Disease Modifying Research Articles

Editorial: Epigenetic modification in neurological diseases

Editorial: Epigenetic modification in neurological diseases

Combined Assessment of Function and Survival to Demonstrate the Effect of Treatment on Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a rare and fatal neurodegenerative disorder for which there are currently no disease-modifying treatments. Recent trials of potential therapies had durations of 12 months, which may be insufficient because of nonrandom missingness due to death. Longer durations, incorporating PSP Rating Scale and survival, can reduce the potential for type II error. Selecting efficacy measures more sensitive to disease modification may facilitate identification of treatment effect. The objective of this study was to evaluate the simulated phase 3 PSP trial assessing the effect of disease-modifying intervention on a novel combined primary endpoint comprising function (PSP Rating Scale) and survival, the Combined Assessment of Function and Survival (CAFS), and to determine operating characteristics of the CAFS. To simulate PSP progression in the trial population, we developed models of PSP Rating Scale and survival using data from published clinical studies. These models were used to define operating characteristics of the CAFS for use in a phase 3 trial. The sample size determined (N = 384; 1:1 randomization) would provide >80% power to detect significant treatment effects on the CAFS compared with placebo. The CAFS provides good operating characteristics and increased power to detect moderate treatment effects on the PSP Rating Scale. We propose a trial design allowing potential detection of treatment effects at a preplanned interim analysis after participants complete 12 months of treatment, with assessment of effects of treatment (≤24 months) on survival. Use of the CAFS could provide a comprehensive and robust estimate of the clinical benefit of future therapies. © 2024 UCB. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Increased adoption of IL-1 pathway inhibition and the steroid-sparing paradigm shift: temporal trends in recurrent pericarditis treatment from the RESONANCE patient registry

Abstract Background Recurrent pericarditis (RP) is a chronic autoinflammatory disease mediated by IL-1 that requires long-term treatment. While the 2015 European Society of Cardiology Guidelines position IL-1 pathway inhibition only after corticosteroids, complications associated with long-term steroid use underscore the importance of steroid-sparing strategies. Rilonacept, an IL-1α and IL-1β cytokine trap, is the only FDA-approved treatment for RP (available since April 2021). RESONANCE, an ongoing 5-year non-interventional US registry of patients (pts) with RP, has collected real-world data from pts cared for by cardiologists with a focus on pericardial disease, with a goal of informing contemporary RP clinical management. Purpose Analysis of temporal trends in RP management from RESONANCE. Methods From a database cut-off (DCO) on 21 December 2023, patient demographics and disease characteristics are reported for 242 active RP pts (excluding RHAPSODY prior participants) at 20 US sites (median [Q1:Q3] 2.1 [1.5:2.6] years and 556 patient-years [PY] of observation). Complete medication class use data were available for 239 pts (total 546 PY). Proportional medication class use prior to initiating rilonacept was analyzed annually across the observation period. Results Mean (standard deviation) age at DCO was 50.2 (16.6) years; 58.1% were female. Median [Q1:Q3] disease duration at DCO from index pericarditis episode was 3.1 [2.2:5] years. Median [Q1:Q3] number of prior recurrences at enrollment was 3 [2:5]. Prior to rilonacept availability, NSAIDs/Colchicine/Aspirin represented the highest proportion of treatment (73% of PY); steroid use was 9% of PY, IL-1 pathway inhibition (anakinra) was 13% of PY, and conventional synthetic disease modifying antirheumatic drugs (csDMARDs) were 0.46% PY (no RP-specific treatment was 5% of PY) (Fig 1). In the years since rilonacept availability, proportional IL-1 pathway inhibition use has increased, from 13% of PY in 2020-21 to 26% of PY in 2023, driven by an increase in rilonacept use (6%, 13%, 16% of PY in 2021, 2022, and 2023, respectively). Over that same period, proportional NSAIDs/Colchicine/Aspirin use (57%-63% of PY) has been consistently 6-times more than proportional steroid use (10%-11% of PY). Among pts who initiated rilonacept (n=81), similar proportions transitioned from NSAIDs/Colchicine/Aspirin as from corticosteroids (Fig 2), a robust trend observed each year. Of those pts transitioning from corticosteroids, 1/3 had used corticosteroids for <30 days and 1/3 for >6 months. Conclusions Real-world data from the RESONANCE registry reveal a temporal shift in RP management in US centers with RP-focused cardiologists, with increased proportional IL-1 pathway inhibition use since rilonacept availability in 2021. Advancing beyond 2015 guideline recommendations, IL-1 pathway inhibition is often being used as steroid-sparing treatment, i.e., after colchicine instead of chronic corticosteroids.

