Disease-modifying Therapies Research Articles

Genetic Biomarkers in Heart Failure: From Gene Panels to Polygenic Risk Scores.

This review aims to provide a comprehensive overview of the current understanding of genetic markers associated with heart failure (HF) and its underlying causative diseases, such as cardiomyopathies. It highlights the relevance of genetic biomarkers in diagnosing HF, predicting prognosis, potentially identifying its preclinical stages and identifying targets to enable the implementation of individualized medicine approaches. The prevalence of HF is increasing due to an aging population but with greater access to disease-modifying therapies. Advanced diagnostic tools such as cardiac magnetic resonance, nuclear imaging, and AI-enabled diagnostic testing are now being utilized to further characterize HF patients. Additionally, the importance of genetic testing in HF diagnosis and management is increasingly being recognized. Genetic biomarkers, including single nucleotide polymorphisms (SNPs) and rare genetic variants, are emerging as crucial tools for diagnosing HF substrates, determining prognosis and increasingly directing therapy. These genetic insights are key to optimizing HF management and delivering personalized treatment tailored to individual patients. HF is a complex syndrome affecting millions globally, characterized by high mortality and significant economic burden. Understanding the underlying etiologies of HF is essential for improving management and clinical outcomes. Recent advances highlight the use of multimodal assessments, including AI-enabled diagnostics and genetic testing, to better characterize and manage HF. Genetic biomarkers are particularly promising in identifying preclinical HF stages and providing personalized treatment options. The genetic contribution to HF is heterogeneous, with both monogenic and polygenic bases playing a role. These developments underscore the shift towards personalized medicine in HF management.

The spectrum of behavioral disorders in amyotrophic lateral sclerosis: current view.

Behavioral disorders, with an average prevalence of 30-60% are important non-motor symptoms in amyotrophic lateral sclerosis (ALS) that have a negative impact on prognosis, management and quality of life, yet the underlying neurobiology is poorly understood. Among people with ALS, apathy, fatigue, anxiety, irritability and other behavioral symptoms are the most prominent, although less frequent than cognitive impairment. The present review explores the current understanding of behavioral changes in ALS with particular emphasis on our current knowledge about their structural and functional brain correlates, substantiating a multisystem degeneration with particular dysfunction of frontal-subcortical circuits and dysfunction of fronto-striatal, frontotemporal and other essential brain systems. The natural history of behavioral dysfunctions in ALS and their relationship to frontotemporal lobe degeneration (FTLD) are not fully understood, although they form a clinical continuum, suggesting a differential vulnerability of non-motor brain networks, ALS being considered a brain network disorder. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of behavioral impairment in ALS. Treatment of both ALS and co-morbid behavioral disorders is a multidisciplinary task, but whereas no causal or disease-modifying therapies for ALS are available, symptomatic treatment of a variety of behavioral symptoms plays a pivotal role in patient care, although the management of behavioral symptoms in clinical care still remains limited.

Circulatory Indicators of Lipid Peroxidation, the Driver of Ferroptosis, Reflect Differences between Relapsing–Remitting and Progressive Multiple Sclerosis

