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Automated detection of lacunes in brain MR images using SAM with robust prompts using self-distillation and anatomy-informed priors.
BACKGROUND: Lacunes, which are small fluid-filled cavities in the brain, are signs of cerebral small vessel disease and have been clinically associated with various neurodegenerative and cerebrovascular diseases. Hence, accurate detection of lacunes is crucial and is one of the initial steps for the precise diagnosis of these diseases. However, developing a robust and consistently reliable method for detecting lacunes is challenging because of the heterogeneity in their appearance, contrast, shape, and size. METHOD: In this study, we propose a lacune detection method using the Segment Anything Model (SAM), guided by point prompts from a candidate prompt generator. The prompt generator initially detects potential lacunes with a high sensitivity using a composite loss function. The true lacunes are then selected using SAM by discriminating their characteristics from mimics such as the sulcus and enlarged perivascular spaces, imitating the clinicians' strategy of examining the potential lacunes along all three axes. False positives are further reduced by adaptive thresholds based on the region wise prevalence of lacunes. RESULTS: We evaluated our method on two diverse, multi-centric MRI datasets, VALDO and ISLES, comprising only FLAIR sequences. Despite diverse imaging conditions and significant variations in slice thickness (0.5-6 mm), our method achieved sensitivities of 84% and 92%, with average false positive rates of 0.05 and 0.06 per slice in ISLES and VALDO datasets respectively. CONCLUSIONS: The proposed method demonstrates robust performance across varied imaging conditions and outperformed the state-of-the-art methods, demonstrating its effectiveness in lacune detection and quantification.
Detection of cognitive deficits years prior to clinical diagnosis across neurological conditions
Abstract Understanding the cognitive trajectory of a neurological disease can provide important insight on underlying mechanisms and disease progression. Cognitive impairment is now well established as beginning many years before the diagnosis of Alzheimer’s disease, but pre-diagnostic profiles are unclear for other neurological conditions that may be associated with cognitive impairment. We analysed data from the prospective UK Biobank cohort with study baseline assessment performed between 2006-2010 and participants followed until 2021. We examined data from 497,252 participants, aged between 38 and 72 years at baseline, with an imaging sub-sample of 42,468 participants. Using time-to-diagnosis and time-from-diagnosis data in relation to time of assessment, we compared a continuous measure of executive function and magnetic resonance imaging brain measures of total grey matter and hippocampal volume in individuals with ischaemic stroke, focal epilepsy, Parkinson’s disease, multiple sclerosis, motor neurone disease (amyotrophic lateral sclerosis) and migraine. Of the 497,252 participants (226,206 [45.5%] men, mean [SD] age, 57.5[8.1] years), 12,755 had ischaemic stroke, 6,758 had a diagnosis of focal epilepsy, 3,315 had Parkinson’s disease, 2,315 had multiple sclerosis, 559 had motor neurone disease and 18,254 had migraine either at study baseline or diagnosed during the follow-up period. Apart from motor neurone disease, all conditions had lower pre-diagnosis executive function compared to controls (assessment performed median 7.4 years before diagnosis). At a group level, focal epilepsy and multiple sclerosis showed a gradual worsening in executive function up to 15 years prior to diagnosis, while ischaemic stroke was characterised by a modest decline for a few years followed by a substantial reduction at the time of diagnosis. By contrast, participants with migraine showed a mild reduction in pre-diagnosis cognition compared to controls which improved following clinical diagnosis. Pre-diagnosis MRI grey matter volume was lower than controls for stroke, Parkinson’s disease and multiple sclerosis (scans performed median 1.7 years before diagnosis), while other conditions had lower volumes post-diagnosis. These cognitive trajectory models reveal disease-specific temporal patterns at a group level, including a long cognitive prodrome associated with focal epilepsy and multiple sclerosis. The findings may help to prioritise risk management of individual diseases and inform clinical decision-making.