Escalation to Biologics After Methotrexate Among US Veterans with Rheumatoid Arthritis Grouped by Rural Versus Urban Areas.

Racial and ethnic disparities in rheumatoid arthritis (RA) outcomes are well recognized. However, whether disparities in RA treatment selection and outcomes differ by urban versus rural residence, independent of race, have not been studied. Our objective was to evaluate whether biologic disease modifying anti-rheumatic drugs (bDMARD) initiation after methotrexate use differs by rural versus urban residence among Veterans with RA. In this retrospective cohort study utilizing national U.S. Veterans Affairs databases, we identified adult patients with RA based on presence of diagnostic codes and DMARD use. We included patients receiving an initial prescription of methotrexate (index date) between 2005 and 2014, with data through 2016 used for follow-up. Urban-rural status was categorized using the Veteran Health Administration's Urban/Rural classification. Our primary outcome of interest was time to biologic initiation within two years of starting methotrexate. Multivariable Cox proportional hazards models were conducted adjusting for demographics, comorbidities, and rheumatoid factor or anti-CCP positivity. Among 17,395 veterans with RA (88% male, 42% with rural residence) fulfilling eligibility criteria, 3,259 (19%) initiated a biologic within the first two years of follow up. In multivariable models, residence in an urban area was associated with a statistically significant higher biologic use compared to rural areas (adjusted hazard ratio (aHR) 1.10, 95% CI 1.02-1.18). Our study found only modest differences in initiation of biologic therapies among rural versus urban residing Veterans with RA in the VA healthcare system. These findings suggest that disparities are not easily explained by rurality within the VA healthcare system.

Association of inflammation with left ventricular mass index in patients with rheumatoid arthritis

Abstract Background Rheumatoid arthritis (RA) is an inflammatory autoimmune disease associated with cardiovascular organ damage. Purpose We explored the association of inflammatory markers with left ventricular (LV) mass index during 22 months of follow-up in patients with RA. Methods Eighty-three outpatients with RA (age 55±12 years, 71 % women) with indication for biological (b) or targeted synthetic (ts) disease modifying antirheumatic drug (DMARD) therapy were examined with echocardiography at baseline and after 22 months. LV mass was indexed for height in the allometric power of 2.7. Serum concentrations of the inflammatory markers, C-reactive protein (CRP), serum amyloid A (SAA) and calprotectin were measured by MALDI-TOF mass spectrometry. Results At baseline, 37% had hypertension, 6% diabetes, 21% obesity and 100% were using b/ts DMARDs. The inflammatory markers decreased during follow-up (all p<0.001), while the LV mass index did not change (33.1±8.1 g/m^2.7 vs. 33.5±7.3 g/m^2.7, p=0.57). The prevalence of hypertension, diabetes and obesity were unchanged at follow-up (p>0.05), but the percentage of patients using b/ts DMARDs had decreased to 83% (p<0.001). In multivariable analyses, higher CRP and SAA at baseline were associated with higher LV mass index at both baseline and follow-up independent of presence of obesity, hypertension, age, sex or treatment with b/ts DMARDs at follow-up (Table 1). Inflammatory markers at follow-up were not associated with LV mass index (Table 1), but use of b/ts DMARDs at follow-up were associated with lower LV mass index after adjusting for inflammatory markers, age, sex, presence of obesity and hypertension (Table 1). Conclusion Higher levels of inflammatory markers at baseline were associated with greater LV mass index in RA patients. The use of immunosuppressive treatment throughout the study period was associated with lower LV mass index at follow-up, pointing to a role of chronic inflammation in LV hypertrophy.

