Mitochondrial disorders are a group of heterogeneous diseases marked by deficiencies in oxidative phosphorylation (OXPHOS). A common subtype, MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes [SLEs]), is primarily linked to variants in mitochondrial transfer RNA (mt-tRNA) genes, yet the molecular mechanisms underlying many of these variants remain poorly understood. We performed a comprehensive assessment of a 14-year-old male patient, including clinical evaluation, genetic testing, histopathology, and functional biochemical analyses of muscle tissue. A systematic literature review was conducted to compare previously reported MT-TS2 variants and their associated phenotypes. We identified a rare m.12244G > A variant in the tRNASer(AGY) gene associated with classical MELAS phenotype. Functional analysis demonstrated impaired mitochondrial translation and OXPHOS dysfunction. Histological findings revealed COX-negative and ragged red fibers, while western blotting indicated downregulation of key mitochondrial proteins. Literature review showed that MT-TS2 variants are associated with variable phenotypes including encephalopathy, myopathy, deafness, diabetes, and retinopathy. Our study provides the first experimental validation of the pathogenicity of the m.12244G > A variant, confirming its deleterious impact on mitochondrial function. This finding expands the genotype spectrum of MELAS and highlights the importance of functional validation for rare mtDNA variants.

Amyotrophic lateral sclerosis (ALS) involves widespread brain network dysfunction, yet the molecular mechanisms linked to these alterations remain poorly understood. We investigated macroscopic structural-functional coupling abnormalities in early-stage ALS (ALS-ES) and their underlying transcriptomic signatures. We analyzed multimodal MRI data from 73 patients with sporadic ALS-ES and 74 age- and sex-matched healthy controls. Structural-functional (SC-FC) coupling was quantified using diffusion tensor imaging and resting-state functional MRI. Machine learning models were constructed to distinguish patients from controls based on network features. Coupling alterations were spatially correlated with neurotransmitter receptor maps and gene expression profiles from the Allen Human Brain Atlas. Key transcriptomic findings were validated using independent single-cell RNA sequencing datasets. While structural connectivity remained largely preserved, functional connectivity was significantly reduced in the somatomotor network (SMN). This mismatch manifested as significant SC-FC network decoupling, particularly within the SMN (pFDR = 0.001). A gradient boosting machine model accurately classified patients, identifying SC-FC coupling in the left precentral gyrus as a primary statistical contributor to the classification model. Decoupling spatially correlated with 5-HT2A and mGluR5 receptor distributions. Imaging-transcriptomics linked network failure to a gene signature enriched for synaptic pathways and microglial markers. Single-cell analysis identified FMN1 as a candidate gene whose glial expression spatially associates with network decoupling. Early-stage ALS is characterized by significant structural-functional network decoupling, primarily in motor systems. This macroscopic failure is linked to specific microglial dysregulation, particularly FMN1 downregulation, providing a multiscale framework bridges statistical neuroimaging signatures with potential cellular pathology.

Sandhoff disease (SD) is a subtype of GM2 gangliosidosis caused by pathogenic variants in Hexosaminidase B (HEXB). It most frequently presents in infancy or early childhood, whereas adult-onset disease is rare and remains incompletely characterized. Here, we describe an adult-onset case of SD presenting as motor neuron disease and provide clinical and mechanistic insights using patient-derived models. The patient was a 34-year-old man with compound heterozygous HEXB variants (c.1598G > A, p.Arg533His and c.1645G > A, p.Gly549Arg) who developed progressive lower limb weakness. Muscle biopsy demonstrated neurogenic changes consistent with denervation, and sural nerve biopsy revealed mild peripheral neuropathy. Nerve conduction studies and electromyography showed widespread neurogenic changes with mildly reduced sensory nerve action potential amplitudes, and leukocyte β-hexosaminidase activity was decreased. To investigate disease mechanisms, we generated induced pluripotent stem cells (iPSCs) from the patient and an isogenic CRISPR-Cas9-corrected control (ISO), and differentiated both lines into motor neurons (MNs). In the SD patient (SDHF)-derived MNs, we observed lysosomal expansion, increased apoptosis, reduced neuronal network excitability, and dysregulated lipidomic profiles. These phenotypes were attenuated in MNs derived from the ISO line, with multiple measures shifting toward those of control (CTL) MNs. Collectively, our findings expand the clinical spectrum of adult-onset SD and support an association between HEXB deficiency and the vulnerability of MNs, while underscoring the value of patient-derived iPSC models for mechanistic studies of lateonset SD.

