ID: 10787043
Title: Pathology of Madras type of motor neuron disease (MMND)--a histological and immunohistochemical study.
Abstract: A neuropathological report of Madras type of motor neuron disease (MMND) is presented and the differences from other forms of MND are discussed. An 18-year-old girl presented with nerve deafness and slowly progressive bulbo-spinal muscular atrophy, characteristic of MMND. Post-mortem examination of the spinal cord showed a severe loss of anterior horn cells, prominent dilatation of vessels, diffuse, but sparse sprinkling of microglial cells and lymphocytes, and demyelination and sclerosis of the ventrolateral columns. Neuronal depletion and marked gliosis was noted in the cochlear nucleus on both sides, while other bulbar motor nuclei were also involved. The cochlear nerve showed demyelination and axonal loss. Trigeminal and vestibular ganglia revealed features of ganglionitis. The possibility of an inflammatory aetiology for MMND needs to be considered.

ID: 14568347
Title: Immunohistochemical study on the distribution of MnSOD in the central nervous system of the transgenic mice expressing a human Cu/Zn SOD mutation.
Abstract: In the present study, we used the SOD1(G93A) mutant transgenic mice as an animal model of amyotrophic lateral sclerosis (ALS) and performed immunohistochemical studies to investigate the changes of MnSOD in the central nervous system of transgenic mice at the age of 8, 13, and 18 weeks. In the spinal cord of wild-type SOD1 (wtSOD1) and SOD1(G93A) transgenic mice, MnSOD-immunoreactive neurons were distributed mainly in the anterior horn, although they were also observed in the posterior horn. The staining intensity of MnSOD was significantly increased in the spinal cord of SOD1(G93A) transgenic mice at presymptomatic and symptomatic stage. In the brainstem of symptomatic SOD1(G93A) transgenic mice, significantly increased immunoreactivity for MnSOD was observed in abducens nucleus, facial nucleus, dorsal motor nucleus of vagus, hypoglossal nucleus, medullary and pontine reticular formation, superior and inferior olivary nucleus, and cochlear nucleus. The present study provides the first evidence that MnSOD immunoreactivity was increased in the central nervous system of SOD(G93A) transgenic mice, suggesting that mitochondria may play an important role in the pathogenesis and progress of ALS. The mechanisms underlying the increased immunoreactivity for MnSOD, and the functional implications of these increases, require elucidation.

ID: 15019581
Title: Reactive astrocytes express PARP in the central nervous system of SOD(G93A) transgenic mice.
Abstract: In the present study, we used the transgenic mice expressing a human Cu/Zn SOD mutation (SOD1(G93A)) as an in vivo model of amyotrophic lateral sclerosis (ALS) and performed immunohistochemical studies to investigate the changes of poly(ADP-ribose) polymerase (PARP) in the central nervous system. In the spinal cord of symptomatic transgenic mice, immunohistochemistry showed intensely stained PARP-immunoreactive glial cells with the appearance of astrocytes, which were confirmed as astrocytes by double-immunofluorescences. In the brainstem and cerebellum, PARP-immunoreactive astrocytes were observed in the medullary and pontine reticular formation, hypoglossal nucleus, vestibular nucleus, cochlear nucleus and cerebellar nuclei. On the contrary, no PARP-immunoreactive glial cells were observed in control mice although PARP-immunoreactive motor neurons were found. In presymptomatic transgenic mice, a few moderately stained neurons were observed, whereas PARP-immunoreactive astrocytes were not detected. The present study provides the first evidence that PARP-immunoreactive astrocytes were found in the central nervous system of symptomatic SOD1(G93A) transgenic mice, suggesting that reactive astrocytes may play an important role in the pathogenesis and progress of ALS.

ID: 22766032
Title: Association of UBQLN1 mutation with Brown-Vialetto-Van Laere syndrome but not typical ALS.
Abstract: Genetic variants in UBQLN1 gene have been linked to neurodegeneration and mutations in UBQLN2 have recently been identified as a rare cause of amyotrophic lateral sclerosis (ALS). To test if genetic variants in UBQLN1 are involved in ALS. 102 and 94 unrelated patients with familial and sporadic forms of ALS were screened for UBQLN1 gene mutations. Single nucleotide variants were further screened in a larger set of sporadic ALS (SALS) patients and unrelated control subjects using high-throughput Taqman genotyping; variants were further assessed for novelty using the 1000Genomes and NHLBI databases. In vitro studies tested the effect of UBQLN1 variants on the ubiquitin-proteasome system (UPS). Only two UBQLN1 coding variants were detected in the familial and sporadic ALS DNA set; one, the missense mutation p.E54D, was identified in a single patient with atypical motor neuron disease consistent with Brown-Vialetto-Van Laere syndrome (BVVLS), for whom c20orf54 mutations had been excluded. Functional studies revealed that UBQLN1E54D protein forms cytosolic aggregates that contain mislocalized TDP-43 and impairs degradation of ubiquitinated proteins through the proteasome. Genetic variants in UBQLN1 are not commonly associated with ALS. A novel UBQLN1 mutation (E45D) detected in a patient with BVVLS altered nuclear TDP-43 localization in vitro, suggesting that UPS dysfunction may also underlie the pathogenesis of this condition.

ID: 38285093
Title: Evidence for alterations in lipid profiles and biophysical properties of lipid rafts from spinal cord in sporadic amyotrophic lateral sclerosis.
Abstract: Amyotrophic lateral sclerosis (ALS) is an age-dependent neurodegenerative disease affecting motor neurons in the spinal cord and brainstem whose etiopathogenesis remains unclear. Recent studies have linked major neurodegenerative diseases with altered function of multimolecular lipid-protein complexes named lipid rafts. In the present study, we have isolated lipid rafts from the anterior horn of the spinal cords of controls and ALS individuals and analysed their lipid composition. We found that ALS affects levels of different fatty acids, lipid classes and related ratios and indexes. The most significant changes affected the contents of n-9/n-7 monounsaturated fatty acids and arachidonic acid, the main n-6 long-chain polyunsaturated fatty acid (LCPUFA), which were higher in ALS lipid rafts. Paralleling these findings, ALS lipid rafts lower saturates-to-unsaturates ratio compared to controls. Further, levels of cholesteryl ester (SE) and anionic-to-zwitterionic phospholipids ratio were augmented in ALS lipid rafts, while sulfatide contents were reduced. Further, regression analyses revealed augmented SE esterification to (mono)unsaturated fatty acids in ALS, but to saturates in controls. Overall, these changes indicate that lipid rafts from ALS spinal cord undergo destabilization of the lipid structure, which might impact their biophysical properties, likely leading to more fluid membranes. Indeed, estimations of membrane microviscosity confirmed less viscous membranes in ALS, as well as more mobile yet smaller lipid rafts compared to surrounding membranes. Overall, these results demonstrate that the changes in ALS lipid rafts are unrelated to oxidative stress, but to anomalies in lipid metabolism and/or lipid raft membrane biogenesis in motor neurons. KEY MESSAGES: The lipid matrix of multimolecular membrane complexes named lipid rafts are altered in human spinal cord in sporadic amyotrophic lateral sclerosis (ALS). Lipid rafts from ALS spinal cord contain higher levels of n-6 LCPUFA (but not n-3 LCPUFA), n-7/n-9 monounsaturates and lower saturates-to-unsaturates ratio. ALS lipid rafts display increased contents of cholesteryl esters, anomalous anionic-to-zwitterionic phospholipids and phospholipid remodelling and reduced sulphated and total sphingolipid levels, compared to control lipid rafts. Destabilization of the lipid structure of lipid raft affects their biophysical properties and leads to more fluid, less viscous membrane microdomains. The changes in ALS lipid rafts are unlikely related to increased oxidative stress, but to anomalies in lipid metabolism and/or raft membrane biogenesis in motor neurons.

