Disease-modifying Treatments Research Articles

P.041 3 year longitudinal health related quality of life in a spinal muscular atrophy cohort

Background: Spinal Muscular Atrophy (SMA) is a rare, genetic disorder marked by motor neuron degeneration, causing progressive muscle weakness. SMA significantly impacts patients and their families. This study investigates HRQOL in a longitudinal SMA cohort. Methods: The study used the Canadian Neuromuscular Disease Registry to examine HRQOL in children aged 6-10 years with genetically confirmed SMA. HRQOL was evaluated using the PedsQL™ Measurement Model. This tool is validated in children and adolescents with various health conditions. The PedsQL Neuromuscular Module which has been validated in SMA was also used. Results: Eight participants completed the PedsQL generic and Neuromuscular Module at timepoint 1 (TP1) and 2 (TP2). The mean scores at TP1 were 49.66 (SD=5.05) for the generic PedsQL and 61.06 (SD=18.37) for the Neuromuscular Module. At TP2, mean scores increased to 59.32 (SD=13.08) and 74.86 (SD=9.88), respectively. The overall mean change over the two timepoints was +9.66 (SD=15.16) for the Generic PedQL and +13.80 (SD=23.03) for the Neuromuscular Module. Six participants were on disease modifying treatment. Conclusions: HRQOL scores in SMA patients improved over the study period. The enhancement in HRQOL may indicate the positive impact of diseases modifying treatments of SMA that became available during that time.

A.1 Repurposing Ambroxol as a disease-modifying treatment for Parkinson’s disease dementia: A phase 2, randomized, double blind placebo-controlled trial

Background: Currently there are no disease modifying treatment for Synucleinopathies including Parkinson’s disease Dementia (PDD). Carrying a mutation in the GBA gene (beta-glucocerebrosidase/ GCAse) is a leading risk factor for synucleinopathies. Raising activity GCAse lowers α-synuclein levels in cells and animal models. Ambroxol is a pharmacological chaperone for GCAse and can raise GCAse levels. Our goal is to test Ambroxol as a disease-modifying treatment in PDD. Methods: We randomized fifty-five individuals with PDD to Ambroxol 1050mg/day, 525mg/day, or placebo for 52 weeks. Primary outcome measures included safety, Alzheimer’s disease Assessment Scale-cognitive (ADAS-Cog) subscale and the Clinician’s Global Impression of Change (CGIC). Secondary outcomes included pharmacokinetics, cognitive and motor outcomes and and plasma and CSF biomarkers. Results: Ambroxol was well tolerated. There were 7 serious adverse events (SAEs) none deemed related to Ambroxol. GCase activity was increased in white blood cells by ~1.5 fold. There were no differences between groups on primary outcome measures. Patients receiving high dose Ambroxol appeared better on the Neuropsychiatric Inventory. GBA carriers appeared to improve on some cognitive tests. pTau 181 was reduced in CSF. Conclusions: Ambroxol was safe and well-tolerated in PDD. Ambroxol may improve biomarkers and cognitive outcomes in GBA1 mutation carrie.rs Ambroxol improved some biomarkerss. ClinicalTrials.gov NCT02914366

Limbic-predominant age-related TDP-43 encephalopathy: Amnestic-predominant cognitive decline beyond Alzheimer’s disease

Alzheimer’s disease (AD) is the main cause of neurodegenerative cognitive impairment leading to dementia. It is characterized by progressively worsening cognitive impairment with a predominant amnestic involvement. However, it is not the sole neurodegenerative disease presenting such symptoms, particularly prevalent among the elderly in our society. Recently, limbic-predominant age-related TDP-43 encephalopathy (LATE) has been identified. The diagnosis of LATE in living individuals is very complex due to the lack of universally applicable diagnostic criteria and reliable biomarkers. Nonetheless, its relevance is not diminished, as up to 20% of cases diagnosed with AD, especially in individuals over 80 years old, are actually due to LATE, and over 50% of AD cases have associated LATE copathology. This narrative review aims to address several aspects related to LATE, including identifying its typical clinical features, gaining a better understanding of its pathogenesis in pure cases and those associated with other neurodegenerative diseases, advancements in diagnostic tools for detecting LATE during life, its anatomopathological definition and staging, and potential advances in treatment. In the current era of potentially disease-modifying anti-amyloid treatments for AD, understanding both pure LATE and its co-pathology with AD is of particular relevance.