BACKGROUND:Usher syndrome 3A (USH3A), caused by mutations in the CLRN1 gene, leads to retinitis pigmentosa and sensorineural hearing loss. While CLRN1's role in inner ear pathology is established, its contribution to retinal degeneration remains poorly understood. METHODS:Retinal organoids derived from a USH3A patient were analyzed using single-cell RNA sequencing and multi-electrode array recording. CLRN1 expression was mapped in human fetal retina and organoids. We assessed the structural, transcriptional, and functional impact of CLRN1 variants on Müller cells and photoreceptors, and evaluated idebenone as a potential targeted therapy. RESULTS:CLRN1 was specifically expressed in Müller cells. CLRN1 variants induced severe retinal degeneration, characterized by outer nuclear layer thinning, impaired photoreceptor gene expression, activated apoptosis, and diminished electrophysiological function. Mechanistically, these variants caused mitochondrial dysfunction in Müller cells, which triggered secondary mitochondrial impairment, oxidative stress, and apoptosis in photoreceptors. Idebenone treatment partially rescued these deficits. CONCLUSIONS:CLRN1-related mitochondrial impairment in Müller cells contributes to the pathogenesis of retinitis pigmentosa in USH3A. These findings identify Müller cell mitochondrial dysfunction as a key disease mechanism and highlight potential therapeutic targets.

BACKGROUND:Sex differences are increasingly recognized as important modifiers of neuroimmune processes in neurodegenerative disorders. However, the sex-associated clinical phenotypes and underlying neuroinflammatory mechanisms in amyotrophic lateral sclerosis (ALS) remain poorly understood. This study integrated multimodal clinical assessments, cerebrospinal fluid (CSF) neuroimmune biomarkers, neuroimaging-based glymphatic metrics, and complementary animal analyses to characterize shared and sex-associated alterations in male and female ALS patients. METHODS:Two independent cohorts including 158 newly diagnosed ALS patients and 112 healthy controls (HCs) underwent evaluations of motor function, cognition, sleep disturbances, and emotional symptoms. Glymphatic function was assessed using choroid plexus volume (CPV), diffusion-derived analysis along the perivascular space (ALPS) index, and white-matter free-water (FW) fraction. In the original cohort, 12 CSF biomarkers spanning astrocytic activation, neuroinflammation, TDP-43 pathology, synaptic dysfunction, and axonal injury were quantified, and glial fibrillary acidic protein (GFAP), interleukin-6 (IL-6), and interleukin-18 (IL-18) were further examined in an independent verification cohort. Complementary neuroimmune alterations were further examined in TDP-43 N390D knock-in mice using ELISA and immunofluorescence. RESULTS:Male ALS patients showed markedly elevated CSF GFAP, IL-6, and IL-18 compared with female ALS patients and HCs after false discovery rate correction (q < 0.05). Female ALS patients exhibited increased CSF IL-6 versus HCs, whereas GFAP and IL-18 levels were unchanged. Female ALS patients also demonstrated more severe depressive symptoms and post-traumatic stress disorder than male ALS patients and HCs (p < 0.05). Both sexes displayed glymphatic impairment characterized by increased CPV and FW and reduced ALPS index, as well as pronounced sleep disturbances relative to HCs (all p < 0.05), with no clear sex-related differences. Complementary animal data showed that, at a fixed chronological age, male TDP-43 N390D mice exhibited more severe motor impairment accompanied by higher brain levels of GFAP, IL-6, and IL-18 and more prominent astrocyte-associated IL-6 and IL-18 signals than female mutant mice. Although microglial activation was also observed in TDP-43 N390D mice, no clear sex-related difference was detected at the sampled age. CONCLUSIONS:This multimodal clinical-translational study reveals sex-associated neuroinflammatory heterogeneity in ALS. Male patients exhibit a more pronounced GFAP-, IL-6-, and IL-18-related inflammatory profile, whereas female patients display more prominent affective disturbances. Glymphatic dysfunction and sleep impairment emerge as common pathological pathways across sexes. These findings highlight sex as a crucial biological variable shaping ALS heterogeneity and underscore the importance of incorporating sex-stratified analyses in future ALS neuroimmune research and clinical trials.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the ATXN2 gene. While typically adult-onset, pediatric cases are rare and exhibit distinct clinical features. Here, we report two pediatric-onset SCA2 cases. A 7-year-old boy with involuntary movements, developmental delay, and 58 CAG repeats, and a 16-year-old boy with tremors and gait instability carrying 44 repeats. Both showed cerebellar atrophy on MRI. A literature review of 22 genetically confirmed pediatric SCA2 cases revealed a strong inverse correlation between CAG repeat length and age at onset (R2 = 0.6131, P < 0.00001). Common features included developmental delay, hypotonia, epilepsy, and dystonia, with 79

