Disease-modifying Treatments Research Articles

Effectiveness, safety, and impact on multiple sclerosis course of anti-CGRP monoclonal antibodies.

Migraine affects up to 40% of people with multiple sclerosis (PwMS). This study aimed to evaluate the effectiveness and safety of the combination of antibodies (mAbs) against CGRP (anti-CGRP mAbs) with disease-modifying treatments (DMTs) for MS (mAb and non-mAbs) and their impact on MS disease course. This retrospective, multicentric study included PwMS from 14 MS Centers, treated with an anti-CGRP mAb and a stable treatment with DMTs. MS outcome measures included clinical relapses, EDSS score, and MRI activity from the year before starting anti-CGRP mAbs at the time of initiation (baseline) and last follow-up. Migraine outcomes included reductions in Monthly Headache Days (MHDs) and analgesic use. Adverse events (AEs) were recorded. Twenty-five patients were included (mean age of 39.4±9.7years). Nine PwMS (36.0%) were treated with non-mAb DMTs and 16 (64.0%) with mAb DMTs. During the concurrent treatment, six patients (24.0%) stopped anti-CGRP mAbs after 12.7±11.6months due to ineffectiveness (n=3) migraine sustained improvement (n=2) and AEs (n=1). MHDs significantly decreased from baseline (22.0±8.2) to the last follow-up (11.5±13.7) (p=0.002). EDSS score did not significantly change from the year before initiating anti-CGRP mAb (1.9±1.4) to baseline (1.9±1.4) and last follow-up (1.9±1.5)(p=0.497). Two patients (8.0%) had a clinical relapse, and one (4.0%) had MRI activity during treatment with anti-CGRP mAbs. Overall, DMTs were discontinued in two patients (8%). Mild AEs were reported in 2 PwMS (8.0%), none leading to discontinuation. Long-term treatment with anti-CGRP mAbs and DMTs for MS showed safety and effectiveness with no significant effect on MS disease course.

Cerebrospinal fluid biomarkers as predictors of multiple sclerosis severity.

Prognostic biomarkers at multiple sclerosis (MS) onset to predict disease severity may help guide initial therapy selection for people with MS. Over 20 disease-modifying treatments (DMTs) of varying levels of risk and efficacy now exist. The ability to predict MS severity would help to identify those patients at higher risk where a highly effective, but potentially risky, therapy would be optimal. The goal of this project was to determine if cerebrospinal fluid (CSF) soluble markers obtained near time of diagnosis can predict disease severity in people with relapsing remitting MS (RRMS). We identified 42 RRMS subjects with 4 or more years of clinical follow-up at our center, 8 subjects with other inflammatory neurological diseases (OIND), and 4 subjects with non-inflammatory neurological diseases (NIND) who had donated CSF samples collected for disease diagnosis. This study evaluated soluble CSF biomarkers chosen to reflect neuroinflammation (chemokine ligand 13 - CXCL13), microglia activity (soluble triggering receptor expressed on myeloid cells 2 - sTREM2), demyelination (myelin basic protein -MBP), axon injury and loss (neurofilament light, heavy, and intermediate chains - NFL, NFH, internexin-alpha - INT-α) and neuronal loss (parvalbumin - PVALB) to determine whether any of these CSF factors might predict future MS disease severity. The main outcome measure was MS Severity Score (MSSS), which takes into account disability accumulation (expanded disability status scale - EDSS) and duration of disease. EDSS at last clinical visit was a secondary outcome measure. Univariate and multivariable regression models were used for analysis. Spearman correlations were performed to evaluate correlation between laboratory and clinical variables. Forty-two RRMS patients with mean 9.4 years follow-up since lumbar puncture (LP) contributed data. Higher NFH, NFL, and sTREM2 each predicted worse MSSS using both univariate and multivariable regression models. Older age at the time of LP predicted worse MSSS both in the univariate and multivariable models. NFL correlated with NFH, and both were positively correlated with sTREM2 and CXCL13. In the combined OIND and NIND comparator group, NFH correlated with both NFL and CXCL13. These data support that CSF sTREM2, NFH, and NFL are predictors of MSSS, a measure of MS disease aggressiveness. This study adds to a growing literature implicating microglial activity and axonal injury in MS progression, starting from early stages of the disease.

