Brain Degeneration in Synucleinopathies Based on Analysis of Cognition and Other Nonmotor Features: A Multimodal Imaging Study.

BACKGROUND: We aimed to characterize subtypes of synucleinopathies using a clustering approach based on cognitive and other nonmotor data and to explore structural and functional magnetic resonance imaging (MRI) brain differences between identified clusters. METHODS: Sixty-two patients (n = 6 E46K-SNCA, n = 8 dementia with Lewy bodies (DLB) and n = 48 idiopathic Parkinson's disease (PD)) and 37 normal controls underwent nonmotor evaluation with extensive cognitive assessment. Hierarchical cluster analysis (HCA) was performed on patients' samples based on nonmotor variables. T1, diffusion-weighted, and resting-state functional MRI data were acquired. Whole-brain comparisons were performed. RESULTS: HCA revealed two subtypes, the mild subtype (n = 29) and the severe subtype (n = 33). The mild subtype patients were slightly impaired in some nonmotor domains (fatigue, depression, olfaction, and orthostatic hypotension) with no detectable cognitive impairment; the severe subtype patients (PD patients, all DLB, and the symptomatic E46K-SNCA carriers) were severely impaired in motor and nonmotor domains with marked cognitive, visual and bradykinesia alterations. Multimodal MRI analyses suggested that the severe subtype exhibits widespread brain alterations in both structure and function, whereas the mild subtype shows relatively mild disruptions in occipital brain structure and function. CONCLUSIONS: These findings support the potential value of incorporating an extensive nonmotor evaluation to characterize specific clinical patterns and brain degeneration patterns of synucleinopathies.

Spatial characterization of the effect of age and sex on macular layer thicknesses and foveal pit morphology.

Characterizing the effect of age and sex on macular retinal layer thicknesses and foveal pit morphology is crucial to differentiating between natural and disease-related changes. We applied advanced image analysis techniques to optical coherence tomography (OCT) to: 1) enhance the spatial description of age and sex effects, and 2) create a detailed open database of normative retinal layer thickness maps and foveal pit shapes. The maculae of 444 healthy subjects (age range 21-88) were imaged with OCT. Using computational spatial data analysis, thickness maps were obtained for retinal layers and averaged into 400 (20 x 20) sectors. Additionally, the geometry of the foveal pit was radially analyzed by computing the central foveal thickness, rim height, rim radius, and mean slope. The effect of age and sex on these parameters was analyzed with multiple regression mixed-effects models. We observed that the overall age-related decrease of the total retinal thickness (TRT) (-1.1% per 10 years) was mainly driven by the ganglion cell-inner plexiform layer (GCIPL) (-2.4% per 10 years). Both TRT and GCIPL thinning patterns were homogeneous across the macula when using percentual measurements. Although the male retina was 4.1 µm thicker on average, the greatest differences were mainly present for the inner retinal layers in the inner macular ring (up to 4% higher TRT than in the central macula). There was an age-related decrease in the rim height (1.0% per 10 years) and males had a higher rim height, shorter rim radius, and steeper mean slope. Importantly, the radial analysis revealed that these changes are present and relatively uniform across angular directions. These findings demonstrate the capacity of advanced analysis of OCT images to enhance the description of the macula. This, together with the created dataset, could aid the development of more accurate diagnosis models for macular pathologies.

Potential Tear Biomarkers for the Diagnosis of Parkinson's Disease-A Pilot Study.

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. In this study, the tear proteome profile of patients with idiopathic PD (iPD, n = 24), carriers of the E46K-SNCA mutation (n = 3) and healthy control (CT, n = 27) subjects was analyzed to identify candidate biomarkers for the diagnosis of PD. An observational, prospective and case-control pilot study was carried out, analyzing the participants tear samples by nano-liquid chromatography-mass spectrometry (nLC-MS/MS) and assessing their neurological impairment. The proteomic data obtained are available at ProteomeXchange with identifier 10.6019/PXD028811. These analyses led to the identification of 560 tear proteins, some of which were deregulated in PD patients and that have been implicated in immune responses, inflammation, apoptosis, collagen degradation, protein synthesis, defense, lipid transport and altered lysosomal function. Of these proteins, six were related to neurodegenerative processes and showed a good capacity to classify patients and controls. These findings revealed that certain proteins were upregulated in the tears of PD patients, mainly proteins involved in lysosomal function. Thus, in this study, tear proteins were identified that are implicated in neurodegeneration and that may be related to an aggressive disease phenotype in PD patients.

