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OPTOGENETIC VISION RESTORATION IN THE FACE OF SECONDARY AND TERTIARY REMODELLING IN THE RD1 MOUSE RETINA.
Photoreceptor loss in retinal degeneration is followed by progressive remodelling of the surviving retina, which may present a barrier to vision restoration. To determine the impact of remodelling on the retina's suitability for therapeutic interventions, we track changes in visual code produced by the optogenetic actuator ReaChR expressed in ON-bipolar cells of the rd1 mouse at 3,5,9 and 12 months. Anatomical analyses confirm these ages encompass phase II (photoreceptor degeneration) to phase III (inner retinal thinning, dysmorphia, pigment epithelium infiltration) remodelling. Multi-electrode array recording from retinal ganglion cells reveal that ReaChR-driven responses to a range of visual stimuli are stable across this age range. Response amplitude, sensitivity and reproducibility all increased between 3 and 5 months, remaining consistent thereafter. Receptive field sizes, contrast sensitivity, and temporal frequency tuning showed minor changes with age. The diversity of retinal ganglion cell coding was maintained, reflected by the diversity captured by unsupervised functional clustering with 11 distinct visual channels retained across ages. Our data indicate that remodelling does not significantly impair, and at early stages may even enhance the surviving retina's ability to support visual restoration. Clinical intervention thus remains viable throughout remodelling, suggesting a wide window in disease progression for therapeutic benefit.
Interaction between native and prosthetic visual responses in optogenetic visual restoration.
Degenerative retinal disorders leading to irreversible photoreceptor death are a common cause of blindness. Optogenetic gene therapy aims to restore vision in affected individuals by introducing light sensitive opsins into the surviving neurons of the inner retina. While up until now the main focus of optogenetic therapy has been on terminally blind individuals, treating at stages where residual native vision is present could have several advantages. Yet, it is still unknown how residual native and optogenetic vision would interact if present at the same time. Using transgenic mice expressing the optogenetic tool ReaChR in ON-bipolar cells, we herein examine this interaction through electroretinography (ERG) and visually evoked potentials (VEP). We find that optogenetic responses show a peculiar ERG signature and are enhanced in retinas without photoreceptor loss. Conversely, native responses are dampened in the presence of ReaChR. Moreover, in VEP recordings we find that optogenetic responses reach the cortex asynchronous to the native response. These findings should be taken into consideration when planning future clinical trials and may direct future preclinical research to optimize optogenetic approaches for visual restoration. The identified ERG signatures moreover may serve to track treatment efficiency in clinical trials.
Retinograd-AI: An Open-Source Automated Fundus Autofluorescence Retinal Image Gradability Assessment for Inherited Retinal Diseases.
PURPOSE: To develop an automated system for assessing the quality of fundus autofluorescence (FAF) images in patients with inherited retinal diseases (IRDs). DESIGN: A retrospective study of imaging data. PARTICIPANTS: Patients with a confirmed molecular diagnosis of IRD who have undergone FAF imaging at Moorfields Eye Hospital. METHODS: A dataset of 2445 FAF images from patients with IRD was marked by 3 expert graders as either gradable (acceptable quality) or ungradable (poor quality), following a strict grading protocol. This dataset was used to train an artificial intelligence (AI) algorithm, Retinograd-AI, which was then applied to predict the gradability label of our entire dataset of 136 631 FAF images. MAIN OUTCOME MEASURES: Fundus autofluorescence gradability of FAF images as predicted and validated against human assessment. RESULTS: Retinograd-AI achieves 91% accuracy on our held-out dataset of 133 images with an area under the receiver operator characteristic curve of 0.94, indicating high performance in distinguishing between gradable and ungradable images. Applying Retinograd-AI to our entire dataset, a small but significant positive association of gradability with age was found (ß = 0.002, P < 0.001). Excluding X-linked conditions, 77.1% of images were rated as gradable in men and 82.3% in women (odds ratio = 1.43, P < 0.001). By genotype, from the 30 most common genetic diagnoses in our dataset, the highest proportion of gradable images was in patients with disease-causing variants in PRPH2 (93.1%), while the lowest was in RDH12 (27.1%). Applying Retinograd-AI to filter images improved the accuracy of a gene prediction classifier from 33.8% to 68.9%. Retinograd-AI is open-sourced and available at https://github.com/Eye2Gene/retinograd-ai. CONCLUSIONS: Retinograd-AI is an open-source AI model for automated retinal image quality assessment of FAF images in IRDs. Automated gradability assessment through Retinograd-AI enables large-scale analysis of retinal images and the development of robust analysis pipelines. Quality assessment is essential for the deployment of AI algorithms, such as Eye2Gene, into clinical settings. Due to the diverse nature of IRD pathologies, Retinograd-AI will be extended to other conditions, either in its current form or through transfer learning and fine-tuning. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Clinical utility of self-reported sleep duration and insomnia symptoms in type 2 diabetes prediction.