Biallelic pathogenic variants in the MYPN gene are a known cause of congenital myopathy, and exonic variants that activate cryptic splice sites have not been previously reported. Here, we report a Chinese proband with congenital myopathy carrying a homozygous nonsense variant, c.2986C>T (p.Arg996Ter), in exon 14 of the MYPN gene. Transcriptional analysis suggested that this variant likely activated a cryptic donor splice site, truncating the last 91 nucleotides of exon 14 during pre-mRNA splicing. Western blotting and immunofluorescence confirmed a deficiency of myopalladin protein in the proband’s skeletal muscle. Our study highlights that exonic variants, particularly those distant from exon-intron junctions, can induce aberrant pre-mRNA splicing. This insight is crucial for interpreting the pathogenicity of variants of uncertain significance and enhancing diagnostic yield in genetic testing.

INTRODUCTION/AIMS:Although asymptomatic or pre-symptomatic Pompe disease is increasingly recognized, early skeletal muscle pathology and the role of residual glycogen at this stage remain unclear. Here, we investigated early muscle pathological changes using human samples and an early-stage Gaa -/- mouse model, focusing on residual glycogen accumulation. METHODS:Clinical, genetic, imaging, and muscle pathological analyses were performed in an asymptomatic Pompe disease patient carrying a novel GAA variant. Skeletal muscle samples from asymptomatic and symptomatic patients, as well as from early-stage and late-stage Gaa -/- mice, were analyzed using histochemistry, immunohistochemistry, immunofluorescence, and Western blotting to assess residual glycogen accumulation and lysosome-associated pathways. RESULTS:We identified a novel mutation, c.361C > T, in an asymptomatic Pompe disease patient. Despite the lack of symptoms, residual glycogen accumulated in muscle lysosomes. Immunohistochemistry showed positive glycogenin expression, while LAMP1 and LC3 were negative, suggesting early glycogenin detection. Western blot revealed increased glycogenin and STBD1, with mild LAMP1 and LC3 upregulation. In 1-month-old Gaa -/- mice, glycogenin, LAMP1, STBD1, and LC3 were all upregulated. Furthermore, immunofluorescence further showed glycogenin/LAMP1 double-positive muscle fibers in both the patient and mice. DISCUSSION:Our study shows that key pathological changes in Pompe disease occur during the asymptomatic stage, with early lysosomal accumulation of residual glycogen. This suggests residual glycogen may serve as a biomarker of early disease activity and a potential target for early intervention, informing disease monitoring and the timing of enzyme replacement therapy (ERT). Further studies are needed to validate its clinical utility and explore strategies for early clearance.

