Disease Modifying Research Articles

Essential components of an effective transition from paediatric to adult neurologist care for adolescents with Duchenne muscular dystrophy; a consensus derived using the Delphi methodology in Eastern Europe, Greece and Israel

PurposeAn increasing number of patients with Duchenne muscular dystrophy (DMD) now have access to improved standard of care and disease modifying treatments, which improve the clinical course of DMD and extend life expectancy beyond 30 years of age. A key issue for adolescent DMD patients is the transition from paediatric- to adult-oriented healthcare. Adolescents and adults with DMD have unique but highly complex healthcare needs associated with long-term steroid use, orthopaedic, respiratory, cardiac, psychological, and gastrointestinal problems meaning that a comprehensive transition process is required. A sub-optimal transition into adult care can have disruptive and deleterious consequences for a patient’s long-term care. This paper details the results of a consensus amongst clinicians on transitioning adolescent DMD patients from paediatric to adult neurologists that can act as a guide to best practice to ensure patients have continuous comprehensive care at every stage of their journey.MethodsThe consensus was derived using the Delphi methodology. Fifty-three statements were developed by a Steering Group (the authors of this paper) covering seven topics: Define the goals of transition, Preparing the patient, carers/parents and the adult centre, The transition process at the paediatric centre, The multidisciplinary transition summary – Principles, The multidisciplinary transition summary – Content, First visit in the adult centre, Evaluation of transition. The statements were shared with paediatric and adult neurologists across Central Eastern Europe (CEE) as a survey requesting their level of agreement with each statement.ResultsData from 60 responders (54 full responses and six partial responses) were included in the data set analysis. A consensus was agreed across 100% of the statements.ConclusionsIt is hoped that the findings of this survey which sets out agreed best practice statements, and the transfer template documents developed, will be widely used and so facilitate an effective transition from paediatric to adult care for adolescents with DMD.

Prevalence of clinical characteristics of lipodystrophy in the US adult population in a healthcare claims database

BackgroundLipodystrophy is characterized by progressive loss of adipose tissue and consequential metabolic abnormalities. With new treatments emerging for lipodystrophy, there is a growing need to understand the prevalence of specific comorbidities that may be commonly associated with lipodystrophy to contextualize the natural history of lipodystrophy without any disease modifying therapy.ObjectiveTo examine the risk of specific clinical characteristics in people living with lipodystrophy (LD) in 2018–2019 compared with the general US population, among the commercially insured US population.MethodsA retrospective cohort study was conducted using the 2018–2019 Clinformatics® Data Mart database. An adult LD cohort (age ≥ 18 years) with at least ≥ 1 inpatient or ≥ 2 outpatient LD diagnoses was created. The LD cohort included non-HIV-associated LD (non-HIV-LD) and HIV-associated LD (HIV-LD) subgroups and compared against age- and sex-matched control groups with a 1:4 ratio from the general population with neither an LD or an HIV diagnosis using odds ratios (ORs) with 95% confidence intervals.ResultsWe identified 546 individuals with non-HIV-LD (mean age, 60.3 ± 14.9 years; female, 67.6%) and 334 individuals with HIV-LD (mean age, 59.2 ± 8.3 years; female, 15.0%) in 2018–2019. Compared with the general population, individuals with non-HIV-LD had higher risks (odds ratio [95% confidence interval]) for hyperlipidemia (3.32 [2.71–4.09]), hypertension (3.58 [2.89–4.44]), diabetes mellitus (4.72 [3.85–5.79]), kidney disease (2.78 [2.19–3.53]), liver fibrosis or cirrhosis (4.06 [1.66–9.95]), cancer (2.20 [1.59–3.01]), and serious infections resulting in hospitalization (3.00 [2.19–4.10]). Compared with individuals with HIV, those with HIV-LD have higher odds of hypertension (1.47 [1.13–1.92]), hyperlipidemia (2.46 [1.86–3.28]), and diabetes (1.37 [1.04–1.79]).ConclusionsLD imposes a substantial burden on affected individuals due to a high prevalence of metabolic comorbidities and other complications as compared with the general non-LD population. Future longitudinal follow-up studies investigating the causality between LD and observed comorbidities are warranted.