Development and validation of a risk prediction model for worsening renal function in patients with incident heart failure

Abstract Background Worsening renal function (WRF) is one of the strongest predictors of outcome in patients with heart failure (HF). The presence of WRF often influences the decision to start, up-titrate, or discontinue disease modifying HF therapies and is one of the key determinants of suboptimal guideline-directed medical therapy. Existing WRF risk scores were developed in hospitalised HF patients to predict in-hospital WRF. Their performance among incident HF is far from ideal. It is therefore important to develop a new WRF risk prediction model in people with newly diagnosed HF. Purpose This study was to develop and validate a clinical risk prediction model for 180-day WRF post diagnosis of incident HF using data from a population-based longitudinal cohort. Methods We developed and validated a multivariable logistic regression model for WRF in the 180 days post diagnosis of incident HF. Data for individuals with incident HF between 2016 to 2021 were extracted from the NELSON study conducted in Tayside, Scotland. WRF was defined as a composite event of (i) having two consecutive eGFRs declined by 40% or greater; (ii) having an eGFR < 15mL/min/1.73m2; (iii) initiation of sustained dialysis; (iv) development of end-stage kidney disease; (v) receiving kidney transplantation; or (vi) kidney related death. Four candidate models included one model using literature knowledge; one multivariable fractional polynomial (MFP) model; and two stepwise selected models based on either Akaike or Bayesian information criterion (AIC or BIC). Calibration and discrimination were assessed, and performance stability were evaluated using optimism corrected performance via 1000 times bootstrapping. Results 4076 individuals (mean age 72.8 ± 13.2; 58% male; 1081 HF with reduced ejection fraction (HFrEF), 646 with HF with mildly reduced ejection fraction (HFmrEF), 1348 HF with preserved ejection fraction (HFpEF), and 1001 HF with unknown ejection fraction (EF)) who were WRF-free when diagnosed with HF were identified. Of these, 2095 (51.4%) were in-patients, and 1981 (48.6%) were out-patients. 285 (7%) patients developed WRF within 180 days post HF diagnosis. The selected MFP model (comprising 12 predictors, Table 1) showed good calibration (slope = 1.00 [0.86, 1.14]; intercept = 0.0 [-0.13, 0.13]) discrimination (C-statistic = 0.69 [95% CI: 0.65, 0.72]), and stability (optimism corrected: calibration slope = 0.94 [0.80, 1.07]; calibration intercept = -0.14 [-0.50, 0.20]; C-statistic = 0.67 [0.64, 0.71]). Discrimination of the developed model significantly outperformed two existing risk scores (Forman and Basel, both with a C-statistic = 0.62 [0.59 – 0.65]). Conclusions We have shown that the developed model performed better in predicting WRF in individuals with newly diagnosed HF. This could have utility in identifying at risk patients with HF early in the disease trajectory for therapies that can reduce renal decline.Calibration of predicted riskModel estimates for predicting 180d WRF

The prevalence of multiple sclerosis in Israel based on validation of a health care organization database

In Israel there is no registry of multiple sclerosis (MS), thus the prevalence of MS is unknown. Clalit Health Services (CHS) is Israel’s largest health care organization. We have developed an algorithm to identify people with MS (PwMS) using CHS database and validated it against a gold-standard diagnosis by expert neurologists. People with a possible diagnosis of MS were identified in CHS database according to ICD-9 code or dispense of MS specific disease modifying treatment (DMT). The electronic medical records (EMRs) of a random sample of 25% of this population, stratified by age and sex were examined to determine positive predictive value (PPV). Another age- and sex- stratified random sample of 15% of pwMS under our care were searched in CHS database to determine database sensitivity (Sn). Finally, a random sample of 40% of people without MS were searched in CHS database to evaluate database specificity (Sp). The best case definition to retrieve pwMS was ICD-9 code 340 as an established diagnosis or at least one dispense of a DMT (PPV = 87%, Sn = 92%, Sp = 90%). Using this definition the prevalence of MS in Israel was 68, 82 and 95 per 100,000 population by the end of 2011, 2016 and 2021, respectively. The prevalence of MS in Israel is rising, in line with the worldwide trend.