Cerebellar lipid dysregulation in SCA3: A comparative study in patients and mice.

Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia and belongs to the family of nine diseases caused by a polyglutamine expansion in the disease-causing protein. In SCA3, a polyglutamine expansion in ATXN3 causes neuron loss in disease-vulnerable brain regions, resulting in progressive loss of coordination and ultimately death. There are no disease-modifying or preventative treatments for this uniformly fatal disorder. Recent studies demonstrate prominent white matter atrophy and microstructural alterations in disease-vulnerable brain regions of SCA3 patients and mouse models. However, the major constituent of white matter - lipids - remains understudied in SCA3. In this study, we conducted the first unbiased investigation of brain lipids in SCA3, focusing on the disease-vulnerable cerebellum of SCA3 postmortem patients and mouse models. Liquid chromatography-mass spectrometry uncovered widespread lipid reductions in patients with SCA3. Lipid downregulation was recapitulated in early- to mid-stage mouse models of SCA3, including transgenic YACQ84 and Knock-in Q300 mice. End-stage Knock-in Q300 mice displayed a progressive reduction in lipid content, highlighting targets that could benefit from early therapeutic intervention. In contrast, Atxn3-Knock-out mice showed mild lipid upregulation, emphasizing a toxic gain-of-function mechanism underlying lipid downregulation in SCA3. We conclude that lipids are significantly altered in SCA3 and establish a platform for continued exploration of lipids in disease through interactive data visualization websites. Pronounced reductions in myelin-enriched lipids suggest that lipid dysregulation could underlie white matter atrophy in SCA3. This study establishes the basis for future work elucidating the mechanistic, biomarker, and therapeutic potential of lipids in SCA3.

A retrospective evaluation of patient characteristics and recommendations of a novel multidisciplinary clinic for persons with advanced disability from multiple sclerosis.

Persons with advanced multiple sclerosis (MS) require care beyond the disease modifying treatments offered in conventional MS clinics to address their complex physical and psychosocial needs. In the novel MS Comprehensive and Palliative Care (MSCPC) Program, an MS neurologist, palliative care specialist, and physiatrist collaborate to identify these needs and improve symptom control. To characterize the medical, physical, and psychosocial concerns of persons with advanced disability from MS and describe the recommended interventions of the MSCPC Program. Retrospective chart review of consecutive patients seen in the MSCPC Program from 2019 to 2022. 54 patients were assessed over 74 clinic appointments. Patients' mean age was 59.4 ± 10.8 years (range 37-81) and mean duration of MS was 24.8 ± 11.8 years (range 2-52); 79.7% of patients had secondary progressive MS with median and mode disease severity (EDSS) of 7.5 and 8.5, respectively (range 4-9.5). 70.3% lived at home with a caregiver; the primary caregiver was the spouse for 51.4% of cases. 85.1% of patients received publicly funded in-home assistance for activities of daily living. The most prevalent sequelae of MS were incontinence (89.9%), spasticity (82.6%), and pain (78.3%). ≥1 symptom was addressed at 95.7% of appointments, most often pain (63.8%), spasticity (60.9%), and bowel (59.4%); medication deprescribing was recommended at 29.0% of appointments. Caregiver burnout was identified at 56.5% of appointments. This novel program identified high prevalence of symptoms and made recommendations to improve symptom control at >95% of appointments, suggesting unmet symptom control needs in persons with advanced disability from MS.