Acute kidney injury in subarachnoid hemorrhage: Exploring its clinical significance and prognostic implications

ObjectivesSubarachnoid hemorrhage (SAH) from spontaneous aneurysm rupture is a debilitating condition with high morbidity and mortality. Patients with SAH remain understudied, particularly concerning the evaluation of incidence and consequences of subsequent acute kidney injury (AKI). In this study, we aim to explore the risk factors and outcomes of AKI in SAH patients. Materials and MethodsInternational Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes were used to query the National Inpatient Sample (NIS) for patients with a diagnosis of SAH between 2010-2019. Subgroup analysis was stratified by AKI diagnosis during the same hospitalization. AKI and non-AKI groups were assessed for baseline clinical characteristics, interventions, complications, and outcomes. Descriptive statistics, multivariate regressions, and propensity score-matching were performed using IBM SPSS 28. ResultsOf 76,553 patients diagnosed with nontraumatic SAH between 2010-2019, 10,634 (13.89 %) had a comorbid diagnosis of AKI. SAH patients with AKI were older (p < 0.01) and more often obese (p < 0.01) compared to the non-AKI group. A multivariate regression found the diagnosis of AKI to be independently correlated with poor functional outcome (p < 0.001), above average length of stay (p < 0.001), and in-hospital mortality (p < 0.001) when controlling for age, SAH severity, and other comorbidities. ConclusionsThis study showed significant association between AKI and adverse outcomes in SAH patients, and a correlation between AKI and heightened complication rates, poor functional outcome, extended hospital stays, and elevated mortality rates. Early detection of AKI in SAH patients is vital to improve their chances of recovery.

Integrating the assessment of quality of life in care and research in pulmonary fibrosis.

Pulmonary fibrosis (PF) negatively influences health-related quality of life (HRQOL). Patients living with PF have voiced the desire for a focus on symptoms and HRQOL in both disease monitoring and treatment decisions. Currently available disease modifying treatments do little to impact HRQOL. Newer studies evaluating pharmacologic and nonpharmacologic therapies targeting symptoms and HRQOL in PF have been conducted with some promising results. There is increasing recognition of the importance of incorporating HRQOL as a higher tier endpoint in clinical trials. Disease-specific measure of HRQOL have been developed for those living with PF, and there is ongoing work to better understand the validity and reliability characteristics of these tools. In addition to research, there is recognition of the potential benefits of measuring HRQOL and symptoms in clinical practice in facilitate integrating patient perspective into care and allow for more personalized treatment approaches. There is increased momentum to discover treatments that impact HRQOL in PF. More work is desperately needed to identify better treatment targets, and to incorporate HRQOL and symptoms as higher tier endpoints in clinical trials. Further work is also needed to address the practicalities of integrating HRQOL measurement into clinical care.

JRK binds satellite III DNA and is necessary for the heat shock response.

JRK is a DNA-binding protein of the pogo superfamily of transposons, which includes the well-known centromere binding protein B (CENP-B). Jrk null mice exhibit epilepsy, and growth and reproductive disorders, consistent with its relatively high expression in the brain and reproductive tissues. Human JRK DNA variants and gene expression levels are implicated in cancers and neuropsychiatric disorders. JRK protein modulates β-catenin-TCF activity but little is known of its cellular functions. Based on its homology to CENP-B, we determined whether JRK binds centromeric or other satellite DNAs. We show that human JRK binds satellite III DNA, which is abundant at the chromosome 9q12 juxtacentromeric region and on Yq12, both sites of nuclear stress body assembly. Human JRK-GFP overexpressed in HeLa cells strongly localises to 9q12. Using an anti-JRK antiserum we show that endogenous JRK co-localises with a subset of centromeres in non-stressed cells, and with heat shock factor 1 following heat shock. Knockdown of JRK in HeLa cells proportionately reduces heat shock protein gene expression in heat-shocked cells. A role for JRK in regulating the heat shock response is consistent with the mouse Jrk null phenotype and suggests that human JRK may act as a modifier of diseases with a cellular stress component.