Cost variation analysis of disease modifying anti rheumatic drugs in Indian market

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease with systemic complications, necessitating treatment to manage inflammation and prevent joint damage. In India, significant cost discrepancies exist among branded formulations of generic drugs, posing a financial burden on patients and impacting treatment adherence. This study focuses on cost differences of disease modifying anti rheumatic drugs (DMARDs) among Indian brands and advocating strict adherence to drug price control order (DPCO) rules and suggests scheduling non-scheduled drugs under DPCO. Methods: This observational study analysed the cost of 6 oral DMARDs across 16 tablet formulations using data from National Pharmaceutical Pricing Authority (NPPA) and DPCO ceiling prices 2024. Number of brands per formulation, cost ratios, percentage variations, and DPCO price violations was analysed. Statistical analysis was performed using Microsoft Excel Office 2021, and Zotero was utilized for managing references. Results: This study highlights significant price variations among DMARDs in the Indian market, with methotrexate 2.5mg exhibiting the highest cost ratio (1:3.63) and percentage cost variation (263.6%). Azathioprine 50mg has the most brands available (23), while sulfasalazine 500mg, sulfasalazine 1000mg, and tofacitinib 11mg are among the formulations with the fewest brands (3 each). Notably, sulfasalazine 500mg and hydroxychloroquine 200mg showed the most frequent instances of pricing violations above DPCO recommendations. Conclusions: Strict regulation for price control and monitoring should be implemented since the DPCO has not yet achieved its goal of enforcing price ceilings, and non-scheduled drugs should be included under DPCO regulations effectively to enhance adherence to RA therapy.

Mechanisms of Action Underlying Conductance-modifying Positive Allosteric Modulators of the NMDA Receptor.

NMDA receptors (NMDARs) are ionotropic glutamate receptors that mediate a slow, Ca2+-permeable component of fast excitatory neurotransmission. Modulation of NMDAR function has the potential for disease modification as NMDAR dysfunction has been implicated in neurodevelopment, neuropsychiatric, neurological, and neurodegenerative disorders. We recently described the thieno[2,3-d]pyrimidin-4-one (EU1622) class of positive allosteric modulators, including several potent and efficacious analogs. Here we have used electrophysiological recordings from Xenopus oocytes, HEK cells, and cultured cerebellar and cortical neurons to determine the mechanisms of action of a representative member of this class of modulator. EU1622-240 enhances current response to saturating agonist (doubling response amplitude at 0.2-0.5 µM), slows the deactivation time course following rapid removal of glutamate, increases open probability, enhances co-agonist potency, and reduces single channel conductance. We also show that EU1622-240 can transform NMDARs so that they can be opened when only glutamate or glycine is bound. EU1622-240-bound NMDARs channels activated by a single agonist (glutamate or glycine) open to a unique conductance level with different pore properties and Mg2+ sensitivity, in contrast to channels arising from activation of NMDARs with both co-agonists bound. These data demonstrate that previously hypothesized distinct gating steps can be controlled by glutamate and glycine binding and shows that the 1622-series modulators enable glutamate- or glycine-bound NMDARs to generate open conformations with different pore properties. The properties of this class of allosteric modulators present intriguing therapeutic opportunities for the modulation of circuit function. Significance Statement NMDA receptors are expressed throughout the CNS and are permeable to calcium. EU1622-240 increases open probability and agonist potency, while reducing single channel conductance and prolonging the deactivation time course. EU1622-240 allows NMDA receptor activation by the binding of one co-agonist (glycine or glutamate), which produces channels with distinct properties. Evaluation of this modulator provides insight into gating mechanisms and may lead to the development of new therapeutic strategies.