ID: 38352376
Title: AAV-based delivery of RNAi targeting Ataxin-2 improves survival, strength, and pathology in mouse models of rapidly and slowly progressive sporadic ALS.
Abstract: Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron death due to nuclear loss and cytoplasmic aggregation of the splice factor TDP-43. Pathologic TDP-43 associates with stress granules (SGs) and downregulating the SG-associated protein Ataxin-2 (Atxn2) using antisense oligonucleotides (ASO) prolongs survival in the TAR4/4 sporadic ALS mouse model, a strategy now in clinical trials. Here, we used AAV-mediated RNAi delivery to achieve lasting and targeted Atxn2 knockdown after a single injection. To achieve this, a novel AAV with improved transduction potency of our target cells was used to deliver Atxn2 -targeting miRNAs. Mouse dosing studies demonstrated 55% Atxn2 knockdown in frontal cortex and 25% knockdown throughout brainstem and spinal cord after intracerebroventricular injection at a dose 40x lower than used in other recent studies. In TAR4/4 mice, miAtxn2 treatment increased mean and median survival by 54% and 45% respectively (p<0.0003). Mice showed robust improvement across strength-related measures ranging from 24-75%. Interestingly, treated mice showed increased vertical activity above wildtype, suggesting unmasking of an FTD phenotype with improved strength. Histologically, lower motor neuron survival improved with a concomitant reduction in CNS inflammatory markers. Additionally, phosphorylated TDP-43 was reduced to wildtype levels. Bulk RNA sequencing revealed correction of 153 genes in the markedly dysregulated transcriptome of mutant mice, several of which are described in the human ALS literature. In slow progressing hemizygous mice, treatment rescued weight loss and improved gait at late time points. Cumulatively the data support the utility of AAV-mediated RNAi against Atxn2 as a robust and translatable treatment strategy for sporadic ALS.

ID: 38472048
Title: VEGF expression disparities in brainstem motor neurons of the SOD1G93A ALS model: Correlations with neuronal vulnerability.
Abstract: Amyotrophic lateral sclerosis (ALS) is a rare neuromuscular disease characterized by severe muscle weakness mainly due to degeneration and death of motor neurons. A peculiarity of the neurodegenerative processes is the variable susceptibility among distinct neuronal populations, exemplified by the contrasting resilience of motor neurons innervating the ocular motor system and the more vulnerable facial and hypoglossal motor neurons. The crucial role of vascular endothelial growth factor (VEGF) as a neuroprotective factor in the nervous system is well-established since a deficit of VEGF has been related to motoneuronal degeneration. In this study, we investigated the survival of ocular, facial, and hypoglossal motor neurons utilizing the murine SOD1G93A ALS model at various stages of the disease. Our primary objective was to determine whether the survival of the different brainstem motor neurons was linked to disparate VEGF expression levels in resilient and susceptible motor neurons throughout neurodegeneration. Our findings revealed a selective loss of motor neurons exclusively within the vulnerable nuclei. Furthermore, a significantly higher level of VEGF was detected in the more resistant motor neurons, the extraocular ones. We also examined whether TDP-43 dynamics in the brainstem motor neuron of SOD mice was altered. Our data suggests that the increased VEGF levels observed in extraocular motor neurons may potentially underlie their resistance during the neurodegenerative processes in ALS in a TDP-43-independent manner. Our work might help to better understand the underlying mechanisms of selective vulnerability of motor neurons in ALS.

ID: 38963135
Title: Adipose mesenchymal stem cells-derived extracellular vesicles exert their preferential action in damaged central sites of SOD1 mice rather than peripherally.
Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving motor neuron (MN) loss in the motor cortex, brainstem and spinal cord leading to progressive paralysis and death. Due to the pathogenetic complexity, there are no effective therapies available. In this context the use of mesenchymal stem cells and their vesicular counterpart is an emerging therapeutic strategy to counteract neurodegeneration. The extracellular vesicles derived from adipose stem cells (ASC-EVs) recapitulate and ameliorate the neuroprotective effect of stem cells and, thanks to their small dimensions, makes their use suitable to develop novel therapeutic approaches for neurodegenerative diseases as ALS. Here we investigate a therapeutic regimen of ASC-EVs injection in SOD1(G93A) mice, the most widely used murine model of ALS. Repeated intranasal administrations of high doses of ASC-EVs were able to ameliorate motor performance of injected SOD1(G93A) mice at the early stage of the disease and produce a significant improvement at the end-stage in the lumbar MNs rescue. Moreover, ASC-EVs preserve the structure of neuromuscular junction without counteracting the muscle atrophy. The results indicate that the intranasal ASC-EVs administration acts in central nervous system sites rather than at peripheral level in SOD1(G93A) mice. These considerations allow us to identify future applications of ASC-EVs that involve different targets simultaneously to maximize the clinical and neuropathological outcomes in ALS in vivo models.

ID: 39569650
Title: Therapeutic potential of simvastatin in ALS: Enhanced axonal integrity and motor neuron survival through Apoa4 and Alb modulation.
Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the effects of simvastatin on the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. The experiment included three groups: C57BL/6 wild-type mice, C57BL/6J SOD1G93A mice treated with PBS (SOD1G93A + PBS), and C57BL/6J SOD1G93A mice treated with simvastatin (SOD1G93A + simvastatin). The primary endpoints were survival rates, body weight changes, performance in pole climbing and suspension tests, and neurological deficit scores. Pathological changes were assessed using hematoxylin and eosin staining, transmission electron microscopy, Nissl staining, and Masson staining. Proteomic and metabolomic analyses were performed to identify differentially expressed proteins (DEPs) and metabolites. Quantitative real-time polymerase chain reaction and western blotting were used to measure gene expression. Although there were no significant differences in survival rates, body weight, pole climbing, and suspension test performance, or neurological deficit scores between the SOD1G93A + simvastatin and SOD1G93A + PBS groups, simvastatin treatment improved axonal organization within the spinal cord, increased the number of neurons, and reduced cytoplasmic swelling and gastrocnemius fibrosis. A total of 47 DEPs and 13 differential metabolites were identified between the SOD1G93A + PBS and SOD1G93A + simvastatin groups. Notably, the expression levels of Apoa4 and Alb were elevated in the SOD1G93A + simvastatin group compared to the SOD1G93A + PBS group. Our results suggest that simvastatin may have potential therapeutic effects in ALS, likely involving the modulation of Apoa4 and Alb expression.

ID: 39672239
Title: GDF15-GFRAL signaling drives weight loss and lipid metabolism in mouse model of amyotrophic lateral sclerosis.
Abstract: Weight loss is a common early sign in amyotrophic lateral sclerosis (ALS) patients and negatively correlates with survival. In different cancers and metabolic disorders, high levels of serum growth differentiation factor 15 (GDF15) contribute to a decrease of food intake and body weight, acting through GDNF family receptor alpha-like (GFRAL). Here we report that GDF15 is highly expressed in the peripheral blood of ALS patients and in the hSOD1G93A mouse model and that GFRAL is upregulated in the brainstem of hSOD1G93A mice. We demonstrate that the localized GFRAL silencing by shRNA in the area postrema/nucleus tractus solitarius of hSOD1G93A mice induces weight gain, reduces adipose tissue wasting, ameliorates the motor function and muscle atrophy and prolongs the survival time. We report that microglial cells could be involved in mediating these effects because their depletion with PLX5622 reduces brainstem GDF15 expression, weight loss and the expression of lipolytic genes in adipose tissue. Altogether these results reveal a key role of GDF15-GFRAL signaling in regulating weight loss and the alteration of and lipid metabolism in the early phases of ALS.

