Current Opinion in Neurology最新文献

Purpose of review: Sarcopenia is a common and relevant health problem in the treatment of geriatric patients. After many years of dealing with the definition of this phenomenon, the focus in the future must be on underlying and treatable pathomechanisms.

Recent findings: The article describes the initial state with regard to the definition of sarcopenia and derives from this the focus on subgroups of sarcopenia with treatable pathomechanisms. One subgroup of neuromuscular sarcopenia, which focuses on the degeneration of the neuromuscular junction, is discussed. In this context, the proteoglycan agrin with its ability to cluster acetylcholine receptors in the postsynaptic membrane of the muscle plays a role. Inactivation of agrin leads to destabilization of the neuromuscular junction and thus to sarcopenia. The resulting neuronal 22 kDa C-terminal agrin fragment should serve as a biomarker of neuromuscular sarcopenia.

Summary: The neuronal C-terminal agrin fragment must be established as a biomarker for neuromuscular sarcopenia, taking renal function into account as the fragment accumulates in renal insufficient patients. On this basis, treatment with agrin could be a therapeutic option for this subgroup of sarcopenia.

Purpose of review: Facioscapulohumeral muscular dystrophy (FSHD) is a progressive inherited myopathy, for which there is currently no cure available. This review focuses on the recent progress in the molecular understanding and treatments of FSHD.

Recent findings: Recent studies on the molecular understanding of FSHD highlight its multifaceted complexity and suggest new targets for therapeutic intervention. Preclinical models, such as the 3D skeletal muscle, provide an easier way to study molecular pathways and serve as a platform for drug screenings. New insights on training and the new international guideline contribute to optimal symptomatic treatment. In parallel, research is advancing with generic and targeted molecular therapies aiming to inhibit DUX4 activity or its downstream effects.

Summary: FSHD is caused by abnormal expression of the DUX4 gene. Our understanding of the molecular mechanisms underlying DUX4 and DUX4 target gene expression remains incomplete. However, advancements continue to clarify the roles of key proteins and genes, which might be of interest for future therapeutic therapies. Current therapies, treatments, and clinical trials for FSHD focus on molecular approaches, gene therapy, and symptom management. These developments indicate a growing focus on precision treatments and functional assessments, paving the way for improved FSHD management.

Purpose of review: We review here novel knock-in models of amyotrophic lateral sclerosis (ALS).

Recent findings: Knock-in mouse models of various familial forms of ALS generally display a mild motor phenotype, with limited progression, that do not recapitulate the full-blown clinical picture of ALS.

Summary: ALS is a devastating neurodegenerative disease in humans. Typically manifesting in the fifth or sixth decade of life, ALS leads to progressive motor dysfunction and death, usually within 2-5 years from symptom onset. A subset of ALS cases are dominantly inherited. Over the last 30 years, multiple mouse models of ALS have been generated, and recent advances in mouse genome editing techniques have enabled the generation of mouse strains carrying orthologous mutations in endogenous genes that mirror those causing familial forms of ALS. Intriguingly, many of these knock-in mouse models develop much milder phenotypes than patients with ALS carrying the same mutations. A full-blown ALS clinical phenotype seems to be only elicited upon overexpression of mutant genes beyond the endogenous levels. Here, we review these novel models and argue that these models could represent how ALS manifests in the mouse species. We also evaluate how these models could be used for characterizing mechanisms and preclinical drug evaluation.

Purpose of review: Chronic idiopathic axonal neuropathy (CIAP) remains a diagnostic challenge, with many cases historically classified as idiopathic due to the absence of identifiable genetic, metabolic, or immune-mediated causes. This review examines recent advancements in understanding CIAP, focusing on novel genetic mutations, autoantibodies, and metabolic pathways that challenge the "idiopathic" designation. Specifically, we highlight sorbitol dehydrogenase (SORD) deficiency and replication factor C subunit 1 (RFC1) repeat expansions, and comment on the controversy surrounding autoantibody-associated small fiber neuropathy (SFN).

