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Background: Creutzfeldt-Jakob disease (CJD) is a rapidly progressive neurodegenerative disorder characterized by neuronal damage. Emerging biomarkers, such as serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), and growth differentiation factor-15 (sGDF-15), are currently being studied for their potential use in this disease., Objectives: This study analyzes the levels of sNfL, sGFAP, and sGDF-15, as well as their relationships, in patients with CJD compared to healthy controls (HC)., Methods: A total of 19 CJD patients and 81 age- and sex-matched HCs were enrolled. Serum levels of sNfL and sGFAP were measured using ultrasensitive immunoassays, while sGDF-15 levels were assessed via ELISA. Statistical analyses included correlation analysis and analysis of covariance (ANCOVA) models., Results: CJD patients showed significantly higher serum levels of sNfL and sGFAP compared to HCs (p <0,001). sNfL levels were positively correlated with both sGFAP (Rho = 0,70; p < 0,001) and sGDF-15 (Rho = 0,60; p = 0,004). Interestingly, sGFAP levels were higher in female CJD patients compared to males (p = 0,001), while no significant difference in sNfL levels was observed between sexes., Conclusions: In conclusion, this study explores the potential of sNfL, sGDF-15, and sGFAP as biomarkers in CJD patients. The higher levels of sNfL and sGFAP in CJD patients compared to healthy controls, along with the observed sex differences in sGFAP, highlight the need for further research into the interaction between astroglia and neurons in CJD, with a focus on sex as a key variable., Competing Interests: Declaration of competing interest All the Authors have no competing interests in relation to this study., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objectives: Editors of scientific journals play a key role in the health-related research process. Our study aims to characterize the demographics, work habits, decision-making processes, and ethical challenges faced by editors of neurological journals and to evaluate associations between editor or journal characteristics and editorial decisions, as well as sources of conflict of interest., Methods: Cross-sectional study involving editors from neurological journals that fell above the 50th percentile in the Scimago rankings. Editors were invited to complete a 16-item anonymous online survey. Data on demographics, editorial processes, decision-making, and ethical issues were collected and analysed., Results: 64 editors completed the survey (35.94% were aged 55-65 years, 68.75% had over 7 years of experience); journals' impact factors(IF) ranged from 1 to 10 (mean 3.412 ± 0.260). When reviewers were blinded to authors, editors relied more on reviewers' decisions (p = < 0.007). Editors with more years of experience relied less on reviewers' decisions (p = 0.009). Higher IF journals were associated with more frequent conflicts of interest between authors (p = 0.019) and reviewers (p = 0.033). Younger editors faced more ethical dilemmas related to scientific conduct and plagiarism (p = 0.008 and p = 0.016). Younger editors and those working for journals with higher IF were more likely to face ethical dilemmas related to editorial decisions (p = 0.016 and p = 0.042)., Discussion: The study highlights relevant aspects of the editorial process in neurological journals, emphasizing the influence of blinding procedures and the inconsistent handling of decision-making and ethical challenges. Addressing these issues through collaboration and standardized guidelines can promote the integrity of the process, ensuring high-quality and trustworthy scientific research., Competing Interests: Declarations. Conflicts of interest: The authors declare that they have no conflict of interest. Ethical approval: The Ethical Committee of the University of Campania "Luigi Vanvitelli" approved the study (protocol number 0014460/i)., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Few studies on multiple sclerosis (MS) have explored the variability of percentage brain volume change (PBVC) measurements obtained from different clinical MRIs. In a retrospective multicentre cohort study, we quantified the variability of annualised PBVC in clinical MRIs., Methods: Clinical MRIs of relapse-onset MS patients were assessed by icobrain. Volumetric data were analysed on same-scanner and different-scanner MRI pairs if they passed quality control criteria. Alignment similarity between two images had to be comparable to same-scanner scan-rescan images., Results: Of 6826 MRIs, 85 % had appropriate volumetric sequences and 4446 serial MRI pairs were analysed. 3334 (75 %) MRI pairs from 1207 patients met the inclusions. The PBVC of included MRI pairs showed variance of 0.78 % for same-scanner pairs and 0.80 % for different-scanner pairs. Further selection of included MRI pairs with the best variance resulted in 1885 (42 %) MRI pairs with PBVC variance of 0.34 %. Excluded MRI pairs with poor alignment similarity had variances of 2.97 % for same-scanner pairs and 20.79 % for different-scanner pairs., Conclusion: Icobrain should be utilised for PBVC determination only on selected MRIs with the best alignment similarity. Applying strict selection criteria for the included MRI pairs and longitudinal imaging on the same scanner remain mandatory to reduce PBVC variability., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Wim Van Hecke reports a relationship with Icometrix NV that includes: board membership and equity or stocks. Diana M. Sima reports a relationship with Icometrix NV that includes: employment. Guy Nagels reports a relationship with Icometrix NV that includes: consulting or advisory and equity or stocks. Femke Podevyn reports a relationship with Icometrix NV that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Importance: Typical cysteine-altering NOTCH3 (NOTCH3cys) variants are highly prevalent (approximately 1 in 300 individuals) and are associated with a broad spectrum of small vessel disease (SVD), ranging from early-onset stroke and dementia (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) to nonpenetrance. A staging system that captures the full NOTCH3-SVD severity spectrum is needed and currently lacking., Objective: To design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3-SVD severity spectrum., Design, Setting, and Participants: A cohort study was performed in which the NOTCH3-SVD severity staging system was developed using a discovery cohort (2019-2020) and validated in independent international CADASIL cohorts (1999-2023) and the UK Biobank. Clinical and imaging data were collected from participants originating from 23 international CADASIL cohorts and from the UK Biobank. Eligibility criteria were presence of a NOTCH3cys variant, availability of brain magnetic resonance imaging, and modified Rankin Scale score. The discovery cohort consisted of 195 NOTCH3cys-positive cases from families with CADASIL; the validation set included 1713 NOTCH3cys-positive cases from 15 countries. The UK Biobank cohort consisted of 101 NOTCH3cys-positive individuals. Data from 2-year (2019-2023) and 18-year (1999-2017) follow-up studies were also analyzed. Data analysis was performed from July 2023 to August 2024., Main Outcomes and Measures: Percentage of cases following the sequence of events of the NOTCH3-SVD stages, and the association between the stages and ischemic stroke, intracerebral hemorrhage, global cognition, processing speed, brain volume, brain microstructural damage, and serum neurofilament light chain (NfL) level., Results: The NOTCH3-SVD staging system encompasses 9 disease stages or substages, ranging from stage 0 (premanifest stage) to stage 4B (end stage). Of all 1908 cases, which included 195 in the discovery cohort (mean [SD] age, 52.4 [12.2] years) and 1713 in the validation cohorts (mean [SD] age, 53.1 [13.0] years), 1789 (94%) followed the sequence of events defined by the NOTCH3-SVD staging system. The NOTCH3-SVD stages were associated with neuroimaging outcomes in the NOTCH3cys-positive cases in the CADASIL cohorts and in the UK Biobank and with cognitive outcomes and serum NfL level in cases from the CADASIL cohorts. The NOTCH3-SVD staging system captured disease progression and was associated with 18-year survival., Conclusions and Relevance: The NOTCH3-SVD staging system captures the full disease spectrum, from asymptomatic individuals with a NOTCH3cys variant to patients with end-stage disease. The NOTCH3-SVD staging system is a simple but effective tool for uniform disease staging in the clinic and in research.

Background and Objectives: Disentangling brain aging from disease-related neurodegeneration in patients with multiple sclerosis (PwMS) is increasingly topical. The brain-age paradigm offers a window into this problem but may miss disease-specific effects. In this study, we investigated whether a disease-specific model might complement the brain-age gap (BAG) by capturing aspects unique to MS., Methods: In this retrospective study, we collected 3D T1-weighted brain MRI scans of PwMS to build (1) a cross-sectional multicentric cohort for age and disease duration (DD) modeling and (2) a longitudinal single-center cohort of patients with early MS as a clinical use case. We trained and evaluated a 3D DenseNet architecture to predict DD from minimally preprocessed images while age predictions were obtained with the DeepBrainNet model. The brain-predicted DD gap (the difference between predicted and actual duration) was proposed as a DD-adjusted global measure of MS-specific brain damage. Model predictions were scrutinized to assess the influence of lesions and brain volumes while the DD gap was biologically and clinically validated within a linear model framework assessing its relationship with BAG and physical disability measured with the Expanded Disability Status Scale (EDSS)., Results: We gathered MRI scans of 4,392 PwMS (69.7% female, age: 42.8 ± 10.6 years, DD: 11.4 ± 9.3 years) from 15 centers while the early MS cohort included 749 sessions from 252 patients (64.7% female, age: 34.5 ± 8.3 years, DD: 0.7 ± 1.2 years). Our model predicted DD better than chance (mean absolute error = 5.63 years, R 2 = 0.34) and was nearly orthogonal to the brain-age model (correlation between DD and BAGs: r = 0.06 [0.00-0.13], p = 0.07). Predictions were influenced by distributed variations in brain volume and, unlike brain-predicted age, were sensitive to MS lesions (difference between unfilled and filled scans: 0.55 years [0.51-0.59], p < 0.001). DD gap significantly explained EDSS changes ( B = 0.060 [0.038-0.082], p < 0.001), adding to BAG (Δ R 2 = 0.012, p < 0.001). Longitudinally, increasing DD gap was associated with greater annualized EDSS change ( r = 0.50 [0.39-0.60], p < 0.001), with an incremental contribution in explaining disability worsening compared with changes in BAG alone (Δ R 2 = 0.064, p < 0.001)., Discussion: The brain-predicted DD gap is sensitive to MS-related lesions and brain atrophy, adds to the brain-age paradigm in explaining physical disability both cross-sectionally and longitudinally, and may be used as an MS-specific biomarker of disease severity and progression.