Recent Advance in Disease Modifying Therapies for Spinal Muscular Atrophy

Abstract Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease characterized by progressive weakness and atrophy of skeletal muscles. With homozygous survival motor neuron 1 (SMN1) gene mutation, all SMA patients have at least one copy of the SMN2 gene, which provides an opportunity for drug targeting to enhance SMN expression. Current three disease modifying drugs, including nusinersen, onasemnogene abeparvovec, and risdiplam, have demonstrated impressive effectiveness in SMA treatment. Nusinersen is an antisense oligonucleotide targeting SMN2 pre-messenger RNA (mRNA) to modify alternative splicing and is effective in SMA children and adults, administrating via intermittent intrathecal injection. Onasemnogene abeparvovec is an adeno-associated viral vector carrying human SMN1 gene, featuring intravenous injection once in a lifetime for SMA patients less than 2 years of the age. Risdiplam is a small molecule also targeting SMN2 pre-mRNA and is effective in SMA children and adults with administration via oral intake once per day. Patients with SMA should receive these disease modifying therapies as soon as possible to not only stabilize disease progression, but potentially obtain neurological improvement. The development in these therapies has benefited patients with SMA and will potentially provide insight in future drug discovery for other neurodegenerative diseases.

EUFOREUM Berlin 2023: Optimizing care for type 2 inflammatory diseases from clinic to AI: A pediatric focus.

The European Forum for Research and Education in Allergy and Airways diseases (EUFOREA) organized its bi-annual forum EUFOREUM in Berlin in November 2023. The aim of EUFOREUM 2023 was to highlight pediatric action plans for prevention and optimizing care for type 2 inflammatory conditions starting in childhood, with a focus on early-stage diagnosis, ensuring neither under- nor overdiagnosis, optimal care, and suggestions for improvement of care. EUFOREA is an international not-for-profit organization forming an alliance of all stakeholders dedicated to reducing the prevalence and burden of chronic respiratory diseases through the implementation of optimal patient care via educational, research, and advocacy activities. The inclusive and multidisciplinary approach of EUFOREA was reflected in the keynote lectures and faculty of the virtual EUFOREUM 2023 (www.euforea.eu/euforeum) coming from the pediatric, allergology, pulmonology, ENT, dermatology, primary health care fields and patients around the central theme of type 2 inflammation. As most type 2 inflammatory conditions may start in childhood or adolescence, and most children have type 2 inflammation when suffering from a respiratory or skin disease, the moment has come to raise the bar of ambitions of care, including prevention, remission and disease modification at an early stage. The current report provides a comprehensive overview of key statements by the faculty of the EUFOREUM 2023 and the ambitions of EUFOREA allowing all stakeholders in the respiratory field to be updated and ready to join forces in Europe and beyond.

Accuracy of glomerular filtration rate estimation using creatinine and cystatin C for identifying and monitoring moderate chronic kidney disease: the eGFR-C study.

Estimation of glomerular filtration rate using equations based on creatinine is widely used to manage chronic kidney disease. In the UK, the Chronic Kidney Disease Epidemiology Collaboration creatinine equation is recommended. Other published equations using cystatin C, an alternative marker of kidney function, have not gained widespread clinical acceptance. Given higher cost of cystatin C, its clinical utility should be validated before widespread introduction into the NHS. Primary objectives were to: (1) compare accuracy of glomerular filtration rate equations at baseline and longitudinally in people with stage 3 chronic kidney disease, and test whether accuracy is affected by ethnicity, diabetes, albuminuria and other characteristics; (2) establish the reference change value for significant glomerular filtration rate changes; (3) model disease progression; and (4) explore comparative cost-effectiveness of kidney disease monitoring strategies. A longitudinal, prospective study was designed to: (1) assess accuracy of glomerular filtration rate equations at baseline (n = 1167) and their ability to detect change over 3 years (n = 875); (2) model disease progression predictors in 278 individuals who received additional measurements; (3) quantify glomerular filtration rate variability components (n = 20); and (4) develop a measurement model analysis to compare different monitoring strategy costs (n = 875). Primary, secondary and tertiary care. Adults (≥ 18 years) with stage 3 chronic kidney disease. Estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations. Measured glomerular filtration rate was the reference against which estimating equations were compared with accuracy being expressed as P30 (percentage of values within 30% of reference) and progression (variously defined) studied as sensitivity/specificity. A regression model of disease progression was developed and differences for risk factors estimated. Biological variation components were measured and the reference change value calculated. Comparative costs of monitoring with different estimating equations modelled over 10 years were calculated. Accuracy (P30) of all equations was ≥ 89.5%: the combined creatinine-cystatin equation (94.9%) was superior (p < 0.001) to other equations. Within each equation, no differences in P30 were seen across categories of age, gender, diabetes, albuminuria, body mass index, kidney function level and ethnicity. All equations showed poor (< 63%) sensitivity for detecting patients showing kidney function decline crossing clinically significant thresholds (e.g. a 25% decline in function). Consequently, the additional cost of monitoring kidney function annually using a cystatin C-based equation could not be justified (incremental cost per patient over 10 years = £43.32). Modelling data showed association between higher albuminuria and faster decline in measured and creatinine-estimated glomerular filtration rate. Reference change values for measured glomerular filtration rate (%, positive/negative) were 21.5/-17.7, with lower reference change values for estimated glomerular filtration rate. Recruitment of people from South Asian and African-Caribbean backgrounds was below the study target. Prospective studies of the value of cystatin C as a risk marker in chronic kidney disease should be undertaken. Inclusion of cystatin C in glomerular filtration rate-estimating equations marginally improved accuracy but not detection of disease progression. Our data do not support cystatin C use for monitoring of glomerular filtration rate in stage 3 chronic kidney disease. This trial is registered as ISRCTN42955626. This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/103/01) and is published in full in Health Technology Assessment; Vol. 28, No. 35. See the NIHR Funding and Awards website for further award information.