Recent findings: Biallelic SORD mutations have emerged as a leading cause of recessive axonal neuropathy, linked to sorbitol accumulation and neurotoxicity, with aldose reductase inhibitors (ARIs) being explored as a potential therapy. RFC1 intronic repeat expansions have been identified as a major genetic contributor to CANVAS and sensory neuropathies, reshaping diagnostic approaches for patients previously classified as idiopathic. Additionally, the identification of autoantibodies such as trisulfated heparin disaccharide (TS-HDS), fibroblast growth factor receptor 3 (FGFR-3), and Plexin D1 in SFN suggests an immune-mediated pathology in a subset of patients but a negative randomized trial of IVIG and lack of specificity of TS-HDS IgM antibody testing questions the relevance of these presumed autoantibodies.

Summary: Advances in genetics, immunology, and metabolic neuropathies are redefining CIAP. The identification of SORD deficiency, RFC1 expansions, and autoantibody-associated SFN highlights the need for biomarker-driven approaches and targeted therapies. Future research should focus on expanding genetic screening, optimizing immunotherapy strategies, and investigating novel metabolic contributors to CIAP, ultimately moving toward precise, mechanism-based diagnoses.

Review purpose: To provide an overview of the recent developments in the field of neurochemical biomarkers of amyotrophic lateral sclerosis (ALS).

Recent findings: Neurofilaments, especially NFL, have been confirmed to be good biomarkers for ALS. NFL may be diagnostically useful but its main role is as prognostic and pharmacodynamic biomarker. Inflammatory biomarkers, especially the chitinases, might also serve as pharmacodynamic biomarkers in treatment trials targeting neuroinflammation. GFAP could reflect cognitive-behavioural impairment. CSF dipeptides are diagnostic biomarkers for ALS caused by the C9ORF72 exanucleotide repeat expansion and may be used to confirm target engagement by experimental drugs. Levels of TDP-43 (virtually the ideal biomarker for ALS) in CSF and plasma have not been demonstrated to be consistently altered in ALS. However, promising advancements have been achieved in seed amplification assays for the protein, in its quantification in plasma extracellular vesicles, and in the measurement of CSF levels of a protein reflecting splicing dysfunction of TDP-43. Finally, blood phosphorylated tau has emerged as an ALS biomarker linked to lower motor neuron (or muscle) pathology.

Summary: NFL is still the best neurochemical biomarker for ALS. However, substantial advances have been recently made, especially regarding detection of TDP-43 and blood phosphorylated tau.

Purpose of review: This review provides an overview of recent advances in fluid-based biomarker research in inflammatory neuropathies, with a particular focus on disease activity monitoring. It explores challenges along the biomarker pipeline and outlines the stage of development of emerging disease activity biomarkers.

Recent findings: Numerous biomarkers have recently been investigated for diagnostic, prognostic and monitoring purposes. Neurofilament light chain has been studied furthest but its clinical utility is limited in most patients. Other recent work has identified new biomarkers reflecting nerve damage, including peripherin, periaxin and Contactin-1. Additionally, potential immunological markers of disease activity have been explored, some more generic (such as chemokines) and others highly disease specific (such as autoantibody titers). Additional candidates have emerged through unbiased high-throughput discovery studies.

Summary: Current fluid-based biomarkers can be grouped into nerve damage or immunological biomarkers. Most have not proceeded beyond discovery and validation stages, except for Neurofilament Light Chain. Biomarker development is challenging due to the inherent rarity and heterogeneity of inflammatory neuropathies, and, in the case of disease activity biomarkers, a lack of reference standard.

Purpose of review: Despite decades of clinical recognition, the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) remains fraught with uncertainty. This review examines major areas of ongoing controversy in the diagnostic evaluation of CIDP, focusing on recent changes to electrodiagnostic criteria, disease boundaries, and emerging concepts of axonal damage.