AIMS/HYPOTHESIS: Suboptimal sleep health is linked to higher risks for incident type 2 diabetes. We aimed to assess the clinical utility of adding self-reported sleep traits to a type 2 diabetes prediction model. METHODS: In this cohort study, we used UK Biobank data and Cox proportional hazards models to examine how self-reported sleep duration and insomnia symptoms were associated with incident type 2 diabetes risk. Harrell's C statistic and net reclassification improvement (NRI) were used to assess whether sleep traits improved the incident type 2 diabetes discrimination and predictive utility achieved using QDiabetes variables, with and without including a type 2 diabetes polygenic risk score (PGS). Independent replication was explored in the Nurses' Health Study, the Nurses' Health Study II and the Health Professionals Follow-up Study. RESULTS: Extremes of sleep duration and occasional or frequent insomnia symptoms were associated with higher risks for incident type 2 diabetes. In the UK Biobank and replication cohorts, adding sleep traits to the QDiabetes risk score did not improve type 2 diabetes prediction (C statistic: QDiabetes alone 0.8933; QDiabetes + sleep duration 0.8939; QDiabetes + insomnia 0.8931; QDiabetes + sleep traits 0.8935). The corresponding total NRI values were: 0.08 (95% CI -0.18, 0.33), 0.04 (95% CI -0.08, 0.16) and 0.04 (95% CI -0.10, 0.18). Inclusion of PGS data marginally improved the type 2 diabetes risk prediction achieved using The QDiabetes calculator, with or without the inclusion of sleep traits in the model (QDiabetes + PGS: C statistic 0.8945; total NRI 0.20 [95% CI 0.12, 0.28]; QDiabetes + PGS + sleep traits: C statistic 0.8946; total NRI 0.18 [95% CI 0.09, 0.27]). CONCLUSIONS/INTERPRETATION: While sleep duration and insomnia symptoms were associated with type 2 diabetes risk, they are not useful for improving type 2 diabetes prediction beyond QDiabetes model performance. Inclusion of a type 2 diabetes PGS marginally improved prediction but lacked clear clinical utility.
MetE: a promising protective antigen for tuberculosis vaccine development
IntroductionTuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a significant global health concern. The existing vaccine, Bacillus Calmette-Guérin (BCG), provides inconsistent protection, highlighting the pressing need for a more effective vaccine. We aimed to identify novel MTB antigens and assess their protective efficacy as TB vaccine candidates.MethodsUsing immunopeptidomics, we identified 64 and 80 unique mycobacterial antigens derived from BCG and MTB, respectively. We prioritised antigens based on HLA allele coverage through an immunoinformatics approach.ResultsThe candidates, hisD, metE, and mmpL12, delivered as DNA vaccines, were evaluated for efficacy in mice using the ex vivo Mycobacterial Growth Inhibition Assay (MGIA) and metE was identified as a promising candidate. In vivo murine MTB challenge experiments confirmed the protective efficacy conferred by metE when formulated as recombinant protein with AS01™ or AddaS03™ adjuvants, compared to the naïve group. The immunogenic profiles of metE formulated in the two different adjuvants differed, with metE-AS01™ inducing antigen-specific IFN-γ, TNF-α, IL-2, IL-17, IgG1 and IgG2a-c, while metE-AddaS03™ induced TNF-α, IL-2, IL-17, IL-4, IgM, IgG1, IgG2b.ConclusionOur findings highlight metE as a promising protective antigen for future TB vaccine development.