The Oxford Cognitive Screen in culturally diverse populations: A comparative study of Suriname and Belgium
Abstract Objective: Post-stroke neurocognitive disorders are highly prevalent, yet screening tools that are fit for culturally diverse populations are scarce. This study evaluates the impact of cultural differences on the Oxford Cognitive Screen (OCS), a stroke-specific screening tool. Methods: To evaluate cultural differences, we compared two populations with varying degrees of cultural diversity and Western, Educated, Industrialized, Rich and Democratic (WEIRD) characteristics. We adapted the Dutch OCS for Suriname through a multi-stage process. Using Bayesian hierarchical regression analysis, we compared 264 Surinamese participants, assessed with the adapted Dutch OCS, with 247 Belgian participants, assessed with the Dutch OCS, while controlling for age and education. We further investigated whether the associations of age and education with performance were comparable between the two populations. Results: Our findings revealed minimal differences in OCS performance between the Belgian and Surinamese populations. Both populations showed similar age-related decline and education-related improvement across all subtests, except for Picture naming, where the age-related decline was more pronounced in the Belgian population. Conclusion: These findings suggest that with minimal adaptation, the OCS is a viable tool for screening post-stroke neurocognitive disorders in culturally diverse populations.
A thematic analysis of patients’ experiences of receiving treatment for Neovascular age-related macular degeneration (nAMD)
Abstract Background/Objectives A positive patient experience is a key element of quality healthcare but data on the patient experience is rarely collected as part of routine care. This study analysed survey and discussion group comments from patients treated for neovascular AMD (nAMD) treatment to identify key elements of the patient experience. Subjects/Methods Free text comments from an online Macular Society member survey and quotes from subsequent, local, in-person patient discussion groups were reviewed. Thematic analysis was used to code the responses and to identify major themes. Results Analysis include 167 free text comments from Macular Society members and quotes from 2 local discussion groups, with patients and their carers. Key themes, important for the patient experience, included: time and availability of appointments, accessibility and duration of clinic visits, the delivery and quality of care, communication and access to written information and confidence in the healthcare team. Conclusions Feedback from patients with nAMD and their carers identified a number of key themes that are associated with either a positive or negative patient experience. Construction of an appropriate patient-reported experience measure and collection of data, either locally or nationally, would help identify areas of the care pathway where improvements may be necessary. Improving the patient experience may encourage adherence to and persistence with treatment and the outcomes.
Early worsening of diabetic retinopathy in individuals with type 2 diabetes treated with tirzepatide: a real-world cohort study.
AIMS/HYPOTHESIS: Early worsening of diabetic retinopathy (EWDR) has been described during treatment with glucagon-like peptide-1 receptor agonists including subcutaneous semaglutide. Whether EWDR occurs after initiating treatment with the potent glucagon-like peptide 1 / gastric inhibitory polypeptide receptor agonist tirzepatide is unknown. METHODS: In this retrospective cohort study using real-world clinical data, we matched 3435 tirzepatide-exposed (≥180 days treatment) individuals with type 2 diabetes 1:1 with 3434 tirzepatide-unexposed individuals for sex, diabetes duration, retinopathy status, HbA1c, number of retinal screening episodes and use of glucose-lowering medications. New-onset diabetic retinopathy and retinopathy progression were explored using conditional logistic regression. RESULTS: Individuals included in the study had tight baseline glycaemic control (mean HbA1c 56.1 ± 15.8 mmol/mol [7.28 ± 1.43%]). New-onset proliferative diabetic retinopathy (PDR) (grade R3M0, R3M1) occurred in 1.1% of tirzepatide-exposed (n=33) and 0.5% of tirzepatide-unexposed (n=17) individuals. Tirzepatide was significantly associated with new-onset PDR in multivariate analysis after adjustment for established risk factors (OR 2.15 [95% CI 1.24, 3.74], p<0.01). However, tirzepatide was also associated with reduced odds of new onset of retinopathy (OR 0.73 [95% CI 0.62, 0.86], p<0.001) in individuals without diabetic retinopathy (R0M0) at initiation in multivariate analysis, and was not significantly associated with retinopathy progression in individuals with mild non-proliferative diabetic retinopathy (NPDR, grade R1M0 or R1M1). CONCLUSIONS/INTERPRETATION: Tirzepatide therapy resulted in significantly increased odds of incident PDR, particularly in individuals with mild NPDR with maculopathy (grade R1M1), or moderate-to-severe NPDR with or without maculopathy (grade R2M0, R2M1). The increase in odds of progression would justify specialist ophthalmologist referral by Early Treatment Diabetic Retinopathy Study (ETDRS) criteria.