ID: 40333935
Title: Histone Deacetylase 6 Brain PET in Amyotrophic Lateral Sclerosis-Frontotemporal Spectrum Disorder.
Abstract: [18F]EKZ-001 is a positron emission tomography (PET) tracer targeting histone deacetylase 6 (HDAC6), an enzyme responsible for intracellular transport and clearance of misfolded proteins. HDAC6 modulation is a promising treatment strategy in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Apart from motor symptoms, people with ALS (pwALS) can show a variable degree of cognitive impairment as part of the ALS-frontotemporal spectrum disorder (ALS-FTSD). This work assessed [18F]EKZ-001 binding in pwALS with variable involvement of FTSD. Twenty-four pwALS (13M/11F, 61 ± 10 years) and 12 healthy controls (HC) (6M/6F, 58 ± 3 years) were included. Thirteen pwALS were cognitively normal (ALS-CN), and eleven pwALS presented with FTSD (ALS-FTSD) ranging from mild cognitive or behavioral impairment to FTD, according to their performance on the Edinburgh cognitive and behavioral ALS screen (ECAS). All subjects underwent dynamic PET-MR imaging with arterial sampling, and regional distribution volumes (VT) were calculated using a Logan graphical analysis. [18F]EKZ-001 VT was significantly lower in pwALS compared to HC. For ALS-CN, the largest reduction was found in the brainstem. For ALS-FTSD, reductions were more widespread in both gray and white matter. No differences in VT were found between pwALS with and without a C9orf72 mutation. [18F]EKZ-001 VT was not correlated with ECAS scores, age, or disease duration. [18F]EKZ-001 binding is lower throughout the brain in pwALS compared to HC. This may be related to a compensatory mechanism to repair intracellular transport defects in ALS or to reduced HDAC6 enzyme availability for [18F]EKZ-001 binding due to sequestration of HDAC6 within protein aggregates.

ID: 40384352
Title: Shape Alterations of Subcortical Nuclei Correlate With Amyotrophic Lateral Sclerosis Progression.
Abstract: Neuroimaging has been increasingly used to assess brain structural alterations in patients with amyotrophic lateral sclerosis (ALS). We aimed to investigate alterations in brain sub-cortical structures and to identify potential neuroimaging biomarkers for disease progression for patients with ALS. A total of 61 patients with ALS were prospectively enrolled and were divided into three subgroups according to disease progression, i.e., fast, intermediate, and slow progression. Sixty-one matched healthy controls (HCs) were also recruited. All participants acquired a brain structural magnetic resonance imaging scan for subcortical volumetric and shape analyses. Neuropsychological testing and functional assessment were performed. Patients with fast progression showed significant shape alterations in basal ganglia and brainstem as compared to the HCs group. In ALS patients with fast progression, shape contractions with atrophic changes were noted in bilateral nucleus accumbens, left caudate, left thalamus, and brainstem; while shape expansion with hypertrophy was noted in the left caudate, left thalamus, and left pallidum (all p < 0.05). There were significant positive correlations of the shape changes of the left thalamus with the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALS-FRS-R) total and limb scores and with disease duration (all p < 0.05). There were positive correlations of left pallidum with anxiety or with disease duration, and of left nucleus accumbens with ALS-FRS-R total or bulbar score, and of brainstem with mini-mental state examination score (all p < 0.05). Extensive shape alterations of subcortical nuclei were noted in patients with fast progression of ALS, implicating subcortical shape being a potential neuroimaging biomarker for ALS progression.

ID: 40440345
Title: Findings from transcriptomics and immunohistochemistry indicate an autoimmune disease targeting brainstem inhibitory interneurons in bovine spastic paresis.
Abstract: Bovine spastic paresis (BSP) is a progressive neuromuscular disease of unknown origin that causes persistent stiffness of the hind limbs. The symptoms are similar to those of human motor neuron diseases such as primary (PLS) or amyotrophic lateral sclerosis (ALS). BSP occurs worldwide in cattle production with an estimated prevalence of <1%. For Germany, this means that around 20,000 Holstein cattle are affected. BSP is generally considered a hereditary disease, but there is no prevention through breeding programs. As a result, BSP not only affects animal welfare but also leads to economic losses in milk and beef production. Here, we used transcriptomics to analyse the brainstem, spinal cord and affected gastrocnemius muscle tissue of eight animals affected by BSP and eight control animals from slaughterhouses to gain new insights into the molecular mechanisms underlying BSP. We found that the expression of several genes was significantly different in animals affected by BSP compared to control animals. Specific genes for inhibitory neurons were downregulated in the brainstems of the affected animals, namely CCK (cholecystokinin), NPY (neuropeptide Y), and SST (somatostatin). These inhibitory neurotransmitters influence cerebral movement control, among other processes. Furthermore, OOSP2 (oocyte secreted protein 2) was found to be significantly upregulated in the affected animals in all tissues. This expression could best be explained by the presence of T-follicular-helper cells which, through interleukin 21, can trigger a TH-2-dominated immune response and lead to autoimmune encephalitis. Further cases were sampled for confirmation and we detected cell infiltrates of activated microglia and T-cells in the brainstem using immunohistochemistry. Microglial foci were significantly more abundant in animals affected by BSP than control animals. We conclude that BSP is caused by an autoimmune reaction directed against inhibitory interneurons in the brainstem and is due to a combination of genetics and environmental influences. This may result in lost controlling influence on the upper motor neurons via extrapyramidal pathways and therefore triggers the specific symptoms of motor neuron disease.

ID: 40543705
Title: Novel Kinesin Family Member 1A Variants Linked to Atypical Parkinsonism Elicit Altered Neuronal Transactive Response DNA Binding Protein 43 kDa Interactions and Dendritic Atrophy.
Abstract: Analysis of induced pluripotent stem cell (iPSC)-derived neurons from the son of a father-son pair with novel familial variants of uncertain significance in kinesin family member 1A (KIF1A) [c.408C>G (p.Asp136Glu); c.3914G>A (p.Arg1305His)] reveal pathologic features of altered transactive response DNA binding protein 43 kDa (TDP-43) localization, interactions, and stunted dendritic arbors. Both patients developed spasticity and parkinsonism in their mid-60s, with the father dying at age 70 years. There was impaired putamenal dopamine uptake with preserved uptake in the caudate nuclei, and decreased anisotropy by tractography in multiple motor pathways. Given shared transcriptional mechanisms of hindbrain and spinal cord developmental patterning among neurons of the motor circuitry, iPSC-derived motor neurons from fibroblasts donated by the son were generated to investigate the impact of KIF1A mutations on TDP-43 subcellular localization, biochemical interactions of endogenous wild type and mutant KIF1A and endogenous TDP-43, and the pathologic impact of these KIF1A variants on dendritic arborization using Sholl analysis. Neuropathologic assessment of the father, who shared the same KIF1A variants, revealed tauopathy and TDP-43 proteinopathy throughout the brainstem. Quantitative imaging of patient iPSC neurons identified TDP-43 mislocalization to the soma and dendritic atrophy. The KIF1A mutant also elicited decreased biochemical interactions of both itself and TDP-43 with a spectrum of known TDP-43-associated proteins. These data suggest that this novel KIF1A mutant mediates altered TDP-43 interactions, stunting of the synaptic architecture, and clinical phenotypes coincident with neurodegenerative movement disorders.