#1021 A phase 3 randomized controlled trial of ravulizumab in adult patients with IgA nephropathy

Abstract Background and Aims The pathogenesis of IgA nephropathy (IgAN) includes the deposition of immune complexes in the kidney and activation of the complement system. Complement components, including C5a (anaphylatoxin) and C5b-9 (membrane attack complex), are generated leading to mesangial inflammation and glomerular injury [1]. Ravulizumab, a humanized monoclonal antibody, is a long-acting complement C5 inhibitor that provides immediate, complete, and sustained inhibition of the terminal complement pathway, thereby targeting a key component of the pathophysiology of IgAN. A phase 2 study of ravulizumab (NCT04564339) demonstrated a rapid effect and significant reduction in proteinuria compared with placebo at week 26 (change from baseline in 24-hour urine protein to creatinine ratio [UPCR] –40.3% vs –10.9%), and treatment was well-tolerated [2]. This abstract describes the study design of the planned phase 3 trial of ravulizumab in adult patients with IgAN. Method This phase 3, randomized, double-blind, placebo-controlled trial (I CAN) will evaluate the efficacy and safety of ravulizumab (IV; weight-based dosing Q8W) in adults with IgAN. Eligibility criteria include a diagnosis of primary IgAN based on kidney biopsy at any point, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 at screening, and UPCR ≥0.75 g/g or urine protein ≥1.0 g/day (Table 1). The study consists of a 6-week screening period, followed by randomization (1:1) of participants to ravulizumab or placebo and a 2-year blinded treatment period (Fig. 1); all patients receive a stable and maximally tolerated dose of renin-angiotensin system inhibitor therapy. Approximately 450 patients will be randomized, stratified by proteinuria (<2 g/g vs ≥2 g/g), eGFR (<45 vs ≥45 mL/min/1.73 m2), and SGLT2i use (yes/no). The co-primary endpoints are change from baseline to week 34 in 24-hour UPCR evaluated on the log scale and the annualized total eGFR slope over 106 weeks. The sample size for the proteinuria endpoint of n = 204 will provide ∼90% power to detect a 35% relative treatment effect in UPCR at week 34 at a one-sided significance level of 0.005. The total sample size of n = 450 for the eGFR endpoint will provide ∼90% power to detect a difference in total annualized eGFR slope of 2.2 mL/min/1.73 m2 at week 106 at a one-sided significance level of 0.025. An open-label exploratory cohort (n = 20) with eGFR 20-29 mL/min/1.73 m2 and with kidney biopsy within 6 months of or during screening will be enrolled and analyzed separately from the main cohort. At completion of the blinded treatment period, all study participants will have the option to enter an open-label ravulizumab access period for up to 2 years. Results The co-primary endpoints are the change in 24-hour UPCR at week 34 and the annualized total eGFR slope over 106 wks. Secondary and exploratory endpoints include change in 24-hour UPCR at weeks 10, 26, 50, and 106, a composite kidney failure endpoint over 106 weeks, reduction in 24-hour UPCR ≥50% from baseline, time to UPCR <1 g/g and <0.3 g/g, and patient reported outcomes on fatigue, quality of life, and work-related productivity. Safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics will be evaluated. Conclusion Through immediate, complete, and sustained inhibition of C5, ravulizumab targets the pathophysiology of IgAN and has the potential to provide a disease modifying treatment option. This pivotal phase 3 study (I CAN) will evaluate the efficacy of ravulizumab in patients with IgAN who are at high risk of disease progression. The trial will evaluate effects on proteinuria and eGFR that may translate to long term kidney function preservation and provide a rapidly acting treatment option for patients living with IgAN.

In vivo human knee varus-valgus loading apparatus for analysis of MRI-based intratissue strain and relaxometry

The diagnosis of early-stage osteoarthritis remains as an unmet challenge in medicine and a roadblock to evaluating the efficacy of disease-modifying treatments. Recent studies demonstrate that unique patterns of intratissue cartilage deformation under cyclic loading can serve as potential biomarkers to detect early disease pathogenesis. However, a workflow to obtain deformation, strain maps, and quantitative MRI metrics due to the loading of articular cartilage in vivo has not been fully developed. In this study, we characterize and demonstrate an apparatus that is capable of applying a varus-valgus load to the human knee in vivo within an MRI environment to enable the measurement of cartilage structure and mechanical function. The apparatus was first tested in a lab environment, then the functionality and utility of the apparatus were examined during varus loading in a clinical 3T MRI system for human imaging. We found that the device enables quantitative MRI metrics for biomechanics and relaxometry data acquisition during joint loading leading to compression of the medial knee compartment. Integration with spiral DENSE MRI during cyclic loading provided time-dependent displacement and strain maps within the tibiofemoral cartilage. The results from these procedures demonstrate that the performance of this loading apparatus meets the design criteria and enables a simple and practical workflow for future studies of clinical cohorts, and the identification and validation of imaging-based biomechanical biomarkers.