Generating evidence to support the role of AI in diabetic eye screening: considerations from the UK National Screening Committee.
Screening for diabetic retinopathy has been shown to reduce the risk of sight loss in people with diabetes, because of early detection and treatment of sight-threatening disease. There is long-standing interest in the possibility of automating parts of this process through artificial intelligence, commonly known as automated retinal imaging analysis software (ARIAS). A number of such products are now on the market. In the UK, Scotland has used a rules-based autograder since 2011, but the diabetic eye screening programmes in the rest of the UK rely solely on human graders. With more sophisticated machine learning-based ARIAS now available and greater challenges in terms of human grader capacity, in 2019 the UK's National Screening Committee (NSC) was asked to consider the modification of diabetic eye screening in England with ARIAS. Following up on a review of ARIAS research highlighting the strengths and limitations of existing evidence, the NSC here sets out their considerations for evaluating evidence to support the introduction of ARIAS into the diabetic eye screening programme.
The Scanning CONfoCal Ophthalmoscopy foR DIAbetic eye screening (CONCORDIA) study paper 1
Abstract Objective This project was to determine the performance of the Zeiss Clarus 700 (Clarus) and the Optos California (Optos) with staged mydriasis in a Diabetic Eye Screening Programme (DESP). Methods Trial participants were recruited from people attending appointments in DESP or Virtual Eye clinics for delayed hospital appointments. Non-mydriatic photographs from the Clarus and Optos cameras were compared to 2-field 45 degrees mydriatic digital photography (the reference standard) and mydriatic photographs compared if the non-mydriatic photos were unassessable (staged mydriasis). Results 1573 patients were recruited. 76 individuals were withdrawn, leaving 1497 individuals (2993 eyes). For the Clarus and the Optos, the sensitivity for any retinopathy were 94.2% (95% CI: 92.9–95.3%) and 91.9% (95% CI: 90.5–93.2%) with specificities of 87.3% (95% CI: 85.4–89.0%) and 78.1% (95% CI: 75.7–80.3%) respectively. For referable DR the sensitivities for the Clarus and Optos were 86.0% (95% CI: 82.9–88.8%) and 77.6% (95% CI: 73.9–80.9%) with specificities of 92.8% (95% CI: 91.7–93.8%) and 95.4% (95% CI: 94.5–96.2%) respectively. The Clarus and Optos without mydriasis produced 100 (3.3%) and 152 (5.1%) unassessable eyes respectively, and after staged mydriasis 51 (1.7%) and 102 (3.4%) respectively with 52 (1.7%) reference standard images unassessable. Conclusions This study reports the performance of the Clarus and the Optos using staged mydriasis in DR screening with wider fields detecting more referable retinopathy peripherally with some reduction in sensitivity centrally for macular lesions.