Visual dysfunction is associated with cognitive impairment in Parkinson's disease.

INTRODUCTION: Visual dysfunction and cognitive impairment are common in Parkinson's disease (PD) but the precise contribution of lower-level visual impairment to visual-input based cognitive performance has not been extensively characterized in PD. METHODS: We included 49 PD patients and 22 healthy controls (HC). Lower-level visual function tests [high and low contrast visual acuity (HCVA and LCVA) and contrast sensitivity (CS)] and a neuropsychological battery (involving visual cognition) were performed. Pairwise correlations between lower-level visual functions and visual cognition were computed and stepwise linear regressions were fitted introducing age, Geriatric Depression Scale, and lower-level visual functions in the model to calculate their predicted effect on visual cognition. RESULTS: Compared to controls, patients presented a significant impairment in all cognitive domains (visual attention, visual processing speed and visual perception, visuospatial abilities, visuoconstructive abilities, and visual memory), and lower-level visual functions. HCVA and LCVA were significantly associated with visual cognition in PD. HCVA explained up to 49.3% and 34.2% of the variability in visual perception and visuospatial abilities, respectively, whereas LCVA was mainly associated with short- and long-term visual memory and visuospatial abilities. CONCLUSION: Lower-level visual dysfunction is highly associated with cognitive performance in PD, when cognitive tests are based on visual input. Our results support that lower-level visual functions should be considered when assessing cognitive status of PD patients and might be useful for predicting cognitive deterioration.

Foveal Pit Morphology Characterization: A Quantitative Analysis of the Key Methodological Steps.

Disentangling the cellular anatomy that gives rise to human visual perception is one of the main challenges of ophthalmology. Of particular interest is the foveal pit, a concave depression located at the center of the retina that captures light from the gaze center. In recent years, there has been a growing interest in studying the morphology of the foveal pit by extracting geometrical features from optical coherence tomography (OCT) images. Despite this, research has devoted little attention to comparing existing approaches for two key methodological steps: the location of the foveal center and the mathematical modelling of the foveal pit. Building upon a dataset of 185 healthy subjects imaged twice, in the present paper the image alignment accuracy of four different foveal center location methods is studied in the first place. Secondly, state-of-the-art foveal pit mathematical models are compared in terms of fitting error, repeatability, and bias. The results indicate the importance of using a robust foveal center location method to align images. Moreover, we show that foveal pit models can improve the agreement between different acquisition protocols. Nevertheless, they can also introduce important biases in the parameter estimates that should be considered.

Retinal Thickness Predicts the Risk of Cognitive Decline in Parkinson Disease.

OBJECTIVE: This study was undertaken to analyze longitudinal changes of retinal thickness and their predictive value as biomarkers of disease progression in idiopathic Parkinson's disease (iPD). METHODS: Patients with Lewy body diseases were enrolled and prospectively evaluated at 3 years, including patients with iPD (n = 42), dementia with Lewy bodies (n = 4), E46K-SNCA mutation carriers (n = 4), and controls (n = 17). All participants underwent Spectralis retinal optical coherence tomography and Montreal Cognitive Assessment, and Unified Parkinson's Disease Rating Scale score was obtained in patients. Macular ganglion cell-inner plexiform layer complex (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thickness reduction rates were estimated with linear mixed models. Risk ratios were calculated to evaluate the association between baseline GCIPL and pRNFL thicknesses and the risk of subsequent cognitive and motor worsening, using clinically meaningful cutoffs. RESULTS: GCIPL thickness in the parafoveal region (1- to 3-mm ring) presented the largest reduction rate. The annualized atrophy rate was 0.63µm in iPD patients and 0.23µm in controls (p < 0.0001). iPD patients with lower parafoveal GCIPL and pRNFL thickness at baseline presented an increased risk of cognitive decline at 3 years (relative risk [RR] = 3.49, 95% confidence interval [CI] = 1.10-11.1, p = 0.03 and RR = 3.28, 95% CI = 1.03-10.45, p = 0.045, respectively). We did not identify significant associations between retinal thickness and motor deterioration. INTERPRETATION: Our results provide evidence of the potential use of optical coherence tomography-measured parafoveal GCIPL thickness to monitor neurodegeneration and to predict the risk of cognitive worsening over time in iPD. ANN NEUROL 2021;89:165-176.