ID: 40607881
Title: Association of Reduced Brain Metabolism With Motor Function and Survival in Amyotrophic Lateral Sclerosis Patients With Neurofilament Heavy (NEFH) Gene Mutation.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that impairs both upper and lower motor neurons. Mutations in the neurofilament heavy (NEFH) gene are associated with a higher risk for ALS. This study aimed to evaluate the brain metabolism in patients with ALS and NEFH gene mutations (NEFH-ALS) and assess its correlation with emotional and cognitive changes. This prospective study enrolled 119 patients with ALS and 128 age- and gender-matched health controls. Study assessments included demographic data collection, questionnaires for motor function, cognition, and depression, and brain F-18 FDG PET/CT (18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT)) scan. Correlation between brain metabolism and clinical questionnaire scores was performed. Chain-mediation model analysis for the NEFH-ALS group was conducted. Cox regression and Kaplan-Meier survival analysis were also performed. There were 26 NEFH-ALS patients. Patients with NEFH-ALS showed brain glucose hypometabolism in the cortex-striatum/limbic system-brainstem circuit when compared with healthy controls (p < 0.05). Decreased brain glucose metabolism was correlated with impairments of motor function (r = 0.477, p = 0.014, FDR corrected p = 0.014), cognitive scores (r = 0.549, p = 0.004, FDR corrected p = 0.009), and depression (r = -0.523, p = 0.009, FDR corrected p = 0.009). This study showed that brain glucose hypometabolism could lead to impairment of motor function, which was mediated by cognition and depression. Survival analysis showed that brain glucose metabolism was an independent prognostic factor for patients with ALS. Reduced brain glucose metabolism in the cortex-striatum/limbic system-brainstem circuit may potentially serve as an independent prognostic factor for patients with ALS and NEFH mutation.

ID: 40650880
Title: Brain atrophy patterns in anti-IgLON5 disease.
Abstract: Anti-IgLON5 disease is an autoimmune encephalitis that presents with a heterogenous clinical phenotype, including sleep disorders, movement abnormalities and bulbar involvement. It is characterized by autoantibodies against IgLON5, 85% association with HLA-DQB1*05:∼ and a brainstem-dominant tauopathy. Cellular and murine models report pathogenic effects of the autoantibodies, and neurodegenerative factors suggest progressive atrophy as a common sequela. However, evidence from in vivo patient data and long-term follow-up is limited, and the degree of progression remains elusive. In this multicentre study, clinical and brain MRI data were collected from 127 patients across 12 countries to investigate the relationships between clinical presentations and the development of distinct brain atrophy patterns. Our data show that most patients develop a complex multisystem phenotype as the disease progresses; however, neuromuscular manifestations rarely emerge at later disease stages. By comparison to healthy controls, this disease presents with severe substructure-specific atrophy, especially affecting the hypothalamus, brainstem, accumbens and basal ganglia, which, in age-independent analyses, show significant ventricular enlargement and also suggest progression of brainstem atrophy over the disease course. Moreover, the focality of atrophy was functionally linked to specific symptoms, with more severe involvement of the basal ganglia in patients with movement disorders, and greater atrophy in the hippocampus and thalamus in patients with cognitive impairment. Taken together, our results provide evidence of distinct atrophy patterns in anti-IgLON5 disease, which closely mirror sites of pathophysiologic processes, including autoantibody binding and tau deposition. Our data emphasize the brainstem as the pathophysiological hub of the disease and provide normative data for the incorporation of atrophy measurements into routine clinical assessments and future treatment studies to monitor disease trajectory and evaluate future treatment strategies.

ID: 40653816
Title: Transcranial Brain Parenchyma Sonographic Findings in Familial and Sporadic Amyotrophic Lateral Sclerosis.
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons. Transcranial sonography (TCS) is a valuable tool for assessing deep brain structures. This study aimed to analyze TCS findings in both sporadic (sALS) and familial ALS (fALS) patients and compare them to healthy controls (HC). This cross-sectional study included 278 patients with sALS and 31 patients with genetically confirmed fALS, and 93 age- and gender- matched HC. TCS was used to assess substantia nigra (SN) and brainstem raphe (BR) echogenicity and third ventricle diameter (TVD). Functional disability was evaluated using the ALS Functional Rating Scale-Revised. BR hypoechogenicity was more frequent in fALS (41.9%) and sALS (37.4%) patients, compared to HC (10.8%) (p < 0.001). Right SN hyperechogenicity was observed in 28.1% of sALS, 16.1% of fALS, and 8.6% of HC (p = 0.004). Left SN hyperechogenicity was found in 33.5% of sALS, 29.0% of fALS, and 4.3% of HC (p = 0.004). SN hyperechogenicity findings on either side were highest in sALS (48.4%) compared to fALS (31.0%) and HC (13.3%) (p < 0.001), with a borderline difference between fALS and sALS (p = 0.08). BR hypoechogenicity and SN hyperechogenicity were more common in male patients. Increased TVD correlated with older age, later disease onset, bulbar onset, and lower MMSE scores. TCS is an easily applicable and sensitive diagnostic tool that offers novel insights into several brainstem structures and identify significant differences in their echogenicity between ALS patients and healthy controls, while pointing out similar but not identical patterns of echogenicity in both ALS forms.

ID: 41005573
Title: The potential role of misfolded wild-type SOD1 protein in sporadic amyotrophic lateral sclerosis (ALS): a review of the evidence.
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterised by the selective loss of motor neurons in the motor cortex, brainstem and spinal cord. In 1993, the first ALS-linked gene mutations were identified in the Cu,Zn superoxide dismutase (SOD1) gene, which account for approximately 20 % of familial ALS cases. The mechanism of toxicity in this subset of patients is thought to arise from a gain-of-toxic function from the protein's propensity to misfold and aggregate into cytoplasmic inclusions. Immunohistochemical studies have shown that misfolded wildtype SOD1 (wtSOD1) is also detected in the motor neurons and glial cells of ALS patients without SOD1 mutations. It is proposed that disrupted, or aberrant, post-translational modifications cause wtSOD1 to adopt a toxic conformation similar to that of the mutant protein. Subsequent mechanistic studies have shown that this misfolded wtSOD1 can disrupt cellular function and lead to motor neuron death through pathways similar to those observed in mutant SOD1-ALS. Given the limited neuroprotective treatments currently available that can effectively slow or reverse disease progression, targeting a pathogenic mechanism that features in both familial and sporadic ALS cases represents a promising therapeutic approach for a broader patient population. This review examines the growing body of evidence that supports or challenges the role of misfolded wtSOD1 in the pathophysiology of sporadic ALS and explores the potential implications of this mechanism in disease progression. Understanding how misfolded wtSOD1 contributes to disease pathogenesis provides new opportunities for developing more widely available treatments for this devastating disease.

ID: 41108075
Title: siRNA for REST ameliorates symptoms in ALS mice and serum REST predicts disease prognosis and survival in ALS patients.
Abstract: Restrictive element-1 silencing transcription factor (REST) is a key repressor of neuronal genes in stem cells and neuronal progenitor cells and its aberrant accumulation has been implicated in the pathophysiology of neurological disorders, such as Huntington's disease, epilepsy, and stroke. Herein, we investigated the role of REST in amyotrophic lateral sclerosis (ALS) pathophysiology and its potential as blood-based predictor of disease prognosis and survival in ALS patients. Intriguingly, REST protein levels were significantly increased in motor cortex, brainstem and spinal cord of superoxide dismutase 1 (SOD1)-G93A mice compared with wild-type mice, both during early and late symptomatic phases of the disease. Notably, intracerebroventricular injections of a siRNA against REST (siREST), mitigated motor neuron loss, counteracted the formation of SOD1 aggregates, and reduced astrogliosis, thus improving behavioral performance and extending the survival of SOD1-G93A mice. Interestingly, ELISA assay showed that serum REST levels were significantly elevated in ALS patients compared with healthy subjects; furthermore, the higher serum REST levels have been found in patients with shorter tracheostomy-free survival. Collectively, we demonstrated that preventing REST increase in brain areas involved in ALS disorder extended the survival of SOD1-G93A mice and showed that serum REST may represent a possible prognostic biomarker in ALS patients.