Evaluation of care with intravitreal aflibercept treatment for UK patients with diabetic macular oedema: DRAKO study 24-month real-world outcomes
Abstract Background/ Objectives DRAKO (NCT02850263) was a 24-month, prospective, observational, multi-centre cohort study that enrolled patients diagnosed with diabetic macular oedema (DMO) including central involvement. The study aimed to evaluate standard of care intravitreal aflibercept (IVT-AFL) treatment in the UK. This analysis describes the 12-month outcomes for patients with prior anti–vascular endothelial growth factor (VEGF) treatment for DMO other than IVT-AFL (C2), and 2-year outcomes for both anti-VEGF treatment–naïve patients (C1) and C2 patients. Methods Study eyes were treated with IVT-AFL as per local standard of care. Mean changes in best-corrected visual acuity (BCVA) in ETDRS letters and central subfield thickness (CST) were stratified by baseline factors. Changes in diabetic retinopathy assessments, glycated haemoglobin A1c levels and vision-related quality of life (QoL) were evaluated alongside numbers of injections administered and safety outcomes. Results For C1, mean (SD) changes from baseline in BCVA of +0.7 (12.7) letters and CST of –123.3 (104.3) µm were observed at Month 24. For C2, mean (SD) changes from baseline for BCVA of + 0.2 (10.2) letters and –0.3 (13.0) letters, and CST of –79.1 (137.6) µm and −91.6 (132.9) µm, were observed at 12 and 24 months, respectively. In Year 2, C1 and C2 patients received a mean of 3.7 and 4.3 injections, respectively. Conclusions Year 2 results indicate that IVT-AFL is an effective treatment for DMO in real-world UK clinical practice, despite relatively low injection numbers. The high baseline visual acuity and QoL scores were maintained and there was further improvement in anatomical outcomes.
Evaluation of standard-of-care intravitreal aflibercept treatment practices in patients with diabetic macular oedema in the UK: DRAKO study outcomes
Abstract Background/Objectives DRAKO (NCT02850263) was a 24-month, prospective, non-interventional, multi-centre cohort study enrolling patients with diabetic macular oedema (DMO) including central involvement. The study evaluated UK standard-of-care intravitreal aflibercept (IVT-AFL) treatment. This analysis describes the treatment pathway and service provision for the anti–vascular endothelial growth factor (VEGF) treatment-naïve (C1) and non-naïve patients (C2) who received prior anti-VEGF treatment for DMO other than IVT-AFL. Methods Mean changes in best-corrected visual acuity and central subfield thickness were measured and stratified by baseline factors, including ethnicity and administration of five initial monthly injections within predefined windows. Clinic visits were classified as treatment only (T1), monitoring assessment only (T2), combined visits (T3) or post-injection visits with no treatment or assessment (T4). Results Median time from decision to treat to treatment was 6 days. As a percentage of total visits, T1, T2, T3 and T4 were 7%, 42%, 48% and 3% for C1 and 11%, 39%, 48% and 2% for C2. Most IVT-AFL injections were administered by healthcare professionals (HCPs) other than doctors (C1, 57.4%; C2, 58.5%). The percentage of treatments associated with a procedure-related adverse event where at least 75% of injections were completed by the same injector role were similar for doctors and other HCPs (C1, 1.1% and 0.8%; C2, 0.7%, and 1.0%). Conclusions Results indicate that upon DMO diagnosis, patients were treated promptly, and most visits were combined (treatment and assessment) or monitoring only. Most IVT-AFL was administered by non-physicians with a similar treatment-related safety profile as IVT-AFL administered by physicians.