#812 Phase 2b ORIGIN study open label extension with atacicept in patients with IgA nephropathy and persistent proteinuria: week 72 interim analysis

Abstract Background and Aims IgA nephropathy (IgAN), the most common primary glomerulonephritis and a significant contributor to ESKD worldwide, is characterized by elevated serum levels of galactose-deficient IgA1 (Gd-IgA1). The production of Gd-IgA1 and its autoantibodies is driven by both the B-cell Activating Factor (BAFF) and A PRoliferation-Inducing Ligand (APRIL) signaling pathways that stimulate maturation, differentiation, and effector function of B cells and plasma cells. Atacicept is a fusion protein targeting both BAFF and APRIL in clinical development for IgAN treatment. The Phase 2b ORIGIN study met the primary endpoint with statistically significant urine protein:creatinine ratio (UPCR) reduction at 24 weeks vs placebo. At 36 weeks, atacicept 150 mg achieved statistically significant and clinically meaningful UPCR reduction, eGFR stabilization, and Gd-IgA1 reduction vs placebo, with similar safety to placebo. This interim analysis reports 72-week results from the open-label extension period. Method The randomized, double-blind, placebo-controlled Phase 2b ORIGIN study included 116 participants with biopsy-proven IgAN, 24 h urine protein >0.75 g/day or UPCR >0.75 g/g, and eGFR ≥30 mL/min/1.73 m2 despite optimized renin–angiotensin system blockade. Participants were randomized to atacicept 150, 75, or 25 mg, vs placebo (2:2:1:2), self-administered by subcutaneous injection once weekly for up to 36 weeks. The double-blind randomized treatment period was followed by an open-label extension in which participants could receive atacicept 150 mg for up to 60 additional weeks, for a total of 96 weeks. For this interim analysis, changes from baseline in eGFR, natural log transformed UPCR, and Gd-IgA1 through 72 weeks were analyzed using a mixed-effects model for repeated measurements. Microscopic hematuria was evaluated on urine dipstick and participants with hematuria grade 1+ or higher at baseline were evaluated for resolution, defined as a decrease to negative/trace, at 72 weeks. Results Of 116 randomized participants in the double-blind period, 106 participants (91%) completed 72 weeks of treatment. At 72 weeks, eGFR total slope estimate was 0.0 mL/min/1.73m2/year and eGFR change from baseline was 0 mL/min/1.73m2 in all participants originally randomized to atacicept (all-atacicept group; n = 82). After switching to open-label atacicept 150 mg, the original placebo group showed eGFR stabilization with −3.2 mL/min/1.73m2 change from baseline at 72 weeks vs −4.9 mL/min/1.73m2 at 36 weeks (Figure 1). At 72 weeks, UPCR change from baseline was −45% in the all-atacicept group and the placebo switch group showed a −47% UPCR change from baseline at 72 weeks vs +3% at 36 weeks (Figure 2). Open-label atacicept 150 mg was also associated with rapid Gd-IgA1 reduction in the placebo switch group at 48 weeks that was sustained through 72 weeks. Hematuria resolution was observed at 72 weeks in 81% (35/43) of participants in the all-atacicept group and 59% (10/17) in the placebo switch group. Atacicept was generally well tolerated during the open-label extension, with a similar rate of infections compared to the double-blind period and one study drug-related serious adverse event. Conclusion At 72 weeks, treatment with atacicept 150 mg was associated with sustained eGFR stability and deepening UPCR reductions, as well as a reversal of the downward eGFR decline in the placebo switch group. Sustained reductions in hematuria were also observed. The open-label extension showed a favorable safety profile similar to the double-blind period. These results support atacicept 150 mg as a potential disease-modifying treatment for IgAN.

#456 Efficacy and safety of iptacopan in patients with primary IgA nephropathy: interim analysis results of the Phase 3 APPLAUSE-IgAN study