ID: 41576445
Title: Noise exposure induces autophagy-modulated nuclear-to-cytoplasmic translocation of TDP-43 in spiral ganglion neurons.
Abstract: Noise exposure contributes to approximately one-third of hearing loss cases worldwide. Despite its substantial global burden, noise-induced hearing loss (NIHL) remains essentially irreversible, largely because its underlying pathogenic mechanisms are not yet fully defined. In this study, we established three noise-induced hearing loss mouse models and evaluated auditory function by measuring auditory brainstem response (ABR) thresholds at multiple time points following noise exposure. In parallel, we examined the spatiotemporal redistribution of TDP-43 and evaluated autophagic flux in spiral ganglion neurons (SGNs) to elucidate their dynamic responses to acoustic stress. Noise exposure triggers marked nucleocytoplasmic translocation and cytoplasmic aggregation of TDP-43 in spiral ganglion neurons (SGNs), accompanied by dynamic alterations in autophagic flux. Using pharmacological modulation, we demonstrate that autophagy critically shapes the fate of TDP-43. Mechanistically, noise-induced stressors such as reactive oxygen species (ROS) likely initiate TDP-43 nuclear export, whereas insufficient autophagic flux impedes aggregate degradation and exacerbates cytoplasmic inclusion formation. Together, these findings reveal autophagy as a key determinant of TDP-43 dynamics in the auditory system and identify the autophagy-TDP-43 axis as a potential therapeutic target for preventing or ameliorating noise-induced hearing loss.

ID: 41813136
Title: ALS and Huntington Disease: Unraveling the Connections between TDP-43 and Huntingtin.
Abstract: Amyotrophic lateral sclerosis (ALS) and Huntington disease (HD) are lethal neurodegenerative diseases affecting motor function. Though their etiology and pathology are distinct, recent evidence suggests commonalities between TAR DNA-binding protein (TDP-43), which is associated with 97% of ALS cases, and huntingtin (HTT), the causative protein of HD. ALS is a heterogeneous, lethal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons, as well as brainstem and spinal cord degeneration. The causes of ALS are complex, variable, and, in some cases, unknown, but most cases involve mislocalization of the protein TDP-43. In contrast, HD is a monogenic, autosomal dominant, lethal neurodegenerative disease caused by polyglutamine expansion in HTT protein and characterized by the progressive loss of neurons in the brain, particularly in the striatum, which results in motor, cognitive, and behavioral changes. Although HD is not typically associated with motor neuron loss, recent evidence suggests a link between HTT and TDP-43 within the context of both ALS and HD, as well as links to related neurodegenerative diseases, such as frontotemporal dementia (FTD) and spinocerebellar ataxia type 2 (SCA2). Herein, we discuss confirmed cases of concurrent ALS and HD and the overlap of underlying disease mechanisms that potentially contribute to the onset and progression of these two devastating neurodegenerative diseases, with a focus on commonalities between TDP-43 and HTT. We propose that elucidating these commonalities will aid in the identification of broad-spectrum disease risk factors and potential overlapping treatment targets.

ID: 41895381
Title: Spiral ligament dysfunction and endocochlear potential loss drive hearing impairment in Niemann-Pick C1 mice.
Abstract: Sensorineural hearing loss is increasingly recognized in Niemann-Pick disease type C (NPC), but the underlying cochlear lesion remains undefined. While prior work emphasized hair-cell (HC) involvement, whether auditory dysfunction instead arises from lateral-wall failure and endocochlear potential (EP) decline is unknown. Npc1-/- mice and littermate controls underwent auditory function test and electrophysiological recordings at postnatal day (P) 35 and P63. Cochlear cytoarchitecture was evaluated using immunohistochemistry and transmission electron microscopy (TEM). To probe cell-type susceptibility, NPC1 was inhibited in Spiral ligament (SLi)-like fibrocytes, HC-like HEI-OC1 cells in vitro. Npc1-/- mice showed elevated low-frequency auditory brainstem response (ABR) thresholds at P35, progressing to pan-frequency impairment and prolonged ABR wave IV-V latencies by P63. HCs, stereocilia bundles, and spiral ganglion cells were preserved. In contrast, EP was markedly reduced. Na⁺/K⁺-ATPase α1 and connexin-26 immunolabeling in the SLi decreased significantly without strial thinning, indicating impaired ion recycling and gap-junction coupling. Filipin staining and TEM revealed progressive free-cholesterol accumulation and vacuolar inclusions in SLi fibrocytes and supporting cells, with secondary involvement of HC regions. In vitro, NPC1 inhibition increased cholesterol in SLi-like fibrocytes but not in HEI-OC1 cells. NPC-related hearing loss arises primarily from SLi dysfunction and EP failure, with secondary HC compromise, rather than degeneration. These findings reposition NPC hearing loss as a disorder of cochlear homeostasis and identify EP preservation and correction of cholesterol trafficking as rational therapeutic targets. Early auditory monitoring may improve clinical outcomes.

ID: 41949031
Title: Greater Cochlear Damage in Otogenic Versus Meningogenic Meningitis: Hearing Rehabilitation Implications.
Abstract: To quantify cochlear and vestibular cellular losses between cases of meningogenic and otogenic meningitis. From the archival human temporal bone collection at the University of Minnesota, we selected specimens with meningitis history and histopathological evidence of labyrinthitis. We grouped specimens into two categories (otogenic and meningogenic) based on infection route and included age-matched controls without ear or central nervous system disease. From 36 temporal bones, we quantitatively assessed outer hair cell (OHC) and inner hair cell (IHC) loss, as well as spiral ganglion neuron (SGN) and Scarpa's ganglion neuron (ScGN) counts, then compared results among groups. Both case groups demonstrated OHC loss compared with controls (p < 0.05), with more severe loss in the otogenic group versus the meningogenic group (p = 0.01). IHC loss occurred only in the otogenic group compared with both meningogenic and control groups (p = 0.019 and < 0.001, respectively). No statistically significant difference was found between IHC loss in meningogenic and control groups (p = 0.382). Both otogenic and meningogenic groups showed significant reduction of SGN and ScGN counts compared with controls (p < 0.05), with no statistically significant differences between the two meningitis groups for either measure (p = 0.993 and 0.762, respectively). Meningitis is associated with loss of cochlear hair cells, SGN and ScGN. The otogenic route demonstrated a greater loss of both IHC and OHC in comparison with the meningogenic route. N/A.