Gene-Specific Effects on Brain Volume and Cognition of TMEM106B in Frontotemporal Lobar Degeneration.

TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN pathogenic variant carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study was to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in patients with sporadic FTD. Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic variant in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic nonpathogenic variant carriers, and noncarrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex, and CDR+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN pathogenic variant carriers under the recessive dosage model (N = 82, beta = 3.25, 95% CI [0.37-6.19], p = 0.034). This was most pronounced in the thalamus in the left hemisphere (beta = 0.03, 95% CI [0.01-0.06], p = 0.006), with a retained association when considering presymptomatic GRN pathogenic variant carriers only (N = 42, beta = 0.03, 95% CI [0.01-0.05], p = 0.003). The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 pathogenic variant carriers (N = 229, beta = 0.36, 95% CI [0.05-0.066], p = 0.021) and in presymptomatic C9orf72 pathogenic variant carriers (N = 106, beta = 0.33, 95% CI [0.03-0.63], p = 0.036), under the recessive dosage model. We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 pathogenic variants. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 pathogenic variant carriers could additionally reflect TMEM106B's effect on divergent pathophysiologic changes before the appearance of clinical symptoms.

Neutrophil activation markers can predict rheumatoid arthritis treatment response to the Janus Kinase 1/2 inhibitor baricitinib.

Neutrophils play an important role in regulating immune and inflammatory responses in rheumatoid arthritis (RA). We assessed whether baricitinib, a JAK1/JAK2 inhibitor, could reduce neutrophil activation, and whether a neutrophil activation score could predict treatment response. Markers of neutrophil activation, calprotectin, and neutrophil extracellular traps (NETs) were analyzed using ELISA in RA plasma (n=271) and healthy controls (n=39). For RA patients, neutrophil activation markers were measured at baseline, 12 weeks, and 24 weeks after treatment with placebo, 2 mg, and 4 mg baricitinib. Whole blood RNA analyses from multiple randomized baricitinib RA trials were performed to study neutrophil-related transcripts (n=1651). Baseline levels of plasma neutrophil markers were elevated in RA patients compared to healthy controls (p<0.001). Baricitinib reduced levels of soluble calprotectin at 12 and 24 weeks, especially in RA patients responding to treatment, as determined by ACR20. Whole blood RNA analysis revealed similar changes in the predominant neutrophil markers calprotectin and FcαRI upon treatment with baricitinib in three randomized clinical trials involving RA patients at various stages of disease modifying therapy. Clustering analysis of plasma activation markers showed elevated levels of calprotectin and NETs, e.g., a neutrophil activation score, at baseline, could predict treatment response to baricitinib. In contrast, CRP levels could not distinguish between responders and non-responders. Neutrophil activation markers may add clinical value in predicting treatment response to baricitinib and other drugs targeting RA. This study supports personalized medicine, in treating RA patients, not only based on symptoms, but also based on immunophenotyping.

The impact of tau-PET in a selected memory clinic cohort: rationale and design of the TAP-TAU study