Poster 271: Improving Non-Invasive Diagnosis and Grading of Cartilage Defects in the Knee - Accuracy of Ultra High Field 7-Tesla MRI as Compared with Arthroscopy

Objectives: Osteoarthritis (OA) is a joint disease characterized by degradation of articular cartilage and subchondral bone. Cartilage injury plays an important role in the pathogenesis of osteoarthritis, and disease modifying treatments aiming to preserve and possibly regenerate cartilage are an area of active interest. Early diagnosis is crucial, as the disease may be more responsive to treatment at an early stage, and there is a critical unmet need for improved non-invasive morphologic cartilage imaging techniques. Standard clinical MRI is performed on a 1.5T or 3T machine. Ultra-high field (UHF) 7-Tesla (7T) magnetic resonance imaging (MRI) is a new technology that offers 2.3x improved signal-to noise ratio (SNR) compared to 3T MRI and 2.8x SNR compared to 1.5T MRI. The purpose of this study was to estimate the accuracy of 7T MRI for the detection and grading of cartilage lesions in the knee. The hypothesis was that 7T images would offer better detection and more accurate grading of chondral lesions than standard clinical grade MRI scans. Methods: In this prospective, paired, blinded study, patients who had undergone a 1.5 or 3T standard of care (SOC) MRI and were scheduled for knee arthroscopy were enrolled (10/2019 to 08/2021) and a study intervention 7T MRI was performed prior to surgery. The study was approved by our institutional review board, and it was funded by the Methodist-Siemens Collaboration. Exclusion criteria included contraindication to MRI (e.g., pacemaker), weight less than 30 kg, and pregnancy. Scans were reviewed by three independent fellowship-trained radiologists who were blinded to clinical and arthroscopic data. Scans were reviewed over 5 days, with a 4 week “washout” period between review of SOC and 7T scans to limit recall bias. Readers were blinded to clinical and arthroscopic data and graded all six articular surfaces of the knee (patella, trochlea, lateral condyle, medial condyle, lateral tibia, medial tibia) using a modified Outerbridge classification system. At the time of arthroscopy, each articular surface was graded by the operating surgeon according to a modified Outerbridge system similar to above, with the exception that Grade 1 = softening of the articular cartilage. The surgeon was blinded to 7T images at the time of arthroscopy, although they had access to the SOC MRI, which was necessary for patient care. Using arthroscopy as the gold standard, we calculated sensitivity and specificity of SOC MRI and 7T MRI. An Outerbridge grade of 0 was classified as negative, while a grade of 1-4 was classified as positive. A secondary analysis of sensitivity and specificity was performed on a per articular surface basis, with 6 articular surfaces per patient after correction for within subject clustered data. A Mann-Whitney U test was used to compare diagnostic scores and ratings between instruments (SOC vs. 7T). Coefficients of variation between observers within each instrument were compared for each variable using a paired sample t-test. Type-I error was set at alpha=0.05 Results: A total of 100 patients (age: 43 ± 14, 54 female, 46 male) were enrolled. 7T MRI resulted in improved sharpness (defined by visibility of nerve fascicles) and shading (based on artifacts) compared to SOC MRI (Figure 1, p &lt; 0.001 for both). There was improved contrast between fluid and cartilage with 7T MRI (using confidence rating at axial mid-patella, p = 0.003). 7T MRI had a higher sensitivity in detecting cartilage lesions for five of the six articular surfaces when using the arthroscopic gold standard, but with lower specificity for all surfaces (Figure 2). Finally, there was improved inter-observer reliability in detecting and grading cartilage defects with 7T compared to SOC MRI (p &lt; 0.05). Conclusion: Based on our findings thus far, 7T MRI appears to result in improved measurement ratings, sensitivity, and inter-observer reliability compared to SOC in detecting cartilage lesions in the knee. Further work is needed to evaluate cost effectiveness of 7T MRI.