A case-control study to investigate the prevalence of obstructive sleep apnea and the utility of the Sleep-Related Breathing Disorder scale of the Pediatric Sleep Questionnaire in children and young people with epilepsy.
STUDY OBJECTIVES: Epilepsy and obstructive sleep apnea syndrome (OSAS) are each relatively common in children. OSAS may affect cognition, such that recognition of OSAS is important for children and young people with epilepsy (CYPWE). Published pilot data reported 55% of CYPWE had symptoms suggestive of OSAS, compared with 7% of typically developing controls. The primary aim of this study was to ascertain OSAS prevalence by polysomnography in CYPWE, with secondary aims being to evaluate the utility of sleep questionnaires in CYPWE. METHODS: CYPWE and age- and sex-matched typically developing controls were studied. A single night of level I attended polysomnography was undertaken, along with questionnaires (Sleep-Related Breathing Disorder scale of the Pediatric Sleep Questionnaire, Pittsburgh Sleep Quality Index, and the childhood and adolescent Epworth Sleepiness Scale). OSAS was defined as obstructive apnea-hypopnea index of ≥ 1 event/h. RESULTS: Polysomnography was performed in 72 children including 48 CYPWE (60% male) and 24 controls (54% male). Mean age (11 years) was similar for CYPWE and controls (P = .42), with slightly higher body mass index z scores (0.7 vs 0.1, P = .03) noted in CYPWE. Mean obstructive apnea-hypopnea index was 0.61 in CYPWE vs 0.42 in controls (P = .62). Despite higher Sleep-Related Breathing Disorder scale of the Pediatric Sleep Questionnaire scores in CYPWE (0.38 vs 0.12, P < .001), no difference in OSAS prevalence (10% vs 4%, P = .78) was found. CYPWE had higher childhood and adolescent Epworth Sleepiness Scale (6 vs 3.5, P = .01) and Pittsburgh Sleep Quality Index (5 vs 3.3, P = .02) scores, indicating greater levels of daytime sleepiness and poorer sleep quality. CONCLUSIONS: The study found no evidence for increased OSAS prevalence in CYPWE, and the utility of the Sleep-Related Breathing Disorder scale of the Pediatric Sleep Questionnaire in predicting OSAS appears limited for CYPWE. CYPWE are, however, demonstrably sleepier and have poorer sleep quality. The cause for these findings remains unclear. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Investigation of Sleep Quality and Prevalence of Sleep-disordered Breathing in Children and Young People With Epilepsy; URL: https://www.clinicaltrials.gov/study/NCT03103841; Identifier: NCT03103841. CITATION: Urquhart DS, McLellan AE, Hill LE, et al. A case-control study to investigate the prevalence of obstructive sleep apnea and the utility of the Sleep-Related Breathing Disorder scale of the Pediatric Sleep Questionnaire in children and young people with epilepsy. J Clin Sleep Med. 2024;20(7):1039-1047.
Yawning as Therapy? The Potential of the Conditioned Yawn Reflex as a Novel Treatment for Insomnia Disorder.
In 1986, Provine, the pioneer of yawning research wrote that 'Yawning may have the dubious distinction of being the least understood, common human behaviour' (p. 120); and so yawning remains some 40 years later, as something of a biological and social curiosity. However, this article examines contemporary scientific understanding of this age-old conundrum, proposing not only that yawning is a universal component of sleep's normal stimulus control paradigm, but that the conditioned yawn reflex might be harnessed to treat insomnia disorder. The core features of yawning as a ubiquitous, involuntary, periodic and conditionable behaviour; its associated actions on arousal, biofeedback and selective attention, as well as thermoregulation and airway patency; and its potential to signal and promote sleep engagement, lead to the proposition that the conditioned yawn reflex as therapy (CYRaT) is a feasible and potentially effective novel therapeutic for sleep-onset and sleep-maintenance insomnia disorder. Much research is required to test this hypothesis, but the article describes preliminary protocols for the administration and testing of CYRaT that might be utilised for this purpose.
The molecular circadian clock: From fundamental mechanisms to therapeutic promise in neurological disorders.