Objective Amyotrophic lateral sclerosis(ALS)is a chronic,progressive degenerative disease affecting both upper and lower motor neurons,primarily characterized by skeletal muscle weakness and atrophy.Notably,the same muscle group may exhibit asynchronous involvement.This study aims to investigate the involvement patterns of the orbicularis oculi(OOc)and orbicularis oris(OOr)in ALS patients,compare the findings with healthy controls(HCs)and myasthenia gravis(MG)patients,and explore the characteristics and clinical significance of facial muscle involvement in ALS.Methods Clinical and neuroelec-trophysiological data were collected and analyzed in ALS patients(ALS group),HCs(HCs group)and MG patients(MG group).Clinical data included age,gender,clinical symptoms and signs,and the revised ALS Functional Rating Scale(ALSFRS-R)score.Split-face(SF)phenomenon was defined as OOc muscle strength being greater than OOr muscle strength.The negative peak amplitudes of compound motor action poten-tial(CMAP)recorded from OOc and OOr,namely CMAPOOc and CMAPOOr,were collected for electrophysio-logical evaluation.Results Number of patients enrolled in each group:137 in the ALS group,42 in the HCS group,and 33 in the MG group.Of the 137 ALS patients,74 presented clinical SF manifestation.The CMAPOOc amplitude in the ALS group was 2.00(1.66,2.40)mV,showing no significant difference compared with 2.20(1.86,2.58)mV in the HCs group(P＞0.05).The CMAPOOr amplitude in the ALS group was significantly lower than that in the HCs group[2.80(1.91,3.85)mV vs.4.50(4.00,5.10)mV,P＜0.0001],while the CMAPOOc/CMAPOOr ratio was significantly higher[0.71(0.54,1.06)vs.0.47(0.40,0.54),P＜0.0001].Compared with ALS patients without SF,those with SF had a higher proportion of bulbar onset ALS(ALS-BO)(26/74 vs.7/63,P=0.0012),a faster disease progression rate[ΔFS:0.75(0.50,1.17)vs.0.50(0.25,1.00),P=0.0081],and lowerALSFRS-Rbulbar scores[9(6,12)vs.12(11,12),P＜0.0001].No SF was observed in all MG patients.The CMAPOOc/CMAPOOr ratio was significantly higher in ALS-BO patients than in MG patients[0.82(0.59,1.22)vs.0.48(0.38,0.59),P＜0.0001].The sensitivity and specificity of SF for distinguishing ALS-BO from MG were 78.79%and 100%,respectively.Conclusions More than half of ALS patients have SF phenomenon,and neuroelectrophysiological indicators can provide objective evidence for SF.SF is correlated with bulbar onset,severe bulbar symptoms and rapid disease progression,and can serve as a poten-tial indicator for the differential diagnosis between ALS-BO and MG.

BACKGROUND:Vasculitic neuropathy (VN) is a disease in which vessel inflammation happens and injures peripheral nerves. Despite increasing awareness, features of VN in mainland China are still understudied. OBJECTIVE:To characterize the clinical, pathological features and outcomes of VN in mainland China, and evaluate clinicopathological correlations: METHODS: We retrospectively reviewed records of VN patients diagnosed pathologically between June 1999 and December 2024, including demographic data, clinical manifestations, biopsy features, and outcomes. RESULTS:112 patients were totally included. All presented with axonal sensorimotor neuropathy, most commonly involving the tibial (90.63%) and peroneal (87.50%) nerves. Systemic VN (SVN) showed more frequent transmural inflammatory cell infiltration (ICI) than non-systemic VN (NSVN) (p = 0.046). Eosinophilic granulomatosis with polyangiitis (EGPA) was more common in VN without ICI than VN with ICI (p = 0.008). In SVN, the ICI-positive exhibited more severe distal upper limb weakness (p = 0.042) and higher thrombosis rates (p = 0.001) than ICI-negative. Of the 63 patients followed, 62 received glucocorticoids with or without immunosuppressants. Thirteen died from multi-organ complications (12 SVN and 1 NSVN), while others achieved remission. The 5-year all-survival rate was 80.23% (95% CI 66.83%- 88.66%). CONCLUSIONS:This first large cohort of VN in mainland China delineates its clinical-pathological features. EGPA showed a lower diagnostic yield on biopsy, suggesting diverse mechanisms of vascular injury. Nerve biopsy remains the diagnostic gold standard. The overall prognosis of VN is relatively favorable, emphasizing the need for early recognition and treatment.

Microglia originate from erythro-myeloid progenitors (EMPs) in the early embryonic yolk sac and migrate into the developing brain, where they differentiate and mature under the regulation of chemokines, cytokines, and growth factors. As resident immune cells in the central nervous system (CNS), microglia maintain neural homeostasis by sensing the microenvironment, clearing pathogens, phagocytosing cellular debris, and modulating neuroinflammation and tissue repair. In response to injury or pathological stimuli, microglia adopt diverse activation states and contribute to synaptic remodeling, neuroimmune signaling, and neuroplasticity. Their pronounced functional heterogeneity during normal neurodevelopment and across diverse neurological disorders underscores the need for robust in vitro models. Human induced pluripotent stem cells (hiPSCs)-derived microglia have emerged as a powerful platform to investigate microglial development, neuroinflammatory responses, and microglia-mediated neurodegeneration. This review summarizes current hiPSCs-to-microglia differentiation strategies, highlighting their advantages, limitations, and applications. We further discuss the application of hiPSCs-derived microglia in modeling neurodegenerative diseases and critically evaluate the opportunities and challenges associated with beneficially modulating microglial function in the contexts of microglial depletion and replacement therapies.