Ferroptosis, a lipid peroxidation- and iron-mediated type of regulated cell death, relates to both neuroinflammation, which is common in relapsing-remitting multiple sclerosis (RRMS), and neurodegeneration, which is prevalent in progressive (P)MS. Currently, findings related to the molecular markers proposed in this paper in patients are scarce. We analyzed circulatory molecular indicators of the main ferroptosis-related processes, comprising lipid peroxidation (malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and hexanoyl–lysine adduct (HEL)), glutathione-related antioxidant defense (total glutathione (reduced (GSH) and oxidized (GSSG)) and glutathione peroxidase 4 (GPX4)), and iron metabolism (iron, transferrin and ferritin) to estimate their contributions to the clinical manifestation of MS and differences between RRMS and PMS disease course. In 153 patients with RRMS and 69 with PMS, plasma/serum lipid peroxidation indicators and glutathione were quantified using ELISA and colorimetric reactions, respectively. Iron serum concentrations were determined using spectrophotometry, and transferrin and ferritin were determined using immunoturbidimetry. Compared to those with RRMS, patients with PMS had decreased 4-HNE (median, 1368.42 vs. 1580.17 pg/mL; p = 0.03). Interactive effects of MS course (RRMS/PMS) and disease-modifying therapy status on MDA (p = 0.009) and HEL (p = 0.02) levels were detected. In addition, the interaction of disease course and self-reported fatigue revealed significant impacts on 4-HNE levels (p = 0.01) and the GSH/GSSG ratio (p = 0.04). The results also show an association of MS course (p = 0.03) and EDSS (p = 0.04) with GSH levels. No significant changes were observed in the serum concentrations of iron metabolism indicators between the two patient groups (p > 0.05). We suggest circulatory 4-HNE as an important parameter related to differences between RRMS and PMS. Significant interactions of MS course and other clinically relevant parameters with changes in redox processes associated with ferroptosis support the further investigation of MS with a larger sample while taking into account both circulatory and central nervous system estimation.

Correlation between MRI utilization and therapy switches in disease-modifying treatments for multiple sclerosis.

Studies measuring the role of magnetic resonance imaging (MRI) in therapeutic decision-making are rare in people with multiple sclerosis (pwMS). This study aimed to measure the association between MRI utilization and disease-modifying therapy (DMT) switches in pwMS. This retrospective cohort study identified pwMS in 2018 from a de-identified national claims database. PwMS who received MRI in 2018 were compared to pwMS not receiving MRI in 2018. PwMS were observed for six months to assess the incidence of DMT switches. The study sample consisted of 11,972 pwMS. 3,931 (32.8%) pwMS received at least one MRI in 2018. Overall, MRI utilization increased the odds of switching DMT (OR = 1.49, 1.79, and 3.01 for 1, 2, and ≥ 3 CNS locations imaged). For those on injectable or platform DMT, any MRI utilization increased the odds of switching DMT (OR = 1.54, 2.00, and 3.48 for 1, 2, and ≥ 3 locations imaged). For those on oral DMT, only receiving MRI of 2 or ≥ 3 locations increased the odds of a DMT switch (OR = 1.36, 1.89, and 2.40 for 1, 2, and ≥ 3 locations). Finally, for pwMS on infusible therapies, there was little evidence that MRI changed the odds of a DMT switch. Among pwMS on injectable or oral DMT, imaging more CNS locations increased the odds of switching DMT after adjusting for age and relapse incidence. For pwMS on high-efficacy infusible DMTs, MRI did not change the odds of switching DMT but remains essential for safety monitoring.

Allele-specific silencing of a dominant SETX mutation in familial amyotrophic lateral sclerosis type 4.

Amyotrophic lateral sclerosis 4 (ALS4) is an autosomal dominant motor neuron disease that is molecularly characterized by reduced R-loop levels and caused by pathogenic variants in senataxin (SETX). SETX encodes an RNA/DNA helicase that resolves three-stranded nucleic acid structures called R-loops. Currently, there are no disease-modifying therapies available for ALS4. Given that SETX is haplosufficient, removing the product of the mutated allele presents a potential therapeutic strategy. We designed a series of siRNAs to selectively target the RNA transcript from the ALS4 allele containing the c.1166T>C mutation (p.Leu389Ser). Transfection of HEK293 cells with siRNA and plasmids encoding either wild-type or mutant (Leu389Ser) epitope tagged SETX revealed that three siRNAs specifically reduced mutant SETX protein levels without affecting the wild-type SETX protein. In ALS4 primary fibroblasts, siRNA treatment silenced the endogenous mutant SETX allele, while sparing the wild-type allele, and restored R-loop levels in patient cells. Our findings demonstrate that mutant SETX, differing from wild-type by a single nucleotide, can be effectively and specifically silenced by RNA interference, highlighting the potential of allele-specific siRNA as a therapeutic approach for ALS4.