Author Correction: A new approach based on targeted pooled DNA sequencing identifies novel mutations in patients with Inherited Retinal Dystrophies.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Parafoveal thinning of inner retina is associated with visual dysfunction in Lewy body diseases.

BACKGROUND: Retinal optical coherence tomography findings in Lewy body diseases and their implications for visual outcomes remain controversial. We investigated whether region-specific thickness analysis of retinal layers could improve the detection of macular atrophy and unravel its association with visual disability in Parkinson's disease. METHODS: Patients with idiopathic Parkinson's disease (n = 63), dementia with Lewy bodies (n = 8), and E46K mutation carriers in the α-synuclein gene (E46K-SNCA) (n = 4) and 34 controls underwent Spectralis optical coherence tomography macular scans and a comprehensive battery of visual function and cognition tests. We computed mean retinal layer thicknesses of both eyes within 1-, 2-, 3-, and 6-mm diameter macular discs and in concentric parafoveal (1- to 2-mm, 2- to 3-mm, 1- to 3-mm) and perifoveal (3- to 6-mm) rings. Group differences in imaging parameters and their relationship with visual outcomes were analyzed. A multivariate logistic model was developed to predict visual impairment from optical coherence tomography measurements in Parkinson's disease, and cutoff values were determined with receiver operating characteristic analysis. RESULTS: When compared with controls, patients with dementia with Lewy bodies had significant thinning of the ganglion cell-inner plexiform layer complex within the central 3-mm disc mainly because of differences in 1- to 3-mm parafoveal thickness. This parameter was strongly correlated in patients, but not in controls, with low contrast visual acuity and visual cognition outcomes (P < .05, False Discovery Rate), achieving 88% of accuracy in predicting visual impairment in Parkinson's disease. CONCLUSION: Our findings support that parafoveal thinning of ganglion cell-inner plexiform complex is a sensitive and clinically relevant imaging biomarker for Lewy body diseases, specifically for Parkinson's disease. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

HGF-rs12536657 and Ocular Biometric Parameters in Hyperopic Children, Emmetropic Adolescents, and Young Adults: A Multicenter Quantitative Trait Study.

INTRODUCTION: Even though ocular refractive state is highly heritable and under strong genetic control, the identification of susceptibility genes remains a challenge. Several HGF (hepatocyte growth factor) gene variants have been associated with ocular refractive errors and corneal pathology. PURPOSE: Here, we assess the association of an HGF gene variant, previously reported as associated with hyperopia, and ocular biometric parameters in a multicenter Spanish cohort. METHODS: An observational prospective multicenter cross-sectional study was designed, including a total of 403 unrelated subjects comprising 188 hyperopic children (5 to 17 years) and 2 control groups: 52 emmetropic adolescents (13 to 17 years) and 163 emmetropic young adults (18 to 28 years). Each individual underwent a comprehensive eye examination including cycloplegic refraction, and topographic and ocular biometric analysis. Genomic DNA was extracted from oral swabs. HGF single nucleotide polymorphism (SNP) rs12536657 was genotyped. Genotypic, allelic, and logistic regression analyses were performed comparing the different groups. A quantitative trait association test analyzing several biometric parameters was also performed using generalized estimating equations (GEEs) adjusting for age and gender. RESULTS: No association between rs12536657 and hyperopia was found through gender-adjusted logistic regression comparing the hyperopic children with either of the two control groups. Significant associations between mean topographic corneal curvature and rs12536657 for G/A (slope = +0.32; CI 95%: 0.04-0.60; p=0.023) and A/A (slope = +0.76; CI 95%: 0.12-1.40; p=0.020) genotypes were observed with the age- and gender-adjusted univariate GEE model. Both flat and steep corneal topographic meridians were also significantly associated with rs12536657 for the G/A and A/A genotypes. No association was found between rs12536657 and any other topographic or biometric measurements. CONCLUSIONS: Our results support a possible role for HGF gene variant rs12536657 in corneal curvature in our population. To our knowledge, this is the first multicenter quantitative trait association study of HGF genotypes and ocular biometric parameters comprising a pediatric cohort.