BackgroundTau-PET is a diagnostic tool with high sensitivity and specificity for discriminating Alzheimer’s disease (AD) dementia from other neurodegenerative disorders in well-controlled research environments. The role of tau-PET in real-world clinical practice, however, remains to be established. The aim of the TAP-TAU study is therefore to investigate the impact of tau-PET in clinical practice.MethodsTAP-TAU is a prospective, longitudinal multi-center study in 300 patients (≥ 50 years old) with mild cognitive impairment or mild dementia across five Dutch memory clinics. Patients are eligible if diagnostic certainty is < 85% after routine dementia screening and if the differential diagnosis includes AD. More specifically, we will include patients who (i) are suspected of having mixed pathology (e.g., AD and vascular pathology), (ii) have an atypical clinical presentation, and/or (iii) show conflicting or inconclusive outcomes on other tests (e.g., magnetic resonance imaging or cerebrospinal fluid). Participants will undergo a [18F]flortaucipir tau-PET scan, blood-based biomarker sampling, and fill out questionnaires on patient reported outcomes and experiences. The primary outcomes are change (pre- versus post- tau-PET) in diagnosis, diagnostic certainty, patient management and patient anxiety and uncertainty. Secondary outcome measures are head-to-head comparisons between tau-PET and less invasive and lower cost diagnostic tools such as novel blood-based biomarkers and artificial intelligence-based classifiers.ResultsTAP-TAU has been approved by the Medical Ethics Committee of the Amsterdam UMC. The first participant is expected to be included in October 2024.ConclusionsIn TAP-TAU, we will investigate the added clinical value of tau-PET in a real-world clinical setting, including memory clinic patients with diagnostic uncertainty after routine work-up. Findings of our study may contribute to recommendations regarding which patients would benefit most from assessment with tau-PET. This study is timely in the dawning era of disease modifying treatments as an accurate etiological diagnosis becomes increasingly important.Trial registrationThis trial is registered and authorized on December 21st, 2023 in EU Clinical Trials with registration number 2023-505430-10-00.

In Search of Spinal Muscular Atrophy Disease Modifiers

The 5q Spinal Muscular Atrophy (SMA) is a hereditary autosomal recessive disease caused by defects in the survival motor neuron (SMN1) gene encoding survival motor neuron (SMN) protein. Currently, it is the leading cause of infantile mortality worldwide. SMA is a progressive neurodegenerative disease with “continuum of clinical severity”, which can be modulated by genetic and epigenetic factors known as disease modifiers (DMs). Individuals (even siblings) with the same defects in SMN1 gene might have strikingly different types of SMA, supposedly due to the impact of DMs. There are several therapeutic options for SMA, all of them focusing on the restoration of the SMN protein levels to normal. Determining DMs and the pathways in which they are involved might aid in enhancing existing curative approaches. Furthermore, DMs might become novel therapeutic targets or prognostic biomarkers of the disease. This narrative review provides a brief overview of the genetics and pathobiology of SMA, and its bona fide modifiers. We describe novel, emerging DMs, approaches and tools used to identify them, as well as their potential mechanisms of action and impact on disease severity. We also propose several disease-modifying molecular mechanisms which could provide a partial explanation of the staggering variability of SMA phenotypes.

Incretin Mimetics as Potential Disease Modifying Treatment for Alzheimer's Disease.

Alzheimer's disease is a devastating neurodegenerative condition that exerts a significant global burden. Despite recent efforts, disease modifying therapies remain extremely limited, with a tremendous proportion of patients having to rely on symptomatic treatment only. Epidemiological and pathological overlaps exist between Alzheimer's disease and diabetes mellitus type 2, with people with diabetes mellitus type 2 at a significantly increased risk of developing Alzheimer's disease in the future. Incretin mimetics, also known as GLP-1/GIP receptor agonists, are useful tools licensed for the treatment of diabetes mellitus type 2 which have recently been the subject of news coverage for their off-label use as weight loss medications. Emerging evidence highlights the possible neuroprotective function of incretin mimetics in models of Alzheimer's disease as well as in clinical studies. This review details the pre-clinical and clinical studies that have explored the effectiveness of incretin mimetics to alleviate Alzheimer's disease associated pathology and cognitive impairment, while also highlighting the progress made to examine the effectiveness of these molecules in Parkinson's disease. Should clinical trials prove effective, incretin mimetics may be able to be repurposed and become useful novel tools as disease-modifying treatments for Alzheimer's disease and other neurodegenerative diseases.

Divergent and Convergent TMEM106B Pathology in Murine Models of Neurodegeneration and Human Disease.