Feasibility and assessment of self-reported dietary recalls among newly diagnosed multiple sclerosis: a quasi-experimental pilot study.

Individuals who are newly diagnosed with clinically isolated syndrome (CIS) or relapsing-remitting multiple sclerosis (RRMS) may choose not to undergo disease-modifying therapies (DMTs) due to concerns about expenses or potential adverse effects. Thus, many individuals will opt for alternative therapies, such as dietary modifications. Among these dietary approaches, the modified Paleolithic elimination diet has shown promise for improving MS-related symptoms; however, restriction of certain food groups can lead to inadequate intake of nutrients. Three-day self-reported 24-h dietary recalls using the Automated Self-Administered 24-h (ASA24) Dietary Assessment Tool were assessed during a 12-month quasi-experimental (i.e., non-randomized) trial among individuals who either voluntarily declined DMTs and received health behavior (HB) intervention, (n = 29) or included DMTs and opted for the standard of care (SOC; n = 15). Participants in the HB group received a multimodal intervention that included dietary modifications, a walking program, and breathing exercises. Usual intake of each micronutrient was estimated and then evaluated with the estimated average requirement (EAR)-cut point method. At 12 months, >80% of both HB and SOC groups completed 3 days of the self-reported 24-h recalls, indicating the potential feasibility of ASA24. From baseline to 12 months, the HB group had a decreased mean ratio in total grains (0.64; 95% CI 0.43-0.93; p = 0.02) and added sugars (0.52; 95% CI 0.35-0.75; p ≤ 0.001), and an increased mean ratio intake of cured meats (1.74; 95% CI 1.05-2.90; p = 0.04); whereas, the SOC group had a decreased mean ratio intake for beef, veal, pork, lamb, and game meat (0.60; 95% CI 0.40-0.90; p = 0.01). At baseline, both groups had high proportions with inadequate intake of vitamin E and calcium. The SOC group also had a high proportion with inadequate intake of vitamin D. By 12-months, the HB group exhibited severe proportions of nutrient inadequacies (>20% of the group) for vitamin D (43.5%), vitamin E (29.1%), calcium (69.9%), and copper (27.8%). The SOC group, following their own diet, had inadequacies for all the same micronutrients, except for copper, as the HB group. The SOC group also had additional inadequacies: vitamin A (21.3%), thiamin (26.3%), riboflavin (24.2%), folate (24.8%), vitamin B12 (27.8%), and zinc (28.2%). Compared to the usual diet, adhering to the modified Paleolithic elimination diet, as a component of a 12-month multimodal intervention, may lead to reduced consumption of specific food groups, such as added sugars, as well as decreased risk of severe proportions of inadequacy for certain nutrients. The utilization of the ASA24 for acquiring dietary recalls from participants with MS may be feasible for future studies. clinicaltrials.gov identifier NCT04009005.

Alzheimer's Disease: Exploring the Landscape of Cognitive Decline.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. The pathology of AD is marked by the accumulation of amyloid beta plaques and tau protein tangles in the brain, along with neuroinflammation and synaptic dysfunction. Genetic factors, such as mutations in APP, PSEN1, and PSEN2 genes, as well as the APOE ε4 allele, contribute to increased risk of acquiring AD. Currently available treatments provide symptomatic relief but do not halt disease progression. Research efforts are focused on developing disease-modifying therapies that target the underlying pathological mechanisms of AD. Advances in identification and validation of reliable biomarkers for AD hold great promise for enhancing early diagnosis, monitoring disease progression, and assessing treatment response in clinical practice in effort to alleviate the burden of this devastating disease. In this paper, we analyze data from the CAS Content Collection to summarize the research progress in Alzheimer's disease. We examine the publication landscape in effort to provide insights into current knowledge advances and developments. We also review the most discussed and emerging concepts and assess the strategies to combat the disease. We explore the genetic risk factors, pharmacological targets, and comorbid diseases. Finally, we inspect clinical applications of products against AD with their development pipelines and efforts for drug repurposing. The objective of this review is to provide a broad overview of the evolving landscape of current knowledge regarding AD, to outline challenges, and to evaluate growth opportunities to further efforts in combating the disease.

