Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disease characterized by marked clinical heterogeneity. While the genetic architecture underlying disease susceptibility is well established, the role of genetic factors in shaping disease prognosis remains clearly defined. In this structured narrative review, we examine available evidence on genetic contribution to key MS prognostic domains. This includes clinical outcomes, such as age at onset, relapse rate, disability progression, neurological sequelae, and cognitive impairment. We also consider radiological measures like brain and spinal cord lesion burden, gadolinium-enhancing lesions, and atrophy, as well as laboratory biomarkers, such as oligoclonal bands and Immunoglobulin G (IgG) index. Overall, current evidence suggests that genetic influences on prognosis are modest and highly heterogeneous. Only a limited number of associations-primarily from genome-wide association studies (GWAS)-have shown consistent replication, whereas many reported findings come from small candidate-gene studies and remain unconfirmed. Among these, the largest GWAS on age-related Multiple Sclerosis Severity Score (MSSS) identified a locus in the DYSF-ZNF638 region reaching genome-wide significance. The strongest evidence from GWAS relates to relapse rate, magnetic resonance imaging (MRI) measures (e.g., thalamic atrophy) and intrathecal IgG synthesis, the latter also reaching genome-wide significance. Interpretation of genotype-phenotype associations is further limited by small sample sizes, limited replication, heterogeneity in study design with the predominance of candidate-gene approaches, variability in outcome definitions, treatment exposure, and population ancestry. These limitations currently preclude the routine use of genetic markers for prognostic stratification in clinical practice. Larger studies and collaborative genetic consortia efforts are needed to improve statistical power and reproducibility. Additionally, emerging epigenetic studies may provide valuable insights into prognosis and disease management. Understanding which genetic factors can predict diverse MS courses could enhance patient management and enable personalized treatment approaches.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are described as a disease continuum, given their shared clinical, genetic and pathological characteristics. Comparisons of clinical and biomarker features within the ALS and behavioural variant FTD (bvFTD) spectrum are of utmost importance for diagnostic and prognostic purposes. This study investigated biomarker differences between cognitively normal patients with ALS (ALS-cn), ALS-FTD patients and bvFTD patients. Participants, genetically screened for known ALS- and FTD-associated mutations, underwent neuropsychological assessments, CSF analysis and 18F-fluorodeoxyglucose PET (18F-FDG-PET). Neuropsychological data were analysed by calculating a composite score for each cognitive domain, averaging the rank-transformed z-scores of all tests measuring the same domain. 18F-FDG-PET was performed using a validated voxel-based SPM method at the single-subject and group levels. To evaluate the ability to differentiate ALS-cn, ALS-FTD and bvFTD using the identified markers, machine-learning models-support vector machine (SVM) and random forest (RF)-were applied, offering a streamlined, data-driven approach to improve diagnostic precision across this spectrum of disorders. Twenty ALS-cn, 19 ALS-FTD and 21 bvFTD patients were included. Neuropsychological composite z-scores revealed significant differences across groups, underlining worse performance in bvFTD regarding memory, visuospatial, language and executive functions. Brain 18F-FDG-PET showed a pattern of hypometabolism that increased from ALS-cn to ALS-FTD and reached its greatest extent in bvFTD. Specifically, brain hypometabolism was confined mainly to the sensorimotor cortices and frontobasal regions in the ALS-cn group, whereas in the ALS-FTD group, it extended to the supplementary motor area and dorsolateral frontal cortex, and in the bvFTD group, it was widespread, further affecting the frontomesial and orbitofrontal cortices. No significant differences in CSF biomarkers were observed between groups. SVM correctly classified 83% of patients, indicating good classification performance, while RF achieved perfect accuracy (100%). The two models shared eight to ten most relevant features for classification, namely age, disease duration from symptom onset to diagnosis, total composite z-score, superior frontal gyrus (left), middle frontal gyrus (left), middle frontal gyrus-pars orbitalis (left and right) and anterior cingulate cortex (left). Our study identified significant differences in biomarkers across neurodegenerative clinical groups within the same disease spectrum. These differences were evident in the neuropsychological profiles and brain hypometabolism patterns among the patient groups, providing valuable insights into the heterogeneity of the ALS-FTD continuum and highlighting distinct disease-related patterns to enhance diagnostic accuracy.