TMEM106B is a lysosomal/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied in vivo using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of TMEM106B in murine models of C9ORF72 -related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy and compare these to postmortem human tissue from patients with C9-ALS/FTD, Alzheimer's disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). We show that there are significant differences between TMEM106B pathology in mouse models and human patient tissue. Importantly, we also identified convergent evidence from both murine models and human patients that links TMEM106B pathology to TDP-43 nuclear clearance specifically in C9-ALS. Similarly, we find a relationship at the cellular level between TMEM106B pathology and phosphorylated Tau burden in Alzheimer's disease. By characterizing endogenous TMEM106B pathology in both mice and human postmortem tissue, our work reveals considerations that must be taken into account when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.

Therapy concepts in type 1 diabetes mellitus treatment: disease modifying versus curative approaches.

For many autoimmune diseases, including type 1 diabetes mellitus (T1DM), efforts have been made to modify the disease process through pharmacotherapy. The ultimate goal must be to develop therapies with curative potential by achieving an organ without signs of parenchymal cell destruction and without signs of immune cell infiltration. In the case of the pancreas, this means regenerated and well-preserved beta cells in the islets without activated infiltrating immune cells. Recent research has opened up the prospect of successful antibody combination therapy for autoimmune diabetes with curative potential. This goal cannot be achieved with monotherapies. The requirements for the implementation of such a therapy with curative potential for the benefit of patients with T1DM and LADA (latent autoimmune diabetes in adults) are considered.

Pregnancy Outcomes from a Multidisciplinary Obstetric-Medicine/Rheumatology Clinic in the United States: A Five-Year Retrospective Analysis.

At Women & Infants Hospital in Providence, Rhode Island, the Specialty Care in Pregnancy clinic combines obstetric-medicine internists with rheumatologists to care for pregnant patients with rheumatologic conditions. These clinics are scarce, with only three known similar clinics in the United States. This study aims to characterize the population cared for in this clinic, identify interventions, and analyze pregnancy outcomes for the birthing parents and newborns. A five-year retrospective chart review was performed from January 1st, 2016, through December 31st, 2021. Of 81 patients, 62% had a clinically diagnosed rheumatic disorder. Of 87 patient visits, which included preconception, prenatal, and postpartum encounters, 54% of patients were taking conventional synthetic disease modifying antirheumatic drugs, and 17% were taking biologic disease modifying antirheumatic drugs. New medications were started in 52% of patients. A total of 52% of pregnancies resulted in live births, with 2% resulting in miscarriages. Prematurity occurred in 19% of newborns, and 9% had intrauterine growth restriction. Our study illustrates the benefits of multidisciplinary care in patients with rheumatologic disorders during their prenatal and perinatal periods. The expertise from both the obstetric-medicine internists and rheumatologists was critical in making complex decisions that weighed the benefits of therapy against potential risks for the fetus. Our multidisciplinary approach resulted in doubling of the number of patients initiating disease modifying therapy and increased prophylaxis with hydroxychloroquine and/or aspirin therapy, as recommended by current guidelines. Additional multidisciplinary clinics of this type would help coordinate care among physicians who frequently treat these high-risk, unique patients and open the door for more research of this understudied population.

Axon guidance genes are regulated by TDP-43 and RGNEF through long-intron removal.