Parental Mosaicism in PAX6 Causes Intra-Familial Variability: Implications for Genetic Counseling of Congenital Aniridia and Microphthalmia.

Mutations in PAX6 are involved in several developmental eye disorders. These disorders have considerable phenotypic variability, ranging from panocular forms of congenital aniridia and microphthalmia to isolated anomalies of the anterior or posterior segment. Here, we describe 3 families with variable inter-generational ocular expression of aniridia, iris coloboma, or microphthalmia, and an unusual transmission of PAX6 mutations from an unaffected or mildly affected parent; all of which raised suspicion of gonosomal mosaicism. We first identified two previously known nonsense mutations and one novel likely pathogenic missense variant in PAX6 in probands by means of targeted NGS. The subsequent segregation analysis by Sanger sequencing evidenced the presence of highly probable mosaic events in paternal blood samples. Mosaicism was further confirmed by droplet digital PCR analysis in several somatic tissues of mosaic fathers. Quantification of the mutant allele fraction in parental samples showed a marked deviation from 50%, with a range between 12 and 29% depending on cell type. Gonosomal mosaicsm was definitively confirmed in one of the families thanks to the availability of a sperm sample from the mosaic father. Thus, the recurrence risk in this family was estimated to be about one-third. This is the first report confirming parental PAX6 mosaicism as a cause of disease recurrence in aniridia and other related phenotypes. In addition, we demonstrated that post-zygotic mosaicism is a frequent and underestimated pathogenic mechanism in aniridia, explaining intra-familial phenotypic variability in many cases. Our findings may have substantial implications for genetic counseling in congenital aniridia. Thus, we also highlight the importance of comprehensive genetic screening of parents for new sporadic cases with aniridia or related developmental eye disease to more accurately assess recurrence risk. In conclusion, somatic and/or gonosomal mosaicism should be taken into consideration as a genetic factor to explain not only families with unaffected parents despite multiple affected children but also variable expressivity, apparent de novo cases, and even uncharacterized cases of aniridia and related developmental eye disorders, apparently lacking PAX6 mutations.

A new approach based on targeted pooled DNA sequencing identifies novel mutations in patients with Inherited Retinal Dystrophies.

Inherited retinal diseases (IRD) are a heterogeneous group of diseases that mainly affect the retina; more than 250 genes have been linked to the disease and more than 20 different clinical phenotypes have been described. This heterogeneity both at the clinical and genetic levels complicates the identification of causative mutations. Therefore, a detailed genetic characterization is important for genetic counselling and decisions regarding treatment. In this study, we developed a method consisting on pooled targeted next generation sequencing (NGS) that we applied to 316 eye disease related genes, followed by High Resolution Melting and copy number variation analysis. DNA from 115 unrelated test samples was pooled and samples with known mutations were used as positive controls to assess the sensitivity of our approach. Causal mutations for IRDs were found in 36 patients achieving a detection rate of 31.3%. Overall, 49 likely causative mutations were identified in characterized patients, 14 of which were first described in this study (28.6%). Our study shows that this new approach is a cost-effective tool for detection of causative mutations in patients with inherited retinopathies.

Multicenter Spanish study of spectral-domain optical coherence tomography in normal children.