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis. An unmet need for targeted disease-modifying treatments addressing its pathophysiology remains. There is compelling evidence for involvement of the alternative complement pathway (AP) in IgAN. Iptacopan binds to Factor B and specifically inhibits the AP. The APPLAUSE-IgAN trial is evaluating the efficacy and safety of iptacopan vs placebo, on top of optimized supportive therapy, in patients with IgAN. Here we present the results of the pre-specified interim analysis (IA) with a focus on the results for key subgroups. Method APPLAUSE-IgAN (NCT04578834), a Phase 3, multicentre, randomised, double-blind, placebo-controlled trial, enrolled adults with biopsy-confirmed IgAN with proteinuria ≥1 g/g by urine−protein creatinine ratio from 24-hour urine collection (UPCR-24h) despite being on a stable dose of maximally tolerated renin-angiotensin-system inhibition (RASi) for 3 months, with or without other background therapy such as sodium-glucose transport protein 2 inhibition (SGLT2i). Patients were randomized 1:1 to iptacopan 200 mg or placebo twice daily for 24 months while remaining on stable supportive therapy. The primary objective of the prespecified IA was to demonstrate superiority of iptacopan vs placebo in reducing UPCR-24h at Month 9 (M9) in the main study population (estimated glomerular filtration rate [eGFR] ≥30 mL/min/1.73 m2 at baseline). Subgroup analyses included baseline age, sex, Asia vs non-Asia region, proteinuria, eGFR, and SGLT2i use. Efficacy analyses were performed on the first 250 patients (n = 125 each for iptacopan and placebo) who reached the M9 visit or discontinued from the study. Safety analyses included all patients of the main population who had received treatment by the time of the IA (iptacopan, n = 222; placebo, n = 221). Results Baseline demographics and disease characteristics were similar between the two arms (Table) and indicative of patients at high risk of IgAN disease progression. Iptacopan was superior to placebo in reducing proteinuria, with reduction in UPCR-24h at M9 relative to baseline of 38.3% (95% CI: 26.0%, 48.6%; 1-sided p < 0.0001) vs placebo (Figure). Subgroup analyses showed that treatment effect consistently favoured iptacopan regardless of baseline age, sex, Asia vs non-Asia region, UPCR-24h or eGFR levels, or SGLT2i use as part of the supportive care (Figure). Treatment-emergent adverse events (TEAEs) occurred in 138 (62.2%) iptacopan vs 153 (69.2%) placebo patients, with the majority being of mild to moderate severity. Treatment-emergent serious AEs were reported in 18 (8.1%) and 11 (5.0%) patients in the iptacopan and placebo arms, respectively. TEAEs leading to treatment discontinuation occurred in 6 patients (2.7%) in each arm. No deaths were reported. Iptacopan treatment did not lead to clinically relevant differences in total cholesterol, low-density lipoprotein cholesterol, and serum triglycerides compared with placebo. Conclusion APPLAUSE-IgAN, the first Phase 3 study confirming the relevance of the AP in IgAN, demonstrated superiority of iptacopan vs placebo, with a significant reduction in proteinuria at M9 (38.3%) that was consistent across key subgroups evaluated. Iptacopan was well tolerated with a favourable safety profile.

#123 Impact of atacicept on hematuria in IGA nephropathy: post-hoc analysis of the phase 2b ORIGIN study

Abstract Background and Aims Patients with IgA nephropathy (IgAN) and persistent hematuria during follow up have a greater decline in renal function than those with minimal or no hematuria, while hematuria resolution has been independently associated with less decline in renal function [1, 2]. Atacicept is a fusion protein targeting both BAFF and APRIL in clinical development for IgAN. The Phase 2b ORIGIN study met the primary endpoint with statistically significant urine protein:creatinine ratio (UPCR) reduction at 24 weeks for atacicept vs placebo. At 36 weeks, atacicept 150 mg achieved statistically significant and clinically meaningful UPCR reduction, eGFR stabilization, and robust reduction of galactose-deficient IgA1 vs placebo, with similar safety to placebo. This post-hoc analysis evaluates changes in hematuria during treatment with atacicept vs placebo over 36 weeks. Method The randomized, double-blind, placebo-controlled Phase 2b ORIGIN study included 116 participants with biopsy-proven IgAN, 24h urine protein >0.75 g/day or UPCR >0.75 g/g, and eGFR ≥30 mL/min/1.73 m2 despite optimized renin–angiotensin system blockade. Participants were randomized to atacicept 150, 75, or 25 mg vs placebo (2:2:1:2) self-administered by subcutaneous injection once weekly for up to 36 weeks. Microscopic hematuria was evaluated at weeks 2, 4, 12, 24, and 36 via urine dipstick at a centralized lab, and hematuria levels were graded negative/trace, 1+, 2+, or 3+. Hematuria improvement was defined as a decrease by ≥1 grade, and resolution was defined as a decrease to negative/trace. Results In the intent-to-treat population, 15 of 33 (45%) participants who received atacicept 150 mg and 19 of 34 (56%) who received placebo had hematuria (1+ or greater) at baseline. Of these, 87% (n = 13/15) on atacicept 150 mg had improved hematuria at 36 weeks vs 32% (n = 6/19) on placebo (p = 0.002), with 80% (n = 12/15) on atacicept 150 mg achieving resolution to negative/trace hematuria vs 5% (n = 1/19) on placebo (p < 0.0001) (Figure). The atacicept 150 mg group steadily improved to lower hematuria grades over 36 weeks, with improvement occurring as early as 4 weeks, while the placebo group had no improvement in hematuria over time. The majority of participants without hematuria at baseline maintained negative or trace levels at 36 weeks. Conclusion In a post-hoc analysis, atacicept treatment was associated with hematuria resolution at 36 weeks in a substantially greater percentage of participants as compared with placebo, with improvements seen as early as 4 weeks. These results add to the growing body of evidence supporting atacicept as a potential disease-modifying treatment for IgAN. Atacicept 150 mg is currently being evaluated in a global Phase 3 randomized placebo-controlled trial.