Circadian rhythms are intrinsic biological processes in all forms of life, governed by a molecular clock, organising physiological and behavioural cycles to align with a 24-hour light-dark cycle. The disruption of these rhythms has been linked to a plethora of neurological conditions and impacting cognitive and metabolic functions. This review offers a clear overview of the genetic and molecular mechanisms that govern the circadian clock. It focuses on the core clock feedback loops, the pathways involved and how these mechanisms are regulated. We explore how clocks in peripheral tissues are synchronised to the suprachiasmatic nucleus and how this is achieved through neuronal and humoral pathways. Additionally, we discuss how dysregulation in circadian rhythms contribute to neurological conditions and potential therapeutic treatments targeting circadian mechanisms. Understanding the mechanisms of circadian dysregulation provides insight into disease pathology and potential therapies. Interventions targeting circadian mechanisms, such as gene and drug delivery systems, show promise to restore rhythms and mitigate neurological symptoms. This review collates current knowledge on circadian biology and its applications addressing neurological dysfunctions, providing a foundation for potential chronotherapeutic interventions.
Neurodegenerative disease in C9orf72 repeat expansion carriers: population risk and effect of UNC13A.
The C9orf72 hexanucleotide repeat expansion (HRE) is the most common monogenetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neurodegenerative disease incidence in C9orf72 HRE carriers has been studied using cohorts from disease-affected families or by extrapolating from population disease incidence, potentially introducing bias. Age-specific cumulative incidence of ALS and dementia was estimated using Kaplan-Meier and competing risk models in C9orf72 HRE carriers compared to matched controls in UK Biobank. Risk modification by UNC13A genotype was examined. Of 490,331 individuals with valid genetic data, 701 had >100 repeats in C9orf72 (median age 55 [IQR 48-62], follow-up 13.4 years [12.3-14.1]). The cumulative incidence of ALS or dementia was 66% [95% CI 57-73%] by age 80 in C9orf72 HRE carriers versus 5.8% [4.5-7.0%] in controls, or 58% [50-64%] versus 5.1% [4.1-6.4%] accounting for the competing risk of other-cause mortality. Forty-one percent of dementia incidence accrued between age 75-80. C-allele homozygosity at rs12608932 in UNC13A increased ALS or dementia risk in C9orf72 HRE carriers (hazard ratio 1.81 [1.18 - 2.78]). C9orf72 HRE disease was incompletely penetrant in this population-based cohort, with risk modified by UNC13A genotype. This has implications for counselling at-risk individuals and modelling expected phenoconversion for prevention trials.
Sleep disruption and its psychological treatment in young people at risk of psychosis: A peer methods qualitative evaluation.
OBJECTIVES: A recent randomized controlled feasibility trial showed that sleep problems in young people at risk of psychosis can be successfully treated with psychological therapy and that this may bring additional benefits such as reducing depression, anxiety and paranoia. Here we report participants' qualitative experience of sleep problems and therapy. DESIGN: A peer-methods qualitative study employing reflexive thematic analysis. METHODS: Semi-structured interviews, co-facilitated by peer researchers, were conducted with 16 young patients at risk of psychosis and having sleep problems who participated in the SleepWell Trial (ISRCTN85601537). Ten interviewees had received the 12-week sleep therapy. RESULTS: Four themes were generated: (1) the challenge to access mental health treatment ('bouncing between services'), (2) sleep problems and mental health difficulties are intertwined ('an obvious link'), (3) flexibility in therapy provision matters ('tailored to me as a person') and (4) improving sleep leads to wider benefits ('fixing the sleep helped everything else'). Participants described a frustrating journey to access mental health treatment, marked by rejection and invalidation, which resulted in hopelessness and often resignation. The interaction between sleep disruption and other mental health difficulties was seen as obvious. Treatment for sleep problems was highly valued. The clear focus, therapeutic style and flexible delivery of the treatment was seen to create patient ownership, active engagement and hope. Participants described transformative changes: better sleep, fewer voices and fears and improved mood and confidence. Improving sleep made a difference to everyday life. CONCLUSIONS: Treating sleep problems in people at risk of psychosis is highly valued and often brings rapid and widespread improvements across a range of domains.
