Diagnosing primary lateral sclerosis: a clinico-pathological study.

Background:  Primary lateral sclerosis (PLS) is a rare motor neuron disease characterized by upper motor neuron degeneration, diagnosed clinically due to the absence of a (neuropathological) gold standard. Post-mortem studies, particularly TDP-43 pathology analysis, are limited.

Methods: This study reports on 5 cases in which the diagnostic criteria for PLS were met, but in which neuropathology findings showed (partially) conflicting results.

Cytoskeleton dysfunction of motor neuron in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by deletions or mutations of survival of motor neuron 1 (SMN1) gene. To date, the mechanism of selective cell death of motor neurons as a hallmark of SMA is still unclear. The severity of SMA is dependent on the amount of survival motor neuron (SMN) protein, which is an essential and ubiquitously expressed protein involved in various cellular processes including regulation of cytoskeletal dynamics.

Single-Nucleus RNA Sequencing Reveals the Spatiotemporal Dynamics of Disease-Associated Microglia in Amyotrophic Lateral Sclerosis.

Disease-associated microglia (DAM) are observed in neurodegenerative diseases, demyelinating disorders, and aging. However, the spatiotemporal dynamics and evolutionary trajectory of DAM during the progression of amyotrophic lateral sclerosis (ALS) remain unclear. Using a mouse model of ALS that expresses a human gene mutation, we found that the microglia subtype DAM begins to appear following motor neuron degeneration, primarily in the brain stem and spinal cord.

Present insights into the progress in gene therapy delivery systems for central nervous system diseases.

Central nervous system (CNS) diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), spinal cord injury (SCI), and ischemic strokes and certain rare diseases, such as amyotrophic lateral sclerosis (ALS) and ataxia, present significant obstacles to treatment using conventional molecular pharmaceuticals. Gene therapy, with its ability to target previously "undruggable" proteins with high specificity and safety, is increasingly utilized in both preclinical and clinical research for CNS ailments. As our comprehension of the pathophysiology of these conditions deepens, gene therapy stands out as a versatile and promising strategy with the potential to both prevent and treat these diseases.

Cerebellar Involvement in Attacks of Aquaporin-4-IgG Positive Neuromyelitis Optica Spectrum Disorder.

Objectives: To characterize the frequency and clinicoradiologic phenotype of cerebellar involvement in attacks of aquaporin-4-IgG positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) which are incompletely captured in current diagnostic criteria.

Methods: Brain MRI scans from patients with AQP4+NMOSD in the Mayo Clinic database were reviewed, and those with cerebellar T2-hyperintense lesions ≤30 days from attack onset were included for clinical and radiologic characterization.

Results: From 432 patients with AQP4+NMOSD, we identified 17 (4%) with cerebellar attacks.

Longitudinal data collection in pediatric and adult patients with 5q spinal muscular atrophy in Latin America: LATAM RegistrAME study - a clinical registry study protocol.

Spinal muscular atrophy is a rare hereditary neurodegenerative disease characterized by progressive motor neuron loss. The most common form of SMA is linked to 5q (5q-SMA) and is classified into subtypes according to the age of onset and maximum motor function achieved. The severity ranges from progressive infantile paralysis and premature death (type 1) to limited motor neuron loss in adults (type 4).

Sex-related differences in amyotrophic lateral sclerosis: A 2-[F]FDG-PET study.

Purpose: We investigated sex-related brain metabolic differences in Amyotrophic Lateral Sclerosis (ALS) and healthy controls (HC).

Methods: We collected two equal-sized groups of male (m-ALS) and female ALS (f-ALS) patients (n = 130 each), who underwent 2-[F]FDG-PET at diagnosis, matched for site of onset, cognitive status and King's stage. We included 168 age-matched healthy controls, half female (f-HC) and half male (m-HC).

Patient-specific responses to splice-modifying treatments in spinal muscular atrophy fibroblasts.

The availability of three therapies for the neuromuscular disease spinal muscular atrophy (SMA) highlights the need to match patients to the optimal treatment. Two of these treatments (nusinersen and risdiplam) target splicing of , but treatment outcomes vary from patient to patient. An incomplete understanding of the complex interactions among SMA genetics, SMN protein and mRNA levels, and gene-targeting treatments, limits our ability to explain this variability and identify optimal treatment strategies for individual patients.

Transmission of Peripheral-blood α-Synuclein Fibrils Exacerbates Synucleinopathy and Neurodegeneration in Parkinson's Disease by Endothelial Lag3 Endocytosis.

Parkinson's disease (PD) is an age-related neurodegenerative disorder. The pathological feature of PD is abnormal alpha-synuclein (α-syn) formation and transmission. Recent evidence demonstrates that α-syn preformed fibrils (α-syn PFF) can be detected in the serum of PD patients.

Ciliopathy interacts with neonatal anesthesia to cause non-apoptotic caspase-mediated motor deficits.