Synaptic dysfunction is increasingly recognized as an early and biologically relevant component of α-synucleinopathies. However, conventional imaging biomarkers mainly assess dopaminergic dysfunction, glucose metabolism, or structural damage rather than presynaptic density itself. Synaptic vesicle glycoprotein 2A (SV2A) PET enables in vivo assessment of presynaptic terminal integrity and may provide complementary information in Parkinson's disease (PD), Parkinson's disease dementia/dementia with Lewy bodies (PDD/DLB), and multiple system atrophy (MSA). This systematic review synthesized the available evidence on SV2A-targeted PET in parkinsonian α-synucleinopathies, focusing on regional imaging patterns, clinical associations, longitudinal findings, and methodological determinants of interpretation. Seventeen reports were included. In PD, the most recurrent finding was reduced SV2A binding in the substantia nigra, although additional involvement of brainstem, caudate, striatal, thalamic, raphe, or cortical regions was reported in selected cohorts. In PDD/DLB, abnormalities appeared broader and more cortical, with evidence of association between cortical SV2A binding and cognitive performance. In MSA, one study suggested a distinct infratentorial and cerebellar pattern with potential relevance for phenotypic stratification. SV2A PET is a promising research biomarker for biological characterization of synucleinopathies. However, the field remains limited by small cohorts, methodological heterogeneity, variable quantification strategies, limited longitudinal evidence, and potential cohort overlap. Multicentre validation and harmonized protocols are required before clinical translation.

Mutations in superoxide dismutase 1 SOD1 are the second most common genetic cause of ALS, usually associated with prevalent lower motor neuron phenotypes. We describe a 66-year-old woman with slowly progressive spastic paraparesis, initially diagnosed as primary lateral sclerosis, who carried a heterozygous p.D91A mutation. Clinical and neurophysiological findings indicated predominant upper motor neuron involvement, an unusual presentation for this mutation. This case broadens the SOD1 phenotypic spectrum and highlights the importance of early genetic testing in atypical motor syndromes, given the availability of targeted therapies where diagnostic delay may limit benefit.

Parkinson's disease (PD) imposes a growing socioeconomic burden due to its increasing prevalence and lack of a cure. Existing treatment options primarily manage motor and nonmotor symptoms but do not halt or slow disease progression, underscoring the urgent need for more effective and preventative strategies. Growing evidence suggests a strong link between immune system dysfunction, chronic inflammation, and the early pathogenesis of Parkinson's disease, often occurring years before the onset of motor symptoms, thereby indicating a critical window for early intervention. In this review, we examine current evidence on non-pharmacological approaches such as dietary changes, physical activity, and gut microbiome regulation, focusing on their potential to modulate both peripheral and central immune responses, thereby influencing the progression of PD. Besides being complementary to standard pharmacological treatments, these approaches not only reduce systemic inflammation but may also help delay, prevent, or improve clinical management of PD by targeting and modulating its immunological foundations.

Severe emotional stress constitutes a significant public-health concern associated with negative health outcomes. Although the clinical effects are well acknowledged, the specific biological mechanisms that translate emotional suffering into systemic disease remain incompletely understood. Psychological stress activates the sympathetic nervous system and hypothalamic–pituitary–adrenal axis, which directly target mitochondria and alter their bioenergetic and redox capacity. For this reason, this narrative review proposes that mitochondria serve as the primary subcellular link in the mind–body connection, as they play a pivotal role in converting neuroendocrine signals into cellular dysfunction. In particular, we focus on the concept of mitochondrial allostatic load (MALT), a framework explaining how the progressive decline in mitochondrial functions, from their initial adaptive roles in energy production, reactive oxygen species signaling, and calcium regulation, to being sources of inflammation and systemic damage, occurs when stress exceeds regulatory limits. We also, discuss how this transition turns mitochondria from adaptive responders into drivers of multi-organ disease. In subsequent sections, we examine diagnostic potentials related to MALT, including the use of biomarkers, such as growth differentiation factor 15, cell-free mitochondrial desoxyribonucleic acid, and functional respirometry. Furthermore, we evaluate mitochondria-targeted therapeutic strategies, encompassing pharmacological compounds, such as mitoquinone mesylate, Skulachev ions, and elamipretide, alongside lifestyle and psychological interventions. Here, we aim to translate MALT biology into clinical applications, positioning mitochondrial health as a target for preventing and treating stress-related disorders. We propose that MALT may serve as a quantifiable bridge between emotional stress and somatic disease, enabling future precision medicine strategies integrating mitochondrial care.