Background: Liver transplantation (LT) is still limited by organ shortage and post-transplant monitoring issues. While machine perfusion techniques allow for improving organ preservation, biomarkers like donor-derived cell-free DNA (dd-cfDNA) and mitochondrial cfDNA (mt-cfDNA) may provide insights into graft injury and viability pre- and post-LT., Methods: A prospective observational cohort study was conducted on LT recipients (n = 45) to evaluate dd-cfDNA as a biomarker of graft dysfunction during the first 6 months after LT. Dd-cfDNA was quantified on blood samples collected pre-LT and post-LT using droplet digital PCR. In livers undergoing dual hypothermic oxygenated machine perfusion (D-HOPE), total cfDNA and mt-cfDNA levels were measured on perfusate samples collected at 30-min intervals. Correlations with graft function and clinical outcomes were assessed., Results: Dd-cfDNA levels peaked post-LT and correlated with transaminase levels and histological injury severity. The longitudinal assessment showed that postoperative complications and rejection were associated with an increase in dd-cfDNA levels. Mt-cfDNA levels in D-HOPE perfusate correlated with graft function parameters post-LT and were higher in patients with early allograft dysfunction and severe complications., Conclusions: This study confirms dd-cfDNA as a marker of graft injury after LT and suggests that perfusate mt-cfDNA levels during D-HOPE correlate with graft function and post-transplant clinical outcome. Integration of these tests into clinical practice may improve transplant management and viability assessment during hypothermic perfusion., (© 2024 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

The interaction between ageing and multiple sclerosis is complex and carries significant implications for patient care. Managing multiple sclerosis effectively requires an understanding of how ageing and multiple sclerosis impact brain structure and function. Ageing inherently induces brain changes, including reduced plasticity, diminished grey matter volume, and ischaemic lesion accumulation. When combined with multiple sclerosis pathology, these age-related alterations may worsen clinical disability. Ageing may also influence the response of multiple sclerosis patients to therapies and/or their side effects, highlighting the importance of adjusted treatment considerations. MRI is highly sensitive to age- and multiple sclerosis-related processes. Accordingly, MRI can provide insights into the relationship between ageing and multiple sclerosis, enabling a better understanding of their pathophysiological interplay and informing treatment selection. This review summarizes current knowledge on the immunopathological and MRI aspects of ageing in the CNS in the context of multiple sclerosis. Starting from immunosenescence, ageing-related pathological mechanisms and specific features like enlarged Virchow-Robin spaces, this review then explores clinical aspects, including late-onset multiple sclerosis, the influence of age on diagnostic criteria, and comorbidity effects on imaging features. The role of MRI in understanding neurodegeneration, iron dynamics and myelin changes influenced by ageing and how MRI can contribute to defining treatment effects in ageing multiple sclerosis patients, are also discussed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background/objectives: The primary life-threatening complication in spinal-bulbar muscular atrophy (SBMA) is ventilatory failure. The present study analyzes the longitudinal patterns of respiratory function tests over a follow-up of 11 years., Methods: We collected data from 9 genetically confirmed SBMA patients. Spirometric measurements [maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), and forced vital capacity (FVC)], serum biochemical indices and SBMA functional rating scale (SBMAFRS) were collected every 6 months for 11 years. An average time curve was utilized to assess the changes in both pulmonary tests and serum biochemical indices of the patients. One-way repeated-measures ANOVA was applied to assess statistical differences. The Spearman's rank correlation coefficient was utilized to evaluate the correlations between the respiratory function tests and serum biochemical and clinical indices., Results: A progressive decrease was observed in the respiratory function tests; the slope of the linear regression was significantly non-zero ( p < 0.0001) for all three time curves. A major decrease was observed for MEP (52%) and MIP (42%), while this was minor for FVC (25%). SBMAFRS score correlated with FVC (r = 0.27), MIP (r = 0.53) and MEP (r = 0.51). MIP and MEP correlated with creatine phosphokinase (r = 0.3, r = 0.25, respectively) and MIP with creatinine levels (r = 0.31)., Conclusions: This longitudinal study shows a progressive decline of spirometric data throughout life in SBMA patients. The decline appears to be related to clinical deterioration and muscle denervation. Spirometric measures relative to maximal strength of the respiratory muscles (MIP and MEP) may have a better predictive value for pulmonary and muscular decline than FVC.

Despite the commonly observed association of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies with bilateral optic neuritis, their connection to uveitis is largely unexplored. The presented case involves a 41-year-old male with uveitis and bilateral optic neuritis, subsequently diagnosed with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). This case, characterized by bilateral optic neuritis associated to anti-MOG antibodies and the concurrent onset of unilateral anterior uveitis, provides further evidence concerning the features of intraocular inflammation in MOGAD. The patient's treatment response, including the use of rituximab due to contraindications to oral steroids, emphasizes the importance of personalized management strategies in MOGAD-associated ocular manifestations., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Vascular mild cognitive impairment (VMCI) is a transitional condition that may evolve into Vascular Dementia(VaD). Hippocampal volume (HV) is suggested as an early marker for VaD, the role of white matter lesions (WMLs) in neurodegeneration remains debated., Objectives: Evaluate HV and WMLs as predictive markers of VaD in VMCI patients by assessing: (i)baseline differences in HV and WMLs between converters to VaD and non-converters, (ii) predictive power of HV and WMLs for VaD, (iii) associations between HV, WMLs, and cognitive decline, (iv)the role of WMLs on HV., Methods: This longitudinal multicenter study included 110 VMCI subjects (mean age:74.33 ± 6.63 years, 60males/50females) from the VMCI-Tuscany Study database. Subjects underwent brain MRI and cognitive testing, with 2-year follow-up data on VaD progression. HV and WMLs were semi-automatically segmented and measured. ANCOVA assessed group differences, while linear and logistic regression models evaluated predictive power., Results: After 2 years, 32/110 VMCI patients progressed to VaD. Converting patients had lower HV(p = 0.015) and higher lesion volumes in the posterior thalamic radiation (p = 0.046), splenium of the corpus callosum (p = 0.016), cingulate gyrus (p = 0.041), and cingulum hippocampus(p = 0.038). HV alone did not fully explain progression (p = 0.059), but combined with WMLs volume, the model was significant (p = 0.035). The best prediction model (p = 0.001) included total HV (p = 0.004) and total WMLs volume of the posterior thalamic radiation (p = 0.005) and cingulate gyrus (p = 0.005), achieving 80% precision, 81% specificity, and 74% sensitivity. Lower HV were linked to poorer performance on the Rey Auditory-Verbal Learning Test delayed recall (RAVLT) and Mini Mental State Examination (MMSE)., Conclusions: HV and WMLs are significant predictors of progression from VMCI to VaD. Lower HV correlate with worse cognitive performance on RAVLT and MMSE tests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

CCDC78 was identified as a novel candidate gene for autosomal dominant centronuclear myopathy-4 (CNM4) approximately ten years ago. However, to date, only one family has been described, and the function of CCDC78 remains unclear. Here, we analyze for the first time a family harboring a CCDC78 nonsense mutation to better understand the role of CCDC78 in muscle., Methods: We conducted a comprehensive histopathological analysis on muscle biopsies, including immunofluorescent assays to detect multiple sarcoplasmic proteins. We examined CCDC78 transcripts and protein using WB in CCDC78 -mutated muscle tissue; these analyses were also performed on muscle, lymphocytes, and fibroblasts from healthy subjects. Subsequently, we conducted RT-qPCR and transcriptome profiling through RNA-seq to evaluate changes in gene expression associated with CCDC78 dysfunction in muscle. Lastly, coimmunoprecipitation (Co-Ip) assays and mass spectrometry (LC-MS/MS) studies were carried out on extracted muscle proteins from both healthy and mutated subjects., Results: The histopathological features in muscle showed novel histological hallmarks, which included areas of dilated and swollen sarcoplasmic reticulum (SR). We provided evidence of nonsense-mediated mRNA decay (NMD), identified the presence of novel CCDC78 transcripts in muscle and lymphocytes, and identified 1035 muscular differentially expressed genes, including several involved in the SR. Through the Co-Ip assays and LC-MS/MS studies, we demonstrated that CCDC78 interacts with two key SR proteins: SERCA1 and CASQ1. We also observed interactions with MYH1, ACTN2, and ACTA1., Conclusions: Our findings provide insight, for the first time, into the interactors and possible role of CCDC78 in skeletal muscle, locating the protein in the SR. Furthermore, our data expand on the phenotype previously associated with CCDC78 mutations, indicating potential histopathological hallmarks of the disease in human muscle. Based on our data, we can consider CCDC78 as the causative gene for CNM4.

