Dysphagia Affecting Quality of Life in Cerebellar Ataxia—a Large Survey

Dysphagia is a common symptom in neurodegenerative disorders and is generally associated with increased mortality. In the clinical care setting of ataxia patients, no systematical and standardized assessment of dysphagia is employed. Its impact on patients’ health-related quality of life is not well understood. To assess the impact of dysphagia in ataxia patients on diet, body weight, and health-related quality of life. We conducted a large survey using self-reported questionnaires for swallowing-related quality of life (Swal-QOL) and a food frequency list in combination with retrospective clinical data of 119 patients with cerebellar ataxia treated in the neurological outpatient clinic of a large German university hospital. Seventeen percent of ataxia patients suffered from dysphagia based on the Swal-QOL score. Less than 1% of all patients reported dysphagia as one of their most disabling symptoms. Dysphagia was associated with unintentional weight loss (p = 0.02) and reduced health-related quality of life (p = 0.01) but did not affect individual nutritional habits (p > 0.05; Chi-squared test). Dysphagia is a relevant symptom in cerebellar ataxia. A systematic screening for dysphagia in patients with cerebellar ataxia would be desirable to enable early diagnosis and treatment

Less Is More - Estimation of the Number of Strides Required to Assess Gait Variability in Spatially Confined Settings

Background: Gait variability is an established marker of gait function that can be assessed using sensor-based approaches. In clinical settings, spatial constraints and patient condition impede the execution of longer distance walks for the recording of gait parameters. Turning paradigms are often used to overcome these constraints and commercial gait analysis systems algorithmically exclude turns for gait parameters calculations. We investigated the effect of turns in sensor-based assessment of gait variability. Methods: Continuous recordings from 31 patients with movement disorders (ataxia, essential tremor and Parkinson's disease) and 162 healthy elderly (HE) performing level walks including 180° turns were obtained using an inertial sensor system. Accuracy of the manufacturer's algorithm of turn-detection was verified by plotting stride time series. Strides before and after turn events were extracted and compared to respective average of all strides. Coefficient of variation (CoV) of stride length and stride time was calculated for entire set of strides, segments between turns and as cumulative values. Their variance and congruency was used to estimate the number of strides required to reliably assess the magnitude of stride variability. Results: Non-detection of turns in 5.8% of HE lead to falsely increased CoV for these individuals. Even after exclusion of these, strides before/after turns tended to be spatially shorter and temporally longer in all groups, contributing to an increase of CoV at group level and widening of confidence margins with increasing numbers of strides. This could be attenuated by a more generous turn excision as an alternative approach. Correlation analyses revealed excellent consistency for CoVs after at most 20 strides in all groups. Respective stride counts were even lower in patients using a more generous turn excision. Conclusion: Including turns to increase continuous walking distance in spatially confined settings does not necessarily improve the validity and reliability of gait variability measures. Specifically with gait pathology, perturbations of stride characteristics before/after algorithmically excised turns were observed that may increase gait variability with this paradigm. We conclude that shorter distance walks of around 15 strides suffice for reliable and valid recordings of gait variability in the groups studied here