ID: 41995948
Title: ATP6V1B2 Regulating Autophagy Flux To Affect Abnormal Auditory Development.
Abstract: To investigate the expression changes of ATP6V1B2 downregulation in Dominant Deafness-Onychodystrophy syndrome (DDOD syndrome), its impact on auditory function, and the underlying molecular mechanisms, thereby clarifying the role of ATP6V1B2 in maintaining inner ear auditory function. RNA interference was used to downregulate ATP6V1B2 expression in HEI-OC1 cells. A DDOD syndrome mouse model was established via cochlear microinjection of ATP6V1B2-specific morpholino, while control mice injected with a scramble morpholino. The expression and localization of ATP6V1B2 in the mouse inner ear were assessed by quantitative real-time polymerase chain reaction (RT-qPCR), immunohistochemistry, and Western blot. Auditory brainstem response (ABR) was measured to evaluate auditory function at different ages (4–36 weeks). Lysosomal H⁺-ATPase (vacuolar-type ATPase [V-ATPase]) and cathepsin-D (Cath-D) activities were detected using enzyme activity assays. Western blot and immunofluorescence were used to analyze lysosomal-associated proteins (LAMP1, LAMP2, TPC1, TPC2) and autophagy-and-apoptosis-related proteins (LC3, Caspase-3, Bcl-2, Bax). Apoptosis, reactive oxygen species (ROS) levels, and mitochondrial membrane potential were quantified by flow cytometry and staining with 2’,7’-dichlorodihydrofluorescein diacetate (DCFH-DA) and 5,5’,6,6’-tetrachloro-1,1’,3,3’-tetraethylbenzimidazolylcarbocyanine iodide (JC-1), respectively. In DDOD model mice, ATP6V1B2 mRNA and protein levels were significantly reduced in the inner ear, with decreased localization in key auditory regions such as cochlear hair cells and spiral ganglion neurons (SGNs), which was accompanied by SGN loss. ABR thresholds were markedly elevated after 28 weeks, indicating progressive auditory dysfunction. Mechanistically, cochlear V-ATPase and Cath-D activities were significantly reduced, while lysosomal membrane proteins (LAMP1, LAMP2) and ion channel proteins (TPC1, TPC2) were upregulated, suggesting lysosomal acidification dysfunction. In HEI-OC1 cells, ATP6V1B2 knockdown led to autophagosome accumulation, increased expression of pro-apoptotic proteins (Bax, Caspase-3), decreased anti-apoptotic Bcl-2, elevated early apoptosis rates, and altered ROS levels. ATP6V1B2 downregulation impairs cochlear lysosomal acidification by reducing V-ATPase activity, leading to autophagic flux blockade, apoptosis activation, and mitochondrial dysfunction, ultimately contributing to SGN degeneration and progressive hearing loss. This study reveals the critical role of ATP6V1B2 in maintaining lysosomal homeostasis and auditory function, providing experimental evidence for DDOD syndrome pathogenesis and identifying potential therapeutic targets for related auditory disorders.

ID: 42029780
Title: Celf4 Regulates Excitability of Bushy Cells in the Cochlear Nucleus of the Mouse Brainstem.
Abstract: The CUGBP Elav-like family 4 (CELF4), an RNA-binding protein, is dynamically expressed in spiral ganglion neurons (SGNs) in the cochlea over development, but how Celf4 is involved in regulating hearing functions is poorly understood. In this study, we generated a Celf4± mouse line and examined changes in the first two synapses along the auditory pathways. Firstly, we found that hearing functions were largely intact in Celf4± mice, with exception of reduced amplitude for Wave II of auditory brainstem responses (ABRs) and increased delays for Wave II and IV, both in case of 4 kHz only. Secondly, we found that counts of inner and outer hair cells (IHCs and OHCs) and SGNs remained unchanged in Celf4± mice, and that the number and function of ribbon synapses between IHCs and SGNs were comparable between WT and Celf4± mice. Lastly, function of the endbulb of Held synapse, formed between auditory nerve fibers (ANFs) of SGNs and bushy cells in the cochlear nucleus, was significantly altered in Celf4± mice. Specifically, synaptic vesicle release was subtly reduced, and excitability of bushy cells was significantly dampened, likely due to a hyperpolarized resting membrane potential. Furthermore, we found that spike kinetics was significantly faster in Celf4± bushy cells, likely caused by a larger fast-inactivating A-type potassium current (IA) found in these cells. In conclusion, we found that Celf4 haploinsufficiency altered transmission at the endbulb of Held synapses in the cochlear nucleus in a significant and multifaceted manner, revealing the roles of Celf4 in regulating hearing functions.

ID: 42105561
Title: Neuritin protects spiral ganglion neurons via NKA-Ca²⁺ homeostasis and CaMKII/MAPK suppression.
Abstract: Spiral ganglion neurons (SGNs) are indispensable for auditory transduction, yet no approved pharmacological therapy exists for sensorineural hearing loss (SNHL). Neuritin has shown neuroprotective effects in the cochlea, but its mechanisms remain unclear. Here, we used a cochlear SGN-specific Neuritin conditional knockout mouse model and an ouabain‑induced SGN injury model to define the role of Neuritin in auditory neuropathy. Neuritin deficiency accelerated age‑related SGNs loss, synaptic degeneration, and progressive elevation of ABR thresholds. Conversely, round‑window delivery of recombinant human Neuritin improved high‑frequency hearing, preserved SGNs density, and restored ribbon synapses after ouabain injury. Transcriptomic profiling of cochlear tissue suggested enrichment of calcium signaling and MAPK pathways. Consistent with these results, Neuritin increased Na⁺/K⁺‑ATPase (NKA) activity, reduced intracellular Ca²⁺ overload, and suppressed phosphorylation of CaMKII and MAPK subfamilies (ERK1/2, p38, JNK). In primary cochlear explants and neuronal cell models, calcium chelation phenocopied the effects of Neuritin, whereas a MAPK activator partially reversed Neuritin‑mediated protection, including reduced apoptosis and improved neurite integrity. These findings support a model in which Neuritin maintains NKA‑dependent calcium homeostasis and restrains CaMKII/MAPK signaling to protect SGNs and auditory function. The study identifies Neuritin‑centered signaling as a therapeutic entry point for SNHL associated with SGN injury.

ID: 42141072
Title: Axonal dying back of upper motor neurons in human ALS.
Abstract: Patients with amyotrophic lateral sclerosis (ALS) typically present with arm, leg, or bulbar weakness. While genetics plays a clear role, it cannot explain why symptoms start focally or how upper (UMN) and lower motor neuron (LMN) systems are linked. In this clinicopathological case series, we examined the relationships between UMN/LMN disease in ten ALS patients. Detailed clinical assessments and motor cortex, brainstem, and spinal cord tissues were collected via rapid autopsy. Tissues were stained for UMN/LMN, myelin, axons, microglia, and pTDP43, and RNA-sequencing was performed. None of the patients had symptoms of frontotemporal dementia (FTD), but all had focal sites of clinical onset and both UMN/LMN involvement. LMN degeneration and microglial activation were highest at disease onset sites. UMN degeneration was present at all spinal cord levels through the medulla, regardless of onset site. Surprisingly, there was no evidence of UMN axonal degeneration above the brainstem. While extensive pTDP43 aggregates were seen in degenerating LMNs, no pTDP43 aggregates were seen in UMN cell bodies or their axons. RNA-sequencing implicated inflammatory pathways at sites of disease onset. Our findings suggest that some ALS patients without FTD have a dying back of UMN axons rather than a primary upper neuronopathy of neurons.

ID: 42168255
Title: PFAS exposure induces hearing loss by targeting cochlear hair cells and spiral ganglion neurons.
Abstract: Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants linked to adverse health effects. Recent epidemiological data suggest an association between PFAS exposure and hearing loss, but underlying mechanisms remain unclear. This study examined PFAS-induced auditory dysfunction in mice exposed to a mixture of five PFAS compounds (2 mg/L each) in drinking water for seven weeks. Ldlr-/- mice were used due to their susceptibility to metabolic dysfunction, a risk factor for hearing loss. Auditory brainstem responses (ABR) indicated that PFAS exposure significantly elevated hearing thresholds by 18-33 dB across multiple frequencies. Distortion product otoacoustic emissions (DPOAEs) revealed impaired outer hair cell (OHC) function, and immunohistochemical analysis indicated a 20% OHC loss in the basal turn of the cochlea. In addition, PFAS exposure reduced ABR wave-1 amplitudes, and caused a 50% reduction in spiral ganglion cell density, indicating impaired auditory nerve function. Overall, this study provides the first evidence for PFAS-induced high-frequency hearing loss in mice. The findings further indicated that cochlear OHCs and spiral ganglion neurons are potential targets in PFAS-induced hearing loss. Together, these data suggest that PFAS exposure elicits a multifaceted ototoxic response, affecting both sensory and neural elements of the cochlea.