Efficacy and Safety of Stem Cell Therapy in Alzheimer's Disease: A Review

Alzheimer's disease (AD) prevalence is a significant public health concern. Tau tangle buildup and different metabolic abnormalities are the primary neuropathological alterations that lead to this illness. Currently, there is a lack of effective treatment for patients with AD due to the complexity of the disease and the lack of a clear understanding of its aetiology. However, stem cell therapy can potentially be used to replace lost neuronal cells. Although this technology is only in its initial stages, it has the potential to transform the treatment of this condition. AD is amenable to disease-modifying treatment with stem cell therapy. Since the early 2000s, there have been more investigations on stem cells, including Mesenchymal Stem Cells (MSCs) and Neural Stem Cells (NSCs), as a result of the failure to produce new medicines for AD. Numerous animal studies have investigated issues relating to stem cells, such as their origin, ability to differentiate, how they are cultured, how they form tumours, how they are injected, and how mobile they are. Clinical trials to test the use of stem cells for AD have been underway since 2010, primarily in East Asia. Although there were no significant immediate or long-term side effects, two phase I investigations on moderate AD have been completed. Neither of these studies revealed any considerable clinical efficacy. Numerous investigations with more complex study designs, established levels, and biomarkers, such as amyloid positron emission tomography among people with mild to moderate AD, are in the works. Stem cell therapy for AD has the potential to alter the condition. The methods of action, preclinical animal studies, human clinical trials, and challenges stem cell therapy for AD faces are all covered in this article. We will also go over current advancements in stem cell research and the pathophysiology of AD, as well as challenges and solutions for employing cell-based therapeutics for AD and associated conditions.

Echocardiographic index of left ventricular performance for prognostication in transthyretin cardiac amyloidosis: the central role of stroke volume index.

Cardiac amyloidosis typically causes restrictive cardiomyopathy, in which the impairment of diastolic function is dominant. Echocardiography provides prognostic information through some important parameters: left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). However, LVEF often remains preserved despite disease progression, and GLS is not routinely performed as it is limited by suboptimal image quality. The stroke volume index (SVi) has already been shown to correlate with mortality in heart failure patients; still, its prognostic role in transthyretin cardiac amyloidosis (TTR-CA) is poorly studied. This prospective study aimed to evaluate the role of SVi in predicting mortality and heart failure hospitalizations in patients with cardiac amyloidosis, comparing it to other parameters of left ventricular performance. Baseline clinical transthoracic echocardiogram and laboratory data were collected prospectively in 115 patients with diagnosed TTR-CA. The outcome was the occurrence of the composite of heart failure hospitalization and death and its association with SVi, LVEF, GLS and MCF was tested by Cox proportional hazard modelling. Over a mean follow-up of 16.1 months (interquartile range 7.4-24.9 months), 29 patients died, and 19 were hospitalized for heart failure. SVi was associated with the composite outcome of death and heart failure hospitalization [hazard ratio 0.96; 95% confidence interval (CI) 0.93-0.99] and remained an independent predictor of outcome after adjustment for NAC stage, mitral regurgitation degree, age and the use of disease-modifying treatment. The best cut-off of SVi to predict outcome was 35 ml/m2 (hazard ratio 2.30; 95% CI 1.03-5.17). SVi is superior to LVEF, MCF, and GLS for prognostication in patients with TTR amyloidosis.

High definition transcranial direct current stimulation as an intervention for cognitive deficits in Alzheimer's dementia: A randomized controlled trial.

Recent disease-modifying treatments for Alzheimer's disease show promise to slow cognitive decline, but show no efficacy towards reducing symptoms already manifested. To investigate the efficacy of a novel noninvasive brain stimulation technique in modulating cognitive functioning in Alzheimer's dementia (AD). Pilot, randomized, double-blind, parallel, sham-controlled study SETTING: Clinical research site at UT Southwestern Medical Center PARTICIPANTS: Twenty-five participants with clinical diagnoses of AD were enrolled from cognition specialty clinics. Treatment consisted of high definition transcranial direct current stimulation (HD-tDCS) delivered for 20 min over the medial prefrontal cortex. Ten sessions of sham, 1 mA, or 2 mA stimulation were received. Cognitive outcomes were measured at baseline, after the last HD-tDCS session, and 8-weeks post-treatment. The primary outcome was change in total learning and delayed recall on the Rey Auditory Verbal Learning Test (RAVLT) immediately post-treatment and at 8-weeks. Secondary outcomes included measures of language, processing speed, and executive functioning. A multi-stage approach was used to examine cognitive outcomes, which included evaluation of effect sizes, statistical effects, and rate of clinically meaningful responses. In this pilot trial, no statistically significant differences on cognitive outcomes were found between sham and active HD-tDCS immediately post-treatment (p's > 0.05). However, moderate-to-large effect sizes were identified for enhanced RAVLT total learning (Cohen's d = 0.69-0.93) and phonemic fluency (d = 1.08-1.49) for both active HD-tDCS conditions compared to sham, with rates of clinically relevant improvement between 25 and 33%. Meaningful enhancement persisted to 8 weeks only for the 1 mA condition. Multiple sessions of HD-tDCS over the medial prefrontal cortex appears to have potential to produce meaningful cognitive enhancements in a proportion of patients having AD with improvements maintained for at least 8 weeks in some. ClinicalTrials.gov (NCT05270408). Registered December 30, 2021.