Background Mitochondrial cardiomyopathy (MCM), a common subtype of mitochondrial disorders accounting for 20-40% of cases, presents significant diagnostic and therapeutic challenges due to genetic heterogeneity and variable clinical phenotypes. Methods We conducted a comprehensive analysis of the clinical, histopathological, molecular, and genetic characteristics of a 23-year-old male with maternally inherited hypertrophic cardiomyopathy (HCM) associated with the homoplasmic m.9997 T > C variant. Results The patient exhibited early-onset exercise intolerance, arrhythmias, and cardiac dysfunction. Cardiac Magnetic Resonance Imaging confirmed asymmetric HCM with left ventricular enlargement. Genetic analysis identified a homoplasmic m.9997T > C variant across multiple tissues (blood, urine, mucosa, muscle). Muscle biopsy revealed typical mitochondrial abnormalities, and reduced expression of complex IV subunits. Conclusion Our findings support the pathogenic association of the homoplasmic m.9997T > C variant in HCM and highlight the clinical significance of homoplasmic mtDNA mutations in tissue-specific mitochondrial disorders, contributing to the broader understanding of homoplasmic mutations in mitochondrial disease.

Mitochondrial diseases (MDs) consist of a heterogeneous spectrum of disorders resulting from mutations in either nuclear or mitochondrial DNA, disrupting the function of multiple organ systems due to the importance of mitochondria in energy generation and metabolic activity. Exploring the association between lactylation and MDs offers valuable insights into the underlying molecular pathology and may reveal new therapeutic strategies for these disorders. Both single-cell RNA sequencing (scRNA-seq) and bulk transcriptomic analyses were used to investigate the potential role of lactylation in MDs. Analytical methods included cellular subtype clustering, lactylation scoring, machine learning-based gene prioritization, immune cell infiltration profiling, regulatory network mapping, and pathway enrichment analyses of key genes. Furthermore, qRT-PCR and Western blotting were performed on skeletal muscle samples from MD patients to experimentally validate gene expression results. The single-cell analysis revealed several distinct immune cell clusters, among which CD4+ T cells exhibited the highest lactylation scores. Machine learning algorithms identified three core genes that were strongly associated with MD pathogenesis and subsequently confirmed in muscle tissue, including EIF3D, SOD1, and RPS26. These genes demonstrated significant correlations with specific immune cell populations, implicating them in immune regulation. Additional network and pathway analyses revealed signaling mechanisms that may contribute to MD development. These results offer novel molecular insights into lactylation-associated mechanisms in MDs and highlight EIF3D, SOD1, and RPS26 as key regulators of immune and metabolic processes. These findings deepen our understanding of MD pathogenesis and suggest potential molecular targets for future therapeutic intervention.

