Retinal ganglion cell and microvascular density loss in hereditary spastic paraplegia.

Background: Hereditary spastic paraplegia (HSP) is characterized by progressive degeneration of distal axons in the long corticospinal tracts. Loss of retinal cells and microvascular networks has neither been suspected nor investigated. We concurrently examined the retinal microvasculature and retinal layer morphology in patients with HSP to assess whether retinal features may portray disease and its progression. Methods: Fifteen patients with HSP and 30 healthy controls were included in this cross-sectional case-control study. Disease severity was assessed with the Spastic Paraplegia Rating Scale (SPRS). Severity of ataxia was determined by the Scale for the Assessment and Rating of Ataxia (SARA). Retinal microvasculature was measured by means of optical coherence tomography angiography (OCT-A) and morphology of retinal layers using structural OCT. Mixed-effects models were applied for data analysis. Results: HSP patients showed significantly reduced vessel density of the superficial vascular plexus (SVP), reduced ganglion cell layer (GCL) volume, reduced inner plexiform layer (IPL) volume and reduced temporal-inferior peripapillary retinal nerve fiber layer (pRNFL) thickness versus healthy controls. GCL volume reduction correlated significantly with the worsening of visual acuity and higher SARA scores. Conclusions: These findings demonstrate that, in HSP both cells and vascular networks of the retina are compromised. Assessment of the retinal GCL, IPL and SVP may aid in diagnosis and monitoring of disease progression as well as provide novel structural outcome measures for clinical trials.

Structural retinal changes in cerebral small vessel disease.

Cerebral small vessel disease (CSVD) is an important contributor to cognitive impairment and stroke. Previous research has suggested associations with alterations in single retinal layers. We have assessed changes of all individual retinal layers in CSVD using high-resolution optical coherence tomography (OCT) for the first time. Subjects with recent magnetic resonance imaging (MRI) underwent macular and peripapillary retinal imaging using OCT for this case-control study. Number and volume ratio index (WMRI) of white matter lesions (WML) were determined on MRI. Data were analyzed using multiple linear regression models. 27 CSVD patients and 9 control participants were included. Ganglion cell layer (GCL) volume was significantly reduced in patients with CSVD compared to age-matched controls (p = 0.008). In patients with CSVD, larger foveal outer plexiform layer (OPL) volume and decreased temporal peripapillary retinal nerve fiber layer (RNFL) thickness were significantly associated with a higher WMRI in linear regression when controlling for age (p ≤ 0.033). Decreased foveal GCL volume and temporal-inferior RNFL thickness at Bruch's membrane opening (MRW), and increased temporal MRW were associated with a higher WML burden (p ≤ 0.037). Thus, we identified alterations in several OCT layers in individuals with CSVD (GCL, OPL, MRW and RNFL). Their potential diagnostic value merits further study.

Changes of the retinal and choroidal vasculature in cerebral small vessel disease.

Cerebral small vessel disease (CSVD) is associated with changes in the retinal vasculature which can be assessed non-invasively with much higher resolution than the cerebral vasculature. To detect changes at a microvascular level, we used optical coherence tomography angiography which resolves retinal and choroidal vasculature. Participants with CSVD and controls were included. White matter lesions were determined on magnetic resonance imaging (MRI). The retinal and choroidal vasculature were quantified using swept-source optical coherence tomography angiography. Data were analysed using linear regression. We included 30 participants (18 females; patients, n = 20; controls, n = 10) with a mean age of 61 ± 10 years. Patients had a higher mean white matter lesion index and number of lesions than controls (p ≤ 0.002). The intraindividual deviation of choriocapillaris reflectivity differed significantly between age-matched patients (0.234 ± 0.012) and controls (0.247 ± 0.011; p = 0.029). Skeleton density of the deep retinal capillaries was significantly associated with the number of lesions on MRI (ß = - 5.3 × 108, 95%-confidence interval [- 10.3 × 108; - 0.2 × 108]) when controlling for age. The choroidal microvasculature and the deep retinal vascular plexus, as quantified by optical coherence tomography angiography, are significantly altered in CSVD. The value of these findings in diagnosing or monitoring CSVD need to be assessed in future studies.

Microvascular Breakdown Due to Retinal Neurodegeneration in Ataxias.