Increasing evidence suggests that anesthesia may induce developmental neurotoxicity, yet the influence of genetic predispositions associated with congenital anomalies on this toxicity remains largely unknown. Children with congenital heart disease often exhibit mutations in cilia-related genes and ciliary dysfunction, requiring sedation for their catheter or surgical interventions during the neonatal period. Here we demonstrate that briefly exposing ciliopathic neonatal mice to ketamine causes motor skill impairments, which are associated with a baseline deficit in neocortical layer V neuron apical spine density and their altered dynamics during motor learning.

Sex-specific DNA methylation differences in Amyotrophic lateral sclerosis.

Sex is an important covariate in all genetic and epigenetic research due to its role in the incidence, progression and outcome of many phenotypic characteristics and human diseases. Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a sex bias towards higher incidence in males. Here, we report for the first time a blood-based epigenome-wide association study meta-analysis in 9274 individuals after stringent quality control (5529 males and 3975 females).

KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons.

Mutations in the microtubule-binding motor protein kinesin 5 A (KIF5A) are implicated in several adult-onset motor neuron diseases, including Amyotrophic Lateral Sclerosis, Spastic Paraplegia Type 10 and Charcot-Marie-Tooth Disease Type 2. While KIF5 family members transport a variety of cargos along axons, the specific cargos affected by KIF5A mutations remain poorly understood. Here, we generated KIF5Anull mutant human motor neurons and analyzed the impact on axonal transport and motor neuron outgrowth and regeneration in vitro.

Mendelian randomization study of causal link from Cerebrospinal fluid metabolomics to neurodegenerative diseases.

To investigate the causal relationships between cerebrospinal fluid (CSF) metabolites and various neurodegenerative diseases (NDDs), we conducted a two-sample Mendelian randomization (MR) analysis. This study utilized summary statistics from genome-wide association studies (GWAS) of CSF metabolites and four common neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). MR methods were employed to determine causal associations, with the inverse variance weighted method as the primary approach.

Croplands proximity is associated with amyotrophic lateral sclerosis incidence and age at onset.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting from an intricate interplay between genetics and environmental factors. Many studies have explored living in rural areas as a possible risk factor for ALS, without focusing simultaneously on incidence, age at onset and phenotypic features.

Objective: To evaluate the effect of croplands residential proximity on ALS incidence and phenotype, focusing on age of onset, site of onset and progression rate.

Cost-utility analysis of newborn screening for spinal muscular atrophy in Japan.

Aims: Spinal muscular atrophy (SMA) is a rare genetic disorder characterized by progressive muscle weakness, atrophy, respiratory failure, and in severe cases, infantile death. Early detection and treatment before symptom onset may substantially improve outcomes, allowing patients to achieve age-appropriate motor milestones and longer survival. We assessed the cost-utility of newborn screening (NBS) for SMA in Japan.

Paraneoplastic Syndromes of the Nervous System in Patients Suffering from SCLC. A Review of the Recent Literature.

Background: Paraneoplastic Neurological Syndromes (PNS) constitute a heterogeneous cluster of disease manifestations related to various cancers. Small Cell Lung Cancer (SCLC) is strongly related to PNS. This narrative review conducted a survey in the available PubMed literature to highlight the appearance of PNSs in SCLC cases and discuss published research highlights on the subject so that general practitioners can be acquainted with the medical phenomenon present in SCLC patients.

RuvBL1/2 reduce toxic dipeptide repeat protein burden in multiple models of C9orf72-ALS/FTD.

A G4C2 hexanucleotide repeat expansion in is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Bidirectional transcription and subsequent repeat-associated non-AUG (RAN) translation of sense and antisense transcripts leads to the formation of five dipeptide repeat (DPR) proteins. These DPRs are toxic in a wide range of cell and animal models.

Harnessing osmotic shock for enhanced intracellular delivery of (nano)cargos.

Efficient intracellular delivery of exogenous (nano)materials is critical for both research and therapeutic applications. The physicochemical properties of the cargo play a crucial role in determining internalization efficacy. Consequently, significant research efforts are focused on developing innovative and effective methodologies to optimize (nano)material delivery.

CK1δ/ε-mediated TDP-43 phosphorylation contributes to early motor neuron disease toxicity in amyotrophic lateral sclerosis.

Hyperphosphorylated TDP-43 aggregates in the cytoplasm of motor neurons is a neuropathological signature of amyotrophic lateral sclerosis (ALS). These aggregates have been proposed to possess a toxic disease driving role in ALS pathogenesis and progression, however, the contribution of phosphorylation to TDP-43 aggregation and ALS disease mechanisms remains poorly understood. We've previously shown that CK1δ and CK1ε phosphorylate TDP-43 at disease relevant sites, and that genetic reduction and chemical inhibition could reduce phosphorylated TDP-43 (pTDP-43) levels in cellular models.