No difference in clinical parameters and drug retention in PsA patients receiving b/tsDMARD monotherapy versus combination with methotrexate: data from the RABBIT-SpA registry

BackgroundThe potential benefit of methotrexate (MTX) in combination with biologic (b) and targeted synthetic (ts) disease modifying anti-rheumatic drugs (DMARDs) in psoriatic arthritis (PsA) is still a matter of debate.ObjectivesTo...

Multi-omics analysis reveals drivers of loss of β-cell function after newly diagnosed autoimmune type 1 diabetes: An INNODIA multicenter study.

Heterogeneity in the rate of β-cell loss in newly diagnosed type 1 diabetes patients is poorly understood and creates a barrier to designing and interpreting disease-modifying clinical trials. Integrative analyses of baseline multi-omics data obtained after the diagnosis of type 1 diabetes may provide mechanistic insight into the diverse rates of disease progression after type 1 diabetes diagnosis. We collected samples in a pan-European consortium that enabled the concerted analysis of five different omics modalities in data from 97 newly diagnosed patients. In this study, we used Multi-Omics Factor Analysis to identify molecular signatures correlating with post-diagnosis decline in β-cell mass measured as fasting C-peptide. Two molecular signatures were significantly correlated with fasting C-peptide levels. One signature showed a correlation to neutrophil degranulation, cytokine signalling, lymphoid and non-lymphoid cell interactions and G-protein coupled receptor signalling events that were inversely associated with a rapid decline in β-cell function. The second signature was related to translation and viral infection was inversely associated with change in β-cell function. In addition, the immunomics data revealed a Natural Killer cell signature associated with rapid β-cell decline. Features that differ between individuals with slow and rapid decline in β-cell mass could be valuable in staging and prediction of the rate of disease progression and thus enable smarter (shorter and smaller) trial designs for disease modifying therapies as well as offering biomarkers of therapeutic effect.

Alzheimer's Disease and Epilepsy: Exploring Shared Pathways and Promising Biomarkers for Future Treatments.

Background: Alzheimer's disease (AD) and epilepsy represent two complex neurological disorders with distinct clinical manifestations, yet recent research has highlighted their intricate interplay. This review examines the association between AD and epilepsy, with particular emphasis on late-onset epilepsy of unknown etiology, increasingly acknowledged as a prodrome of AD. It delves into epidemiology, pathogenic mechanisms, clinical features, diagnostic characteristics, treatment strategies, and emerging biomarkers to provide a comprehensive understanding of this relationship. Methods: A comprehensive literature search was conducted, identifying 128 relevant articles published between 2018 and 2024. Results: Findings underscore a bidirectional relationship between AD and epilepsy, indicating shared pathogenic pathways that extend beyond traditional amyloid-beta and Tau protein pathology. These pathways encompass neuroinflammation, synaptic dysfunction, structural and network alterations, as well as molecular mechanisms. Notably, epileptic activity in AD patients may exacerbate cognitive decline, necessitating prompt detection and treatment. Novel biomarkers, such as subclinical epileptiform activity detected via advanced electroencephalographic techniques, offer promise for early diagnosis and targeted interventions. Furthermore, emerging therapeutic approaches targeting shared pathogenic mechanisms hold potential for disease modification in both AD and epilepsy. Conclusions: This review highlights the importance of understanding the relationship between AD and epilepsy, providing insights into future research directions. Clinical data and diagnostic methods are also reviewed, enabling clinicians to implement more effective treatment strategies.