Evaluation of standard of care intravitreal aflibercept treatment of diabetic macular oedema treatment-naive patients in the UK: DRAKO study 12-month outcomes
Abstract Objectives DRAKO (NCT02850263) is a 24-month, prospective, non-interventional, multi-centre cohort study which enroled patients diagnosed with centre-involving diabetic macular oedema (DMO). The study aims to evaluate standard of care with intravitreal aflibercept (IVT-AFL) treatment in the UK. This analysis describes the anti-vascular endothelial growth factor (anti-VEGF) treatment-naive patient cohort after 12-month follow-up. Methods Study eyes were treated with IVT-AFL as per local standard of care. The mean change in best-corrected visual acuity (BCVA) and central subfield thickness (CST) from baseline at 12 months were measured and stratified by baseline factors. The number of injections and safety data were also evaluated. Results A total of 507 patients were enroled from 35 centres. Mean (SD) baseline BCVA was 71.4 (12.0) letters and CST was 448.7 (88.7) µm, with 63.1% of patients presenting with baseline BCVA ≥ 70 letters (mean 78.1). Mean (SD) change in BCVA of 2.5 (12.2) letters and CST of −119.1 (116.4) µm was observed at month 12. A 7.3 letter gain was observed in patients with baseline BCVA < 70 letters. Mean number (SD) of injections in year one was 6.4 (2.1). No significant adverse events were recorded. Conclusion Year one results indicated that IVT-AFL was an effective treatment for DMO in standard of care UK clinical practice, maintaining or improving visual acuity in treatment-naive patients with good baseline visual acuity, despite some patients being undertreated versus the summary of product characteristics. These results also demonstrated the clinical importance and meaningful impact of diabetic retinopathy screening in the UK.
The Usefulness of Serum Biomarkers in the Early Stages of Diabetic Retinopathy: Results of the EUROCONDOR Clinical Trial
The main aim of this study was to evaluate the ability of serum biomarkers to predict the worsening of retinal neurodysfunction in subjects with type 2 diabetes. For this purpose, we measured selected molecules (N-epsilon-carboxy methyl lysine (CML), laminin P1 (Lam-P1), and asymmetric dimethylarginine (ADMA)) in the serum of 341 participants of the EUROCONDOR study at baseline, 24, and 48 weeks. Retinal neurodysfunction was assessed by measuring implicit time (IT) using multifocal electroretinography, and structural changes were examined by spectral domain–optical coherence tomography. The values of IT at baseline were directly correlated with baseline serum concentrations of CML (r = 0.135, p = 0.013). Furthermore, in the placebo group, increase in CML concentration throughout follow-up correlated with the IT (r = 0.20; p = 0.03). Baseline serum levels of CML also correlated with macular retinal thickness (RT) (r = 0.231; p < 0.001). Baseline Lam-P1 levels correlated with the increase of the RT at the end of follow-up in the placebo group (r = 0.22; p = 0.016). We provide evidence that CML may be a biomarker of both retinal neurodysfunction and RT, whereas Lam-P1 was associated with RT only. Therefore, circulating levels of these molecules could provide a complementary tool for monitoring the early changes of diabetic retinopathy (DR).
Do people with dementia die at their preferred location of death? A systematic literature review and narrative synthesis.
AIM: place of death is an important component of the quality of a person's death. The aim of this study was to undertake a systematic review and narrative synthesis of the literature concerning place of death of people with dementia and the preferences for location of death of people with dementia as well as family carers and healthcare providers preferred location of death for patients with dementia. METHODS AND RESULTS: studies relying on death certificate data show that patients with dementia die more commonly in care homes than other locations contrasting with prospective studies which show that death is more common in own residence and hospital. Age (older), gender (male), availability of hospital and nursing home beds and enrolment in hospice, influence place of death. There is very limited evidence of patients, family carers and healthcare providers' views on preferred location of death for patients with dementia and the only study included reported that, family carers views are more agreed to rather than patients own views regarding place of death. CONCLUSION: this study on place of death raises exploratory questions on end-of-life care for patients with dementia which has implications on health and social care policies related to dementia.