The Gut-Brain Axis in Parkinson's Disease.

Parkinson's disease (PD) involves both the central nervous system (CNS) and enteric nervous system (ENS), and their interaction is important for understanding both the clinical manifestations of the disease and the underlying disease pathophysiology. Although the neuroanatomical distribution of pathology strongly suggests that the ENS is involved in disease pathophysiology, there are significant gaps in knowledge about the underlying mechanisms. In this article, we review the clinical presentation and management of gastrointestinal dysfunction in PD. In addition, we discuss the current understanding of disease pathophysiology in the gut, including controversies about early involvement of the gut in disease pathogenesis. We also review current knowledge about gut α-synuclein and the microbiome, discuss experimental models of PD-linked gastrointestinal pathophysiology, and highlight areas for further research. Finally, we discuss opportunities to use the gut-brain axis for the development of biomarkers and disease-modifying treatments.

NEUROFILAMENTS AS A POTENTIAL BIOMARKER IN PATIENTS WITH MULTIPLE SCLEROSIS: A REVIEW OF LITERATURE

Background: Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system (CNS) characterized by demyelination, axonal damage and loss of neurons. Its growing incidence has determined the need for more intensive research towards effective models for managing disease progression and evaluation of treatment response. Finding clinically relevant biomarkers has been a significant challenge. Purpose: This review aims to summarize the findings from current relevant literature sources on neurofilaments as a potential biomarker of diagnostic and prognostic value in patients with MS. Results: Recently, neurofilaments have been identified as the most promising and informative biomarkers of axonal damage and loss. Neurofilament concentration demonstrates a strong association with the disease course, activity and progression, disability accumulation and response to disease-modifying treatment. A significant correlation with future relapse rates, symptom worsening and risk of conversion from clinically isolated syndrome (CIS) to definite MS has also been established. Several MS therapies have demonstrated a substantial reduction in neurofilament levels upon treatment initiation. Conclusion: The results available from real-world studies and clinical trials regarding neurofilaments as a reliable predictor and indicator of MS disease course are encouraging. They have consistently proven to be of utility if integrated into the diagnostic and therapeutic algorithm of MS patients. This review encompasses undeniable data confirming the considerable potential of neurofilaments for becoming the first globally verified biomarker for MS. The accessibility, safety, low cost and possibility for serial evaluation make the neurofilaments the perfect component to be implemented in routine clinical tests for MS.

Evaluation of the biodistribution and preliminary safety profile of a novel brain-targeted manganese dioxide-based nanotheranostic system for Alzheimer’s disease

A novel brain-targeted and reactive oxygen species-activatable manganese dioxide containing nanoparticle system functionalized with anti-amyloid-β antibody (named aAβ-BTRA-NC) developed by our group has shown great promise as a highly selective magnetic resonance imaging (MRI) contrast agent for early detection and multitargeted disease-modifying treatment of Alzheimer’s disease (AD). To further evaluate the suitability of the formulation for future clinical application, we investigated the safety, biodistribution, and pharmacokinetic profile of aAβ-BTRA-NC in a transgenic TgCRND8 mouse AD model, wild type (WT) littermate, and CD-1 mice. Dose-ascending studies demonstrated that aAβ-BTRA-NC was well-tolerated by the animals up to 300 μmol Mn/kg body weight [b.w.], 3 times the efficacious dose for early AD detection without apparent adverse effects; Histopathological, hematological, and biochemical analyses indicated that a single dose of aAβ-BTRA-NC did not cause any toxicity in major organs. Immunotoxicity data showed that aAβ-BTRA-NC was safer than commercially available gadolinium-based MRI contrast agents at an equivalent dose of 100 μmol/kg b.w. of metal ions. Intravenously administered aAβ-BTRA-NC was taken up by main organs with the order of liver, kidneys, intestines, spleen, followed by other organs, and cleared after one day to one week post injection. Pharmacokinetic analysis indicated that the plasma concentration profile of aAβ-BTRA-NC followed a 2-compartmental model with faster clearance in the AD mice than in the WT mice. The results suggest that aAβ-BTRA-NC exhibits a strong safety profile as a nanotheranostic agent which warrants more robust preclinical development for future clinical applications.