ID: 42404717
Title: Multi-modal deep learning model for bipolar depression adolescents with verbal auditory hallucinations.
Abstract: To develop a multimodal deep learning-based classification model for adolescent bipolar depression (ABD) with verbal auditory hallucinations (AVHs). A retrospective analysis was conducted on 47 untreated ABD patients within 30 days, between January 2024 and August 2025. Comprehensive clinical data were collected, including sex, age, age at onset, years of education, and the presence of suicidal or self-harming behaviors. Based on the PANSS P3 score and the presence of AVHs, patients were divided into a hallucination group (P3 score > 3, n = 24) and a non-hallucination group (P3 score ≤ 3, n = 23). All participants underwent 1H-MRS scanning of the ventromedial prefrontal cortex (vmPFC). A multimodal deep learning model was constructed using MRS-derived features in combination with clinical parameters. The model achieved an optimal classification accuracy of 71.43% on the fixed test set, as obtained by the second-fold model. This best-performing model demonstrated balanced and stable classification performance for both positive and negative samples, with precision, recall, and F1-score all reaching 0.75. This study proposes a novel multimodal Transformer-based framework and evaluates its effectiveness in classifying ABD patients experiencing depressive episodes with AVHs. The results suggest that the advanced model architecture, incorporating mechanisms such as bidirectional cross-attention and an Ensemble of Experts classifier, can effectively integrate heterogeneous data and achieve a test accuracy of 71.43% on a small dataset, indicating preliminary technical feasibility.

ID: 42405367
Title: Enigmatic Case of Adult-Onset Langerhans Cell Histiocytosis with Aggressive Bony Involvement.
Abstract: Langerhans cell histiocytosis (LCH) is a rare hematologic neoplasm predominantly affecting children, with adult-onset cases being exceedingly uncommon. Neurological presentations, including spinal cord compression and cranial neuropathies, represent atypical manifestations that often lead to diagnostic delays. We present a 20-year-old previously healthy female who presented with progressive back pain, bilateral lower extremity weakness, and left-sided hearing loss. Imaging revealed a thoracic epidural mass causing severe spinal stenosis with additional diffuse osteolytic lesions. Initial biopsies showed nonspecific lymphoplasmacytic infiltrates. The patient subsequently developed cranial nerve palsies and dysphagia over several months. Definitive diagnosis required three biopsies, with the final petrous bone specimen demonstrating characteristic LCH histology and positive immunostaining for CD1a, S100, and Langerin. Treatment with zoledronic acid failed; subsequent therapy with cytarabine followed by cladribine plus hydroxyurea achieved partial radiographic and clinical improvement, though complicated by treatment-related sepsis. This case highlights the diagnostic and therapeutic challenges of adult LCH, given its rarity, variable presentation, and limited treatment guidelines. Multiple tissue samples with appropriate immunohistochemical staining may be required for diagnosis. Adult LCH treatment remains empirical, often extrapolated from pediatric data, with systemic therapies carrying significant toxicity risks. Greater awareness and adult-specific clinical trials are urgently needed.

ID: 42406125
Title: Detailed clinical characteristics of musical hallucinations in 81 patients.
Abstract: Musical hallucinations are perceptions of music without an external source. Approximately 500 publications on this topic have appeared over the past 35 years. Prior literature has largely consisted of case reports and small series, with only limited systematic studies on the characterisation of mixed pathology, relation to hearing loss, spatial localisation, and multimodal features. We conducted a retrospective analysis of baseline data from a prospective cohort study of 81 individuals experiencing musical hallucinations. Participants underwent assessment with the Musical Hallucinations (MuHa) Questionnaire-a tailored, non-validated semi-structured survey/interview-alongside additional questionnaires, EEG, neuroimaging, and audiological testing. The present analysis focuses on baseline phenomenological characteristics derived from the MuHa Questionnaire in 80 eligible participants. Analyses were exploratory and descriptive. Mean age was 65 years, with a slight female predominance. Hallucinations were most often perceived as internal, while external localisation was more common with familiar music and in individuals with (asymmetric) hearing loss. Underlying causes included psychiatric disorders (50%), hearing loss (50%), structural neurological changes (28%), and frequently combinations thereof (28%). A notable new finding was the high prevalence of tinnitus and multimodal hallucinations, involving up to six sensory modalities; these were generally associated with internal localisation, except in isolated hearing loss. Musical content spanned multiple genres, most commonly religious music. Hallucinations were considered burdensome in over 65% of the cases, and most participants reported little control; behavioral strategies such as distraction or listening to external music provided only temporary relief in about 20%. Musical hallucinations may be more common than previously appreciated within broader multimodal perceptual syndromes and mixed etiologies, suggesting a more distributed pathophysiology than traditionally assumed. Their burden and limited controllability highlight the need for further mechanistic and therapeutic research.

ID: 42409477
Title: Inherited dentin defects with comorbidities.
Abstract: Inherited dentin defects comprise a group of rare genetic conditions that disrupt the normal formation, structure, and function of tooth dentin. Disorders such as dentinogenesis imperfecta and dentin dysplasia often have distinctive dental manifestations, including altered tooth color and translucency, abnormal crown and pulp morphology, foreshortened roots, and increased susceptibility to wear and fracture. The genetic sequence variations underlying selected dentin defects can also contribute to multisystem comorbidities, affecting skeletal, ocular, auditory, or kidney development, depending on the specific syndrome involved. The authors' objective in this review was to synthesize genetic and clinical information on selected disorders affecting tooth dentin. By means of integrating case descriptions and clinical phenotypes, they aimed to help readers understand these disorders and visualize their key features alongside genetic and clinical management strategies. Given the rarity of these conditions, the authors drew on original reports featuring clinical photographs and radiographs, adapting these images into figures. Through searches of PubMed and Online Mendelian Inheritance in Man databases, more than 60 genes and conditions were reviewed. The authors summarized selected inherited dentin disorders with systemic involvement, outlining their genetic etiologies, characteristic oral and radiographic findings, associated comorbidities, and evidence-based dental management strategies, highlighting the need for integrated care in affected patients. Accurate diagnosis of inherited dentin defects is complicated by means of overlapping clinical features and the variability of systemic involvement. Timely recognition and multidisciplinary management are crucial for optimizing oral health and addressing broader medical needs.

ID: 42410792
Title: Causal associations of white blood cell subtypes with age-related hearing loss: A Mendelian randomization study.
Abstract: While elevated white blood cell (WBC) counts are associated with auditory decline, the causal nature of this relationship remains elusive due to potential residual confounding. We utilized 2-sample Mendelian randomization (MR) to assess potential causal relationships between 5 genetically predicted WBC subtypes and the risk of age-related (ARHL) and sensorineural hearing loss. Two-sample MR analyses were conducted using summary statistics from large-scale genome-wide association studies. Causal estimates were assessed via inverse variance weighted, weighted median, weighted mode, and MR-Egger regression methods. Robustness was verified through extensive sensitivity analyses, including Cochran's Q tests, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), Radial MR, and leave-one-out tests, to detect heterogeneity and horizontal pleiotropy. Genetically predicted higher neutrophil counts were significantly associated with a reduced risk of ARHL (odds ratio [OR] = 0.9765, 95% confidence intervals [CI] = 0.9646-0.9886, P = .0002, false discovery rate [FDR] = 0.0015). Nominally significant protective associations were also observed for higher eosinophil (OR = 0.9883, 95% CI = 0.9777-0.9991, P = .0344, FDR = 0.1148) and lymphocyte counts (OR = 0.9858; 95% CI = 0.9745-0.9972, P = .0148, FDR = 0.0739). No significant heterogeneity or pleiotropy was detected in the final analyses for these associations. No causal associations were found between any WBC counts and sensorineural hearing loss. MR Steiger tests confirmed the consistency in causal directions. This MR study provides genetic evidence for a causal protective association between higher neutrophil counts and a reduced risk of ARHL. The potential roles of eosinophils and lymphocytes in ARHL warrant further investigation.