Neurochemical Differences in Spinocerebellar Ataxia Type 14 and 1

Autosomal-dominant spinocerebellar ataxias (SCA) are neurodegenerative diseases characterized by progressive ataxia. Here, we report on neurometabolic alterations in spinocerebellar ataxia type 1 (SCA1; SCA-ATXN1) and 14 (SCA14; SCA-PRKCG) assessed by non-invasive 1H magnetic resonance spectroscopy. Three Tesla 1H magnetic resonance spectroscopy was performed in 17 SCA14, 14 SCA1 patients, and in 31 healthy volunteers. We assessed metabolites in the cerebellar vermis, right cerebellar hemisphere, pons, prefrontal, and motor cortex. Additionally, clinical characteristics were obtained for each patient to correlate them with metabolites. In SCA14, metabolic changes were restricted to the cerebellar vermis compared with widespread neurochemical alterations in SCA1. In SCA14, total N-acetylaspartate (tNAA) was reduced in the vermis by 34%. In SCA1, tNAA was reduced in the vermis (24%), cerebellar hemisphere (26%), and pons (25%). SCA14 patients showed 24% lower glutamate+glutamine (Glx) and 46% lower γ-aminobutyric acid (GABA) in the vermis, while SCA1 patients showed no alterations in Glx and GABA. SCA1 revealed a decrease of aspartate (Asp) in the vermis (62%) and an elevation in the prefrontal cortex (130%) as well as an elevation of myo-inositol (Ins) in the cerebellar hemisphere (51%) and pons (46%). No changes of Asp and Ins were detected in SCA14. Beyond, glucose (Glc) was increased in the vermis of both SCA14 (155%) and SCA1 (247%). 1H magnetic resonance spectroscopy revealed differing neurochemical profiles in SCA1 and SCA14 and confirmed metabolic changes that may be indicative for neuronal loss and dysfunctional energy metabolism. Therefore, 1H magnetic resonance spectroscopy represents a helpful tool for in-vivo tracking of disease-specific pathophysiology

Investigation of Visual System Involvement in Spinocerebellar Ataxia Type 14

Spinocerebellar ataxia type 14 (SCA-PRKCG, formerly SCA14) is a rare, slowly progressive disorder caused by conventional mutations in protein kinase Cγ (PKCγ). The disease usually manifests with ataxia, but previous reports suggested PRKCG variants in retinal pathology. To systematically investigate for the first time visual function and retinal morphology in patients with SCA-PRKCG. Seventeen patients with PRKCG variants and 17 healthy controls were prospectively recruited, of which 12 genetically confirmed SCA-PRKCG patients and 14 matched controls were analyzed. We enquired a structured history for visual symptoms. Vision-related quality of life was obtained with the National Eye Institute Visual Function Questionnaire (NEI-VFQ) including the Neuro-Ophthalmic Supplement (NOS). Participants underwent testing of visual acuity, contrast sensitivity, visual fields, and retinal morphology with optical coherence tomography (OCT). Measurements of the SCA-PRKCG group were analyzed for their association with clinical parameters (ataxia rating and disease duration). SCA-PRKCG patients rate their vision-related quality of life in NEI-VFQ significantly worse than controls. Furthermore, binocular visual acuity and contrast sensitivity were worse in SCA-PRKCG patients compared with controls. Despite this, none of the OCT measurements differed between groups. NEI-VFQ and NOS composite scores were related to ataxia severity. Additionally, we describe one patient with a genetic variant of uncertain significance in the catalytic domain of PKCγ who, unlike all confirmed SCA-PRKCG, presented with a clinically silent epitheliopathy. SCA-PRKCG patients had reduced binocular vision and vision-related quality of life. Since no structural retinal damage was found, the pathomechanism of these findings remains unclear

Functionally Relevant Maculopathy and Optic Atrophy in Spinocerebellar Ataxia Type 1