A 6-month supported online program for the treatment of persecutory delusions: Feeling Safer.
BACKGROUND: Based on an efficacious face-to-face theory-driven psychological therapy for persecutory delusions in the context of psychosis, we set out to develop a scalable guided 6-month online program. The aim was an intervention that patients can easily access and use, produces large clinical effects, and can be supported by a range of mental health professionals in less contact time than face-to-face therapy. We report here the proof-of-concept testing. At least moderate-sized clinical effects were required to progress to a randomized controlled trial (RCT). METHODS: In the 6-month Feeling Safer online program, a certified medical device, patients complete a brief assessment and then are provided with up to 10 modules that match their difficulties. Regular remote meetings with a mental health professional also take place. These may be supplemented by in-person visits. A pre- to post-treatment cohort trial was conducted with 14 patients with persistent persecutory delusions. The primary outcome was the Psychotic Symptoms Rating Scale (PSYRATS)-Delusions. RESULTS: Satisfaction and usability ratings of the program were high. Very large reductions in persecutory delusions were observed (PSYRATS mean reduction = 7.1, 95% C.I. = 3.4, 10.8, n = 13, Cohen's d = 3.0). There were large improvements in paranoia, anxiety, depression, agoraphobic distress, psychological wellbeing, meaningful activity, personal recovery, recovering quality of life, and moderate improvements in insomnia, agoraphobic avoidance, and quality of life. CONCLUSIONS: The clinical effects associated with Feeling Safer were very high, comparable to those seen in the evaluations of the face-to-face therapy, and enable progression to an RCT.
Dose-dependent and tissue-specific adverse effects of exogenous glucocorticoids: insights for optimizing clinical practice.
PURPOSE: There is limited data on dose-specific metabolic effects of exogenous glucocorticoids (GC) doses. This study aimed to investigate the differential tissue-specific and dose-dependent effects of low-to-intermediate prednisolone doses on insulin sensitivity and bone metabolism in healthy individuals. METHODS: We performed a post-hoc pooled analysis of three independent clinical trials, each administering one week of daily prednisolone at 10 mg, 15 mg, or 20 mg, in a total of 30 different healthy male volunteers (aged 18-65; BMI 20-35 kg/m²; normal kidney function). Outcome measures included: changes in liver (endogenous glucose production-EGP, β-hydroxybutyrate-OHB), muscle (M/I value, Glucose disposal-Gd) and adipose tissue (NEFA, glycerol) insulin sensitivity assessed across a hyperinsulinemic-euglycemic clamp. Bone turnover was evaluated through osteocalcin levels. RESULTS: Prednisolone 10 mg had minimal impact on metabolic parameters. 15 mg and 20 mg caused similar reductions (no dose effects) in liver (time effect p
Lower risk of dementia with AS01-adjuvanted vaccination against shingles and respiratory syncytial virus infections.
AS01-adjuvanted shingles (herpes zoster) vaccination is associated with a lower risk of dementia, but the underlying mechanisms are unclear. In propensity-score matched cohort studies with 436,788 individuals, both the AS01-adjuvanted shingles and respiratory syncytial virus (RSV) vaccines, individually or combined, were associated with reduced 18-month risk of dementia. No difference was observed between the two AS01-adjuvanted vaccines, suggesting that the AS01 adjuvant itself plays a direct role in lowering dementia risk.