Social determinants of health affect disease severity among preschool children with sickle cell disease

AbstractIndividuals with sickle cell disease (SCD) face the burden of managing a lifelong chronic illness, increasing vulnerability to social determinants of health (SDoH). However, how SDoH contributes to health disparities is understudied. We hypothesized that preschool children with SCD living in poor neighborhoods with higher socio-economic distress would experience increased acute care utilization (ACU; described as emergency department visits plus hospitalizations) despite disease-modifying therapy. Participants' home addresses (aged 0-6 years) were mapped using census tract environmental data from the US Department of Agriculture Food Access Research Atlas. In multivariable analyses controlled for sickle genotype and disease-modifying therapies (hydroxyurea and chronic transfusion), SDoH indicators, that is, limited access to food, lack of vehicle, low income, and inadequate education, were associated with higher ACU. Living in households with children >1 mile from a supermarket was associated with more hospitalizations (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.13-1.85) and ACU (OR, 1.37; 95% CI, 1.06-1.80) among children with SCD (aged <6 years). In households with at least 1 bachelor's degree, children with SCD experienced less ACU (OR, 0.67; 95% CI, 0.50-0.93) and hospitalizations (OR, 0.67; 95% CI, 0.49-0.92). Preschool children with SCD with limited access to food and transportation are at a higher risk of acute complications despite receiving free evidence-based therapy and social support. The family education level may have a protective effect. Although SDoH in crowded households and health care maintenance visits were not a focus of this study, future research should consider these factors. Understanding the SCD and SDoH association is crucial for directing resources to improve affected children's health.

Role of Medicinal Plants in the Management of Multiple Sclerosis.

There is a rapid spread of Multiple Sclerosis disorder across the globe, around 2.8 million cases of Multiple Sclerosis in the world. Multiple Sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by demyelination, neuroinflammation, and a wide spectrum of clinical manifestations. Many drugs have been tested on MS patients but there is no effective treatment for MS till now. So to inhibit the symptoms caused by MS we performed a study in which we identified various naturally occurring materials with neuroprotective effects on the body that can treat Multiple Sclerosis. The therapeutic strategies portion of the paper reviews the array of disease-modifying therapies currently available for MS management. This paper evaluated their mechanisms of action, efficacy, and safety profiles. It also addressed emerging treatment paradigms by using different naturally occurring materials, including personalized medicine approaches and novel therapies in development. This paper provides a comprehensive overview of the current state of knowledge regarding MS, focusing on its pathogenesis, diagnostic approaches, and therapeutic strategies.

Impacts on study design when implementing digital measures in Parkinson's disease-modifying therapy trials.

Parkinson's Disease affects over 8.5 million people and there are currently no medications approved to treat underlying disease. Clinical trials for disease modifying therapies (DMT) are hampered by a lack of sufficiently sensitive measures to detect treatment effect. Reliable digital assessments of motor function allow for frequent at-home measurements that may be able to sensitively detect disease progression. Here, we estimate the test-retest reliability of a suite of at-home motor measures derived from raw triaxial accelerometry data collected from 44 participants (21 with confirmed PD) and use the estimates to simulate digital measures in DMT trials. We consider three schedules of assessments and fit linear mixed models to the simulated data to determine whether a treatment effect can be detected. We find at-home measures vary in reliability; many have ICCs as high as or higher than MDS-UPDRS part III total score. Compared with quarterly in-clinic assessments, frequent at-home measures reduce the sample size needed to detect a 30% reduction in disease progression from over 300 per study arm to 150 or less than 100 for bursts and evenly spaced at-home assessments, respectively. The results regarding superiority of at-home assessments for detecting change over time are robust to relaxing assumptions regarding the responsiveness to disease progression and variability in progression rates. Overall, at-home measures have a favorable reliability profile for sensitive detection of treatment effects in DMT trials. Future work is needed to better understand the causes of variability in PD progression and identify the most appropriate statistical methods for effect detection.