Background: NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised., Methods: In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants., Findings: Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches., Interpretation: We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD., Funding: The Wellcome Trust, the MRC., Competing Interests: Declaration of interests Wendy Chung is on the board of directors of Prime Medicine. Stephan Zuchner has received consultancy honoraria from Neurogene, AegleaBioTherapeutics, Applied Therapeutics, and is an unpaid officer of the TGP foundation, all unrelated to the present manuscript. Elisa Fazzi has received honoraria from GW Pharma. Nicola De Stefano has received honoraria from Biogen-Idec, Genzyme, Immunic, Merck, Novartis, Roche, Celgene, and Teva for consulting services, speaking, and travel support. He serves on advisory boards for Merck, Novartis, Biogen-Idec, Immunic, Roche, and Genzyme, and he has received research grant support from the Italian MS Society. Lyn R Griffiths has received grants from the Australian National Health and Medical Research Council, Variant Bio, US Department of Defense and US Migraine Research Foundation as well as honoraria from Teva, Springer Nature, and Association of Migraine Disorders and she is Board of Censors, Diagnostic Genomics Human Genetics Assoc Australia and member of the Human Genetics Australasia Advisory Board. Hugh S Markus has received peer reviewed grants from the Medical Research Council, British Heart Foundation, National Institute of Health Research, and the Alzheimer Society, and is editor in chief of the International Journal of Stroke., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Spinal cord (SC) atrophy obtained from structural magnetic resonance imaging has gained relevance as an indicator of neurodegeneration in various neurological disorders. The common method to assess SC atrophy is by comparing numerical differences of the cross-sectional spinal cord area (CSA) between time points. However, this indirect approach leads to considerable variability in the obtained results. Studies showed that this limitation can be overcome by using a registration-based technique. The present study introduces the Structural Image Evaluation using Normalization of Atrophy on the Spinal Cord (SIENA-SC), which is an adapted version of the original SIENA method, designed to directly calculate the percentage of SC volume change over time from clinical brain MRI acquired with an extended field of view to cover the superior part of the cervical SC. In this work, we compared SIENA-SC with the Generalized Boundary Shift Integral (GBSI) and the CSA change. On a scan-rescan dataset, SIENA-SC was shown to have the lowest measurement error than the other two methods. When comparing a group of 190 Healthy Controls with a group of 65 Multiple Sclerosis patients, SIENA-SC provided significantly higher yearly rates of atrophy in patients than in controls and a lower sample size when measured for treatment effect sizes of 50%, 30% and 10%. Our findings indicate that SIENA-SC is a robust, reproducible, and sensitive approach for assessing longitudinal changes in spinal cord volume, providing neuroscientists with an accessible and automated tool able to reduce the need for manual intervention and minimize variability in measurements., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nicola De Stefano reports financial support was provided by National Recovery and Resilience Plan (PNRR), and also relationship with Biogen, Merck, Novartis, Sanofi, Roche, Teva, FISM that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Rosa Cortese reports a relationship with Roche, Merck Serono, Janssen, Novartis, Sanofi that includes: speaking and lecture fees and travel reimbursement. Ferran Prados reports a relationship with National Institute for Health and Care Research (NIHR) Biomedical Research Centres (BRC) at University College London (UCL) that includes: employment, funding grants, speaking and lecture fees, and travel reimbursement. Massimiliano Calabrese reports a relationship with Roche, Sanofi Genzyme, Merck Serono, Biogen Idec, Teva, and Novartis Pharma that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To evaluate: (1) the distribution of gray matter (GM) atrophy in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), and relapsing-remitting multiple sclerosis (RRMS); and (2) the relationship between GM volumes and white matter lesions in various brain regions within each disease., Methods: A retrospective, multicenter analysis of magnetic resonance imaging data included patients with MOGAD/AQP4+NMOSD/RRMS in non-acute disease stage. Voxel-wise analyses and general linear models were used to evaluate the relevance of regional GM atrophy. For significant results (p < 0.05), volumes of atrophic areas are reported., Results: We studied 135 MOGAD patients, 135 AQP4+NMOSD, 175 RRMS, and 144 healthy controls (HC). Compared with HC, MOGAD showed lower GM volumes in the temporal lobes, deep GM, insula, and cingulate cortex (75.79 cm 3 ); AQP4+NMOSD in the occipital cortex (32.83 cm 3 ); and RRMS diffusely in the GM (260.61 cm 3 ). MOGAD showed more pronounced temporal cortex atrophy than RRMS (6.71 cm 3 ), whereas AQP4+NMOSD displayed greater occipital cortex atrophy than RRMS (19.82 cm 3 ). RRMS demonstrated more pronounced deep GM atrophy in comparison with MOGAD (27.90 cm 3 ) and AQP4+NMOSD (47.04 cm 3 ). In MOGAD, higher periventricular and cortical/juxtacortical lesions were linked to reduced temporal cortex, deep GM, and insula volumes. In RRMS, the diffuse GM atrophy was associated with lesions in all locations. AQP4+NMOSD showed no lesion/GM volume correlation., Interpretation: GM atrophy is more widespread in RRMS compared with the other two conditions. MOGAD primarily affects the temporal cortex, whereas AQP4+NMOSD mainly involves the occipital cortex. In MOGAD and RRMS, lesion-related tract degeneration is associated with atrophy, but this link is absent in AQP4+NMOSD. ANN NEUROL 2024;96:276-288., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose of Review: Tumor entities represent an increasing indication for liver transplantation (LT). This review addresses the most contentious indications of LT in transplant oncology., Recent Findings: Patient selection based on tumor biology in LT for colorectal cancer liver metastases (CRLM) demonstrated promising long-term outcomes and preserved quality of life despite high recurrence rates. In selected cases, LT for intrahepatic cholangiocarcinoma (iCCA) is feasible, with acceptable survival even in high-burden cases responsive to chemotherapy. LT following a strict neoadjuvant protocol for perihilar cholangiocarcinoma (pCCA) resulted in long-term outcomes consistently surpassing benchmark values, and potentially outperforming liver resection., Summary: While preliminary results are promising, prospective trials are crucial to define applications in routine clinical practice. Molecular profiling and targeted therapies pave the way for personalized approaches, requiring evolving allocation systems for equitable LT access., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Research work has shown that hippocampal subfields are atrophic to varying extents in multiple sclerosis (MS) patients. However, studies examining the functional implications of subfield-specific hippocampal damage in early MS are limited. We aim to gain insights into the relationship between hippocampal atrophy and memory function by investigating the correlation between global and regional hippocampal atrophy and memory performance in early MS patients., Methods: From the Italian Neuroimaging Network Initiative (INNI) dataset, we selected 3D-T1-weighted brain MRIs of 219 early relapsing remitting (RR)MS and 246 healthy controls (HC) to identify hippocampal atrophic areas. At the time of MRI, patients underwent Selective-Reminding-Test (SRT) and Spatial-Recall-Test (SPART) and were classified as mildly (MMI-MS: n.110) or severely (SMI-MS: n:109) memory impaired, according to recently proposed cognitive phenotypes., Results: Early RRMS showed lower hippocampal volumes compared to HC (p < 0.001), while these did not differ between MMI-MS and SMI-MS. In MMI-MS, lower hippocampal volumes correlated with worse memory tests (r = 0.23-0.37, p ≤ 0.01). Atrophic voxels were diffuse in the hippocampus but more prevalent in cornu ammonis (CA, 79%) than in tail (21%). In MMI-MS, decreased subfield volumes correlated with decreases in memory, particularly in the right CA1 (SRT-recall: r = 0.38; SPART: r = 0.34, p < 0.01). No correlations were found in the SMI-MS group., Conclusion: Hippocampal atrophy spreads from CA to tail from early disease stages. Subfield hippocampal atrophy is associated with memory impairment in MMI-MS, while this correlation is lost in SMI-MS. This plays in favor of a limited capacity for an adaptive functional reorganization of the hippocampi in MS patients., (© 2024. The Author(s).)

Progression independent of relapse activity (PIRA), a recent concept to formalize disability accrual in multiple sclerosis (MS) independent of relapses, has gained popularity as a potential clinical trial outcome. We discuss its shortcomings and appraise the challenges of implementing it in clinical settings, experimental trials, and research. The current definition of PIRA assumes that acute inflammation, which can manifest as a relapse, and neurodegeneration, manifesting as progressive disability accrual, can be disentangled by introducing specific time windows between the onset of relapses and the observed increase in disability. The term PIRMA (progression independent of relapse and MRI activity) was recently introduced to indicate disability accrual in the absence of both clinical relapses and new brain and spinal cord MRI lesions. Assessing PIRMA in clinical practice is highly challenging because it necessitates frequent clinical assessments and brain and spinal cord MRI scans. PIRA is commonly assessed using Expanded Disability Status Scale, a scale heavily weighted toward motor disability, whereas a more granular assessment of disability deterioration, including cognitive decline, using composite measures or other tools, such as digital tools, would possess greater utility. Similarly, using PIRA as an outcome measure in randomized clinical trials is also challenging and requires methodological considerations. The underpinning pathobiology of disability accumulation, that is not associated with relapses, may encompass chronic active lesions (slowly expanding lesions and paramagnetic rim lesions), cortical lesions, brain and spinal cord atrophy, particularly in the gray matter, diffuse and focal microglial activation, persistent leptomeningeal enhancement, and white matter tract damage. We propose to use PIRA to understand the main determinant of disability accrual in observational, cohort studies, where regular MRI scans are not included, and introduce the term of "advanced-PIRMA" to investigate the contributions to disability accrual of the abovementioned processes, using conventional and advanced imaging. This is supported by the knowledge that MRI reflects the MS pathogenic mechanisms better than purely clinical descriptors. Any residual disability accrual, which remains unexplained after considering all these mechanisms with imaging, will highlight future research priorities to help complete our understanding of MS pathogenesis.

Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of the disease and underlies the progression of disability, which proceeds relentlessly and independently of clinical and radiological relapses (PIRA). The complex system of pathological events driving "chronic" worsening is likely linked with the early accumulation of compartmentalized inflammation within the central nervous system as well as insufficient repair phenomena and mitochondrial failure. These mechanisms are partially lesion-independent and differ from those causing clinical relapses and the formation of new focal demyelinating lesions; they lead to neuroaxonal dysfunction and death, myelin loss, glia alterations, and finally, a neuronal network dysfunction outweighing central nervous system (CNS) compensatory mechanisms. This review aims to provide an overview of the state of the art of neuropathological, immunological, and imaging knowledge about the mechanisms underlying the smoldering disease activity, focusing on possible early biomarkers and their translation into clinical practice. ANN NEUROL 2024;96:1-20., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: ChatGPT is an open-source natural language processing software that replies to users' queries. We conducted a cross-sectional study to assess people living with Multiple Sclerosis' (PwMS) preferences, satisfaction, and empathy toward two alternate responses to four frequently-asked questions, one authored by a group of neurologists, the other by ChatGPT., Methods: An online form was sent through digital communication platforms. PwMS were blind to the author of each response and were asked to express their preference for each alternate response to the four questions. The overall satisfaction was assessed using a Likert scale (1-5); the Consultation and Relational Empathy scale was employed to assess perceived empathy., Results: We included 1133 PwMS (age, 45.26 ± 11.50 years; females, 68.49%). ChatGPT's responses showed significantly higher empathy scores (Coeff = 1.38; 95% CI = 0.65, 2.11; p > z < 0.01), when compared with neurologists' responses. No association was found between ChatGPT' responses and mean satisfaction (Coeff = 0.03; 95% CI = - 0.01, 0.07; p = 0.157). College graduate, when compared with high school education responder, had significantly lower likelihood to prefer ChatGPT response (IRR = 0.87; 95% CI = 0.79, 0.95; p < 0.01)., Conclusions: ChatGPT-authored responses provided higher empathy than neurologists. Although AI holds potential, physicians should prepare to interact with increasingly digitized patients and guide them on responsible AI use. Future development should consider tailoring AIs' responses to individual characteristics. Within the progressive digitalization of the population, ChatGPT could emerge as a helpful support in healthcare management rather than an alternative., (© 2024. The Author(s).)