BACKGROUND: Neurodegenerative ataxias are devastating disorders of the cerebellum and spinal cord, accompanied by death of retinal ganglion cells, leading to relentlessly progressive decline of motor coordination and permanent disability. Retinal microvascular affection has not yet been determined. OBJECTIVES: The aim of this study is to assess whether retinal microvascular alterations occur and, if so, whether they are concurrent with or follow cell death in the retina in neurodegenerative diseases. METHODS: This study involves the cross-sectional observational study of 43 patients with ataxia and 43 controls enrolled from August 1, 2018, to September 30, 2020. The extent of ataxia was determined by the Scale for the Assessment and Rating of Ataxia. Changes in retinal vasculature were examined by optical coherence tomography angiography (OCT-A) and retinal cell and fiber density by OCT in ataxias concurrently. RESULTS: When comparing the ataxia cohort with healthy subjects, ataxia patients exhibited reduced vessel density in the radial peripapillary capillary (RPC) network (P = 0.005), capillary density inside the optic nerve head (cdONH) (P < 0.001), nasal superficial vascular plexus (P = 0.03) as well as reduced ganglion cell layer (GCL) volume (P = 0.04), and temporal peripapillary retinal nerve fiber layer thickness (P = 0.04). Mixed effect analysis modeling laterality confirmed these findings. CONCLUSIONS: These findings demonstrate a distinct pattern of concurrent changes in vessel density of the retinal superficial vascular complex, encompassing the superficial vascular plexus, RPC network and cdONH, and retinal GCL volume, providing new insights into the ongoing degeneration in ataxias. Our findings may have relevance for design of novel therapeutic approaches for ataxias and possibly other neurodegenerative diseases.

Retinal and Choroidal Capillary Perfusion Are Reduced in Hypertensive Crisis Irrespective of Retinopathy.

Purpose: Hypertensive crisis causes end-organ damage through small-vessel damage as described histologically. Noninvasive optical coherence tomography angiography (OCTA) makes it possible to image retinal and choroidal capillaries on a microscopic level in vivo. We quantified eye vessel perfusion changes in hypertensive crisis using OCTA. Methods: Patients with hypertensive crisis (systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg) and age-matched healthy controls were included in the study. OCTA en face 3 × 3-mm images of the superficial and deep retinal layers and the choriocapillaris were acquired. Outcome parameters included vessel density (VD) and vessel skeleton density (VSD) of the superficial and deep retinal layers, as well as flow voids of the choriocapillaris. Results: Twenty-eight eyes of 17 patients and 31 age-matched control eyes of 18 healthy subjects were included. VD and VSD of the deep retinal layer were significantly reduced in hypertensive crisis (P ≤ 0.004). Choriocapillaris signal intensity was more heterogeneous in patients, and flow voids exhibited confluence with a larger average area and a lower absolute count (P ≤ 0.045). These changes were independent of time since onset of hypertensive crisis and of the presence and extent of retinopathy. Deep retinal changes were associated with renal end-organ failure (P = 0.045). Conclusions: Hypertensive crisis is associated with a significant reduction in retinal and choroidal capillary perfusion based on OCTA findings. These alterations are independent of retinopathy and related to end-organ damage. Translational Relevance: OCTA might help distinguish hypertensive urgency from hypertensive emergency earlier than currently possible.

AhR and IDO1 in pathogenesis of Covid-19 and the "Systemic AhR Activation Syndrome:" a translational review and therapeutic perspectives.