Relapse-Associated and Relapse-Independent Contribution to Overall Expanded Disability Status Scale Progression in Multiple Sclerosis Patients Diagnosed in Different Eras.

The introduction of disease-modifying therapies for multiple sclerosis (MS) has led to a deceleration of disease course over the years. Although decreased relapse rate constitutes a factor, the role of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) in MS course deceleration is still unclear. We retrospectively examined long-term Expanded Disability Status Scale (EDSS) progression in patients referred to the MS Center of Montichiari (Italy) and diagnosed with relapsing-remitting MS from 1980 to 2022. To isolate PIRA, we deducted all EDSS changes associated with relapses from overall EDSS change. We compared the relative contribution of PIRA and RAW to EDSS progression in patients diagnosed in different periods using mixed-effects models. A total of 1,405 patients were included in the study, of whom 231 were diagnosed in 1980-1996 (pre-treatment era), 577 in 1997-2008 (injectable disease-modifying therapy era), and 597 after 2008 (oral drugs, monoclonal antibodies, and anti-CD20 era). Across ages, both PIRA and RAW were reduced in patients diagnosed in more recent periods as compared with earlier periods. The average contribution of PIRA to overall EDSS progression was already predominant in patients diagnosed in 1980-1996 (78%) and in 1997-2008 (76%), but it was significantly increased (p = 0.0009) in patients diagnosed in later years (87%). The deceleration of MS course observed throughout the years is determined not only by fewer RAW events, but also by a reduction in PIRA. However, the shift toward a mostly relapse-independent progression highlights the importance of evaluating new therapies based on their effect on PIRA. ANN NEUROL 2024.

A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis.

Myeloproliferative neoplasms are stem cell-driven cancers associated with a large burden of morbidity and mortality. Most patients present with early-stage disease, but a substantial proportion progress to myelofibrosis or secondary leukemia, advanced cancers with a poor prognosis and high symptom burden. Currently, it remains difficult to predict progression, and therapies that reliably prevent or reverse fibrosis are lacking. A major bottleneck to the discovery of disease-modifying therapies has been an incomplete understanding of the interplay between perturbed cellular and molecular states. Several cell types have individually been implicated, but a comprehensive analysis of myelofibrotic bone marrow is lacking. We therefore mapped the cross-talk between bone marrow cell types in myelofibrotic bone marrow. We found that inflammation and fibrosis are orchestrated by a "quartet" of immune and stromal cell lineages, with basophils and mast cells creating a TNF signaling hub, communicating with megakaryocytes, mesenchymal stromal cells, and proinflammatory fibroblasts. We identified the β-galactoside-binding protein galectin-1 as a biomarker of progression to myelofibrosis and poor survival in multiple patient cohorts and as a promising therapeutic target, with reduced myeloproliferation and fibrosis in vitro and in vivo and improved survival after galectin-1 inhibition. In human bone marrow organoids, TNF increased galectin-1 expression, suggesting a feedback loop wherein the proinflammatory myeloproliferative neoplasm clone creates a self-reinforcing niche, fueling progression to advanced disease. This study provides a resource for studying hematopoietic cell-niche interactions, with relevance for cancer-associated inflammation and disorders of tissue fibrosis.

Passive Anti-amyloid Beta Monoclonal Antibodies: Lessons Learned over Past 20 Years.