Hepatocellular carcinoma (HCC) remains the leading oncological indication for liver transplantation (LT), with evolving and broadened inclusion criteria. Immune checkpoint inhibitors (ICIs) gained a central role in systemic HCC treatment and showed potential in the peri-transplant setting as downstaging/bridging therapy before LT or as a treatment for HCC recurrence following LT. However, the antagonistic mechanisms of action between ICIs and immunosuppressive drugs pose significant challenges, particularly regarding the risk of acute rejection (AR). This review analyzes the main signaling pathways targeted by ICI therapies and summarizes current studies on ICI therapy before and after LT. The literature on this topic is limited and highly heterogeneous, precluding definitive evidence-based conclusions. The use of ICIs before LT appears promising, provided that a sufficient wash-out period is implemented. In contrast, the results of post-LT ICI therapy do not support its wide clinical application due to high AR rates and overall poor response to treatment. In the future, modern graft preservation techniques might support the selection of good ICI responders, but data from high-level studies are urgently needed.

Background: Cognitive impairment (CI) is a common and disabling feature of people with multiple sclerosis (pwMS), but its underlying mechanisms are heterogenous and not fully understood. A role of infiltrating immune cells in the meninges and brain parenchyma has been hypothesized. This study aimed to explore the hypothesis that intrathecal B cells might influence cognitive performance in pwMS., Methods: A retrospective study was performed on 39 newly diagnosed pwMS who underwent cerebrospinal fluid (CSF) analysis. Kappa (κ)-index was measured as a biomarker of intrathecal B cell activation. Cognitive performance was assessed using the Brief Repeatable Battery of Neuropsychological Tests (BRBN). Brain T2 lesions number (T2LN) and volume (T2LV) together with brain, cortical grey matter, thalamic and hippocampal volumes were calculated to account for MRI-visible damage., Results: κ-index was higher in pwMS with verbal memory impairment (median 99.6, range 58.5-195.2 vs. median 37.2, range 2.3-396.9, p < 0.001), and it was negatively associated with BRBN tests exploring verbal memory and information processing speed. In multivariate models, higher κ-index was confirmed to be independently associated with worse scores of BRBN tests exploring verbal memory and with a higher probability of verbal memory impairment., Conclusion: Intrathecal B cells might drive memory impairment in pwMS independently of brain damage visible on MRI scans., Competing Interests: Declaration of competing interest LG participated on advisory boards for, and received writing honoraria and travel grants from Almirall, Biogen, Euroimmun, Fujirebio, Lilly, Merck, Mylan, Novartis, Roche, Sanofi, Siemens Healthineers and Teva. AM participated on advisory boards for, and received writing honoraria and travel grants to attend national and international conferences from Alexion, Almirall, Biogen Idec, Merck, Mylan, Novartis, Sanofi and Teva. NDS participated on advisory boards for and received speaker or writing honoraria and funding for travelling from Bayer, Biogen Idec, Bristol, Genzyme, Immunic, Merck, Novartis, Roche, and Teva. MDF participated on advisory boards and steering committees for and received speaker or writing honoraria, research support and funding for travelling from Alexion, BMS, Bayer, Biogen Idec, Genzyme, Horizon, Janssen, Merck, Mylan, Novartis, Roche, Siemens Healthineers, Teva and Viatris. NS, GB, SS, AF, EDS, AV, and LP report no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background and Objectives: Vidofludimus calcium suppressed MRI disease activity compared with placebo in patients with relapsing-remitting multiple sclerosis (RRMS) in the first cohort of the phase 2 EMPhASIS study. Because 30 mg and 45 mg showed comparable activity on multiple end points, the study enrolled an additional low-dose cohort to further investigate a dose-response relationship., Methods: In a randomized, placebo-controlled, phase 2 trial, patients with RRMS, aged 18-55 years, and with ≥2 relapses in the last 2 years or ≥1 relapse in the last year, and ≥1 gadolinium-enhancing brain lesion in the last 6 months. Patients were randomly assigned (1:1:1) vidofludimus calcium (30 or 45 mg) or placebo in cohort 1 and vidofludimus calcium (10 mg) or placebo (4:1) in cohort 2 for 24 weeks. The primary end point was the cumulative number of combined unique active (CUA) lesions at week 24. Secondary end points were clinical outcomes and safety., Results: Across cohorts 1 and 2, 268 patients were randomized to placebo (n = 81), 10 mg (n = 47) vidofludimus calcium, 30 mg (n = 71) vidofludimus calcium, or 45 mg (n = 69) vidofludimus calcium. The mean cumulative CUA lesions over 24 weeks was 5.8 (95% CI 4.1-8.2) for placebo, 5.9 (95% CI 3.9-9.0) for 10 mg treatment group, 1.4 (95% CI 0.9-2.1) for 30 mg treatment group, and 1.7 (95% CI 1.1-2.5) for 45 mg treatment group. Serum neurofilament light chain decreased in a dose-dependent manner. The number of patients with confirmed disability worsening after 24 weeks was 3 (3.7%) patients receiving placebo and 3 (1.6%) patients receiving any dose of vidofludimus calcium. Treatment-emergent adverse events occurred in 35 (43%) placebo patients compared with 11 (23%) and 71 (37%) patients in the 10 mg or any dose of vidofludimus calcium groups, respectively. The incidence of liver enzyme elevations and infections were similar between placebo and any dose of vidofludimus calcium. No new safety signals were observed., Discussion: Compared with placebo, vidofludimus calcium suppressed the development of new brain lesions with daily doses of 30 mg and 45 mg, but not 10 mg, establishing the lowest efficacious dose is 30 mg., Classification of Evidence: This study provides Class II evidence that among adults with active RRMS and ≥1 Gd+ brain lesion in the past 6 months, the cumulative number of active lesions decreased with vidofludimus calcium., Trial Registration Information: ClinicalTrials.gov (NCT03846219) and EudraCT (2018-001896-19).

Cortical myelin loss and repair in multiple sclerosis (MS) have been explored in neuropathological studies, but the impact of these processes on neurodegeneration and the irreversible clinical progression of the disease remains unknown. Here, we evaluated in vivo cortical demyelination and remyelination in a large cohort of people with all clinical phenotypes of MS followed up for 5 years using magnetization transfer imaging (MTI), a technique that has been shown to be sensitive to myelin content changes in the cortex. We investigated 140 people with MS (37 clinically isolated syndrome, 71 relapsing-MS, 32 progressive-MS), who were clinically assessed at baseline and after 5 years and, along with 84 healthy controls, underwent a 3 T-MRI protocol including MTI at baseline and after 1 year. Changes in cortical volume over the radiological follow-up were computed with a Jacobian integration method. Magnetization transfer ratio was employed to calculate for each patient an index of cortical demyelination at baseline and of dynamic cortical demyelination and remyelination over the follow-up period. The three indices of cortical myelin content change were heterogeneous across patients but did not significantly differ across clinical phenotypes or treatment groups. Cortical remyelination, which tended to fail in the regions closer to CSF (-11%, P < 0.001), was extensive in half of the cohort and occurred independently of age, disease duration and clinical phenotype. Higher indices of cortical dynamic demyelination (β = 0.23, P = 0.024) and lower indices of cortical remyelination (β = -0.18, P = 0.03) were significantly associated with greater cortical atrophy after 1 year, independently of age and MS phenotype. While the extent of cortical demyelination predicted a higher probability of clinical progression after 5 years in the entire cohort [odds ratio (OR) = 1.2; P = 0.043], the impact of cortical remyelination in reducing the risk of accumulating clinical disability after 5 years was significant only in the subgroup of patients with shorter disease duration and limited extent of demyelination in cortical regions (OR = 0.86, P = 0.015, area under the curve = 0.93). In this subgroup, a 30% increase in cortical remyelination nearly halved the risk of clinical progression at 5 years, independently of clinical relapses. Overall, our results highlight the critical role of cortical myelin dynamics in the cascade of events leading to neurodegeneration and to the subsequent accumulation of irreversible disability in MS. Our findings suggest that early-stage myelin repair compensating for cortical myelin loss has the potential to prevent neuro-axonal loss and its long-term irreversible clinical consequences in people with MS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Numerous therapies are currently available to modify the disease course of multiple sclerosis (MS). Magnetic resonance imaging (MRI) plays a pivotal role in assessing treatment response by providing insights into disease activity and clinical progression. Integrating MRI findings with clinical and laboratory data enables a comprehensive assessment of the disease course. Among available MS treatments, cladribine is emerging as a promising option due to its role as a selective immune reconstitution therapy, with a notable impact on B cells and a lesser effect on T cells. This work emphasizes the assessment of MRI's contribution to MS treatment, particularly focusing on the influence of cladribine tablets on imaging outcomes, encompassing data from pivotal and real-world studies. The evidence highlights that cladribine, compared with placebo, not only exhibits a reduction in inflammatory imaging markers, such as T1-Gd+, T2 and combined unique active (CUA) lesions, but also mitigates the effect on brain volume loss, particularly within grey matter. Importantly, cladribine reveals early action by reducing CUA lesions within the first months of treatment, regardless of a patient's initial conditions. The selective mechanism of action, and sustained efficacy beyond year 2, combined with its early onset of action, collectively position cladribine tablets as a pivotal component in the therapeutic paradigm for MS. Overall, MRI, along with clinical measures, has played a substantial role in showcasing the effectiveness of cladribine in addressing both the inflammatory and neurodegenerative aspects of MS., (© 2024. The Author(s).)