Background: Spinocerebellar ataxia type 1 (SCA-ATXN1) is an inherited progressive ataxia disorder characterized by an adult-onset cerebellar syndrome combined with nonataxia signs. Retinal or optic nerve affection are not systematically described. Objectives: To describe a retinal phenotype and its functional relevance in SCA-ATXN1. Methods: We applied optical coherence tomography (OCT) in 20 index cases with SCA-ATXN1 and 22 healthy controls (HCs), investigating qualitative changes and quantifying the peripapillary retinal nerve fiber layer (pRNFL) thickness and combined ganglion cell and inner plexiform layer (GCIP) volume as markers of optic atrophy and outer retinal layers as markers of maculopathy. Visual function was assessed by high- (HC-VA) and low-contrast visual acuity (LC-VA) and the Hardy-Rand-Rittler pseudoisochromatic test for color vision. Results: Five patients (25%) showed distinct maculopathies in the ellipsoid zone (EZ). Furthermore, pRNFL (P < 0.001) and GCIP (P = 0.002) were reduced in patients (pRNFL, 80.86 ± 9.49 μm; GCIP, 1.84 ± 0.16 mm3) compared with HCs (pRNFL, 97.02 ± 8.34 μm; GCIP, 1.98 ± 0.12 mm3). Outer macular layers were similar between groups, but reduced in patients with maculopathies. HC-VA (P = 0.002) and LC-VA (P < 0.001) were reduced in patients (HC-VA [logMAR]: 0.01 ± 010; LC-VA [logMAR]: 0.44 ± 0.16) compared with HCs (HC-VA [logMAR]: –0.12 ± 0.08; LC-VA [logMAR]: 0.25 ± 0.05). Color vision was abnormal in 2 patients with maculopathies. Conclusions: A distinct maculopathy, termed EZ disruption, as well as optic atrophy add to the known nonataxia features in SCA-ATXN1. Whereas optic atrophy may be understood as part of a widespread neurodegeneration, EZ disruption may be explained by effects of ataxin-1 gene or protein on photoreceptors. Our findings extend the spectrum of nonataxia signs in SCA-ATXN1 with potential relevance for diagnosis and monitoring

Moebius Syndrome Awareness Day 2016 at Oregon State University

Moebius Syndrome is a congenital neurological disorder that results in weakness or paralysis of the sixth and seventh cranial nerves, resulting in inability to form facial expression. The current study examined the relationship between orientation of describing Moebius Syndrome and the participant ratings of pictures of individuals with Moebius Syndrome of friendliness and capability. The medical model is a description of Moebius Syndrome focusing on symptoms and treatment. The social model is a description focusing on how Moebius affects patient’s lives and social relationships. Participants were then asked to rate pictures of people with Moebius Syndrome in terms of friendliness and capability on a five-point scale. It was hypothesized that participants chosen to participate in the social model would rate the pictures higher on both dimensions than participants in the medical model. Participants were invited to create a sign with what others should know about Moebius Syndrome. These signs were then analyzed for content using Linguistic Inquiry and Word Count (LIWC) software. Signs were separated into medical and social model and compared across five categories. It was hypothesized that signs created after the social model would reflect a higher percentage of social words, whereas medical signs would reflect more medical terms. It was found that there was no significant difference between social and medical model groups in how participants rated pictures in terms of both variables. Participants were asked to rate their knowledge of Moebius Syndrome before and after the intervention on a five-point scale. It was found that knowledge about the condition significantly increased during the course of the intervention. Signs created after partaking in the social model of disability scored significantly higher in the “social” category. Signs created after hearing the medical model of disability resulted in significantly higher in the “medical” and “body” categories. Regardless of model received, participants felt social understanding was significantly more important than finding treatments and cures. The results of this study indicate that informing participants of Moebius Syndrome results in an increase of knowledge. This would indicate that the intervention was successful, regardless of the insignificance between groups on progression of knowledge. Overall, knowledge intervention in a population of college students, faculty and community members results in increased knowledge and positive ratings of capability and friendliness

Responsiveness of the Scale for the Assessment and Rating of Ataxia and Natural History in 884 Recessive and Early Onset Ataxia Patients

The Scale for the Assessment and Rating of Ataxia (SARA) is the most widely applied clinical outcome assessment (COA) for genetic ataxias, but presents metrological and regulatory challenges. To facilitate trial planning, we characterize its responsiveness (including subitem-level relations to ataxia severity and patient-focused outcomes) across a large number of ataxias, and provide first natural history data for several of them.Subitem-level correlation- and distribution-based analysis of 1637 SARA assessments in 884 patients with autosomal-recessive/early-onset ataxia (370 with 2-8 longitudinal assessments), complemented by linear mixed-effects modeling to estimate progression and sample sizes.While SARA subitem responsiveness varied between ataxia severities, gait/stance showed a robust granular linear scaling across the broadest range (SARA25; 2.7-fold sample size). Use of a novel rank-optimized SARA without subitems finger-chase and nose-finger reduces sample sizes by 20-25%.This study comprehensively characterizes COA properties and annualized changes of the SARA across and within a large number of ataxias. It suggests specific approaches for optimizing its responsiveness that might facilitate regulatory qualification and trial design. This article is protected by copyright. All rights reserved

Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis

Smooth muscle cell (SMC) proliferation is a hallmark of vascular injury and disease. Global hypomethylation occurs during SMC proliferation in culture and in vivo during neointimal formation. Regardless of the programmed or stochastic nature of hypomethylation, identifying these changes is important in understanding vascular disease, as maintenance of a cells' epigenetic profile is essential for maintaining cellular phenotype. Global hypomethylation of proliferating aortic SMCs and concomitant decrease of DNMT1 expression were identified in culture during passage. An epigenome screen identified regions of the genome that were hypomethylated during proliferation and a region containing Collagen, type XV, alpha 1 (COL15A1) was selected by ‘genomic convergence' for characterization. COL15A1 transcript and protein levels increased with passage-dependent decreases in DNA methylation and the transcript was sensitive to treatment with 5-Aza-2′-deoxycytidine, suggesting DNA methylation-mediated gene expression. Phenotypically, knockdown of COL15A1 increased SMC migration and decreased proliferation and Col15a1 expression was induced in an atherosclerotic lesion and localized to the atherosclerotic cap. A sequence variant in COL15A1 that is significantly associated with atherosclerosis (rs4142986, P = 0.017, OR = 1.434) was methylated and methylation of the risk allele correlated with decreased gene expression and increased atherosclerosis in human aorta. In summary, hypomethylation of COL15A1 occurs during SMC proliferation and the consequent increased gene expression may impact SMC phenotype and atherosclerosis formation. Hypomethylated genes, such as COL15A1, provide evidence for concomitant epigenetic regulation and genetic susceptibility, and define a class of causal targets that sit at the intersection of genetic and epigenetic predisposition in the etiology of complex diseas

Involvement of Essential Signaling Cascades and Analysis of Gene Networks in Diabesity

(1) Aims: Diabesity, defined as diabetes occurring in the context of obesity, is a serious health problem that is associated with an increased risk of premature heart attack, stroke, and death. To date, a key challenge has been to understand the molecular pathways that play significant roles in diabesity. In this study, we aimed to investigate the genetic links between diabetes and obesity in diabetic individuals and highlight the role(s) of shared genes in individuals with diabesity. (2) Methods: The interactions between the genes were analyzed using the Search Tool for the Retrieval of Interacting Genes (STRING) tool after the compilation of obesity genes associated with type 1 diabetes (T1D), type 2 diabetes (T2D), and maturity-onset diabetes of the young (MODY). Cytoscape plugins were utilized for enrichment analysis. (3) Results: We identified 546 obesity genes that are associated with T1D, T2D, and MODY. The network backbone of the identified genes comprised 514 nodes and 4126 edges with an estimated clustering coefficient of 0.242. The Molecular Complex Detection (MCODE) generated three clusters with a score of 33.61, 16.788, and 6.783, each. The highest-scoring nodes of the clusters were , , and genes. The genes from cluster 1 were enriched in FOXO-mediated transcription of oxidative stress, renin secretion, and regulation of lipolysis in adipocytes. The cluster 2 genes enriched in Src homology 2 domain-containing (SHC)-related events triggered by , regulation of lipolysis in adipocytes, and GRB2: SOS produce a link to mitogen-activated protein kinase (MAPK) signaling for integrins. The cluster 3 genes ere enriched in IGF1R signaling cascade and insulin signaling pathway. (4) Conclusion: This study presents a platform to discover potential targets for diabesity treatment and helps in understanding the molecular mechanism.The APC was funded by Qatar University Internal Grant number [QUST-2-CHS-2020-12