Alzheimer's disease (AD) is a neurodegenerative disorder that significantly impairs cognitive and functional abilities, placing a substantial burden on both patients and caregivers. Current symptomatic treatments fail to halt the progression of AD, highlighting the urgent need for more effective disease-modifying therapies (DMTs). DMTs under development are classified as either passive or active on the basis of their mechanisms of eliciting an immune response. While this review will touch on active immunotherapies, we primarily focus on anti-amyloid beta monoclonal antibodies (mAbs), a form of passive immunotherapy, discussing their multifaceted role in AD treatment and the critical factors influencing their therapeutic efficacy. With two mAbs now approved and prescribed in the clinical setting, it is crucial to reflect on the lessons learned from trials of earlier mAbs that have shaped their development and contributed to their current success. These insights can then guide the creation of even more effective mAbs, ultimately enhancing therapeutic outcomes for patients with AD while minimizing adverse events.

Oral State and Salivary Cortisol in Multiple Sclerosis Patients.

Background: MS patients experience gradual and progressive functional limitation, bulbar symptoms, cognitive dysfunction, and psychiatric disorders that can impinge on oral status. This study aimed to investigate the oral state, oral hygiene habits, and salivary cortisol levels in patients with relapsing-remitting multiple sclerosis (RRMS) compared to healthy controls. It also evaluated systemic parameters: disease duration, type of Disease Modifying Therapy (DMT), disability score, professional activity, and smoking in the study group. Methods: This study included 101 patients (71 women and 30 men, aged 16-71 years) and 51 healthy volunteers (36 women and 15 men, aged 28-82 years). The oral examination assessed the number of teeth, type and number of dental fillings and prosthetic restoration, oral hygiene state, and salivary cortisol. Results: It was found that MS patients had significantly more professional activity, swallowing problems, pronunciation issues, dry mouth, and taste disturbances than the control group. They brushed their teeth twice daily significantly less often. The API was higher, while the SBI was lower in MS patients. Disease duration positively correlated with age and number of missing teeth. The Expanded Disability Status Scale positively correlated with age, disease duration, number of missing teeth, number of composite fillings, and right and left-hand Nine Hole Peg test scores, and negatively correlated with the Sulcus Bleeding Index. Salivary cortisol levels did not differ between groups and correlated only with the disability scale. Conclusions: MS patients require ongoing dental care and preventive measures to manage both general and oral health symptoms effectively.

Brain volume loss in relapsing multiple sclerosis: indirect treatment comparisons of available disease-modifying therapies.

Brain volume loss (BVL) has been identified as a predictor of disability progression in relapsing multiple sclerosis (RMS). As many available disease-modifying treatments (DMTs) have shown an effect on slowing BVL, this is becoming an emerging clinical endpoint in RMS clinical trials. In this study, a systematic literature review was conducted to identify BVL results from randomized controlled trials of DMTs in RMS. Indirect treatment comparisons (ITCs) were conducted to estimate the relative efficacy of DMTs on BVL using two approaches: a model-based meta-analysis (MBMA) with adjustment for measurement timepoint and DMT dosage, and a network meta-analysis (NMA). In the MBMA, DMTs associated with significantly reduced BVL versus placebo at two years included fingolimod (mean difference [MD] = 0.25; 95% confidence interval [CI] = 0.15 - 0.36), ozanimod (MD = 0.26; 95% CI = 0.12 - 0.41), teriflunomide (MD = 0.38; 95% CI = 0.20 - 0.55), alemtuzumab (MD = 0.38; 95% CI = 0.10 - 0.67) and ponesimod (MD = 0.71; 95% CI = 0.48 - 0.95), whereas interferons and natalizumab performed the most poorly. The results of NMA analysis were generally comparable with those of the MBMA. Limitations of these analyses included the potential for confounding due to pseudoatrophy, and a lack of long-term clinical data for BVL. Our findings suggest that important differences in BVL may exist between DMTs. Continued investigation of BVL in studies of RMS is important to complement traditional disability endpoints, and to foster a better understanding of the mechanisms by which DMTs can slow BVL.