Fiber-specific white matter (WM) changes are promising neuroimaging markers to evaluate upper motor neuron damage in amyotrophic lateral sclerosis (ALS) patients. However,to our knowledge, no studies have specifically applied fixel-based analysis (FBA) to investigate fiber-specific WM changes in King’s stage 1 ALS patients in vivo.” To fill this gap in the literature, we performed a retrospective analysis to identify early fiber-specific WM alterations in a large group of sporadic early-stage ALS (ALS-ES) patients and their correlation with clinical data. According to the new "Gold Coast" criteria and the King’s clinical staging system, we defined ALS patients at King’s stage 1 as ALS-ES patients, which corresponds to the earliest symptomatic phase . In this study, 64 newly diagnosed ALS-ES patients and 80 demographic-matched healthy controls (HCs) were included. Then, a novel diffusion-weighted imaging-based approach, fixel-based analysis (FBA), was performed to explore fiber-specific WM alterations in ALS-ES patients and HCs. Three FBA metrics, fiber density (FD), fiber-bundle cross-section (FC), and fiber density and cross-section (FDC), were analysed. Compared with HCs, ALS-ES patients had significantly decreased FD values and FDC values mainly in the bilateral corticospinal tract (CST) and corpus callosum (CC) regions. Compared with HCs, in ALS-ES patients, the FC values were significantly decreased mainly in the bilateral CST regions, while were significantly increased in the CC regions. Moreover, FDC values significantly correlated with motor deficits in ALS-ES patients. Our findings suggest that FBA metrics can provide valuable and complementary fixel-level information regarding the early WM degenerative process in ALS. In a large cohort, using a novel DWI-based approach, we first demonstrated a clear profile of early fiber-specific brain white matter alterations in sporadic patients with amyotrophic lateral sclerosis. • Using fixel-based analysis, we demonstrated that fiber-bundle cross-section (FC) values, fiber density (FD) values, and fiber density and cross-section (FDC) values were significantly decreased in the bilateral corticospinal tract regions in early-stage ALS patients. • Moreover, FC values were significantly increased, while FD values were significantly reduced in the corpus callosum regions in early-stage ALS patients. • Our findings may have important applications in assisting early diagnosis in ALS patients.

G-quadruplex structures in mitochondrial DNA (mtG4DNA) have been implicated in mitochondrial genome regulation and cellular metabolism, yet their spatial organization within mitochondrial nucleoids remains poorly understood. A central challenge is that mtG4DNA cannot be readily distinguished from mitochondrial double-stranded DNA (mt-dsDNA) in living cells, which has limited direct analysis of topological remodeling under stress and disease conditions. Here, we report SDMNA, a mitochondria-targeted fluorescent probe that enables topology-resolved imaging of mtDNA in situ. Built on a Y-shaped triphenylamine scaffold, SDMNA generates distinct optical responses to different mtDNA conformations. Binding to G4DNA imposes stronger conformational restriction on the probe, resulting in increased fluorescence intensity and a longer fluorescence lifetime relative to duplex binding. Together with its large Stokes shift and high photostability, these properties support fluorescence lifetime imaging microscopy and STED nanoscopy for quantitative discrimination of mtG4DNA and mt-dsDNA in living cells. Using this approach, we identify condition-dependent remodeling of mitochondrial DNA topology in oxidative stress, replicative senescence, and FUS-mutant amyotrophic lateral sclerosis patient-derived fibroblasts. These findings establish SDMNA as a platform for probing mitochondrial nucleoid organization and mtDNA structural remodeling in aging- and disease-associated mitochondrial dysfunction.

Abstract Importance Recently, increasing studies have demonstrated that blood p-tau 217, the most promising diagnostic biomarker for Alzheimer's disease (AD), is increased and originated from muscle damage in amyotrophic lateral sclerosis (ALS) patients. These findings suggested that blood total p-tau 217 may partly derive from muscle damage. Thus, there is an urgent need for identifying blood brain-derived p-tau 217, but not blood total p-tau 217 which may contain muscle-derived p-tau 217, and other brain-derived biomarkers in order to reduce the potential peripheral interference in its adoption in assisting early diagnosis in AD patients. Objective To explore whether serum brain-derived p-tau 217 is a more promising diagnostic biomarker and has less peripheral interference than total p-tau 217 for AD patients in a large multicentre cohort. To examine whether serum synaptic vesicle glycoprotein 2A (SV2A) is a potential biomarker for assessing brain damage in AD patients. To examine whether serum p-tau 217 is a specific lower motor neuron (LMN) damage biomarker for ALS patients. Design, Setting, and Participants This cross-sectional study was conducted in 3 independent cohorts and a total of 1198 participants, including 325 AD patients, 235 ALS patients, 289 LMN disease controls (LMNDCs), 145 dementia controls (DDCs), and 204 cognitive intact healthy controls (CIHCs). Main Outcomes and Measures Serum brain-derived p-tau 217, total p-tau 217, SV2A, and NfL were measured based on single molecular detection technique. Results Serum brain-derived p-tau 217 was significantly increased in AD patients compared to ALS patients, DDCs, LMNDCs and CIHCs, while serum p-tau 217 was significantly increased in both ALS patients and AD patients compared to DDCs, LMNDCs and CIHCs after familywise error correction (p < 0.05). Serum SV2A was significantly decreased in AD patients than in other groups. Moreover, area under the curve for serum brain-derived p-tau 217 in differentiating AD from other groups were 0.927-0.954. Conclusions and Relevance Our findings suggest that serum brain-derived p-tau 217 and SV2A are more specific diagnostic biomarkers for reflecting brain damage and may not be disturbed by peripheral damage for AD patients. Moreover, we suggest that serum p-tau 217 is a specific LMN damage biomarker for ALS patients. Keywords: AD, ALS, p-tau 217, brain-derived p-tau 217, SV2A ### Competing Interest Statement The authors have declared no competing interest. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board of Qilu Hospital of Shandong University gave ethical approval for this work (approval number: KYLL-202412-067-1). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The anonymized data underlying this study are not publicly available due to privacy and ethical restrictions. They may be made available to qualified researchers from the corresponding author upon reasonable request, subject to review by the corresponding authors and approval by the Institutional Review Board of Qilu Hospital of Shandong University. Key Research and Development Program of Shandong Province, 2025CXPT133 National Natural Science Foundation of China, 82471429, 82071412, 82171395