Vineland-3 Growth Scale Values: Psychometric Properties for Clinical Trial Readiness in SCN2A.

Purpose: The Vineland Adaptive Behavior Scales-3rd Edition (Vineland-3) is one of the most used measures of adaptive behavior among those with sodium channel protein type 2 subunit alpha related disorders (SCN2A-RDs). Several disease-modifying treatments are in early trials for SCN2A-RDs, and as such, clinical outcome assessments (COAs) are necessary. The Vineland-3 introduced growth scale values (GSVs), which are useful for measuring within-person change and thus may be useful in future clinical trials. The purpose of this study was to evaluate the psychometric properties of the Vineland-3 GSVs in SCN2A-RDs in preparation for future clinical trials. Methods: A sample of 65 individuals with SCN2A-RDs (mean = 108, SD = 76.0 months) was recruited for a clinical trial readiness study. The Vineland-3 Comprehensive Interview was administered by trained raters at regular intervals. Multiple psychometric properties were evaluated, including floor and ceiling effects, split-half internal consistency, test-retest reliability, and inter-rater reliability (on approximately 20% of all completions). Results: Floor effects were relatively infrequent on the GSV metric but occurred on all subdomains using the norm-referenced v-scale metric. Split-half and test-retest reliability were excellent for all subdomains (rxx >0.95 and inter-class correlation coefficient [ICC] >0.90, respectively), except for coping, which still maintained adequate reliability (rxx = 0.87, ICC = 0.65). Inter-rater reliability was also very strong, though it was more variable (αkripp range 0.78-1.00). Conclusion: The Vineland-3 holds great potential as a COA in SCN2A-RDs; it exhibited very strong psychometric properties in this sample. This is a prerequisite level of evidence needed to demonstrate that a measure is fit-for-purpose for future clinical trials. While some reliability was high, some domains (e.g., domestic) still exhibited problems related to floor effects, which may suggest that they are less relevant to this population. Future studies should expand on this with mixed-methods research for prioritizing concepts of interest on the Vineland-3.

Valvular heart disease in transthyretin cardiac amyloidosis

Abstract Introduction Amyloidosis cardiomyopathy (CM) is known to be associated with valvular heart disease (VHD) and particularly with aortic stenosis (AS). However, previous studies included both immunoglobulin light-chain CM and transthyretin amyloid CM (ATTR-CM), with limited data focussing specifically on ATTR-CM. Furthermore, VHD assessment was mostly limited to isolated significant VHD, and the difference in outcome between isolated and multiple VHD is largely unknown. Aim To evaluate the prevalence and prognostic value of significant VHD in ATTR-CM patients, including the differences in outcome between isolated and multiple significant VHD, with or without AS. Methods Patients with ATTR-CM were retrospectively included in this multicentric study. Significant VHD was defined as at least moderate VHD. The study endpoint was a composite of heart failure hospitalisations and all-cause death. Results A total of 694 ATTR-CM patients (mean age 75 ±13 years, 74% male) were included, and 302 (44%) presented with significant VHD (Figure 1). These patients were older (81±9 vs. 71±13, p<0. 001), had more cardiovascular risk factors, lower left ventricular ejection fraction (50±12 vs. 54±12, p<0.001) and more pulmonary arterial hypertension (76% vs. 45%, p<0.001), as compared to patients without significant VHD. Among patients with significant VHD, only 98 patients had VHD including AS (isolated AS in 45%; multiple VHD with AS in 55%), while the majority (n=204) had VHD without AS (isolated in 64%, multiple VHD in 36%) (Figure 1). During a median follow-up of 16 (6 - 33) months, 214 (31%) patients reached the study endpoint. Univariable Cox regression analysis identified significant VHD as a predictor of worse outcomes (HR: 3.486; 95% CI: 2.627 - 4.626; p < 0.001), which remained significant in the multivariable Cox regression analysis (HR: 1.879;95%CI:1.182 - 2.987;p=0.008), after adjusting for transthyretin amyloid cardiomyopathy phenotype, disease-modifying treatment, coronary artery disease, atrial fibrillation, renal function, New York Heart Association III-IV, polyneuropathy, electrocardiographic abnormalities, left ventricular stroke volume, interventricular septum thickness, left atrial dilatation, tricuspid annular plane systolic excursion, and arterial pulmonary hypertension(Figure2). Further stratification based on the presence of significant AS, and according to isolated or multiple VHD, revealed that patients isolated significant AS (HR:2.399;95%CI 1.179 – 4.884;p=0.016), and patients with multiple VHD including significant AS, had the highest risk for adverse outcomes (HR:3.542; 95%CI: 1.809 - 6.935;p<0.001)(Figure 2). Conclusion In ATTR-CM, significant VHD is strongly associated with poor prognosis, with the highest risk for adverse events in patients with significant multiple VHD including AS. These findings underscore the importance of VHD assessment for risk stratification and possibly targeted treatment in this patient population. The distribution of significant VHD.