ID: 42414200
Title: Creak Derived from CAPE-V Sentences in Patients with AdLd and pMTD.
Abstract: The purpose of this study was to evaluate whether acoustic creak (%) derived from the Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) sentences differentiates adductor laryngeal dystonia (AdLD) from primary muscle tension dysphonia (pMTD). In this retrospective study, acoustic recordings from 42 patients (21 with AdLD and 21 with pMTD) at a tertiary voice center were analyzed. Participants produced six CAPE-V sentences during a standardized voice evaluation. Recordings were segmented and analyzed using an automated algorithm to compute percent creak (%), defined as creak duration relative to total voicing duration. Smoothed cepstral peak prominence (CPP) was also extracted. Hierarchical binomial logistic regression models evaluated whether creak alone or creak in combination with CPP predicted the diagnostic group. Mean creak (%) values were comparable between groups. Creak (%) did not significantly predict the diagnostic group (P > 0.05). Inclusion of CPP did not improve model performance. Creak distributions were positively skewed in both groups, with notable interindividual variability. Creak derived from CAPE-V sentences does not differentiate AdLD from pMTD. These findings suggest that stimulus characteristics, particularly sentence length and the associated respiratory-phonatory demands, may influence the discriminative validity of creak. Further research is required to clarify its clinical utility across speech tasks.

ID: 42414477
Title: Dynamic heart rate variability assessment based on fixed-frequency auditory perturbation in prolonged disorders of consciousness.
Abstract: Accurate differentiation between unresponsive wakefulness syndrome/vegetative state (UWS/VS) and minimally conscious state or emergence from the minimally conscious state (MCS/EMCS) remains clinically challenging in prolonged disorders of consciousness (pDoC), particularly when behavioral responses fluctuate or motor output is limited. We investigated whether short-term heart rate variability (HRV) responses to a standardized 40-Hz auditory perturbation could provide complementary bedside physiological information. Fifty-five patients with pDoC underwent a 10-minute protocol consisting of a 5-minute resting baseline followed by 5 minutes of binaural 40-Hz amplitude-modulated auditory stimulation, with continuous ECG recording. Resting HRV features showed no clear group-level separation between UWS/VS and MCS/EMCS, whereas stimulus-evoked time-domain changes, particularly ΔNN50 and ΔpNN50, differed between groups after false-discovery-rate correction. Exploratory logistic regression models based on NN50- and pNN50-related response features showed measurable internal held-out test performance. These findings suggest that standardized auditory-evoked HRV dynamics may provide a low-burden physiological complement to repeated Coma Recovery Scale-Revised assessment. The results remain exploratory and require validation in larger independent cohorts.

ID: 42414704
Title: How I do it: microvascular decompression for hemifacial spasm using an inferior ventrolateral brainstem approach.
Abstract: Hemifacial spasm is commonly caused by a vascular compression of the facial nerve at its root exit zone (REZ), at brainstem. Microvascular decompression provides long-term cure in approximately 90% of the patients (delayed in one-third). Based on more than three hundred procedures, the authors advocate an inferior ventro-lateral brainstem approach. This trajectory optimizes access to the REZ, while minimizing traction on the cerebellum, the cochleo-vestibular nerve, and the labyrinthine artery. Decompression should be achieved by transposing the offending vessel (PICA, AICA, either alone or associated with a vertebro-basilar- dolichoectatic artery). Monitoring of brainstem auditory evoked potentials can be useful during learning curve.

ID: 42416036
Title: The criticome as the window of becoming: Toward a novel and comprehensive framework for understanding the critical period of information integration in human development.
Abstract: Critical periods of synaptic plasticity represent windows of extraordinary neural malleability that fundamentally shape brain architecture and function and can determine brain health for decades to come. Yet neuroscience lacks adequate terminology to describe the totality of experiential information integrated during these periods. We propose a conceptually novel term: criticome, as the complete ensemble of sensory, motor, social, cultural, and environmental information recorded during critical periods from prenatal development through approximately age 25, with the recognition that this boundary is probabilistic and domain-specific rather than fixed. Our original framework is grounded in six coupled neurobiological mechanisms: GABAergic regulation through parvalbumin-positive interneurons, perineuronal net dynamics, myelination, epigenetic regulation, neuromodulatory maturation, and developmental synaptic pruning. Their collective state determines what experience can be integrated and how stable the outcome is. The criticome reframes cultural specificity, implicit bias, aesthetic preference, and interpersonal attraction as variations in integrated content rather than differences in brain architecture, and reconceptualizes autism, schizophrenia, post-traumatic stress, major depression, and culture-bound syndromes as developmental rather than purely synaptic disorders. The same plasticity that allows Mozart to emerge from early auditory exposure also produces the lasting damage seen in institutional deprivation, ideological indoctrination, and chronic geopolitical trauma. This framework carries practical consequences for therapeutic timing, educational policy, cultural competence in mental healthcare, and interventions aimed at reopening plasticity in adulthood, while simultaneously raising urgent questions about how screen-mediated environments now shape criticomes during the windows when neural architecture is most malleable.

ID: 42416242
Title: Morphometric anatomy of the middle cranial fossa via the anterior petrosal (Kawase) approach: a bilateral cadaveric study.
Abstract: The anterior petrosal (Kawase) approach is a well-established extradural corridor to the petroclival and upper clival regions; however, comprehensive bilateral morphometric data describing middle cranial fossa anatomy, particularly in Southeast Asian populations, remain limited. To provide a comprehensive morphometric description of the microsurgical anatomy of the middle cranial fossa through the anterior petrosal (Kawase) approach based on bilateral cadaveric dissections. A descriptive cadaveric study was performed on 21 formalin-fixed adult Vietnamese cadaveric heads (42 sides). Standardized extradural dissections following the anterior petrosal approach were conducted, and predefined linear and angular morphometric measurements of key osseous, neural, and vascular landmarks were obtained bilaterally. The greater superficial petrosal nerve (GSPN), trigeminal ganglion, cochlea, internal auditory canal (IAC), superior semicircular canal, and petrous internal carotid artery were consistently identified in all specimens. The mean GSPN length was 10.66 ± 2.44 mm. Key inter-foraminal and neurovascular distances included a mean distance of 29.68 ± 1.97 mm from the foramen spinosum to the zygomatic root and 11.70 ± 2.44 mm between the foramen ovale and foramen rotundum. Cochlear-related measurements demonstrated mean distances of 3.39 ± 0.98 mm to the geniculate ganglion and 4.56 ± 1.29 mm to the internal carotid artery genu. Angular analysis showed a mean angle of 121.82 ± 15.38° between the GSPN and arcuate eminence, 104.07 ± 13.25° between the GSPN and superior semicircular canal, and 45.42 ± 12.09° between the IAC and superior semicircular canal. Paired right-left comparisons demonstrated overall bilateral symmetry across most linear and angular parameters, with a significant side-to-side difference observed only in the IAC-SSC angle. This study provides a comprehensive bilateral morphometric characterization of the middle cranial fossa via the anterior petrosal approach in a Vietnamese population. The findings confirm the reliability of key anatomical landmarks, delineate their spatial relationships, and demonstrate predominantly bilateral symmetry, thereby offering population-specific anatomical data that may support surgical planning, neuronavigation, and training in skull base surgery.