Regulatory T cells attenuate chronic inflammation and cardiac fibrosis in hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart muscle disorder. Although the biophysical mechanisms by which gene variants in sarcomeric proteins disrupt cardiomyocyte function are largely understood, the cellular and molecular pathways leading to the complex, variable, and adverse remodeling of the non-myocyte compartment are unexplained. Here, we report that postmortem and explanted human HCM hearts exhibited chronic focal leukocyte infiltration and prominent activation of immune cells. Gene set enrichment analysis (GSEA) revealed that active immune responses were present in the mid- and late-stage HCM human hearts and in mouse hearts from several HCM mouse models. The alpha cardiac actin 1-E99K (Actc1E99K) HCM mouse model was selected for the study because it closely recapitulates the features of progressive remodeling and fibrosis seen in advanced disease in patients. Genetic depletion of lymphocytes in recombination activating gene 1-knockout (Rag-1KO) mice led to marked exacerbation of adverse cardiac remodeling in the Actc1E99K mice. Detailed characterization of cardiac regulatory T cells (Treg cells) demonstrated a time-dependent increase in Actc1E99K hearts with altered immunosuppressive profiles. Adoptive transfer of splenic Treg cells reduced cardiac fibrosis and improved systolic dysfunction in Actc1E99K mice with or without lymphocytes. In addition, low-dose interleukin-2 (IL-2)/anti-IL-2 complex (IL-2/c), which specifically induced Treg cell expansion in vivo, ameliorated cardiac fibrosis and reduced macrophage infiltration and activation in Actc1E99K mice. These data contribute to our understanding of HCM and support the use of Treg cells as a clinically testable therapeutic strategy for cardiac fibrosis in the HCM heart.
Aficamten Treatment for Symptomatic Obstructive Hypertrophic Cardiomyopathy: 48-Week Results From FOREST-HCM.
BACKGROUND: Long-term safety and efficacy data for aficamten in symptomatic obstructive hypertrophic cardiomyopathy are needed. OBJECTIVES: This study aims to evaluate 48-week experience from the ongoing FOREST-HCM (A Follow-Up, Open-Label, Research Evaluation of Sustained Treatment With Aficamten [CK-3773274] in Hypertrophic Cardiomyopathy) study. METHODS: Obstructive hypertrophic cardiomyopathy participants in an aficamten study (REDWOOD-HCM [Dose-finding Study to Evaluate the Safety, Tolerability, PK, and PD of CK-3773274 in Adults With HCM; NCT04219826]; SEQUOIA-HCM [Aficamten vs Placebo in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT05186818]) could enroll in this phase 2/3, open-label, extension study. Participants received aficamten 5 mg once daily titrated ≤20 mg based on site-read echocardiographic assessments of Valsalva left ventricular outflow tract gradient and left ventricular ejection fraction. RESULTS: From May 2021 to October 2023, 213 participants enrolled; 46 participants with 48 weeks of follow-up were evaluated (mean age: 59.7 years; female: n = 26 [56.5%]). There were rapid, substantial, and sustained reductions in mean resting (-40 ± 34 mm Hg) and Valsalva peak left ventricular outflow tract gradient (-53 ± 39 mm Hg) from baseline to week 48. A total of 82% experienced ≥1 NYHA functional class improvement; 31% experienced a 20-point improvement in Kansas City Cardiomyopathy Questionnaire-Clinical Summary score. There were substantial reductions (mean change) in maximum left ventricular wall thickness (-1.2 ± 1.6 mm; P < 0.0001), left atrial volume index (-3.5 ± 6.6 mL/m2; P = 0.0008), lateral E/e' (-2.2 ± 6.1; P = 0.02), and cardiac biomarkers (P ≤ 0.0031). Aficamten was well tolerated with 2 (4.3%) asymptomatic and transient instances of left ventricular ejection fraction <50% (range: 47%-49%), neither resulting in drug discontinuation, and no new-onset atrial fibrillation. CONCLUSIONS: Aficamten treatment over 48 weeks was well tolerated and associated with substantial and durable relief of obstruction and symptom burden, lower cardiac biomarker levels, and cardiac phenotypic changes, which may indicate favorable cardiac remodeling. (A Follow-Up, Open-Label, Research Evaluation of Sustained Treatment With Aficamten [CK-3773274] in Hypertrophic Cardiomyopathy [FOREST-HCM]; NCT04848506).
Quantification of Optical Coherence Tomography Features in >3500 Patients with Inherited Retinal Disease Reveals Novel Genotype-Phenotype Associations.