Background: Cognitive impairment is a common clinical manifestation in people with multiple sclerosis (PwMS) and significantly impacts patients' quality life. Cognitive assessment is crucial for treatment decisions and understanding disease progression. Several neuropsychological batteries are used in MS, including the Brief Repeatable Battery of Neuropsychological Tests (BRB-N), Minimal Assessment of Cognitive Function in MS (MACFIMS), and Brief International Cognitive Assessment for MS (BICAMS). However, normative data for BRB-N version A in Italy are outdated., Objectives: To revise and update normative data for the BRB-N version A in the Italian population., Methods: From the Italian Neuroimaging Network Initiative (INNI) database, we retrospectively selected 342 healthy subjects (172 males and 170 females) evaluated at four Italian INNI-affiliated sites (Milan, Siena, Rome, Naples). The subjects underwent neuropsychological assessment using the BRB-N version A. Regression-based method relying on scaled scores was used to calculate demographic correction procedures., Results: No significant differences were found in age, education, and sex distribution among the four sites (p ≥ 0.055). Regression analysis provided normative data to calculate demographically adjusted z-scores for each BRB-N version A test., Discussion: This study provides updated normative data for the BRB-N version A in the Italian population. The use of a regression-based method and scaled scores ensures consistency with other neuropsychological batteries commonly used in Italy, namely MACFIMS and BICAMS. The availability of updated normative data increases reliability of neuropsychological assessment of cognitive function in Italian PwMS and other clinical populations using BRB-N version A, providing valuable insights for both clinical and research applications., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: In REFLEX, subcutaneous interferon beta-1a (sc IFN β-1a) delayed the onset of multiple sclerosis (MS) in patients with a first clinical demyelinating event (FCDE)., Objectives: This post hoc analysis aimed to determine whether baseline serum neurofilament light (sNfL) chain can predict conversion to MS and whether correlations exist between baseline sNfL and magnetic resonance imaging (MRI) metrics., Methods: sNfL was measured for 494 patients who received sc IFN β-1a 44 μg once weekly (qw; n  = 168), three times weekly (tiw; n  = 161), or placebo ( n  = 165) over 24 months. Median baseline sNfL (26.1 pg/mL) was used to define high/low sNfL subgroups. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox's proportional hazard model to determine factors influencing the risk of conversion to MS. Kaplan-Meier estimates calculated median time-to-conversion to MS (McDonald 2005 criteria) or clinically definite MS (CDMS; Poser criteria). Correlations between sNfL and MRI findings were assessed using Spearman's rank correlation coefficient ( r )., Results: Multivariable models indicated that high baseline sNfL was associated with the likelihood of converting to MS and inversely to time-to-conversion (HR = 1.3, 95% CI: 1.03-1.64; p  = 0.024). Significant additional factors affecting conversion to McDonald MS were on-study treatment (sc IFN β-1a/placebo; qw: HR = 0.59, 95% CI: 0.46-0.76; tiw: HR = 0.45, 95% CI: 0.34-0.59), classification of FCDE (monofocal/multifocal; HR = 0.69, 95% CI: 0.55-0.85), and most baseline imaging findings (T2 and T1 gadolinium-enhancing [Gd+] lesions; HR = 1.02, 95% CI: 1.01-1.03 and HR = 1.07, 95% CI: 1.03-1.11); all p  ⩽ 0.001. Conversion to CDMS showed similar results. At month 24, sNfL was strongly correlated with a mean number of combined unique active ( r  = 0.71), new T2 ( r  = 0.72), and new T1 Gd+ ( r  = 0.60) lesions; weak correlations were observed between sNfL and clinical outcomes for all treatment groups., Conclusion: Higher baseline sNfL was associated with an increased risk of MS conversion, a risk that was mitigated by treatment with sc IFN β-1a tiw., Trial Registration: ClinicalTrials.gov identifier: NCT00404352. Date registered: 28 November 2006., (© The Author(s), 2024.)

Introduction: NPC1 mutations are responsible for Niemann-Pick disease type C (NPC), a rare autosomal recessive neurodegenerative disease. Patients harbouring heterozygous NPC1 mutations may rarely show parkinsonism or dementia. Here, we describe for the first time a large family with an apparently autosomal dominant late-onset Alzheimer's disease (AD) harbouring a novel heterozygous NPC1 mutation., Methods: All the five living siblings belonging to the family were evaluated. We performed clinical evaluation, neuropsychological tests, assessment of cerebrospinal fluid markers of amyloid deposition, tau pathology and neurodegeneration (ATN), structural neuroimaging and brain amyloid-positron emission tomography. Oxysterol serum levels were also tested. A wide next-generation sequencing panel of genes associated with neurodegenerative diseases and a whole exome sequencing analysis were performed., Results: We detected the novel heterozygous c.3034G>T (p.Gly1012Cys) mutation in NPC1 , shared by all the siblings. No other point mutations or deletions in NPC1 or NPC2 were found. In four siblings, a diagnosis of late-onset AD was defined according to clinical characterisation and ATN biomarkers (A+, T+, N+) and serum oxysterol analysis showed increased 7-ketocholesterol and cholestane-3β,5α,6β-triol., Discussion: We describe a novel NPC1 heterozygous mutation harboured by different members of a family with autosomal dominant late-onset amnesic AD without NPC-associated features. A missense mutation in homozygous state in the same aminoacidic position has been previously reported in a patient with NPC with severe phenotype. The alteration of serum oxysterols in our family corroborates the pathogenic role of our NPC1 mutation. Our work, illustrating clinical and biochemical disease hallmarks associated with NPC1 heterozygosity in patients affected by AD, provides relevant insights into the pathogenetic mechanisms underlying this possible novel association., Competing Interests: Competing interests: HZ has served at scientific advisory boards and/or as a consultant for AbbVie, Acumen, Alector, ALZ Path, Annexon, Apellis, Artery Therapeutics, AZ Therapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Programme (outside submitted work). None of the other authors have a conflict of interest to disclose., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Given the huge impact of the COVID-19 pandemic, it appears of paramount importance to assess the cognitive effects on the population returning to work after COVID-19 resolution. Serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) represent promising biomarkers of neuro-axonal damage and astrocytic activation. In this cohort study, we explored the association between sNfL and sGFAP concentrations and cognitive performance in a group of 147 adult workers with a previous asymptomatic SARS-CoV-2 infection or mild COVID-19, one week and, in 49 of them, ten months after SARS-Cov2 negativization and compared them to a group of 82 age and BMI-matched healthy controls (HCs). sNfL and sGFAP concentrations were assessed using SimoaTM assay Neurology 2-Plex B Kit. COVID-19 patients were interviewed one-on-one by trained physicians and had to complete a list of questionnaires, including the Cognitive Failure Questionnaire (CFQ). At the first assessment (T0), sNfL and sGFAP levels were significantly higher in COVID-19 patients than in HCs (p < 0.001 for both). The eleven COVID-19 patients with cognitive impairment had significantly higher levels of sNfL and sGFAP than the others (p = 0.005 for both). At the subsequent follow-up (T1), sNfL and sGFAP levels showed a significant decrease (median sNfL 18.3 pg/mL; median sGFAP 77.2 pg/mL), although they were still higher than HCs (median sNfL 7.2 pg/mL, median sGFAP 63.5 pg/mL). Our results suggest an ongoing damage involving neurons and astrocytes after SARS-Cov2 negativization, which reduce after ten months even if still evident compared to HCs., (© 2024. The Author(s).)

Objective: To identify novel biomarkers as an alternative diagnostic tool for limb girdle muscular dystrophy (LGMD)., Background: LGMD encompasses a group of muscular dystrophies characterized by proximal muscles weakness, elevated CK levels and dystrophic findings on muscle biopsy. Heterozygous CAPN3 mutations are associated with autosomal dominant LGMD-4, while biallelic mutations can cause autosomal recessive LGMD-1. Diagnosis is currently often based on invasive methods requiring muscle biopsy or blood tests. In most cases Western blotting (WB) analysis from muscle biopsy is essential for a diagnosis, as muscle samples are currently the only known tissues to express the full-length CAPN3 isoform., Methods: We analyzed CAPN3 in a cohort including 60 LGMD patients. Selected patients underwent a complete neurological examination, electromyography, muscle biopsy, and skin biopsies for primary fibroblasts isolation. The amount of CAPN3 was evaluated by WB analysis in muscle and skin tissues. The total RNA isolated from muscle, fibroblast and urine was processed, and cDNA was used for qualitative analysis. The expression of CAPN3 was investigated by qRT-PCR. The CAPN3 3D structure has been visualized and analyzed using PyMOL., Results: Among our patients, seven different CAPN3 mutations were detected, of which two were novel. After sequencing CAPN3 transcripts from fibroblast and urine, we detected different CAPN3 isoforms surprisingly including the full-length transcript. We found comparable protein levels from fibroblasts and muscle tissue; in particular, patients harboring a novel CAPN3 mutation showed a 30% reduction in protein compared to controls from both tissues., Conclusions: Our findings showed for the first time the presence of the CAPN3 full-length transcript in urine and skin samples. Moreover, we demonstrated surprisingly comparable CAPN3 protein levels between muscle and skin samples, thus allowing us to hypothesize the use of skin biopsy and probably of urine samples as an alternative less invasive method to assess the amount of CAPN3 when molecular diagnosis turns out to be inconclusive.

Background: To assess the state of neurological scientific research in Italy in the time interval 2020-2023., Methods: Elsevier's modular integrated platform "SciVal" was used to analyze bibliometric research products starting from scientific production data uploaded onto Scopus. We considered the research area "Neurology" in the 01/01/2020-14/06/2023 time interval, and the following variables were extracted: number of published studies, number of citations, Field-Weighted Citation Impact, and percentage of international collaborations. The contribution of Italian scientists to the neurological research was compared to that of the other nations., Results: Research identified 90,633 scientific papers in the neurological area worldwide, with a total of 472,750 citations. The products assigned to Italian groups were 6670 (53,587 citations, Field-Weighted Citation Impact 1.68, 41% international collaborations)., Conclusions: According to the present study, Italian neurological research 2020 to 2023 ranks fifth globally and third in Europe., (© 2023. Fondazione Società Italiana di Neurologia.)