Clarifying the association of CSF Aβ, tau, BACE1, and neurogranin with AT(N) stages in Alzheimer disease.

Current AT(N) stratification for Alzheimer's disease (AD) accounts for complex combinations of amyloid (A), tau proteinopathy (T) and neurodegeneration (N) signatures. Understanding the transition between these different stages is a major challenge, especially in view of the recent development of disease modifying therapy. This is an observational study, CSF levels of Tau, pTau181, pTau217, Aβ38/40/42, sAPPα/β, BACE1 and neurogranin were measured in the BALTAZAR cohort of cognitively impaired patients and in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Biomarkers levels were related to the AT(N) framework. (A) and (T) were defined in BALTAZAR with CSF Aβ42/40 ratio and pTau217 respectively, and in ADNI with amyloid and tau PET. (N) was defined using total CSF tau in both cohorts. As expected, CSF Aβ42 decreased progressively with the AD continuum going from the A-T-N- to the A + T + N + profile. On the other hand, Tau and pTau181 increased progressively with the disease. The final transition from A + T + N- to A + T + N + led to a sharp increase in Aβ38, Aβ42 and sAPP levels. Synaptic CSF biomarkers BACE1 and neurogranin, were lowest in the initial A + T-N- stage and increased with T + and N + . CSF pTau181 and total tau were closely related in both cohorts. The early transition to an A + phenotype (A + T-N-) primarily impacts synaptic function. The appearance of T + and then N + is associated with a significant and progressive increase in pathological Alzheimer's disease biomarkers. Our main finding is that CSF pTau181 is an indicator of N + rather than T + , and that N + is associated with elevated levels of BACE1 protein and beta-amyloid peptides. This increase may potentially fuel the amyloid cascade in a positive feedback loop. Overall, our data provide further insights into understanding the interconnected pathological processes of amyloid, tau, and neurodegeneration underlying Alzheimer's disease.

A systematic review of economic evaluations of orphan medicines for the management of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a rare inherited autosomal recessive progressive disease of a varying phenotype, with varying clinical symptoms, and as a result the patients suffering from it require multiple types of care. It was deemed useful to conduct a systematic literature review on the pharmacoeconomic evaluations of all currently registered disease-modifying therapies in order to inform policy and highlight research gaps. Pharmacoeconomic analyses written in English and published after 2016 were considered for inclusion. PubMed/Medline, Global Health and Embase were systematically and separately searched between 16 October and 23 October 2023. Hand-searching was also conducted on PubMed based on reference lists of published literature. After the exclusion criteria were applied, 14 studies were included. BMJ checklist was used for quality assessment and the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist was used to assess the quality of reporting of all included studies. Data extraction was performed manually. Regarding evidence synthesis, data were heterogeneous and are thus presented based on comparison. This study confirms the need for pharmacoeconomic analyses (cost-effectiveness or cost-utility) also in cases when the cost of treatment is very high and the incremental cost-effectiveness ratio values exceed the usual, acceptable values for standard therapy. Specific willingness to pay thresholds for orphan medicines are of the utmost importance, to allow patients with SMA to have access to safe and effective treatments. With such economic evaluations, it is possible to compare the value of medications with the same indication, but it should be emphasized that in the interpretation of data and in making decisions about the use of medicines, the impact of new knowledge should be considered.