Steady Moderate Exercise Confers Resilience Against Neurodegeneration and Neuroinflammation in a Mouse Model of Parkinson’s Disease

Intensive aerobic exercise slows the progression of movement disorders in Parkinson's disease (PD) and is therefore recommended as an important component of treatment for PD patients. Studies in animal models of PD have shown that vigorous exercise has neuroprotective effects, and emerging evidence suggests that it may be a disease-modifying treatment in humans. However, many people with PD may not be able to participate in vigorous exercise because of multiple medical conditions that severely limit their physical activity. In this study, we have shown that chronic MPTP treatment in sedentary mice resulted in loss of dopaminergic neurons in the SNpc, decreased levels of neurotrophins, BDNF and GDNF, and increased levels of inflammatory markers and pro-inflammatory changes in immunocompetent cells. Moderate exercise, initiated both before and after chronic MPTP treatment, significantly attenuated the loss of dopaminergic neurons and increased BDNF and GDNF levels even above those in sedentary control mice. No signs of inflammation were observed in MPTP-treated mice, either when training began before or after MPTP treatment. Training induced beneficial changes in the dopaminergic system, increased levels of neurotrophins and suppression of inflammation were similar for both steady moderate (present data) and intense training (our previously published data). This suggests that there is a kind of saturation when the percentage of rescued dopaminergic neurons reaches the highest possible value, and therefore further increases in exercise intensity do not enhance neuroprotection. In conclusion, our present results compared with the previous data show that increasing exercise intensity beyond the level used in this study does not increase the neuroprotective effect of aerobic training in a mouse model of Parkinson's disease.

Brain Age as a New Measure of Disease Stratification in Huntington's Disease.

Despite advancements in understanding Huntington's disease (HD) over the past two decades, absence of disease-modifying treatments remains a challenge. Accurately characterizing progression states is crucial for developing effective therapeutic interventions. Various factors contribute to this challenge, including the need for precise methods that can account for the complex nature of HD progression. This study aims to address this gap by leveraging the concept of the brain's biological age as a foundation for a data-driven clustering method to delineate various states of progression. Brain-predicted age, influenced by somatic expansion and its impact on brain volumes, offers a promising avenue for stratification by stratifying subgroups and determining the optimal timing for interventions. To achieve this, data from 953 participants across diverse cohorts, including PREDICT-HD, TRACK-HD, and IMAGE-HD, were meticulously analyzed. Brain-predicted age was computed using sophisticated algorithms, and participants were categorized into four groups based on CAG and age product score. Unsupervised k-means clustering with brain-predicted age difference (brain-PAD) was then employed to identify distinct progression states. The analysis revealed significant disparities in brain-predicted age between HD participants and controls, with these differences becoming more pronounced as the disease progressed. Brain-PAD demonstrated a correlation with disease severity, effectively identifying five distinct progression states characterized by significant longitudinal disparities. These findings highlight the potential of brain-PAD in capturing HD progression states, thereby enhancing prognostic methodologies and providing valuable insights for future clinical trial designs and interventions. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Preparing the way for novel blood-based biomarkers and disease-modifying treatments for Alzheimer's disease in the NHS in the UK.