Importance: Multiple sclerosis (MS) misdiagnosis remains an important issue in clinical practice., Objective: To quantify the performance of cortical lesions (CLs) and central vein sign (CVS) in distinguishing MS from other conditions showing brain lesions on magnetic resonance imaging (MRI)., Design, Setting, and Participants: This was a retrospective, cross-sectional multicenter study, with clinical and MRI data acquired between January 2010 and May 2020. Centralized MRI analysis was conducted between July 2020 and December 2022 by 2 raters blinded to participants' diagnosis. Participants were recruited from 14 European centers and from a multicenter pan-European cohort. Eligible participants had a diagnosis of MS, clinically isolated syndrome (CIS), or non-MS conditions; availability of a brain 3-T MRI scan with at least 1 sequence suitable for CL and CVS assessment; presence of T2-hyperintense white matter lesions (WMLs). A total of 1051 individuals were included with either MS/CIS (n = 599; 386 [64.4%] female; mean [SD] age, 41.5 [12.3] years) or non-MS conditions (including other neuroinflammatory disorders, cerebrovascular disease, migraine, and incidental WMLs in healthy control individuals; n = 452; 302 [66.8%] female; mean [SD] age, 49.2 [14.5] years). Five individuals were excluded due to missing clinical or demographic information (n = 3) or unclear diagnosis (n = 2)., Exposures: MS/CIS vs non-MS conditions., Main Outcomes and Measures: Area under the receiver operating characteristic curves (AUCs) were used to explore the diagnostic performance of CLs and the CVS in isolation and in combination; sensitivity, specificity, and accuracy were calculated for various cutoffs. The diagnostic importance of CLs and CVS compared to conventional MRI features (ie, presence of infratentorial, periventricular, and juxtacortical WMLs) was ranked with a random forest model., Results: The presence of CLs and the previously proposed 40% CVS rule had a sensitivity, specificity, and accuracy for MS of 59.0% (95% CI, 55.1-62.8), 93.6% (95% CI, 91.4-95.6), and 73.9% (95% CI, 71.6-76.3) and 78.7% (95% CI, 75.5-82.0), 86.0% (95% CI, 82.1-89.5), and 81.5% (95% CI, 78.9-83.7), respectively. The diagnostic performance of the CVS (AUC, 0.89 [95% CI, 0.86-0.91]) was superior to that of CLs (AUC, 0.77 [95% CI, 0.75-0.80]; P < .001), and was increased when combining the 2 imaging markers (AUC, 0.92 [95% CI, 0.90-0.94]; P = .04); in the random forest model, both CVS and CLs outperformed the presence of infratentorial, periventricular, and juxtacortical WMLs in supporting MS differential diagnosis., Conclusions and Relevance: The findings in this study suggest that CVS and CLs may be valuable tools to increase the accuracy of MS diagnosis.

Background: The assessment of treatment response is a crucial step for patients with relapsing-remitting multiple sclerosis on disease-modifying therapies (DMTs). We explored whether a scoring system developed within the MAGNIMS (MRI in Multiple Sclerosis) network to evaluate treatment response to injectable drugs can be adopted also to oral DMTs., Methods: A multicentre dataset of 1200 patients who started three oral DMTs (fingolimod, teriflunomide and dimethyl fumarate) was collected within the MAGNIMS network. Disease activity after the first year was classified by the 'MAGNIMS' score based on the combination of relapses (0-≥2) and/or new T2 lesions (<3 or ≥3) on brain MRI. We explored the association of this score with the following 3-year outcomes: (1) confirmed disability worsening (CDW); (2) treatment failure (TFL); (3) relapse count between years 1 and 3. The additional value of contrast-enhancing lesions (CELs) and lesion location was explored., Results: At 3 years, 160 patients experienced CDW: 12% of them scored '0' (reference), 18% scored '1' (HR=1.82, 95% CI 1.20 to 2.76, p=0.005) and 37% scored '2' (HR=2.74, 95% CI 1.41 to 5.36, p=0.003) at 1 year. The analysis of other outcomes provided similar findings. Considering the location of new T2 lesions (supratentorial vs infratentorial/spinal cord) and the presence of CELs improved the prediction of CDW and TFL, respectively, in patients with minimal MRI activity alone (one or two new T2 lesions)., Conclusions: Early relapses and substantial MRI activity in the first year of treatment are associated with worse short-term outcomes in patients treated with some of the oral DMTs., Competing Interests: Competing interests: SR has received honoraria from Biogen, MS, Novartis and Teva for consulting services, speaking and/or travel support. LP has received consulting fees from Biogen, Novartis and Roche; speaker honoraria from Biogen, Genzyme, Merck Serono, Novartis and Teva; travel grants from Biogen, Genzyme, Novartis and Teva; research grants from the Italian MS Society (Associazione Italiana Sclerosi Multipla) and Genzyme. SA-A reports no disclosure relevant to the manuscript. POA received honoraria for lecturing and participation in advisory boards, and/or travel expenses for attending congresses and meetings from Almirall, Biogen, BMS-Celgene, Janssen, Merck, Mylan, Novartis, Roche Sanofi-Genzyme and Teva. AB received speaker honoraria and/or compensation for consulting service and/or speaking activities from Biogen, Roche, Merck, Celgene and Genzyme. OC receives research grant support from the Multiple Sclerosis Society of Great Britain and Northern Ireland, the NIHR and the NIHR UCLH Biomedical Research Centre. She is the Deputy Editor of Neurology, for which she receives an honorarium. NDS has received honoraria from Biogen-Idec, Bristol Myers Squibb, Celgene, Genzyme, Immunic, Merck Serono, Novartis, Roche and Teva for consulting services and speaking; serves on advisory boards for Merck, Novartis, Biogen-Idec, Roche, Genzyme and Immunic; has received research grant support from the Italian MS Society. MF is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche and Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia, Eli Lilly, Genzyme, Janssen, Merck Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda and Teva; participation in advisory boards for Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme and Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol Myers Squibb, Lilly, Novartis and Sanofi-Genzyme; receives research support from Biogen Idec, Merck Serono, Novartis, Roche, the Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla and ARiSLA (Fondazione Italiana di Ricerca per la SLA). VF reports no disclosure relevant to the manuscript. NE has served as a member of advisory boards for Biogen, Merck, Novartis and Roche; has received grant income from the UK Multiple Sclerosis Society, MRC, PCORI and NIHR. CE has received funding for travelling and speaker honoraria from Biogen Idec and Bayer Schering. AGal has received honoraria from Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi-Genzyme and Teva for consulting services, speaking and/or travel support. AGar has received funding from the UK Multiple Sclerosis Society and has received speaker honoraria from the Multiple Sclerosis Academy. SG reports no disclosure relevant to the manuscript. SH has received travel funding and/or speaker honoraria from Biogen, Roche, Genzyme, Novartis, Bial, CSL Behring and Merck Serono. MK has received funding for travel and speaker honoraria from Bayer, Novartis, Merck, Biogen Idec and Teva Pharmaceutical Industries; and serves on scientific advisory boards for Biogen Idec, Merck Serono, Roche, Novartis and Gilead. ML has received honoraria from Biogen, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Almirall and Bayer for consulting services, speaking and/or travel support. MM has served on scientific advisory boards for Bayer Schering, Biogen, Sanofi-Genzyme, Merck, Novartis, Teva, Mylan and Almirall; and has received consulting and/or speaker fees, research support or travel grants from Almirall, Bayer Schering, Biogen, CSL Behring, Sanofi-Genzyme, Merck, Novartis, Teva, Roche and Ultragenix. XM has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Abbvie, Actelion, Alexion, Biogen, Bristol Myers Squibb/Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Immunic, Janssen Pharmaceuticals, Medday, Merck, Mylan, Nervgen, Novartis, Sandoz, Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, MSIF and NMSS. CP has served on scientific advisory boards and received consulting and/or speaker fees from Almirall, Alexion, Biogen, Janssen, Roche, Merck and Novartis; and has received research support from Almirall, Biogen, Roche, Merck and Novartis. PP received speaker honoraria from Roche, Biogen, Novartis, Merck Serono, Bristol Myers Squibb and Genzyme; has received research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. JR has received speaking honoraria and personal compensation for participating in advisory boards from Biogen-Idec, Genzyme, Merck Serono, Mylan, Novartis, Roche, Teva and Sanofi-Aventis. MAR received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen and Roche; received speaker honoraria from AstraZeneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono, Novartis, Roche, Sanofi and Teva; and receives research support from the MS Society of Canada, the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders. AR serves on scientific advisory boards for Novartis, Sanofi-Genzyme, Synthetic MR, TensorMedical, Roche, Biogen and OLEA Medical; and has received speaker honoraria from Bayer, Sanofi-Genzyme, Merck Serono, Teva Pharmaceutical Industries, Novartis, Roche, Bristol Myers and Biogen. MLS reports no disclosure relevant to the manuscript. MZ has received honoraria for lecturing or participating in advisory boards, or financial support for attending scientific meetings from Alexion, Biogen, BMS-Celgene, Janssen, Genzyme, Merck, Novartis and Sanofi. CT received honoraria for speaking and travel grants from Biogen, Sanofi-Aventis, Merck Serono, Bayer-Schering, Teva, Genzyme, Almirall and Novartis. CG has received speaker honoraria and/or travel expenses for attending meetings from Bayer Schering Pharma, Sanofi-Aventis, Merck, Biogen, Novartis and Almirall., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Alzheimer's disease (AD) represents the most prevalent type of neurodegenerative dementia and the sixth leading cause of death worldwide. The so-called "non-calcemic actions" of vitamin D have been increasingly described, and its insufficiency has already been linked to the onset and progression of the main neurological diseases, including AD. Immune-mediated Aβ plaque's phagocytosis and clearance, immune response, oxidative stress, and mitochondrial function are all influenced by vitamin D, and these functions are considered relevant in AD pathogenesis. However, it has been shown that the genomic vitamin D signaling pathway is already impaired in the AD brain, making things more complicated. In this paper, we aim to summarise the role of vitamin D in AD and review the results of the supplementation trials in AD patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Whether the degree of inflammation (and its resolution) and neurodegeneration after treatment initiation predicts disease progression in multiple sclerosis (MS) remains unclear., Objectives: To assess the predictive value of magnetic resonance imaging (MRI)-derived brain and lesion volume (LV) changes in years 1 and 2 of treatment for disease progression., Methods: Patients receiving early interferon beta-1a treatment in REFLEX/REFLEXION ( N = 262) were included. Predictive regression models included new/enlarging LV (positive activity), disappearing/shrinking LV (negative activity), and global/central atrophy during years 1 and 2., Results: Faster global atrophy and/or pseudo-atrophy and positive lesion activity in years 1 and 2 related to an increased probability and faster conversion to clinically definite multiple sclerosis (CDMS). Negative lesion activity in year 1 and slower central atrophy in year 2 were predictive of confirmed disability progression (9-Hole Peg Test). Positive lesion activity in year 2 was predictive of faster global atrophy, while positive lesion activity in years 1 and 2 was predictive of faster central atrophy., Conclusions: A higher degree of global atrophy and/or pseudo-atrophy in year 1 was predictive of CDMS. Positive lesion activity in any year was related to CDMS and neurodegeneration. Disability was related to negative lesion activity in year 1 and slower central atrophy in year 2., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: R.M.M. has received research support from Merck. I.B. has received research support from Merck, Novartis, Teva, and the Dutch MS Research Foundation. N.D.S. is a consultant for Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva; has grants or grants pending from FISM and Novartis; is on the speakers’ bureaus of Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva; and has received travel funds from Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. B.M.J.U. reports research support and/or consultancy fees from Biogen, Genzyme, Merck, Novartis, Roche, Teva, and Immunic Therapeutics. F.B. is a steering committee or Data Safety Monitoring Board member for Biogen, Merck, ATRI/ACTC, and Prothena; is a consultant for Roche, Celltrion, Rewind Therapeutics, Merck, IXICO, Jansen, and Combinostics; is a co-founder and shareholder of Queen Square Analytics Ltd.; and has research agreements with Merck, Biogen, GE Healthcare, and Roche. H.V. has received research support from Merck, Novartis, Pfizer, and Teva; consulting fees from Merck, and speaker honoraria from Novartis; all funds were paid to his institution. M.M.S. serves on the editorial board of Neurology and Frontiers in Neurology; receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS, and ZonMW (Vidi grant, project number 09150172010056); and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, EIP, Sanofi, MedDay, and Merck. E.K., E.M.M.S., R.A.v.S., G.G., and M.B. report no disclosures.