BACKGROUND:Female sex increases the risk of levodopa-induced dyskinesias in Parkinson's disease (PD). While levodopa-sparing effects of monoamine oxidase-B inhibitors (iMAO-B) are established, sex differences in response to safinamide remain unexplored. OBJECTIVES:To evaluate sex differences in longitudinal (9 ± 3 months) changes in levodopa dose and total levodopa-equivalent daily dose (LEDD) with safinamide 100 mg. METHODS:We included 259 PD patients treated with safinamide 100 mg (cases, n = 130) or never exposed to iMAO-B (controls, n = 129). The primary outcome was the sex × treatment interaction on the change in levodopa daily dose adjusted for body weight. RESULTS:Safinamide 100 mg improved UPDRS-III scores and reduced OFF-time independently of sex. A significant sex × treatment interaction emerged for change in weight-adjusted levodopa dose and total LEDD, with greater reduction in women (p = 0.025 and 0.045, respectively). CONCLUSIONS:Safinamide 100 mg provides a larger levodopa-sparing effect in women, supporting sex-specific optimization of dopaminergic therapy in PD management.

Growing evidence supports the importance of immune processes in Parkinson’s disease (PD). However, there is a need to improve the quality of observational clinical studies investigating the role of immunity in PD. In this context, an expert panel from the COST Action IMMUPARKNET (CA21117) aimed to develop guidance recommendations for conducting optimal immune profiling in PD. Firstly, criteria for inclusion and exclusion of participants, clinical data collection and participant stratification have been considered. Secondly, brain imaging of neuroinflammation has been reviewed. Finally, this review discusses sample collection, handling and storage of biological samples. In conclusion, this document aims to guide the scientific community in the optimal design of immune profiling studies in PD, so that we can generate robust and reliable data to advance our knowledge in this field.

Introduction: Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are severe complications of patients with systemic sclerosis (SSc). Currently, there are a few tests for early identification of these conditions, although they are invasive and time-consuming. Extracellular vesicles (EVs) offer a promising possibility for gathering information on tissue health. This study aims to characterize EVs in cases of systemic sclerosis complicated by pulmonary hypertension and pulmonary fibrosis. Methods: A cohort of 58 patients with SSc was evaluated, including 14 with pulmonary hypertension, 17 with pulmonary fibrosis, and 27 without complications. Additionally, 11 healthy subjects, matched for sex and age, served as a control group. EVs were characterized by using a MACSplex kit to analyze the expression of 37 membrane markers. Results: After the overall analysis, we show that EVs from SSc patients had higher expression of CD146, CD42a, and CD29 (p = 0.03, p = 0.02 and p = 0.05) but lower expression of HLA-ABC with respect to the control patients (p = 0.02). Multivariate analyses demonstrated that only CD42a has a significant association with the disease (p = 0.0478). In group comparative analyses (PAH, ILD, uncomplicated systemic sclerosis (named SSc no PAH no ILD), and controls), CD3 and CD56 were higher in PAH patients, with respect to the controls, ILD, and the group SSc no PAH no ILD (CD3: p = 0.01, p = 0.003, p = 0.0005; CD56: p = 0.002, p < 0.0001, p = 0.0002). HLA-DR showed higher expression in PAH patients with respect to ILD patients (p = 0.02), CD25 showed higher expression in PAH patients with respect uncomplicated SSc (p = 0.02), and CD42a showed higher expression in PAH patients with respect to the controls (p = 0.03); nevertheless, multivariate analyses demonstrated that only CD3 retained its association with PAH. Conclusions: The expression of CD42a, a platelet-derived marker indicating endothelial damage, suggests its potential to provide information on the state of the microcirculation in systemic sclerosis. The higher expression of CD3 on the surface of the EVs in PAH patients might indicate increased T-cell activity in tissues, with a possible association with the development of pulmonary hypertension.

(1) Background: Multiple sclerosis (MS) is a biologically highly heterogeneous disease and has poor predictability at diagnosis. Moreover, robust data indicate that early disease activity strongly correlates with future disability. Therefore, there is a need for strong and reliable biomarkers from diagnosis to characterize and identify patients who require highly effective disease-modifying treatments (DMTs). Several biomarkers are promising, particularly neurofilament light chains (NFLs), but the relevance of others is less consolidated. (2) Methods: We evaluated a panel of axonal damage and inflammatory biomarkers in cerebrospinal fluid (CSF) and matched serum obtained from a cohort of 60 newly diagnosed MS patients. Disability at diagnosis, negative prognostic factors, and the initial DMT prescribed were carefully recorded. (3) Results: We observed correlations between different axonal biomarkers: CSF and serum NFL versus CSF total tau; and between the inflammatory marker osteopontin (OPN) and axonal biomarkers CSF p-Tau, CSF total tau, and serum NFL. CSF and serum NFL and total tau, as well as CSF OPN, positively correlated with EDSS at diagnosis. Moreover, CSF and serum NFL levels were increased in patients with gadolinium-enhancing lesions (p = 0.01 and p = 0.04, respectively) and in those treated with highly effective DMT (p = 0.049). Furthermore, CSF OPN and both CSF and serum NFL levels significantly differentiated patients based on EDSS, with a combined ROC AUC of 0.88. We calculated and internally validated biomarker (in particular serum NFL) thresholds that significantly identified patients with higher disability. Finally, CSF OPN levels and dissemination in the spinal cord were significant predictors of EDSS at diagnosis. (4) Conclusions: These preliminary exploratory data confirm the pathological interconnection between inflammation and axonal damage from early disease stages, contributing to early disability. Follow-up data, such as longitudinal disability scores, repeated serum measurements, a healthy control group, and external validation of our results, are needed. We suggest that combining several fluid biomarkers may improve the clinical characterization of patients.