DNA Methylation in the Anti-Mullerian Hormone Gene and the Risk of Disease Activity in Multiple Sclerosis.

Multiple sclerosis (MS) has a complex pathobiology, with genetic and environmental factors being crucial players. Understanding the mechanisms underlying heterogeneity in disease activity is crucial for tailored treatment. We explored the impact of DNA methylation, a key mechanism in the genetics-environment interplay, on disease activity in MS. Peripheral immune methylome profiling using Illumina Infinium MethylationEPIC BeadChips was conducted on 249 untreated relapsing-remitting MS patients, sampled at the start of disease-modifying treatment (DMT). A differential methylation analysis compared patients with evidence of disease activity (EDA) to those with no evidence of disease activity (NEDA) over 2 years from DMT start. Utilizing causal inference testing (CIT) and Mendelian randomization (MR), we sought to elucidate the relationships between DNA methylation, gene expression, genetic variation, and disease activity. Four differentially methylated regions (DMRs) were identified between EDA and NEDA. Examining the influence of single nucleotide polymorphisms (SNPs), 923 variants were found to account for the observed differences in the 4 DMRs. Importantly, 3 out of the 923 SNPs, affecting DNA methylation in a DMR linked to the anti-Mullerian hormone (AMH) gene, were associated with disease activity risk in an independent cohort of 1,408 MS patients. CIT and MR demonstrated that DNA methylation in AMH acts as a mediator for the genetic risk of disease activity. This study uncovered a novel molecular pathway implicating the interaction between DNA methylation and genetic variation in the risk of disease activity in MS, emphasizing the role of sex hormones, particularly the AMH, in MS pathobiology. ANN NEUROL 2024;96:289-301.

Slovenian Memory Clinic Organization with the Introduction of Potential New Alzheimer's Disease Treatment.

Slovenia, situated in Central Europe with a population of 2.1 million, has an estimated 44,278 individuals with mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's dementia, rendering them potential candidates for disease-modifying treatment (DMT), such as lecanemab. We identified 114 potential candidates whose real-life expenses for diagnostic process surmount to more than €80,000. Treating all potential candidates nationwide would amount to €1.06 billion, surpassing Slovenia's entire annual medication expenditure for 2022 (€743 million). The introduction of DMTs and the associated logistics, along with potential complications, will significantly change societal, professional, and patient approach to treatment of Alzheimer's disease.

Delayed initiation of disease modifying therapy increases relapse frequency and motor disability in pediatric onset multiple sclerosis

ObjectiveTo evaluate association between time to initiation of disease modifying treatment (DMT) and outcomes in pediatric-onset Multiple Sclerosis (POMS). MethodsA retrospective analysis of children with POMS from two tertiary referral pediatric Neuroimmunology clinics. Outcome measures comprised annualized relapse rate (ARR), MRI lesion burden (T1, T2-FLAIR, and post-GAD contrast sequences), EDSS, and 25-ft walk duration at the latest follow-up visit. Univariate and multivariate analysis using linear and logistic regression models were used to assess associations between patient characteristics and outcomes. ResultsIn total, 68 patients were reviewed. More than half of patients were female (62 %) and 32 (47 %) were Hispanic/LatinX. Median age at diagnosis was 14.2 years (IQR: 11.0–16.5), and median duration from diagnosis to the latest follow-up was 2.5 years (IQR: 1.6–4.6). Sensory (29.4 %), brainstem (23.5 %), and pyramidal (19.1 %) symptoms were most common. Interferon beta (32.4 %), dimethyl fumarate (27.9 %) and rituximab (26.5 %) were the most frequently used first-line DMT. Patients had a median ARR of 0.5 (IQR: 0.08–0.84), and EDSS score of 1.0 (IQR: 0.0–2.0) at the most recent follow-up. Delayed DMT initiation correlated with higher ARR (R = 0.38, p = 0.0016) and longer 25-ft walk duration (R = 0.34, p = 0.0077). In multivariate analysis, delayed DMT remained a significant predictor of higher ARR (p = 0.002) and longer 25-ft walk duration (p = 0.047). Delayed DMT initiation and use of low/moderate efficacy DMT predicted GAD enhancing lesions at the latest follow-up (p = 0.004 and 0.019 respectively). ConclusionDelayed DMT initiation in POMS is linked to unfavorable outcomes, including higher ARR and longer 25-ft walk duration.

Efficacy of long-term albumin therapy in the treatment of decompensated cirrhosis.