Recent findings: Recent literature highlights three key areas of diagnostic uncertainty: the evolution and limitations of electrodiagnostic criteria; the diagnostic boundary between CIDP and antimyelin-associated glycoprotein (anti-MAG0 antibody neuropathy; and the recognition of CIDP cases that do not fulfil electrodiagnostic criteria, raising interest in axonal variants and the potential role of biomarkers such as neurofilaments. Across these domains, discrepancies between empirical evidence and expert-based guidelines persist, contributing to misdiagnosis and treatment variability.

Summary: Current CIDP criteria, though improved, remain partly based on expert opinion rather than empirical validation. The clinical heterogeneity of CIDP and its overlap with mimicking disorders further complicate diagnosis. A broader, more flexible diagnostic framework - integrating electrophysiology, biomarkers, and treatment response - is essential to enhance diagnostic accuracy and guide therapy. Future research should focus on refining criteria to strengthen electrodiagnostic standards and better accommodate atypical and axonal presentations.

Purpose of review: Although amyotrophic lateral sclerosis (ALS) epidemiology has been increasingly characterized in many regions, data from Arabic countries remain limited. This review aims to summarize the current knowledge on the burden of ALS in Arabic Mediterranean countries, with a particular focus on Egypt.

Recent findings: ALS exhibits significant geographic and ethnic variability in terms of incidence, phenotype, and genetic background. Data from the Global Burden of Disease Study 2021 show that Egypt has one of the lowest age-standardized rates of ALS incidence, prevalence, and mortality in the Mediterranean basin. During the past three decades, Egypt has seen a notable decline in ALS-related Disability-Adjusted Life Years and deaths, in contrast to neighboring countries. A national registry has recently been initiated to enhance epidemiological surveillance in the country.

Summary: ALS in Arabic Mediterranean countries presents a distinct epidemiological profile. These differences likely reflect a combination of genetic, demographic, and healthcare-related factors. Strengthening national registries and promoting regional collaborations will be crucial for gaining a deeper understanding of the determinants of ALS in these underrepresented populations.

Purpose of review: To summarize recent advancements in artificial intelligence-driven lesion segmentation and novel neuroimaging modalities that enhance the identification and characterization of multiple sclerosis (MS) lesions, emphasizing their implications for clinical use and research.

Recent findings: Artificial intelligence, particularly deep learning approaches, are revolutionizing MS lesion assessment and segmentation, improving accuracy, reproducibility, and efficiency. Artificial intelligence-based tools now enable automated detection not only of T2-hyperintense white matter lesions, but also of specific lesion subtypes, including gadolinium-enhancing, central vein sign-positive, paramagnetic rim, cortical, and spinal cord lesions, which hold diagnostic and prognostic value. Novel neuroimaging techniques such as quantitative susceptibility mapping (QSM), χ-separation imaging, and soma and neurite density imaging (SANDI), together with PET, are providing deeper insights into lesion pathology, better disentangling their heterogeneities and clinical relevance.

Summary: Artificial intelligence-powered lesion segmentation tools hold great potential for improving fast, accurate and reproducible lesional assessment in the clinical scenario, thus improving MS diagnosis, monitoring, and treatment response assessment. Emerging neuroimaging modalities may contribute to advance the understanding MS pathophysiology, provide more specific markers of disease progression, and novel potential therapeutic targets.

Purpose of review: Neurological infections are a significant cause of morbidity and mortality. This review aims to summarize current insights and developments for sex and gender differences in the epidemiology, clinical presentation, and prognosis of neurological infections.

Recent findings: Sex refers to the biological and physiological factors that define males and females. Gender, on the other hand, refers to characteristics that are socially constructed. Both aspects are central to infectious disease pathogenesis, and clinical and scientific evidence of their relevance in neuroinfections is emerging. Indeed, differences in exposure to pathogens and genetic and hormonal factors modulate immune responses and modify the susceptibility, clinical course, and response to the treatment of neurological infections.

Summary: Recognizing and addressing sex and gender differences in neurological infections is crucial for tailoring diagnostic, therapeutic, and preventive strategies. Our review underscores the importance of considering sex and gender in clinical practice and research to improve patient care and outcomes.