The pathophysiology of cognitive impairment (CI) in multiple sclerosis (MS) remains unclear. Meningeal B cell aggregates may contribute to cortical grey matter pathology. Cerebrospinal fluid (CSF), kappa free light chains (KFLC), and KFLCs-Index (kappa-Index) are reliable quantitative markers of intrathecal synthesis, but few data have been presented exploring the association with CI, and no data are present for lambda FLC (LFLC) in MS. We evaluated cognition using the Brief International Cognitive Assessment for MS (BICAMS) battery and collected serum and CSF at diagnosis in newly diagnosed drug-naïve MS patients. We observed that patients with impaired verbal memory and overall CI showed increased CSF KFLCs (respectively p: 0.0003 and p: 0.003) and kappa-Index (respectively p: 0.01 and p: 0.02) compared to those with normal verbal memory and no CI. Patients with CI also displayed lower CSF LFLCs (p: 0.04) and lambda-Index (p: 0.001); however, only CSF KFLC negatively correlated with normalized results of verbal memory (for age, sex, and educational levels), even after correction for EDSS (r: −0.27 p: 0.01). Finally, CSF FKLC and kappa-Index were significant predictors of verbal memory in a multivariate analysis. Our results, suggest that intrathecal B cell activity might contribute to CI development in MS patients.

Alzheimer’s disease (AD) is a neurodegenerative disorder defined clinically by progressive cognitive decline and memory impairment and pathologically by the accumulation of amyloid-beta plaques, tau neurofibrillary tangles, neuroinflammation, and immune system dysregulation. Peripheral biomarkers are gaining attention as valuable tools for elucidating neuroinflammatory mechanisms in the AD continuum, with potential implications for diagnosis and prognosis. Among these, the neutrophil-to-lymphocyte ratio (NLR) has emerged as a promising systemic inflammatory marker. NLR, a readily available and cost-effective parameter derived from routine blood tests, reflects the balance between innate and adaptive immune responses. Elevated NLR has been associated with AD and mild cognitive impairment (MCI), showing correlations with disease severity, amyloid burden, and neuroinflammation. Increased neutrophil counts may contribute to neurodegeneration through oxidative stress and pro-inflammatory cytokine release, while decreased lymphocyte levels suggest impaired adaptive immunity. However, despite growing evidence, the clinical utility of NLR in AD remains debated due to heterogeneity in study populations and confounding factors, such as comorbidities and medication effects. This review provides a comprehensive analysis of the association between NLR and AD throughout the disease continuum. Future research should prioritize longitudinal studies and integrative approaches that combine NLR with other inflammatory and neurodegenerative markers to enhance early diagnosis and personalized therapeutic strategies.

Parkinson’s disease (PD) affects more than one million people in the EU. It currently has no definitive cure, meaning that patients rely only on symptomatic treatments, which themselves are burdened by side effects. The need for advancements in both knowledge and available treatments is thus strongly felt by patients, caregivers, and health operators. This unmet need sparked the idea of orchestrating a collaborative effort via a common network – IMMUPARKNET (The role of IMMUnity in tackling PARKinson’s disease through a Translational NETwork). The IMMUPARKNET COST Action focuses on challenges in PD and its related crosstalk with immune response. Although widely recognized, the role of immunity in the onset and development of PD is still unclear. The main goal of IMMUPARKNET is to fill this knowledge gap by establishing an innovative, interdisciplinary research network and fostering exchanges of expertise among specialists from different countries and institutions. As we gather scientists and clinicians who study immunity in PD and related fields, IMMUPARKNET will establish the first nucleus of a multidisciplinary ecosystem that aims to harmonize efforts and approaches, both in research and clinical practice, to boost the development of ground-breaking treatments for PD. Through meetings, training schools, webinars, position papers, and review manuscripts, IMMUPARKNET will lead fruitful exchanges of know-how among experts in the field. The IMMUPARKNET structure revolves around 5 working groups, with a total of 157 active members from 34 different countries. Of these active members, 58.5% are young researchers, while 67.5% come from Inclusiveness Target Countries (ITC - less research-intensive COST Members; https://www.cost.eu/about/members/). IMMUPARKNET output will facilitate the improved sharing and development of research resources, straightening the road to novel treatments and identifying where existing ones can be repurposed, all, ultimately and hopefully, finding a cure for PD.