Predicting Cognition and Affective Changes in Newly Diagnosed Parkinson’s Disease Through Longitudinal Data-Driven Clustering
Background: Although primarily characterised as a motor disorder, Parkinson’s Disease (PD) also presents with non-motor symptoms, including cognitive decline and affective dysfunction, which are major predictors of quality of life and mortality for individuals. However, factors associated with these non-motor symptom trajectories remain under-characterised. Purpose: This study aimed to investigate predictors of cognitive and affective function over a 5-year follow-up period using data from the Progressive Parkinson’s Marker Initiative. Results: Fuzzy C-means clustering analysis of year-5 cognitive and affective function scores showed two clusters. The second group (n = 96) were older and had worse cognition, affective, and motor functioning at year-5 follow-up compared to the first (n = 213). Predictors of cluster membership was assessed in n = 113 individuals for whom data on all variables of interest were available (cluster 1/2 = 79/34). Cluster membership at 5-year follow-up was significantly predicted by baseline cognitive and affective function, as well as decreased levels of CSF amyloid-beta and increased CSF concentrations of phosphorylated-tau at baseline. Alternative non-linear supervised machine learning model (support vector regressor) using the same predictors improved classification accuracy by 5%. Conclusion: Our analysis highlights that including established biomarkers of other neurocognitive disorders (namely, amyloid-beta and phosphorylated-tau) also has utility for predicting cognitive and affective trajectory in PD. This suggests that assessing a multi-modal panel of prognostic markers, beyond clinical symptom presentation alone, may have utility for informing prognosis of cognitive and affective outcomes in PD. This is significant, potentially allowing for the earlier development of personalised therapeutic interventions for those at highest risk of impairment within these non-motor domains.
Design considerations for C9orf72 disease prevention trials
Abstract The idea that it might be possible to prevent some forms of amyotrophic lateral sclerosis and frontotemporal dementia has finally come of age. The hexanucleotide repeat expansion in the C9orf72 gene accounts for ∼10% of all amyotrophic lateral sclerosis and 10-15% of all frontotemporal dementia diagnoses, with the two clinical syndromes co-manifesting in a significant number of patients. As a result, clinically unaffected carriers of pathogenic C9orf72 repeat expansions are currently the largest identifiable population at significantly elevated risk for both amyotrophic lateral sclerosis and frontotemporal dementia, and in whom it might be possible to prevent the emergence of clinically manifest disease. Strategies for the design of disease prevention trials among clinically unaffected C9orf72 carriers have begun to emerge separately in the amyotrophic lateral sclerosis and frontotemporal dementia fields. However, recognition of the need to define neurodegenerative diseases based on biology underscores the need to consider all potential clinical manifestations of a C9orf72 repeat expansion together, rather than the traditional siloed approach of focusing on only amyotrophic lateral sclerosis or only frontotemporal dementia. Indeed, emerging clinical and biological markers that might be used to quantify pre-symptomatic disease progression and to predict the short-term risk of phenoconversion to clinically manifest disease are shared across the phenotypic spectrum. Given the anticipated progress in the development of therapeutic strategies to target the C9orf72 repeat expansion, and the enthusiasm for prevention trials among the unaffected C9orf72 repeat expansion carrier population, now is the time to begin work on the design of disease prevention trials. To this end, The Association for Frontotemporal Degeneration and the ALS Association supported a multi-stakeholder workshop (in Washington D.C., June 2024) to unify efforts to design a prevention trial for the population at elevated genetic risk for the phenotypic spectrum of C9orf72 disease. Here we describe recommendations emanating from this Workshop for the selection of outcome measures, delineation of eligibility criteria, optimal use of biomarkers and digital health technologies, potential analytic frameworks, and relevant regulatory considerations related to C9orf72 disease prevention trials. We also emphasize the importance of the amyotrophic lateral sclerosis and frontotemporal dementia communities working together in partnership with the C9orf72 repeat expansion carrier community, the regulatory authorities, and the broader drug development community.
Non-Inferiority Trials in Stroke Research: What Are They, and How Should We Interpret Them?
Randomized clinical trials are important in both clinical and academic stroke communities with increasing numbers of new design concepts emerging. One of the "less traditional" designs that have gained increasing interest in the last decade is non-inferiority trials. Whilst the concept might appear straightforward, the design and interpretation of non-inferiority trials can be challenging. In this review, we will use exemplars from clinical trials in the stroke field to provide an overview of the advantages and limitations of non-inferiority trials and how they should be interpreted in stroke research.