, thus ocular examination can be used as a noninvasive screening tool to investigate pathological changes in the CNS associated with CAS. In this review, ocular signs of CAS and the retinal manifestations of CAS-associated microvascular dysfunction are discussed. The advantages and limitation of methods that are capable of imaging the ocular circulation (including funduscopy, fluorescein angiography, Doppler sonography, optical coherence tomography [OCT] and optical coherence tomography angiography [OCTA]) are discussed. The potential use of dynamic retinal vessel analysis (DVA), which allows for direct visualization of neurovascular coupling responses in the CNS, for understanding microvascular contributions to cognitive decline in CAS patients is also considered.

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BACKGROUND AND OBJECTIVES: This paper reports a quantitative analysis of the effects of joint photographic experts group (JPEG) image compression of retinal fundus camera images on automatic vessel segmentation and on morphometric vascular measurements derived from it, including vessel width, tortuosity and fractal dimension. METHODS: Measurements are computed with vascular assessment and measurement platform for images of the retina (VAMPIRE), a specialized software application adopted in many international studies on retinal biomarkers. For reproducibility, we use three public archives of fundus images (digital retinal images for vessel extraction (DRIVE), automated retinal image analyzer (ARIA), high-resolution fundus (HRF)). We generate compressed versions of original images in a range of representative levels. RESULTS: We compare the resulting vessel segmentations with ground truth maps and morphological measurements of the vascular network with those obtained from the original (uncompressed) images. We assess the segmentation quality with sensitivity, specificity, accuracy, area under the curve and Dice coefficient. We assess the agreement between VAMPIRE measurements from compressed and uncompressed images with correlation, intra-class correlation and Bland-Altman analysis. CONCLUSIONS: Results suggest that VAMPIRE width-related measurements (central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), arteriolar-venular width ratio (AVR)), the fractal dimension (FD) and arteriolar tortuosity have excellent agreement with those from the original images, remaining substantially stable even for strong loss of quality (20% of the original), suggesting the suitability of VAMPIRE in association studies with compressed images.

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Evidence is accumulating that cognitive function, and visual impairment may be related. In this pilot study, we investigated whether multifractal dimension and lacunarity analyses performed in sectoral regions of the retina may reveal changes in patients with cognitive impairment (CI) that may be masked in the study considering the whole retinal branching pattern. Prospective age-matched subjects (n = 69) with and with no CI and without the presence of any ophthalmic history were recruited (age > 55+ years). The Montreal Cognitive Assessment (MoCA) was used to measure CI, and full-field electroretinogram (ERG) was performed. Also, visual performance exams were conducted using the Rabin cone contrast test (CCT). Quantification of the retinal structure was performed in retinal fundus images [45 o field of view (FOV), optic disk centered] with excellent quality for all individuals [19 healthy controls (HC) and 20 patients with CI] after evaluating the inclusion and exclusion criteria in all study participants recruited (n = 69). The skeletonized vasculature network that comprised the whole branching pattern observable in the full 45° FOV was obtained for each image and divided into nine equal regions (superotemporal, superior, superonasal, macular, optic disk, nasal, inferotemporal, inferior, and inferonasal). The multifractal behavior was analyzed by calculating the generalized dimension Dq (Do, D1, and D2), the lacunarity parameter (Λ), and singularity spectrum f(α) in the nine sectoral skeletonized images as well as in the skeletons that comprised the whole branching pattern observable in the full 45° FOV. The analyses were performed using the ImageJ program together with the FracLac plug-in. Independent sample t-tests or Mann Whitney U test and Pearson correlation coefficient were used to find associations between all parameters in both groups. The effect size (Cohen's d) of the difference between both groups was also assessed. A p-value < 0.05 was considered statistically significant. Significant correlations between multifractal and Λ parameters with the MoCA and implicit time ERG-parameter were observed in the regional analysis. In contrast, no trend was found when considering the whole retinal branching pattern. Analysis of combined structural-functional parameters in sectoral regions of the retina, instead of individual retinal biomarkers, may provide a useful clinical marker of CI.

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Cognitive impairment and dementia are major medical, social, and economic public health issues worldwide with significant implications for life quality in older adults. The leading causes are Alzheimer's disease (AD) and vascular cognitive impairment/dementia (VCID). In both conditions, pathological alterations of the cerebral microcirculation play a critical pathogenic role. Currently, the main pathological biomarkers of AD-ß-amyloid peptide and hyperphosphorylated tau proteins-are detected either through cerebrospinal fluid (CSF) or PET examination. Nevertheless, given that they are invasive and expensive procedures, their availability is limited. Being part of the central nervous system, the retina offers a unique and easy method to study both neurodegenerative disorders and cerebral small vessel diseases in vivo. Over the past few decades, a number of novel approaches in retinal imaging have been developed that may allow physicians and researchers to gain insights into the genesis and progression of cerebromicrovascular pathologies. Optical coherence tomography (OCT), OCT angiography, fundus photography, and dynamic vessel analyzer (DVA) are new imaging methods providing quantitative assessment of retinal structural and vascular indicators-such as thickness of the inner retinal layers, retinal vessel density, foveal avascular zone area, tortuosity and fractal dimension of retinal vessels, and microvascular dysfunction-for cognitive impairment and dementia. Should further studies need to be conducted, these retinal alterations may prove to be useful biomarkers for screening and monitoring dementia progression in clinical routine. In this review, we seek to highlight recent findings and current knowledge regarding the application of retinal biomarkers in dementia assessment.

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PURPOSE: Pathological alterations within optic nerve axons and progressive loss of the parental retinal ganglion cell (RGC) bodies are characteristics of glaucomatous neuropathy. Abnormally elevated intraocular pressure (IOP) is thought to be the major risk factor for most forms of glaucomatous changes, while lowering of the IOP is the mainstream of treatment. However, the pathophysiological mechanisms involved in neurodegenerative changes are poorly understood. It remains still a matter of debate whether elevated IOP harms the neurons directly or indirectly through alterations in the retinal vascularization. METHODS: We analysed morphological and molecular changes within the retina exposed to elevated IOP in an animal model of glaucoma in vivo, in retinal explants and in cultured dissociated retinal cells each incubated under elevated air pressure in vitro, imitating elevated IOP. RESULTS: Although ß-III-tubulin expressing RGCs decreased within the course of the disease, total amount of ß-III-tubulin protein within the retina increased, leading to the assumption that other cells than RGCs abnormally express ß-III-tubulin due to elevated IOP. Surprisingly, we found that ß-III-tubulin, a marker developmentally regulated and specifically expressed in neurons under normal conditions, was strongly up-regulated in desmin-, PDGFR-ß- and α-SMA-positive pericytes as well as in endothelin-1-positive endothelial cells both in vivo under elevated IOP and in vitro under elevated culture atmosphere pressure that simulated IOP elevation. Beta-III-tubulin-driven signalling pathways (ERK 1/2, pERK1/2 and cdc42/Rac) were also regulated. CONCLUSION: The unprecedented regulation of neuron-specific ß-III-tubulin in pericytes and endothelial cells is likely associated with a role of the retinal vasculature in the IOP-induced development and manifestation of glaucomatous degenerative optic nerve response.