Elevated plasma and CSF neurofilament light chain concentrations are stabilized in response to mutant huntingtin lowering in the brains of Huntington’s disease mice

BackgroundTherapeutic approaches aimed at lowering toxic mutant huntingtin (mHTT) levels in the brain can reverse disease phenotypes in animal models of Huntington's disease (HD) and are currently being evaluated in clinical trials. Sensitive and dynamic response biomarkers are needed to assess the efficacy of such candidate therapies. Neurofilament light chain (NfL) is a biomarker of neurodegeneration that increases in cerebrospinal fluid (CSF) and blood with progression of HD. However, it remains unknown whether NfL in biofluids could serve as a response biomarker for assessing the efficacy of disease-modifying therapies for HD.MethodsLongitudinal plasma and cross-sectional CSF samples were collected from the YAC128 transgenic mouse model of HD and wild-type (WT) littermate control mice throughout the natural history of disease. Additionally, biofluids were collected from YAC128 mice following intracerebroventricular administration of an antisense oligonucleotide (ASO) targeting the mutant HTT transgene (HTT ASO), at ages both before and after the onset of disease phenotypes. NfL concentrations in plasma and CSF were quantified using ultrasensitive single-molecule array technology.ResultsPlasma and CSF NfL concentrations were significantly elevated in YAC128 compared to WT littermate control mice from 9 months of age. Treatment of YAC128 mice with either 15 or 50 µg HTT ASO resulted in a dose-dependent, allele-selective reduction of mHTT throughout the brain at a 3-month interval, which was sustained with high-dose HTT ASO treatment for up to 6 months. Lowering of brain mHTT prior to the onset of regional brain atrophy and HD-like motor deficits in this model had minimal effect on plasma NfL at either dose, but led to a dose-dependent reduction of CSF NfL. In contrast, initiating mHTT lowering in the brain after the onset of neuropathological and behavioural phenotypes in YAC128 mice resulted in a dose-dependent stabilization of NfL increases in both plasma and CSF.ConclusionsOur data provide evidence that the response of NfL in biofluids is influenced by the magnitude of mHTT lowering in the brain and the timing of intervention, suggesting that NfL may serve as a promising exploratory response biomarker for HD.

Disease-modifying therapies for Parkinson disease: lessons from multiple sclerosis.

The development of disease-modifying therapies (DMTs) for neurological disorders is an important goal in modern neurology, and the associated challenges are similar in many chronic neurological conditions. Major advances have been made in the multiple sclerosis (MS) field, with a range of DMTs being approved for relapsing MS and the introduction of the first DMTs for progressive MS. By contrast, people with Parkinson disease (PD) still lack such treatment options, relying instead on decades-old therapeutic approaches that provide onlysymptomatic relief. To address this unmet need, an in-person symposium was held in Toronto, Canada, in November 2022 for international researchers and experts in MS and PD to discuss strategies for advancing DMT development. In this Roadmap article, we highlight discussions from the symposium, which focused on therapeutic targets and preclinical models, disease spectra and subclassifications, and clinical trial design and outcome measures. From these discussions, we propose areas for novel or deeper exploration in PD using lessons learned from therapeutic development in MS. In addition, we identify challenges common to the PD and MS fields that need to be addressed to further advance the discovery and development of effective DMTs.

Ozanimod: A Review in Relapsing Forms of Multiple Sclerosis.

Ozanimod (Zeposia®), an orally administered sphingosine 1-phosphate (S1P) receptor modulator (S1PRM) that is selective for the S1P1 and S1P5 receptor subtypes, is approved in the USA for relapsing forms of multiple sclerosis (RMS). In pivotal phase III clinical trials in patients with RMS, ozanimod significantly reduced annualised relapse rates and the number of new or enlarging T2 lesions and gadolinium-enhancing lesions, and was associated with reduced brain volume loss, compared with interferon (IFN)-β1a. However, there were no significant differences in 3- and 6-month disability progression between the groups. Ozanimod was generally well tolerated, with the most common adverse reactions including upper respiratory tract infection and hepatic transaminase elevation. Efficacy and tolerability were sustained over more than 6 years with continued treatment. S1PRM-related adverse events seen with ozanimod are generally manageable with screening and/or monitoring. Notably, ozanimod does not require first-dose cardiac monitoring in the USA. In conclusion, ozanimod is a valuable once-daily oral disease-modifying therapy that extends the available treatment options for patients with RMS.