Preparing the way for novel blood-based biomarkers and disease-modifying treatments for Alzheimer's disease in the NHS in the UK.

An online multidomain lifestyle intervention to prevent cognitive decline in at-risk older adults: a randomized controlled trial.

Effective, scalable dementia prevention interventions are needed to address modifiable risk factors given global burden of dementia and challenges in developing disease-modifying treatments. A single-blind randomized controlled trial assessed an online multidomain lifestyle intervention to prevent cognitive decline over 3 years. Participants were dementia-free community-dwelling Australians aged 55-77 years with modifiable dementia risk factors. Eligible participants (n = 6,104, 64% female) were randomized 1:1 to a personalized schedule of online coaching in two to four modules (targeting physical activity, nutrition, cognitive activity and depression or anxiety) or a control group that received module-eligible information only. At 3 years, the mean change in a global cognitive composite, the primary outcome, was met. The mean changes in z scores were 0.28 (95% confidence interval (CI): 0.25-0.32) for intervention, 0.10 (95% CI: 0.07-0.13) for control and 0.18 (95% CI: 0.13-0.23, P < 0.001) for the between-group difference. Trial-related adverse events occurred in 19 (0.60%) intervention and 1 (0.03%) control participant. Randomization of this internet-delivered lifestyle intervention tailored to individual dementia risk factors resulted in significantly better cognition in older adults over 3 years. This intervention is scalable with the potential for population-level rollout that may delay cognitive decline in the general community. Australian New Zealand ClinicalTrials.gov registration: ACTRN12618000851268.

New and Emerging Biological Therapies for Myasthenia Gravis: A Focussed Review for Clinical Decision-Making.

Myasthenia gravis (MG) is a rare autoimmune disease characterised by exertion-induced muscle weakness that can lead to potentially life-threatening myasthenic crises. Detectable antibodies are directed against specific postsynaptic structures of the neuromuscular junction. MG is a chronic condition that can be improved through therapies, but to date, not cured. Standard treatment has been unchanged for decades and includes symptomatic treatment with acetylcholine-esterase inhibitors and disease-modifying treatment with steroids, steroid-sparing immunosuppressants and thymectomy. Overall, a relevant proportion of patients does not achieve a satisfactory clinical improvement under standard treatment. Additionally, long-term therapy with steroids can cause significant side effects and latency to clinical improvement with standard steroid-sparing immunosuppressants and after thymectomy can take months to years. In recent years, treatment of MG has changed fundamentally due to improved evidence from phase 3 trials and the regulatory approval of complement inhibitors and FcRn inhibitors as add-on treatment options. This provides new optimism for substantially more patients reaching minimal manifestation status and has led to a shift in treatment strategy with more targeted therapies being employed early in the course of the disease, especially in patients with high disease activity. In this focussed review, we provide an overview of the diagnosis, classification and standard treatment of MG, followed by data from randomised controlled trials on the modern drugs already available for therapy and those still in the final stages of clinical development. In the second part, we provide an overview of real-world data for already approved therapies and outline how the availability of new biologicals is changing both clinical decision-making and patient journey.

Value contribution of leniolisib in the Treatment of Activated PI3Kδ syndrome (APDS) in Spain using Multi-Criteria Decision Analysis (MCDA).

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS) is an ultra-rare, potentially life-threatening disease that lacks approved treatments in Spain. This study aimed to apply Multi-Criteria Decision Analysis (MCDA) to assess the value of the first pharmacological treatment for APDS in Spain. A multidisciplinary group of 8 experts evaluated the selective PI3Kδ inhibitor leniolisib against Standard of Care (SoC). An MCDA framework tailored for Orphan Drugs (ODs), consisting of 5 comparative and 2 quantitative non-comparative criteria, was used. Re-scoring followed a group discussion. Leniolisib scored higher than SoC in all criteria, including efficacy and safety. It was deemed highly valuable as the first disease-modifying treatment, with a positive therapeutic impact and potential to improve patients' quality of life. Additionally, leniolisib may lead to cost savings. The supporting data was considered of high quality. Based on MCDA methodology and stakeholder experience in APDS management, leniolisib is seen as a value-added treatment option compared to SoC in Spain.