Covid-19 is the acute illness caused by SARS-CoV-2 with initial clinical symptoms such as cough, fever, malaise, headache, and anosmia. After entry into cells, corona viruses (CoV) activate aryl hydrocarbon receptors (AhRs) by an indoleamine 2,3-dioxygenase (IDO1)-independent mechanism, bypassing the IDO1-kynurenine-AhR pathway. The IDO1-kynurenine-AhR signaling pathway is used by multiple viral, microbial and parasitic pathogens to activate AhRs and to establish infections. AhRs enhance their own activity through an IDO1-AhR-IDO1 positive feedback loop prolonging activation induced by pathogens. Direct activation of AhRs by CoV induces immediate and simultaneous up-regulation of diverse AhR-dependent downstream effectors, and this, in turn, results in a "Systemic AhR Activation Syndrome" (SAAS) consisting of inflammation, thromboembolism, and fibrosis, culminating in multiple organ injuries, and death. Activation of AhRs by CoV may lead to diverse sets of phenotypic disease pictures depending on time after infection, overall state of health, hormonal balance, age, gender, comorbidities, but also diet and environmental factors modulating AhRs. We hypothesize that elimination of factors known to up-regulate AhRs, or implementation of measures known to down-regulate AhRs, should decrease severity of infection. Although therapies selectively down-regulating both AhR and IDO1 are currently lacking, medications in clinical use such as dexamethasone may down-regulate both AhR and IDO1 genes, as calcitriol/vitamin D3 may down-regulate the AhR gene, and tocopherol/vitamin E may down-regulate the IDO1 gene. Supplementation of calcitriol should therefore be subjected to epidemiological studies and tested in prospective trials for prevention of CoV infections, as should tocopherol, whereas dexamethasone could be tried in interventional trials. Because lack of physical exercise activates AhRs via the IDO1-kynurenine-AhR signaling pathway increasing risk of infection, physical exercise should be encouraged during quarantines and stay-at-home orders during pandemic outbreaks. Understanding which factors affect gene expression of both AhR and IDO1 may help in designing therapies to prevent and treat humans suffering from Covid-19.

Impact of visual impairment on physical activity in early and late age-related macular degeneration.

BACKGROUND: Modifiable risk factors for age-related macular degeneration (AMD) include smoking, nutrition and likely physical activity (PA). Levels of PA, however, are impacted by any visual impairment which makes the assessment of any association with AMD difficult. PURPOSE: To assess the impact of visual impairment under both high and low luminance conditions on levels of PA in early and late AMD. METHODS: Ninety participants with early to late AMD underwent a clinical assessment including conventional best-corrected visual acuity, low luminance visual acuity, contrast sensitivity and the Moorfields acuity test. PA was recorded using a wrist-worn accelerometer (GENEActiv, Activeinsights) on seven consecutive days. Patient characteristics were compared with the Wilcoxon rank-sum test and determinants of moderate-to-vigorous-PA (MVPA) were assessed using linear regression models. RESULTS: Mean age was 73.9 ± 8.5 years (range 50-89) and 47 subjects (52.2%) were women. Average MVPA time was longer in the early (355.1 ± 252.0 minutes/week) compared to the late AMD group (162.2 ± 134.6 minutes/week; p<0.001). Using linear regression, age [ß = -0.25; 95% confidence interval (CI): -12.9; -0.8, p = 0.028] and AMD stage (ß = -0.28; 95% CI: -230.9, -25.0; p = 0.015) but not visual impairment on any of the employed tests were associated with MVPA (minutes/week). CONCLUSIONS: We found late AMD to be associated with reduced PA. As performance on any of the visual tests was not associated with PA, this association cannot entirely be explained by functional impairment. More research is needed to further explore the association of PA and AMD as PA may be a potentially modifiable risk factor.

Clemastine effects in rat models of a myelination disorder.

BackgroundPelizaeus Merzbacher disease (PMD) is a dysmyelinating disorder of the central nervous system caused by impaired differentiation of oligodendrocytes. This study was prompted by findings that antimuscarinic compounds enhance oligodendrocyte differentiation and remyelination in vitro. One of these compounds, clemastine fumarate, is licensed for treatment of allergic conditions. We tested whether clemastine fumarate can promote myelination in two rodent PMD models, the myelin-deficient and the PLP transgenic rat.MethodsPups were treated with daily injections of clemastine (10-30 mg/kg/day) on postnatal days 1-21. Neurologic phenotypes and myelination patterns in the brain, optic nerves, and spinal cords were assessed using histological techniques.ResultsNo changes in neurological phenotype or survival were observed even at the highest dose of clemastine. Postmortem staining with Luxol fast blue and myelin basic protein immunohistochemistry revealed no evidence for improved myelination in the CNS of treated rats compared to vehicle-treated littermates. Populations of mature oligodendrocytes were unaffected by the treatment.ConclusionThese results demonstrate lack of therapeutic effect of clemastine in two rat PMD models. Both models have rapid disease progression consistent with the connatal form of the disease. Further studies are necessary to determine whether clemastine bears a therapeutic potential in milder forms of PMD.