This review analyzes the role of TNF-α and its increase in biological fluids in mild cognitive impairment, and Alzheimer's disease (AD). The potential inhibition of TNF-α with pharmacological strategies paves the way for preventing AD and improving cognitive function in people at risk for dementia. We conducted a narrative review to characterize the evidence in relation to the involvement of TNF-α in AD and its possible therapeutic inhibition. Several studies report that patients with RA and systemic inflammatory diseases treated with TNF-α blocking agents reduce the probability of emerging dementia compared with the general population. Animal model studies also showed interesting results and are discussed. An increasing amount of basic scientific data and clinical studies underscore the importance of inflammatory processes and subsequent glial activation in the pathogenesis of AD. TNF-α targeted therapy is a biologically plausible approach for cognition preservation and further trials are necessary to investigate the potential benefits of therapy in populations at risk of developing AD.

Background and Purpose: Thalamic atrophy occurs from the earliest phases of MS; however, this measure is not included in clinical practice. Our purpose was to obtain a reliable segmentation of the thalamus in MS by comparing existing automatic methods cross-sectionally and longitudinally., Materials and Methods: MR images of 141 patients with relapsing-remitting MS (mean age, 38 years; range, 19-58 years; 95 women) and 69 healthy controls (mean age, 36 years; range, 22-69 years; 47 women) were retrieved from the Italian Neuroimaging Network Initiative repository: T1WI, T2WI, and DWI at baseline and after 1 year (136 patients, 31 healthy controls). Three segmentation software programs (FSL-FIRST, FSL-MIST, FreeSurfer) were compared. At baseline, agreement among pipelines, correlations with age, disease duration, clinical score, and T2-hyperintense lesion volume were evaluated. Effect sizes in differentiating patients and controls were assessed cross-sectionally and longitudinally. Variability of longitudinal changes in controls and sample sizes were assessed. False discovery rate-adjusted P < .05 was considered significant., Results: At baseline, FSL-FIRST and FSL-MIST showed the highest agreement in the results of thalamic volume ( R = 0.87, P < .001), with the highest effect size for FSL-MIST (Cohen d = 1.11); correlations with demographic and clinical variables were comparable for all software. Longitudinally, FSL-MIST showed the lowest variability in estimating thalamic volume changes for healthy controls (SD = 1.07%), the highest effect size (Cohen d = 0.44), and the smallest sample size at 80% power level (15 subjects per group)., Conclusions: Multimodal segmentation by FSL-MIST increased the robustness of the results with better capability to detect small variations in thalamic volumes., (© 2023 by American Journal of Neuroradiology.)

Objective: The purpose of this study was to evaluate the extent to which treatment effect on magnetic resonance imaging (MRI)-derived measures of brain atrophy and focal lesions can mediate, at the trial level, the treatment effect on cognitive outcomes in multiple sclerosis (MS)., Methods: We collected all published randomized clinical trials in MS lasting at least 2 years and including as end points: active MRI lesions (defined as new/enlarging T2 lesions), brain atrophy (defined as a change in brain volume between month 12 and month 24), and change in cognitive performance (assessed by the Paced Auditory Serial Addition Test [PASAT]). Relative reductions were used to quantify the treatment effect on MRI markers (lesions and atrophy), whereas the standardized mean difference (Hedges g) between baseline and follow-up cognitive assessment was used to quantify the treatment effects on cognition. A linear regression, weighted for trial size, was used to assess the relationship between the treatment effects on MRI markers and cognition., Results: Fourteen trials including more than 8,813 patients with MS were included in the meta-regression. Treatment effect on cognition was strongly associated with the treatment effect on brain atrophy (R 2  = 0.79, p < 0.001), but was not correlated with the treatment effect on active MRI lesions (R 2  = 0.16, p = 0.14)., Interpretation: Results reported here suggest that brain atrophy, a well-established MRI marker in MS clinical trials, can be used as a main outcome for clinical trials with drugs targeting cognitive impairment and neurodegeneration. ANN NEUROL 2023;94:925-932., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Current therapeutic strategies in multiple sclerosis (MS) target neurodegeneration. However, the integration of atrophy measures into the clinical scenario is still an unmet need., Purpose: To compare methods for whole-brain and gray matter (GM) atrophy measurements using the Italian Neuroimaging Network Initiative (INNI) dataset., Study Type: Retrospective (data available from INNI)., Population: A total of 466 patients with relapsing-remitting MS (mean age = 37.3 ± 10 years, 323 women) and 279 healthy controls (HC; mean age = 38.2 ± 13 years, 164 women)., Field Strength/sequence: A 3.0-T, T1-weighted (spin echo and gradient echo without gadolinium injection) and T2-weighted spin echo scans at baseline and after 1 year (170 MS, 48 HC)., Assessment: Structural Image Evaluation using Normalization of Atrophy (SIENA-X/XL; version 5.0.9), Statistical Parametric Mapping (SPM-v12); and Jim-v8 (Xinapse Systems, Colchester, UK) software were applied to all subjects., Statistical Tests: In MS and HC, we evaluated the intraclass correlation coefficient (ICC) among FSL-SIENA(XL), SPM-v12, and Jim-v8 for cross-sectional whole-brain and GM tissue volumes and their longitudinal changes, the effect size according to the Cohen's d at baseline and the sample size requirement for whole-brain and GM atrophy progression at different power levels (lowest = 0.7, 0.05 alpha level). False discovery rate (Benjamini-Hochberg procedure) correction was applied. A P value <0.05 was considered statistically significant., Results: SPM-v12 and Jim-v8 showed significant agreement for cross-sectional whole-brain (ICC = 0.93 for HC and ICC = 0.84 for MS) and GM volumes (ICC = 0.66 for HC and ICC = 0.90) and longitudinal assessment of GM atrophy (ICC = 0.35 for HC and ICC = 0.59 for MS), while no significant agreement was found in the comparisons between whole-brain and GM volumes for SIENA-X/XL and both SPM-v12 (P = 0.19 and P = 0.29, respectively) and Jim-v8 (P = 0.21 and P = 0.32, respectively). SPM-v12 and Jim-v8 showed the highest effect size for cross-sectional GM atrophy (Cohen's d = -0.63 and -0.61). Jim-v8 and SIENA(XL) showed the smallest sample size requirements for whole-brain (58) and GM atrophy (152), at 0.7 power level., Data Conclusion: The findings obtained in this study should be considered when selecting the appropriate brain atrophy pipeline for MS studies., Evidence Level: 4., Technical Efficacy: Stage 1., (© 2023 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