Durable suppression of seizures in a preclinical model of KCNT1 genetic epilepsy with divalent small interfering RNA.

Gain-of-function variants in the KCNT1 gene, which encodes a sodium-activated potassium ion channel, drive severe early onset developmental epileptic encephalopathies including epilepsy of infancy with migrating focal seizures and sleep-related hypermotor epilepsy. No therapy provides more than sporadic or incremental improvement. Here, we report suppression of seizures in a genetic mouse model of KCNT1 epilepsy by reducing Kcnt1 transcript with divalent small interfering RNA (siRNA), an emerging variant of oligonucleotide technology developed for the central nervous system. The ATL-201 molecule is two identical synthetic double-stranded siRNAs, covalently linked, with 100% nucleotide base pair match to sequence present in both human KCNT1 and mouse Kcnt1 that does not contain any known pathogenic variant. ATL-201 activity was tested in cortical neurons cultured from wild-type mice and in mice homozygous for Kcnt1-Y777H, the mouse ortholog to the human pathogenic KCNT1-Y796H missense variant. Seizures and nest-building behavior were measured in freely behaving Kcnt1-Y777H mice. The number and duration of seizures were measured by electrocorticography in mice dosed with ATL-201 or phosphate-buffered saline in a 6-month durability study and in a 2-month dose-efficacy study. In vitro, ATL-201 reduced KCNT1 transcript from whole-cell lysate and eliminated potassium currents from KCNT1 channels in heterologous expression. ATL-201 also eliminated sodium-activated potassium currents recorded from individual cortical neurons. Invivo, ATL-201 suppressed seizures in Kcnt1-Y777H homozygous mice in a dose-dependent manner with near-complete suppression from 2 weeks to at least 4 months. Kcnt1-Y777H mice had defects in nest building, whereas in ATL-201-treated mice nest building was equivalent to wild-type mice. Patients with KCNT1-driven epilepsy experience up to hundreds of seizures per day and have severe impairment in cognitive, motor, and language development and high mortality. The dose-dependent efficacy and long durability of ATL-201 in mice show promise for ATL-201 as a disease-modifying treatment of KCNT1 epilepsy.

Advances in neural stem cells in aging and age-related neurodegenerative diseases

With aging, neural stem cells (NSCs) undergo age-related changes, including metabolic abnormalities, disrupted protein homeostasis, mitochondrial dysfunction, reduced genetic stability, and more notably, a diminished capacity for proliferation and differentiation. These changes may contribute to the development of age-related neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In these conditions, disease-specific pathological changes may interact with age-related alterations of NSCs, resulting in impairment of neurogenesis, which further leads to cognitive, mood, and motor decline. Based on these changes, potential therapeutics targeting neurogenesis and stem cell-based therapies may restore the functions of NSCs and replace the degenerated neurons, aiming to ameliorate functional decline in these neurodegenerative diseases. While stem cell-based therapies, including stem cell transplantation and stem cell secretome therapy, show great potential in the treatment of neurodegenerative diseases, challenges in tumorigenesis, immune rejection, and extraction or storage of the stem cell secretome need to be further addressed. A better understanding of age- and disease-related changes in NSCs, the underlying mechanism driving these changes, and the benefits and drawbacks of the therapeutic approaches may provide insights for novel disease-modifying interventions for the future treatment of these diseases.