Decompensated liver cirrhosis has a poor prognosis, with a median overall survival of two to four years, which is worse than for many oncological disorders. These patients are highly susceptible to infections due to increased systemic inflammation leading to kidney failure and death. The aim was to study the efficacy of albumin in reducing episodes of decompensation, preventing bacterial infection, kidney dysfunction and mortality. Study involved patients with Child B or C cirrhosis with an albumin level below 3.0g/dL, who were administered 20% human albumin weekly with standard medical treatment (SMT) for threemonths or till serum albumin levels were 4.0g/dL (whichever is earlier) and compared with age and sex-matched controls who received only SMT. The primary end-point was six-month mortality and the secondary end-points were reduction in infections, kidney dysfunction, ascites recurrence, hepatic encephalopathy (HE), gastrointestinal (GI) bleed and complications of cirrhosis. From September 2021 to January 2023, 88 cases and 86 controls were taken and followed up for sixmonths. Overall, six-month survival was not statistically significant between groups (95.1% vs. 91.9%; p = 0·330). The incidence of recurrence of ascites (34.09% vs. 59.3%, p < 0.001), kidney dysfunction (6.8% vs. 24.4%, p < 0.001), HE (15.9% vs, 37.2%, p = 0.015), spontaneous bacterial peritonitis(SBP) (3.4% vs 17.4%, p = 0.002) and non-SBP infections (7.9% vs. 18.6%, p = 0.038) were significantly less in cases as compared with controls; however, GI bleed (14.8% vs. 17.4%, p = 0.632) was not statistically significant. Long-term human albumin acts as a disease-modifying treatment in patients with decompensated cirrhosis.

Targeted Therapy of Multiple Sclerosis: A Case for Antigen-Specific Tregs.

Multiple sclerosis is an autoinflammatory condition that results in damage to myelinated neurons in affected patients. While disease-modifying treatments have been successful in slowing the progression of relapsing-remitting disease, most patients still progress to secondary progressive disease that is largely unresponsive to disease-modifying treatments. Similarly, there is currently no effective treatment for patients with primary progressive MS. Innate and adaptive immune cells in the CNS play a critical role in initiating an autoimmune attack and in maintaining the chronic inflammation that drives disease progression. In this review, we will focus on recent insights into the role of T cells with regulatory function in suppressing the progression of MS, and, more importantly, in promoting the remyelination and repair of MS lesions in the CNS. We will discuss the exciting potential to genetically reprogram regulatory T cells to achieve immune suppression and enhance repair locally at sites of tissue damage, while retaining a fully competent immune system outside the CNS. In the future, reprogramed regulatory T cells with defined specificity and function may provide life medicines that can persist in patients and achieve lasting disease suppression after one cycle of treatment.

Medical Costs and Caregiver Burden of Delivering Disease-Modifying Alzheimer’s Treatments with Different Duration and Route of Administration

BackgroundMultiple disease modifying treatment for Alzheimer’s disease are currently in clinical development or have been recently approved for use. They have vastly different treatment properties but so far, little work has been done to quantify the impact of treatment properties on the treatment’s value in terms of medical and social care costs and caregiver burden.ObjectivesThis study aims to analyze how the mode of treatment administration, treatment frequency and duration, and monitoring requirements affect the value of disease modifying treatments. In order to isolate these effects, we compare five hypothetical disease modifying treatments with equal efficacy and safety: (1) chronic bi-weekly intravenous infusion, (2) chronic four-weekly intravenous infusion, (3) 52 weeks fixed duration four-weekly intravenous infusion, (4) chronic subcutaneous injections, and (5) chronic oral prescription on their direct medical costs, caregiver burden, and preservation of treatment value.DesignSurvey of Alzheimer’s disease treatment clinics and retrospective data analysis.SettingUnited States.MeasurementsDirect medical cost and caregiver burden of treatment administration and monitoring compared to gross treatment benefit.ResultsChronic bi-weekly infusion treatment had the highest direct medical cost ($45,208) and caregiver burden ($6,095), reducing the treatment value by 44%, while oral treatment with the lowest direct medical cost ($1,983) and caregiver burden ($457) reduced the treatment value by only 2%. Substantial caregiver burden was reported from the survey, with a reported average of 2.3 hours for an office visit and infusion, 44 minutes of round-trip travel time, and 78% of patients being accompanied by a caregiver for treatment.ConclusionBurden of chronic intravenous treatments exceed the gross medical and social care cost savings and value of caregiver benefit. The results suggest the need for less complex treatments that require fewer clinic visits to preserve the economic value of disease modifying treatments.