In this datanote we present data from 31 iRBD (idiopathic Rapid eye movement (REM) sleep Behaviour Disorder) patients followed throughout three years to assess their eventual phenoconversion to Parkinson’s disease and other established neurodegenerative conditions. iRBD is a prodromal condition of neurological pathologies such as Parkinson’s disease. We evaluated transcription factor mRNA levels in CD4+ T cells as predictive biomarkers of phenoconversion in iRBD, showing that among the transcription factors mRNA levels analysed, STAT1, GATA3 and FOXP3 mRNA levels may be used to predict phenoconversion. In particular, we found that CD4+ T cells from converters had higher STAT1, and lower GATA3 and FOXP3 mRNA levels. According to ROC curve analysis STAT1 levels provided a good discrimination, GATA3 levels an excellent discrimination of future converters and not-converters, while discrimination provided by FOXP3 levels was acceptable.

Ravulizumab, a monoclonal antibody against C5, is not currently approved for juvenile myasthenia gravis (MG). We are presenting a 14-year-old Moroccan girl diagnosed with antibody-positive generalized MG first treated with pyridostigmine 240 mg, prednisone 1 mg/kg/day, and thymectomy. Her clinical status remained unchanged (MG Foundation of America Clinical Classification: IIIa) with azathioprine 3 mg/kg, and steroids up to 2 mg/kg/day. She also required three rescue therapies over the subsequent 8 months, gained 10 kg, and had insomnia. We started compassionate ravulizumab treatment, as part of Alexion Pharmaceuticals expanded access program. At screening, the Myasthenia Gravis–Activities of Daily Living scale total score was 4, and Quantitative Myasthenia Gravis total scores were 13 (handgrip and forced vital capacity not performed). She continued her treatment every 8 weeks, and, at week 60, her Myasthenia Gravis–Activities of Daily Living scale total score was 0, and Quantitative Myasthenia Gravis total score was 1. This status was achieved despite an ongoing steroid tapering, that was possibly allowed using a rapidly-acting treatment. No significant infection or adverse effects were collected. We are presenting the first case of juvenile MG treated with ravulizumab. Clinical assessment showed at week 60 an improvement of 12 points according to the Quantitative Myasthenia Gravis scoring system, and 3 points to the Myasthenia Gravis–Activities of Daily Living scale total score. This case report supports the efficacy and safety of ravulizumab in MG patients aged <18 years.

BACKGROUND:The outcome of levodopa/carbidopa intestinal gel (LCIG) in Parkinson's disease carriers of GBA1 mutations (GBA-PD) remains uncertain. OBJECTIVE:To evaluate the safety and efficacy of LCIG in a large PD cohort, focusing on GBA1 variants. METHODS:This multicenter, retrospective, longitudinal "real-world" study included consecutive patients with advanced PD treated with LCIG at 31 Italian centers; data were collected at baseline, 1-, 5-year, and last-available follow-up. RESULTS:Data from 512 PD patients (59% male, mean age and disease duration at LCIG initiation 67.0 ± 8.0 and 12.9 ± 5.0 years, respectively) were analyzed. GBA1 genotyping was available for 306 patients (60%), of whom 40 (13%) had GBA1 mutations or risk variants. Mean follow-up on LCIG was 3.9 ± 2.9 years; 5-year follow-up data were available for 159 subjects. At baseline, GBA-PD had a younger age, shorter PD duration, worse cognition, and more hallucinations than noncarriers. At 1- and 5-year follow-up, LCIG improved motor and non-motor symptoms, OFF-time, and dyskinesias in the entire population. In GBA-PD, MDS-UPDRS parts I, II, and III scores did not change, while part IV score improved significantly less than in noncarriers; cognition and orthostatic hypotension symptoms worsened more rapidly. Multivariate analysis of predictors for adverse events and LCIG discontinuation found no significant contribution from GBA1 mutation status. CONCLUSIONS:GBA1 status does not increase the risk of adverse events or LCIG discontinuation. LCIG is a safe option for advanced GBA-PD, even in patients with cognitive impairment at baseline. However, GBA-PD experiences lower efficacy on motor disability and complications and faster cognitive decline than noncarriers.