Hydroxy Chloroquine Prophylaxis Experience in Doctor Community with COVID-19 in West Bengal

Background The Indian Council of Medical Research (ICMR)National task Force for COVID-19 reviewed the data on in-vitro testing of Hydroxy Chloroquine (HCQ)for antiviral efficacy against SARS-CoV-2, safety profile and recommended it’s use for prophylaxis among health care workers (HCWs). The efficacy of HCQ against Covid -19 has been the subject of contradictory results. Given the need for insights into the clinical outcomes and side effects among doctors on prophylaxis with hydroxychloroquine, we conducted a retrospective analysis of doctors treated at home or hospital with COVID-19 infection.MethodsThe data was collected by direct interview, electronic data transfer from COVID-19 positive doctors using real-time reverse transcription-polymerase chain reaction (RT-PCR) test from two medical colleges, friends and relatives of doctors who voluntarily provided their illness information during the period of August, 26 to Nov 25, 2020.ResultsA total of 117 doctors participated in study. Out of 117 covid positive doctors, 76 received no HCQ prophylaxis and 41 received prophylaxis till the onset of the symptom. Out of 117 positive doctors, 32(27%) developed moderate to severe (MS) illness. Nine doctors (22%) developed MS in HCQ group and none of them died. Out of no HCQ group 23(30%) developed MS illness and 7(9%) died. There was no statistically significant relation between use of HCQ and outcomes of disease. The most common (22%) side effect of HCQ prophylaxis was related to gastrointestinal system. Conclusions Hydroxy Chloroquine has a disease modifying effect on COVID-19 disease although it is not robust.

Effect of biologic agents and inflammation on lipid levels and cardiovascular risk in rheumatoid arthritis patients

BackgroundCardiovascular disease (CVD) is the main cause of mortality in Rheumatoid Arthritis (RA). ObjectiveTo investigate the effect of biologic disease modifying anti-rheumatic drugs (bDMARDs) on lipids and CVD risk and evaluate associations with changes in systemic inflammation. MethodsPatients with RA initiating a bDMARD were evaluated at baseline, 3 and 6 months later. Longitudinal mixed effects models examined the association of individual biologics with changes in lipid levelsm Reynolds Risk Score (RRS) and Framingham risk score. Mediation by CRP, clinical disease activity index (CDAI) or swollen joint count on lipid changes were modeled using structural equation models. The correlation between CRP changes and LDL changes was estimated. Changes of LDL-C at 6 months among patients with low baseline LDL-C (<90 mg/dl) vs higher baseline LDL-C(90–130, and >130 mg/dl) were compared. The association between LDL-C changes across baseline LDL-C groups and disease activity improvement was evaluated. Results1698 bDMARD initiations were analyzed. Patients initiating tocilizumab had a significant increase in lipid levels but RRS at 3 and 6 months was similar across all biologics. Framingham risk score increased for patients treated with tocilizumab. Mediator analyses were statistically significant for the effects of CRP on lipid levels. Increases in LDL-C from baseline were independent of clinical response. An association of changes from baseline CRP and LDL-C were observed across all of the bDMARDs studied. ConclusionModerate increases in lipid levels on bDMARD treatment were not associated with an increased CVD risk by RRS regardless of the bDMARD initiated. Changes in CRP were significantly associated with changes in lipids in a mediator analysis.

P045 An international Delphi consensus to define a clinically appropriate definition of disease modification for plaque psoriasis

P045 An international Delphi consensus to define a clinically appropriate definition of disease modification for plaque psoriasis

Features of depressive disorders in patients with multiple sclerosis and their medical correction