Acupuncture for the treatment of the pain-fatigue-sleep disturbance-numbness/tingling symptom cluster in breast cancer survivors: a feasibility trial

PurposeBreast cancer survivors following disease-modifying treatment frequently experience multiple-concurrent symptoms (Jansana et al. in Int J Cancer 149(10):1755 1767, 2021), negatively impacting their quality of life and increasing the risk of polypharmacy (Alwhaibi et al. in J Oncol Pharm Pract 26(5):1052 1059, 2020). This study evaluates the feasibility and acceptability of acupuncture for the management of the pain-fatigue-sleep disturbance-numbness/tingling symptom cluster in breast cancer survivors, and investigates relationships between the symptom cluster and Traditional Chinese Medicine (TCM) syndrome diagnosis.MethodsThis was a single-arm, pre-test/post-test feasibility trial conducted at Chris O’Brien Lifehouse Hospital, Australia. Breast cancer survivors who completed treatment and experienced clinically significant levels of two or more symptoms (pain, fatigue, sleep disturbance, numbness/tingling) were eligible to participate in the individualized, pragmatic 6-week acupuncture intervention. The primary outcome was feasibility and acceptability. Effectiveness was explored using a symptom cluster mean score.ResultsTwenty women enrolled in the study over an 11-week period and 90% completed the study. Most women agreed or completely agreed that acupuncture was feasible (85%), acceptable (90%), and appropriate (90%). Both mean and composite symptom cluster scores were significantly reduced (p < 0.001), as were individual symptom scores in fatigue (p < 0.001), sleep disturbance (p = 0.04), and numbness/tingling (p = 0.01). TCM syndromes most closely associated with this symptom cluster were Spleen qi deficiency and Heart fire. No adverse events were reported.ConclusionThis study demonstrated that acupuncture was safe and feasible, justifying a powered randomized control trial. Preliminary findings suggest beneficial effects of acupuncture for the management of the pain-fatigue-sleep disturbance-numbness/tingling symptom cluster for women with breast cancer. TCM syndromes identified in this trial may be used to guide acupuncture treatment protocols.Clinical trial registration: This trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12622000590763) on 21 April 2022.

Neuronal Circuit Dysfunction in Amyotrophic Lateral Sclerosis.

The primary neural circuit affected in Amyotrophic Lateral Sclerosis (ALS) patients is the corticospinal motor circuit, originating in upper motor neurons (UMNs) in the cerebral motor cortex which descend to synapse with the lower motor neurons (LMNs) in the spinal cord to ultimately innervate the skeletal muscle. Perturbation of these neural circuits and consequent loss of both UMNs and LMNs, leading to muscle wastage and impaired movement, is the key pathophysiology observed. Despite decades of research, we are still lacking in ALS disease-modifying treatments. In this review, we document the current research from patient studies, rodent models, and human stem cell models in understanding the mechanisms of corticomotor circuit dysfunction and its implication in ALS. We summarize the current knowledge about cortical UMN dysfunction and degeneration, altered excitability in LMNs, neuromuscular junction degeneration, and the non-cell autonomous role of glial cells in motor circuit dysfunction in relation to ALS. We further highlight the advances in human stem cell technology to model the complex neural circuitry and how these can aid in future studies to better understand the mechanisms of neural circuit dysfunction underpinning ALS.

Changes in the diagnostic trajectory of transthyretin cardiac amyloidosis over six years.

Awareness of transthyretin amyloid cardiomyopathy (ATTR-CM) has increased over the years due to diagnostic and therapeutic developments. Timely initiation of novel disease-modifying treatments improves both morbidity and mortality, which underlines the necessity for a prompt diagnosis. Nevertheless, early diagnosis of ATTR-CM remains challenging. This is a retrospective observational cohort study of patients diagnosed with ATTR-CM. Between 2016 and 2023, 87 patients were diagnosed with cardiac amyloidosis of which 65 (75%) patients with ATTR-CM and 22 (25%) patients with light chain amyloidosis. This study included 65 ATTR-CM patients (mean age 77 ± 7years; 86% male) of whom 59 (91%) with wild-type ATTR-CM (ATTRwt) and six (9%) with variant ATTR-CM. We observed a surge in ATTR-CM diagnoses from 3 patients/year (2016-2020) to 16 patients/year (2021-2023), driven by ATTRwt. Nevertheless, the interval between the onset of heart failure symptoms and ATTR-CM diagnosis has not changed significantly (2016-2020 27.3months [18.6-62.4]; 2021-2023 30.0months [8.6-57.2]; p = 0.546), driven by time to referral. Red flags for ATTR-CM preceded diagnosis by several years: left ventricular hypertrophy (79%, 5.8years [3.3-7.0]) and carpal tunnel syndrome (49%, 6.8years [2.3-12.1]). Despite the presence of typical red flags, symptom-to-diagnosis duration has remained similar driven by time to referral. Improved recognition of red flags for ATTR-CM could reduce the time to diagnosis and improve overall recognition.