BACKGROUND:Using multi-shell diffusion MRI, we aimed to identify whether corticospinal tract (CST) subfiber damage can be detected in prediagnostic amyotrophic lateral sclerosis (ALS) patients. We also explored whether the combination of serum neurofilament light chain (NfL) levels and CST subfiber abnormalities may provide better diagnostic performance in differentiating prediagnostic ALS patients from disease controls (DCs) and healthy controls (HCs) than single markers. METHODS:In this retrospective study, prediagnostic ALS was used as an operational term for patients who presented at baseline with chronic progressive limb weakness or bulbar symptoms, had no clinically evident typical UMN signs, and were subsequently confirmed to have sporadic ALS according to the Awaji criteria during longitudinal follow-up. Patients whose final diagnosis was not ALS after follow-up were classified as disease controls. Probabilistic tractography was performed on baseline MRI data to assess CST subfiber damage in 47 ALS patients, 20 DCs, and 51 HCs. RESULTS:Compared with Controls, ALS patients had significantly lower neurite density index (NDI) values of CST subfibers, particularly those originating from the primary and supplementary motor cortex. The diagnostic performance of the combined model incorporating serum NfL and CST subfiber NDI values in differentiating prediagnostic ALS patients from HCs and DCs was 0.925 and 0.928, respectively, which was better than that of single markers (0.634-0.886 and 0.699-0.856, respectively). CONCLUSIONS:Our findings suggest that CST subfibers NDI values are promising neuroimaging markers for detecting in vivo UMN degeneration in prediagnostic ALS. Moreover, combining blood and neuroimaging markers may further improve early diagnostic performance.

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a progressive, fatal multisystem disorder characterized by significant genotypic and geographic heterogeneity. Despite recent therapeutic breakthroughs, overlapping clinical features frequently lead to misdiagnosis and delayed intervention. A comprehensive narrative review of the literature was conducted to synthesize recent advancements in the epidemiology, diagnostic workflows, and therapeutic landscape of ATTRv-PN, with an emphasis on clinical translation and multidisciplinary management. The epidemiological profile of ATTRv-PN highlights region-specific variant distributions (e.g., p.Val50Met, p.Ala117Ser). The diagnostic paradigm has shifted towards prioritizing early genetic testing and minimally invasive biopsies, complemented by emerging serum biomarkers like neurofilament light chain (NfL) and advanced neuroimaging. Therapeutically, the landscape has been transformed by disease-modifying therapies (DMTs). Gene-silencing agents (siRNAs and ASOs) and TTR stabilizers have demonstrated robust efficacy in halting neuropathy progression. Furthermore, novel modalities, including amyloid-depleting monoclonal antibodies and in vivo CRISPR/Cas9 gene-editing therapies, show unprecedented promise in ongoing clinical trials. ATTRv-PN has entered an era of precision medicine. Overcoming diagnostic delays through “red-flag” recognition and routine genetic screening is imperative. Early, stage-adapted initiation of DMTs within a multidisciplinary care framework is crucial for optimizing long-term patient outcomes.