Evaluation of transcriptomic changes after photobiomodulation in spinal cord injury

Spinal cord injury (SCI) is a significant cause of lifelong disability, with no available disease-modifying treatments to promote neuroprotection and axon regeneration after injury. Photobiomodulation (PBM) is a promising therapy which has proven effective at restoring lost function after SCI in pre-clinical models. However, the precise mechanism of action is yet to be determined. Here, we used an in-vivo model of SCI in adult rats that received daily PBM (660 nm, 24 mW/cm2, 1 min) and at three days post-injury, the injured spinal cord segment was harvested and subjected to whole transcriptome sequencing and subsequent pathway analysis (generally applicable gene-set enrichment (GAGE)). Pathway analysis demonstrated 1275 differentially expressed genes (DEGs) after PBM treatment, of which 397 were upregulated and 878 were downregulated. Key pathways were significantly enriched, including 8.6-fold enrichment of “neuron projection morphogenesis” (adjusted p = 8.10 × 10− 14), with upregulation of Notch3, Slit1/Robo2 and Sema3g pathways. Ribosomal and oxidative phosphorylation pathways and NADH dehydrogenase were downregulated, and there was upregulation of ATP-dependent activity, cAMP and calcium signalling pathways. Key genes in apoptotic pathways were downregulated, as were S100 and cyclo-oxygenase components. Together, our study supports the favourable effects of PBM in promoting neuroregeneration and suppressing apoptosis after neurological injury. Further findings from pathway analysis suggest that downregulation of metabolism-associated pathways is a mechanism by which acute post-injury mitochondrial dysfunction may be averted by PBM therapy.

Novel Monoclonal Antibodies for the Treatment of Alzheimers Disease using KISUNLA Drug

For persons with early-stage sympathetic Alzheimer's disease (AD), including those with mild cognitive impairment and mild congitive dementia stages of the disease with confirmed amyloid pathology, KISUNLA (donanemab-azbt) is a disease-modifying treatment. Nearly half of research participants finished their course of treatment with Kisunla within a year, making it the first and only amyloid plaque targeting medication that uses a limited duration treatment regimen based on amyloid plaque elimination. For those with early-stage sympathetic Alzheimer's disease who desperately require an efficient therapeutic alternative, Kisunla shows extremely significant results

Unravelling ATTR Cardiac Amyloidosis in Iceland: A Nationwide Epidemiological Study

Introduction: Cardiac amyloidosis (CA) arises from the deposition of misfolded amyloid proteins in the heart's extracellular matrix, leading to significant cardiac disease. Recent data suggest that CA is under recognised and advances in treatment have increased focus on this condition with the intention of implementing treatment earlier to improve prognosis. There is limited knowledge regarding the prevalence of Transthyretin-CA (ATTR-CA) on a national level, particularly in Iceland. Therefore, this study represents the first nationwide effort to evaluate the baseline characteristics, diagnostics, and treatment of ATTR-CA in Iceland. Methods: A retrospective study of all patients diagnosed with ATTR-CA in Iceland from 6 May 2013 to 11 March 2024 were identified in the Icelandic Cardiac Amyloid Registry (ICE-CAR) created in 2023 by heart failure (HF) specialists at Landspitali University Hospital in Reykjavik, Iceland. Diagnosis was based on different combinations of transthoracic echocardiography (TTE), an elevated Perugini score on bone scintigraphy and heart biopsies, as well measurements of free light chains, M-component measurements in blood and urine. Patients were grouped according to the National Amyloidosis Centre (NAC) prognostic staging system for ATTR-CA. Results: In total, 65 patients with ATTR-CA were identified (males n=60, females n=5, median age 81.4 years [IQR 75.5-85.5 years]), all wild-type and no mutant variant. Diagnosis was made with myocardial biopsy in 7 cases. Upon diagnosis, 83% of the patients had an interventricular septum thickness of ≥15mm and 92% showed a posterior wall thickness of ≥12mm. Approximately 57% of patients belonged to New York Heart Association (NYHA) functional class I-II. The HF phenotypes according to left ventricular ejection fraction (LVEF) were distributed as follows: reduced (HFrEF) n=24 (37%), mildly reduced (HFmrEF) n=9 (14%), preserved (HFpEF) n=29 (44.5%), and unknown LVEF n=3 (4.5%). A total of 54 patients had reported NAC stage: Stage I 23 (35.4%), Stage II 20 (30.8%), Stage III 11 (16.9%). Around 32% received disease modifying treatment. Conclusion Despite the low NYHA class observed in the study population, our findings in Iceland's nationwide assessment of ATTR-CA indicate more advanced age and lower LVEF at diagnosis compared to other studies. This highlights the critical need for early detection and appropriate therapeutic interventions in managing ATTR-CA.