PURPOSE: To quantify spectral-domain optical coherence tomography (SD-OCT) images cross-sectionally and longitudinally in a large cohort of molecularly characterized patients with inherited retinal disease (IRDs) from the UK. DESIGN: Retrospective study of imaging data. PARTICIPANTS: Patients with a clinical and molecularly confirmed diagnosis of IRD who have undergone macular SD-OCT imaging at Moorfields Eye Hospital (MEH) between 2011 and 2019. We retrospectively identified 4,240 IRD patients from the MEH database (198 distinct IRD genes), including 69,664 SD-OCT macular volumes. METHODS: Eight features of interest were defined: retina, fovea, intraretinal cystic spaces (ICS), subretinal fluid (SRF), subretinal hyper-reflective material (SHRM), pigment epithelium detachment (PED), ellipsoid zone loss (EZ-loss) and retinal pigment epithelium loss (RPE-loss). Manual annotations of five b-scans per SD-OCT volume was performed for the retinal features by four graders based on a defined grading protocol. A total of 1,749 b-scans from 360 SD-OCT volumes across 275 patients were annotated for the eight retinal features for training and testing of a neural-network-based segmentation model, AIRDetect-OCT, which was then applied to the entire imaging dataset. MAIN OUTCOME MEASURES: Performance of AIRDetect-OCT, comparing to inter-grader agreement was evaluated using Dice score on a held-out dataset. Feature prevalence, volume and area were analysed cross-sectionally and longitudinally. RESULTS: The inter-grader Dice score for manual segmentation was ≥90% for retina, ICS, SRF, SHRM and PED, >77% for both EZ-loss and RPE-loss. Model-grader agreement was >80% for segmentation of retina, ICS, SRF, SHRM, and PED, and >68% for both EZ-loss and RPE-loss. Automatic segmentation was applied to 272,168 b-scans across 7,405 SD-OCT volumes from 3,534 patients encompassing 176 unique genes. Accounting for age, male patients exhibited significantly more EZ-loss (19.6mm 2 vs 17.9mm 2 , p<2.8×10 -4 ) and RPE-loss (7.79mm 2 vs 6.15mm 2 , p<3.2×10 -6 ) than females. RPE-loss was significantly higher in Asian patients than other ethnicities (9.37mm 2 vs 7.29mm 2 , p<0.03). ICS average total volume was largest in RS1 (0.47mm 3 ) and NR2E3 (0.25mm 3 ), SRF in BEST1 (0.21mm 3 ) and PED in EFEMP1 (0.34mm 3 ). BEST1 and PROM1 showed significantly different patterns of EZ-loss (p<10 -4 ) and RPE-loss (p<0.02) comparing the dominant to the recessive forms. Sectoral analysis revealed significantly increased EZ-loss in the inferior quadrant compared to superior quadrant for RHO (Δ=-0.414 mm 2 , p=0.036) and EYS (Δ=-0.908 mm 2 , p=1.5×10 -4 ). In ABCA4 retinopathy, more severe genotypes (group A) were associated with faster progression of EZ-loss (2.80±0.62 mm 2 /yr), whilst the p.(Gly1961Glu) variant (group D) was associated with slower progression (0.56 ±0.18 mm 2 /yr). There were also sex differences within groups with males in group A experiencing significantly faster rates of progression of RPE-loss (2.48 ±1.40 mm 2 /yr vs 0.87 ±0.62 mm 2 /yr, p=0.047), but lower rates in groups B, C, and D. CONCLUSIONS: AIRDetect-OCT, a novel deep learning algorithm, enables large-scale OCT feature quantification in IRD patients uncovering cross-sectional and longitudinal phenotype correlations with demographic and genotypic parameters.
Gamma activation spread reflects disease activity in amyotrophic lateral sclerosis.
OBJECTIVE: A non-invasive measure of cerebral motor system dysfunction would be valuable as a biomarker in amyotrophic lateral sclerosis (ALS). Task-based magnetoencephalography (tMEG) measures the magnetic fields generated by cortical neuronal oscillatory activity during task performance. Gamma activations are periods of high-power and high-frequency cortical oscillations integral to motor control. METHODS: tMEG was undertaken during 60 bilateral isometric hand grip exercises in ALS (n = 42) and compared with healthy controls (HC, n = 33). Gamma activation spread (GAS) was estimated by calculating the number of activated regions during each 100 ms time-bin and compared statistically between groups. Gamma activation patterns were visualised by plotting each participant's brain activity separately as a 2-dimensional video. RESULTS: There was no difference in grip strength between groups. GAS was greatly increased in the ALS group compared to HC (p