Patients with multiple sclerosis (MS) often have comorbid symptoms that reduce their quality of life; these include a high prevalence of depression, anxiety, cognitive impairment, and increased fatigue. Although these problems manifest themselves in a wide range, clinicians do not always succeed in differentiating them due to their disguise by underlying disease. The detection of depressive disorders, as well as pharmacological treatment, is an important area of therapeutic intervention. Currently, there are no clinical recommendations regulating the treatment of affective disorders in MS patients, which makes it difficult to select therapy and affects the rehabilitation potential of the patient. The purpose of this study was to investigate the manifestations of depressive disorders in patients with multiple sclerosis, as well as the choice of drug correction. Patients and methods: The study involved 113 patients with a clinically confirmed diagnosis of multiple sclerosis receiving DMTs (disease modifying therapies). The age of the patients at the time of examination ranged from 15 to 60 years (mean age 39.7±10.91). Among those examined, 77% (87 patients) were women, and 23% (26 patients) were men. Taking into account the course of the disease, the MS patients were distributed as follows: 80.5% (91 patients) had a remitting course, and 19.5% (22 patients) had a secondary progressive course. The disability indicator varied in the patients with RMS (2.89±0.16 points) and the patients (5.0±0.24 points). The A. Beck’s scale, the asthenic state scale (ASS), and the point scale for assessing the condition were used. Results and discussion: The study presents two groups of patients: with multiple sclerosis (study group), 113 participants with depressive disorders, and a group of 70 participants with depressive disorders (comparison group). The study revealed that the level of depressive disorders in the MS patients was mainly represented by mild and moderate depression, while in the comparison group moderate and severe depressive disorders were more common. Indicators of depressive manifestations in the patients in the comparison group were also higher. In almost equal proportions, the patients of the compared groups experienced: "a sense of punishment", "indecision", "loss of performance", a feeling of "increased fatigue", "decreased appetite or loss of appetite", and a feeling of being "engulfed by bodily sensations", according to the Beck questionnaire. These experiences varied and depended on the severity of depressive disorder. When selecting therapy, the neurological status of the patients as well as clinical symptoms of depression, which were combined into clinical symptomatic forms, were taken into account. Drugs that could enhance neurological disorders were excluded. The drugs from the SSRI and SNRI groups were mostly selected. Using a score assessment of the condition before and after the prescription, the MS patients evaluated the effect of the received therapy, where statistically significant differences were obtained for the following drugs: escitalopram p&lt;0.001, sertraline, fluvoxamine, and agomelatine p&lt;0.01, and paroxetine slightly lower than p&lt;0.05. Conclusion: Multiple sclerosis is not only a concern for neurologists, but also psychiatrists, since anxiety and depression occur in every second patient. Timely diagnosis of depressive disorders, as well as the synthesis of knowledge in the field of the development of multiple sclerosis taking into account neurological symptoms, will help clinicians prescribe pharmacotherapy in a timely manner, thereby improving the rehabilitation potential and quality of life of MS patients.

Clinical utility of the Lumipulse™ immunoassay for plasma neurofilament light chain in multiple sclerosis

ObjectiveBlood neurofilament light chain (NfL) is robustly associated with disease worsening in multiple sclerosis (MS), though potentially affected by concomitant factors also determining neuro-axonal loss. We investigated the association between plasma NfL (pNfL) measured with Lumipulse™ immunoassay and demographic and clinical variables in MS. MethodsThis cross-sectional study included 685 people with MS (age 49.7 ± 12.4 years; sex 65.55% females). On the same day, we collected plasma samples, along with demographics, comorbidities, and clinical variables (MS disease duration, expanded disability status scale (EDSS), Symbol Digit Modalities Test (SDMT), descriptor of disease progression, current disease modifying treatment (DMT), number of previous DMTs, evidence of disease activity in the past year (i.e. relapse or MRI new lesions), EDSS progression). pNfL was evaluated using Lumipulse™ fully automated chemiluminescent enzyme immunoassay. ResultsOn multivariable linear regression model, higher pNfL was associated with higher EDSS (Coeff = 1.73; 95%CI 0.78, 2.68; p < 0.01), recent disease activity (Coeff = 15.70; 95%CI = 5.35, 26.06; p < 0.01), and presence of cardiovascular comorbidity (Coeff = 3.84; 95%CI 0.48, 7.20; p = 0.025). Lower pNfL was found in patients on DMT treatment (Coeff = −10.23; 95%CI -18.42, −2.04; p = 0.015), when compared with no DMT (reference). For 77.81% of our population there was correspondence between pNfL levels and two previously-validated cutoffs. ConclusionspNfL measured using Lumipulse™ confirms known associations with MS activity, disability and treatments, and related confounding (e.g., cardiovascular comorbidity), thus granting further utilization in research and clinical practice.

Gut-Brain Axis in Focus: Polyphenols, Microbiota, and Their Influence on α-Synuclein in Parkinson's Disease.