In this work we present BIANCA-MS, a novel tool for brain white matter lesion segmentation in multiple sclerosis (MS), able to generalize across both the wide spectrum of MRI acquisition protocols and the heterogeneity of manually labeled data. BIANCA-MS is based on the original version of BIANCA and implements two innovative elements: a harmonized setting, tested under different MRI protocols, which avoids the need to further tune algorithm parameters to each dataset; and a cleaning step developed to improve consistency in automated and manual segmentations, thus reducing unwanted variability in output segmentations and validation data. BIANCA-MS was tested on three datasets, acquired with different MRI protocols. First, we compared BIANCA-MS to other widely used tools. Second, we tested how BIANCA-MS performs in separate datasets. Finally, we evaluated BIANCA-MS performance on a pooled dataset where all MRI data were merged. We calculated the overlap using the DICE spatial similarity index (SI) as well as the number of false positive/negative clusters (nFPC/nFNC) in comparison to the manual masks processed with the cleaning step. BIANCA-MS clearly outperformed other available tools in both high- and low-resolution images and provided comparable performance across different scanning protocols, sets of modalities and image resolutions. BIANCA-MS performance on the pooled dataset (SI: 0.72 ± 0.25, nFPC: 13 ± 11, nFNC: 4 ± 8) were comparable to those achieved on each individual dataset (median across datasets SI: 0.72 ± 0.28, nFPC: 14 ± 11, nFNC: 4 ± 8). Our findings suggest that BIANCA-MS is a robust and accurate approach for automated MS lesion segmentation., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Purpose: Serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are promising neuro-axonal damage and astrocytic activation biomarkers. Susac syndrome (SS) is an increasingly recognized neurological condition and biomarkers that can help assess and monitor disease evolution are highly needed for the adequate management of these patients. sNfL and sGFAP levels were evaluated in patients with SS and their clinical relevance in the relapse and remission phase of the disease was assessed., Methods: As part of a multicentre study that enrolled patients diagnosed with SS from six international centres, sNfL and sGFAP levels were assessed in 22 SS patients (nine during a relapse and 13 in remission) and 59 age- and sex-matched healthy controls using SimoaTM assay Neurology 2-Plex B Kit., Results: Serum NfL levels were higher than those of healthy controls (p < 0.001) in SS patients and in both subgroups of patients in relapse and in remission (p < 0.001 for both), with significantly higher levels in relapse than in remission (p = 0.008). sNfL levels showed a negative correlation with time from the last relapse (r = -0.663; p = 0.001). sGFAP levels were slightly higher in the whole group of patients than in healthy controls (p = 0.046) and were more pronounced in relapse than in remission (p = 0.013)., Conclusion: In SS patients, both sNFL and sGFAP levels increased compared with healthy controls. Both biomarkers had higher levels during clinical relapse and much lower levels in remission. sNFL was shown to be time sensitive to clinical changes and can be useful to monitor neuro-axonal damage in SS., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy, also known as familial amyloid polyneuropathy (FAP), represents a progressive, heterogeneous, severe, and multisystemic disease caused by pathogenic variants in the TTR gene. This autosomal-dominant neurogenetic disorder has an adult onset with variable penetrance and an inconstant phenotype, even among subjects carrying the same mutation. Historically, ATTRv amyloidosis has been viewed as a non-inflammatory disease, mainly due to the absence of any mononuclear cell infiltration in ex vivo tissues; nevertheless, a role of inflammation in its pathogenesis has been recently highlighted. The immune response may be involved in the development and progression of the disease. Fibrillary TTR species bind to the receptor for advanced glycation end products (RAGE), probably activating the nuclear factor κB (NF-κB) pathway. Moreover, peripheral blood levels of several cytokines, including interferon (IFN)-gamma, IFN-alpha, IL-6, IL-7, and IL-33, are altered in the course of the disease. This review summarizes the current evidence supporting the role of the immune response in ATTRv amyloidosis, from the pathological mechanisms to the possible therapeutic implications.

Background: The relative contribution of changes in the cerebral white matter (WM) and cortical gray matter (GM) to the transition to dementia in patients with mild cognitive impairment (MCI) is not yet established. In this longitudinal study, we aimed to analyze MRI features that may predict the transition to dementia in patients with MCI and T 2 hyperintensities in the cerebral WM, also known as leukoaraiosis., Methods: Sixty-four participants with MCI and moderate to severe leukoaraiosis underwent baseline MRI examinations and annual neuropsychological testing over a 2 year period. The diagnosis of dementia was based on established criteria. We evaluated demographic, neuropsychological, and several MRI features at baseline as predictors of the clinical transition. The MRI features included visually assessed MRI features, such as the number of lacunes, microbleeds, and dilated perivascular spaces, and quantitative MRI features, such as volumes of the cortical GM, hippocampus, T 2 hyperintensities, and diffusion indices of the cerebral WM. Additionally, we examined advanced quantitative features such as the fractal dimension (FD) of cortical GM and WM, which represents an index of tissue structural complexity derived from 3D-T 1 weighted images. To assess the prediction of transition to dementia, we employed an XGBoost-based machine learning system using SHapley Additive exPlanations (SHAP) values to provide explainability to the machine learning model., Results: After 2 years, 18 (28.1%) participants had transitioned from MCI to dementia. The area under the receiving operator characteristic curve was 0.69 (0.53, 0.85) [mean (90% confidence interval)]. The cortical GM-FD emerged as the top-ranking predictive feature of transition. Furthermore, aggregated quantitative neuroimaging features outperformed visually assessed MRI features in predicting conversion to dementia., Discussion: Our findings confirm the complementary roles of cortical GM and WM changes as underlying factors in the development of dementia in subjects with MCI and leukoaraiosis. FD appears to be a biomarker potentially more sensitive than other brain features., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Marzi, Scheda, Salvadori, Giorgio, De Stefano, Poggesi, Inzitari, Pantoni, Mascalchi and Diciotti.)

Background: Covid-19 pandemic impacted on management of people with Multiple Sclerosis (pwMS). Level of satisfaction of pwMS regarding the care received by the staff of Multiple Sclerosis Centers (MSCs) during the pandemic was not fully investigated. In a large patient-centered multicenter study, the therapeutic adherence and quality of care of MSCs was assessed., Methods: In April-May 2021, an online survey was widespread by 16 Italian MSCs. Frequencies, percentages and/or means and standard deviations were calculated to describe the sample. ANOVAs were performed to evaluate the effect of sociodemographic and clinical variables on overall pwMS' rating of MSC assistance., Results: 1670 pwMS completed the survey (67.3% women). During the pandemic, 88% did not change their disease modifying therapy schedule, and 89.1% reached their MSCs with no or little difficulties. Even if only 1.3% of participants underwent a tele-health follow-up visit with their MSC staff, the 80.1% believed that tele-health services should be improved regardless of pandemic. 92% of participants were satisfied of how their MSC took charge of their needs; ANOVAs revealed an effect of disease duration on pwMS' level of satisfaction on MSCs management during the pandemic., Conclusions: The results revealed an efficient MSCs response to Covid-19 pandemic and provided the basis for the implementing of tele-health services that would further improve the taking charge of patients, particularly those with longer disease, higher disability, and/or living far from their MSC., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Antonio Gallo reports a relationship with Biogen that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Gallo reports a relationship with Merck Serono that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Gallo reports a relationship with Mylan ITALIA Srl that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Gallo reports a relationship with Novartis that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Gallo reports a relationship with Roche that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Gallo reports a relationship with Sanofi Genzyme that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Gallo reports a relationship with Teva Health that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Lorena Lorefice reports a relationship with Biogen that includes: consulting or advisory and speaking and lecture fees. Lorena Lorefice reports a relationship with Novartis that includes: consulting or advisory and speaking and lecture fees. Lorena Lorefice reports a relationship with Sanofi that includes: consulting or advisory and speaking and lecture fees. Lorena Lorefice reports a relationship with Sanofi Genzyme that includes: consulting or advisory and speaking and lecture fees. Lorena Lorefice reports a relationship with Merck Serono that includes: consulting or advisory and speaking and lecture fees. Lorena Lorefice reports a relationship with Teva Health that includes: consulting or advisory and speaking and lecture fees. Lorena Lorefice reports a relationship with Almirall Ltd that includes: speaking and lecture fees. Alvino Bisecco reports a relationship with Biogen that includes: consulting or advisory and speaking and lecture fees. Alvino Bisecco reports a relationship with Roche that includes: consulting or advisory and speaking and lecture fees. Alvino Bisecco reports a relationship with Merck & Co Inc that includes: consulting or advisory and speaking and lecture fees. Alvino Bisecco reports a relationship with Celgene Corp Los Angeles that includes: consulting or advisory and speaking and lecture fees. Alvino Bisecco reports a relationship with Sanofi Genzyme that includes: consulting or advisory and speaking and lecture fees. Massimiliano Calabrese reports a relationship with Biogen that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with Bristol Myers Squibb that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with Celgene Corp Los Angeles that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with Sanofi Genzyme that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with Merck Serono that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with Novartis that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with Roche that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with International Progressive MS Alliance that includes: funding grants. Massimiliano Calabrese reports a relationship with Ministry of Health that includes: funding grants. Massimiliano Di Filippo reports a relationship with Bayer AG that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Biogen Italy that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Sanofi Genzyme that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Merck & Co Inc that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Mylan ITALIA Srl that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Novartis that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Roche that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Siemens Healthineers that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Teva Health that includes: speaking and lecture fees and travel reimbursement. Gioacchino Tedeschi reports a relationship with Teva Health that includes: board membership. Gioacchino Tedeschi reports a relationship with Roche that includes: board membership. Gioacchino Tedeschi reports a relationship with Eli Lilly Italy that includes: board membership. Gioacchino Tedeschi reports a relationship with Allergan US that includes: board membership. Gioacchino Tedeschi reports a relationship with Sanofi-Aventis US LLC that includes: speaking and lecture fees and travel reimbursement. Gioacchino Tedeschi reports a relationship with Merck Serono Ltd that includes: speaking and lecture fees and travel reimbursement. Gioacchino Tedeschi reports a relationship with Bayer Schering Pharma AG that includes: speaking and lecture fees and travel reimbursement. Gioacchino Tedeschi reports a relationship with Biogen Italy that includes: speaking and lecture fees and travel reimbursement. Gioacchino Tedeschi reports a relationship with Novartis that includes: speaking and lecture fees and travel reimbursement., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)