Rho guanine nucleotide exchange factor (RGNEF) is a guanine nucleotide exchange factor (GEF) mainly involved in regulating the activity of Rho-family GTPases. It is a bi-functional protein, acting both as a guanine exchange factor and as an RNA-binding protein. RGNEF is known to act as a destabilizing factor of neurofilament light chain RNA (NEFL) and it could potentially contribute to their sequestration in nuclear cytoplasmic inclusions. Most importantly, RGNEF inclusions in the spinal motor neurons of ALS patients have been shown to co-localize with inclusions of TDP-43, the major well-known RNA-binding protein aggregating in the brain and spinal cord of human patients. Therefore, it can be hypothesized that loss-of-function of both proteins following aggregation may contribute to motor neuron death/survival in ALS patients. To further characterize their relationship, we have compared the transcriptomic profiles of neuronal cells depleted of TDP-43 and RGNEF and show that these two factors predominantly act in an antagonistic manner when regulating the expression of axon guidance genes. From a mechanistic point of view, our experiments show that the effect of these genes on the processivity of long introns can explain their mode of action. Taken together, our results show that loss-of-function of factors co-aggregating with TDP-43 can potentially affect the expression of commonly regulated neuronal genes in a very significant manner, potentially acting as disease modifiers. This finding further highlights that neurodegenerative processes at the RNA level are the result of combinatorial interactions between different RNA-binding factors that can be co-aggregated in neuronal cells. A deeper understanding of these complex scenarios may lead to a better understanding of pathogenic mechanisms occurring in patients, where more than one specific protein may be aggregating in their neurons.

Key Risk-Factors Contributing to Cardiovascular Disease: Lifestyle Modifications to Improve Cardiovascular Health

Cardiovascular disease is a preventable public health issue. The aim of this review is to identify modifiable risk-factors for cardiovascular disease and recommend lifestyle modification to prevent cardiovascular disease. PubMed, ScienceDirect, SAGE, Google Scholar, World Health Organisation websites, as well as public and community health textbooks, were hand searched and academic resources which are relevant for this review were selected for inclusion. Cardiovascular disease is leading cause of deaths in all continents of the world. While deaths from cardiovascular disease is increasing in Africa and Asia, it is decreasing in Australia and fluctuating in the USA. Premature deaths from cardiovascular disease are preeminent across middle income countries in Europe compared with high income countries. Cardiovascular disease is higher in rural areas of South America compared with urban areas. Trends in lifestyle patterns, including physical inactivity, smoking behaviour, and diets contribute to cardiovascular disease-prone conditions. Prevention includes health promotion activities that facilitate healthy living across life course and limit the initial onset of cardiovascular disease. Investment in prevention is the critical sustainable solution for the cardiovascular disease epidemic. Adopting WHO existing policies within individual countries in Africa, Asia, and middle-income countries in Europe, and ensuring robust implementation of such policies across life course and from different layers of sectors such as education and workplaces would have wider impacts in reducing risk and cardiovascular disease burden in the respective continents. Government of countries with worsening cardiovascular events should also increase health financing and focus on strengthening primary health care services for prevention and treatment of cardiovascular disease.

Sex differences in use of potentially teratogenic disease modifying treatments for multiple sclerosis and degree of hormonal contraception overlap in women between 2007–2021: An Australian population-based study

BackgroundDisease modifying treatments (DMTs) for multiple sclerosis (MS) have varying levels of teratogenic potential, but whether this influences DMT prescribing patterns by sex or concurrent use of hormonal contraception in women is unknown. This study aimed to examine patterns in dispensing of DMTs in women and men with MS, and hormonal long-acting reversible contraceptive (LARC) overlap at DMT initiation among women. MethodsPopulation cohort study using 10% random sample of the Australian Pharmaceutical Benefits Scheme dispensing data (2007–2021). DMT dispensing data were evaluated separately for women and men aged 18–49 years. Hormonal LARC overlap was determined by receipt of contraceptive dispensing where the expected duration of efficacy overlapped with the DMT dispensing date. ResultsDMTs with teratogenic potential (cladribine, sphingosine-1-phosphates and teriflunomide) were less likely to be commenced in women than men aged 18–39 (OR 0.70, 0.51–0.96), but not in those aged 40–49 (OR 0.93, 0.60–1.43). Hormonal LARC overlap was higher among those commenced DMTs with teratogenic potential compared with interferons (aOR 2.52, 1.14, 5.55). ConclusionSex and age differences in DMT utilisation were observed based on teratogenic potential. Hormonal LARC overlap appears higher in those receiving potentially teratogenic DMTs, but overall rates remain low.