With the recognition of the importance of the gut-brain axis in Parkinson's disease (PD) etiology, there is increased interest in developing therapeutic strategies that target α-synuclein, the hallmark abhorrent protein of PD pathogenesis, which may originate in the gut. Research has demonstrated that inhibiting the aggregation, oligomerization, and fibrillation of α-synuclein are key strategies for disease modification. Polyphenols, which are rich in fruits and vegetables, are drawing attention for their potential role in this context. In this paper, we reviewed how polyphenols influence the composition and functional capabilities of the gut microbiota and how the resulting microbial metabolites of polyphenols may potentially enhance the modulation of α-synuclein aggregation. Understanding the interaction between polyphenols and gut microbiota and identifying which specific microbes may enhance the efficacy of polyphenols is crucial for developing therapeutic strategies and precision nutrition based on the microbiome.

Advantages and Challenges of Platform Trials for Disease Modifying Therapies in Parkinson's Disease.

Traditional drug development in Parkinson's disease (PD) faces significant challenges because of its protracted timeline and high costs. In response, innovative master protocols are emerging and designed to address multiple research questions within a single overarching protocol. These trials may offer advantages such as increased efficiency, agility in adding new treatment arms, and potential cost savings. However, they also present organizational, methodological, funding, regulatory, and sponsorship challenges. We review the potential of master protocols, focusing on platform trials, for disease modifying therapies in PD. These trials share a common control group and allow for the termination or addition of treatment arms during a trial with non-predetermined end. Specific issues exist for a platform trial in the PD field considering the heterogeneity of patients in terms of phenotype, genotype and staging, the confounding effects of symptomatic treatments, and the choice of outcome measures with no consensus on a non-clinical biomarker to serve as a surrogate and the slowness of PD progression. We illustrate these aspects using the examples of the main PD platform trials currently in development with each one targeting distinct goals, populations, and outcomes. Overall, platform trials hold promise in expediting the evaluation of potential therapies for PD. However, it remains to be proven whether these theoretical benefits will translate into increased production of high-quality trial data. Success also depends on the willingness of pharmaceutical companies to engage in such trials and whether this approach will ultimately hasten the identification and licensing of effective disease-modifying drugs. © 2024 International Parkinson and Movement Disorder Society.

An interim exploratory proteomics biomarker analysis of a phase 2 clinical trial to assess the impact of CT1812 in Alzheimer's disease

CT1812 is a novel, brain penetrant small molecule modulator of the sigma-2 receptor (S2R) that is currently in clinical development for the treatment of Alzheimer's disease (AD). Preclinical and early clinical data show that, through S2R, CT1812 selectively prevents and displaces binding of amyloid beta (Aβ) oligomers from neuronal synapses and improves cognitive function in animal models of AD. SHINE is an ongoing phase 2 randomized, double-blind, placebo-controlled clinical trial (COG0201) in participants with mild to moderate AD, designed to assess the safety and efficacy of 6 months of CT1812 treatment. To elucidate the mechanism of action in AD patients and pharmacodynamic biomarkers of CT1812, the present study reports exploratory cerebrospinal fluid (CSF) biomarker data from 18 participants in an interim analysis of the first set of patients in SHINE (part A). Untargeted mass spectrometry-based discovery proteomics detects >2000 proteins in patient CSF and has documented utility in accelerating the identification of novel AD biomarkers reflective of diverse pathophysiologies beyond amyloid and tau, and enabling identification of pharmacodynamic biomarkers in longitudinal interventional trials. We leveraged this technique to analyze CSF samples taken at baseline and after 6 months of CT1812 treatment. Proteome-wide protein levels were detected using tandem mass tag-mass spectrometry (TMT-MS), change from baseline was calculated for each participant, and differential abundance analysis by treatment group was performed. This analysis revealed a set of proteins significantly impacted by CT1812, including pathway engagement biomarkers (i.e., biomarkers tied to S2R biology) and disease modification biomarkers (i.e., biomarkers with altered levels in AD vs. healthy control CSF but normalized by CT1812, and biomarkers correlated with favorable trends in ADAS-Cog11 scores). Brain network mapping, Gene Ontology, and pathway analyses revealed an impact of CT1812 on synapses, lipoprotein and amyloid beta biology, and neuroinflammation. Collectively, the findings highlight the utility of this method in pharmacodynamic biomarker identification and providing mechanistic insights for CT1812, which may facilitate the clinical development of CT1812 and enable appropriate pre-specification of biomarkers in upcoming clinical trials of CT1812.