PURPOSE: To compile a multicenter normative database of retinal nerve fibre layer (RNFL) and macular thicknesses and macular volume values in healthy Caucasian children 4-17 years using spectral-domain optical coherence tomography (SD-OCT). To analyse variations in the OCT measurements as a function of age, sex, refraction, and axial length (AL). METHODS: An observational, multicenter and cross-sectional study among 301 healthy Caucasian children recruited at three Spanish centres was performed. To compile the database, each child underwent a dilated eye examination and a cycloplegic refraction, five AL measurements (IOL Master; Carl Zeiss Meditec, Dublin, CA, USA), five OCT scans with Cirrus OCT: three peripapillary RNFL scans (Optic Disc Cube 200X200 protocol) and two macular scans (Macular Cube 512X128 protocol). One eye of each subject was selected randomly for analysis. RESULTS: Two hundred eighty-three children (117 boys, 41.34%; 166 girls, 58.66%) were included in this study. The mean age of the children was 9.58 ± 3.12 years (range, 4-17). The mean SE was +0.63 ± 1.65 D; (range, -4.88 to +5.25). The mean AL was 22.94 ± 1.10 mm (range, 20.10-26.27). The mean global RNFL thickness was 97.40 ± 9.0 µm (range, 77-121.7 µm). Multivariate analysis showed a positive correlation between the RNFL and spherical equivalent (SE) (p = 0.014). The mean central macular thickness was 253.85 ± 19.76 µm, the average thickness 283.62 ± 14.08 µm, and the mean macular volume 10.22 ± 0.49 µm(3) . Multivariate analysis showed a positive correlation between central macular thickness and age (p < 0.001). Boys had a significantly thicker central macula than girls (p < 0.001). CONCLUSIONS: Normative paediatric SD-OCT data might facilitate use of SD-OCT for assessing childhood ophthalmic diseases. This study provides a multicenter paediatric normative database of SD-OCT peripapillary RNFL and macular data.

Morphology of retinal vessels in the optic disk in a Göttingen minipig experimental glaucoma model.

OBJECTIVE: To compare the morphology of normal, healthy Gottingen minipig retinal vessels of the optic disk with experimentally induced glaucomatous optic disks in order to identify the glaucomatous excavation. Present results were compared to human glaucoma findings. PROCEDURE: Sixteen eyes from eight Göttingen minipigs were studied using fundoscopic photography and fluorescein angiography. Experimental glaucoma was then induced in the left eyes over 14 months, and changes in the optic disk vessels were assessed using fundoscopic photography and fluorescein angiography. The changes were compared with those previously reported in humans. RESULTS: Regarding the number of vessels, the location from where they emerge and the sectors of the optic disk that they cross, arterial and retinal vessels in Göttingen minipigs present a more asymmetric layout than in humans. The central excavation is filled by the central venous ring. Changes in the glaucomatous optic disk include arteriolar incurvation, and sometimes, nasal, and peripheral displacement of the arterioles that emerge between the ganglion cell axons of the neuroretinal ring. No angiographic changes were observed in the experimental glaucoma model. CONCLUSIONS: The changes in the glaucomatous optic disk of the minipig imply a predominant involvement of the arterioles. However, in humans with primary open-angle glaucoma (POAG), both the arterioles and the venules are displaced, and the central excavation is easier to distinguish, because of the absence of a central venous ring.

Occlusive vasculitis and optic disk neovascularization associated with neuroretinitis.

PURPOSE: To report a case of neuroretinitis associated with ischemic nasal branch retinal vein occlusion, periphlebitis, and neovascularization of the optic disk. METHODS: Case report. RESULTS: A 32-year-old man presented with a typical image of neuroretinitis, retinal hemorrhages and sheathing of the retinal veins in the nasal retina. His left hand had been bitten by a kitten 8 weeks before. Serology for Bartonella henselae was negative. On the 6th week of follow-up, optic disk neovascularization developed, which required retinal photocoagulation. Photocoagulation was performed again at the 12th and 18th week revision since further new vessels had developed. At the 32nd week of follow-up neovascularization had regressed. CONCLUSIONS: Neuroretinitis may be associated with severe complications such as retinal vascular occlusions and optic disk neovascularization.

Intravenous immunoglobulin therapy for refractory ocular cicatricial pemphigoid: case report.

PURPOSE: To report the favorable outcome of a patient with severe ocular cicatricial pemphigoid, which was refractory to conventional treatment but recovered after intravenous immunoglobulin therapy. METHODS: A case report. RESULTS: Conventional therapy failed to control the ocular symptoms of this patient, which are typical of the disease. However, the patient improved remarkably in response to pulsed intravenous human immunoglobulin therapy. CONCLUSIONS: We achieved stabilization of the disease around the seventh intravenous immunoglobulin cycle, thus contributing to satisfactory postoperative evolution after limbal allograft transplantation and facilitating the performance of intraocular surgical procedures, such as phacoemulsification, with improvement in best-corrected visual acuity.