搜索结果：Clinical neuropathology

Multiple sclerosis (MS) shows pronounced pathological and clinical variability between individuals, reflecting differences in genetic susceptibility, inflammatory activity, and tissue repair. This variability complicates efforts to relate lesion pathology to clinical trajectories. In previous work in the Netherlands Brain Bank MS autopsy cohort (NBB-MS), we showed that relative proportions of different lesion types, lesion load, and microglia/macrophage activity score, associate with clinical severity, while also revealing marked inter-individual variability. Here, we extend these observations by examining whether selected donor-specific pathological features relate to genetic background, quantitative lesion type distributions, and clinical disease course, and thereby help contextualize this heterogeneity.Brain tissue from 287 NBB-MS donors was assessed for the presence of the donor-specific pathological features, namely perivascular cuffs, microglial nodules, broad rim lesions (BRLs), and remyelination efficiency. Perivascular cuffs and microglial nodules were more prevalent among carriers of the MS susceptibility allele HLA-DRB1*15:01 (rs3135388). BRLs and perivascular cuffs were enriched in carriers of the MS severity-associated SNP in the DYSF-ZNF638 locus (rs10191329). Perivascular cuffs associated with increased microglia/macrophage activation score and decreased age at death. Microglial nodules in the normal appearing white matter associated with a higher proportion of active lesions. BRLs were linked to increased proportions of active and mixed active/inactive lesions, higher brainstem lesion rate, and a higher age related MS severity score. Poor remyelination efficiency associated with a higher proportion of mixed active/inactive and inactive lesions, and a shorter disease duration.Together, these findings show that specific pathological features of donors relate to genetic risk, lesion type distribution, and clinical outcome. Integrating these donor-specific pathological features alongside lesion classification will enable a more biologically refined interpretation of post-mortem MS tissue study results and will improve understanding of inter-individual heterogeneity in MS.

Primary Progressive Aphasia (PPA) clinical syndromes do not align consistently with underlying pathology. This study aimed to identify language markers for specific neuropathologies using both standard clinical tests and narrative speech analysis. We analyzed data from 82 autopsy-confirmed PPA cases, including Alzheimer's disease (AD), transactive DNA-binding protein 43 (TDP-43) type C (TDP-C), Pick's disease, and 4R-tauopathies (progressive supranuclear palsy/ cortico-basal degeneration (PSP/CBD). Linear mixed-effects regression was used to analyze performance on standardized aphasia tests and narrative speech variables. TDP-C showed severe semantic deficits but high fluency, while AD was distinguished by impaired repetition. Narrative analysis differentiated 4R-Tauopathies: CBD patients demonstrated significantly poorer syntax and irregular verb inflection than PSP or Pick's, whereas PSP showed the lowest fluency. While standard tests effectively capture lexical-semantic features in AD and TDP-C, narrative measures reveal subtle grammatical and fluency differences critical for distinguishing specific tauopathies. This study outlines a more robust approach for predicting underlying pathology in PPA.

Risk stratification in non-ischemic cardiomyopathies (NICM) remains challenging despite guideline-based phenotypic classification using multimodal diagnostics including endomyocardial biopsy (EMB). We aimed to identify EMB-derived histological and molecular markers that improve phenotypic characterization and long-term risk stratification in patients with NICM. In this prospective cohort study, 703 consecutive patients with symptomatic NICM underwent standardized multimodal evaluation, including clinical assessment, cardiac imaging, and endomyocardial biopsy. Biopsy specimens were analyzed using histology, immunohistochemistry, and targeted myocardial mRNA profiling. Associations between endomyocardial markers, and fibroinflammatory remodeling, imaging parameters, and molecular signatures were assessed cross-sectionally. Long-term prognostic relevance was evaluated using survival and multivariable prediction analyses during follow-up of up to fifteen years for all-cause mortality, cardiovascular mortality, implantable cardioverter-defibrillator (ICD) implantation, and appropriate ICD discharge. Elevated myocardial Gremlin-1 expression was associated with increased fibrosis, adverse cardiac remodelling, reduced left ventricular function, and enrichment of pro-fibrotic and inflammatory mRNA signalling pathways. Myocardial and circulating Gremlin-1 expression was independently associated with all-cause and cardiovascular mortality, and ICD implantation and discharge. Machine learning-based phenotyping using histological EMB data identified Gremlin-1 as a key predictive feature of poor prognosis. Incorporation of Gremlin-1 into predictive models significantly improved long-term cardiovascular risk stratification in NICM patients. Our results unveil that Gremlin-1 is associated with inflammation and cardiac remodelling in patients with NICM, and patients with Gremlin-1+ EMB and high plasmatic Gremlin-1 concentrations are at elevated risk to develop adverse cardiovascular events. Thus, the histological evaluation of Gremlin-1 may help to improve risk discrimination and management of NICM and HF patients. Non-ischemic cardiomyopathy (NICM) refers to diseases in which the heart muscle becomes abnormal and unable to pump effectively, without being caused by blocked coronary arteries. Predicting which patients will develop serious complications remains difficult using current clinical tests. We examined whether information from small heart tissue samples could improve long-term risk prediction. We analysed 703 NICM patients who underwent comprehensive clinical assessment and endomyocardial biopsy. Heart tissue was assessed for markers of inflammation and scarring, including the protein Gremlin-1, and patients were followed for up to fifteen years for major cardiovascular outcomes. Higher Gremlin-1 expression and circulating Gremlin-1 were associated with scarring, reduced heart function, and increased risk of adverse outcomes. These findings suggest that tissue-based biomarkers including Gremlin-1 may support more accurate risk stratification and personalized management in NICM.

Urinary dysfunction has been reported in association with myasthenic syndromes, including myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS), but evidence regarding its prevalence, clinical impact, pathophysiology, and management remains limited. This scoping review synthesizes the available evidence on urinary symptoms, diagnostic approaches, pathophysiological features, treatment-related associations, and sex-specific findings in these disorders. A literature search was conducted in PubMed, LIVIVO, Epistemonikos, and the Cochrane Library in accordance with PRISMA guidelines. Of 774 records identified, eight studies met the inclusion criteria, comprising two case reports, three case-control studies, one prospective study, and two retrospective observational studies. Seven studies addressed MG and one addressed LEMS; no eligible studies were identified for CMS. Reported urinary symptoms were predominantly storage lower urinary tract symptoms (LUTS), including urinary incontinence, urgency, nocturia, and increased frequency, whereas voiding and bladder-emptying abnormalities were described less consistently. Diagnostic approaches were heterogeneous and included questionnaires, clinical examination, urodynamic testing, imaging, and autonomic assessments. Proposed mechanisms remain uncertain, with limited evidence supporting contributions from pelvic floor weakness, autonomic dysfunction, and cholinesterase inhibitor exposure. Treatment-related associations were largely observational and most consistently implicated pyridostigmine in symptom worsening, while evidence for specific treatment of urinary symptoms was sparse. Sex-specific analyses were limited and did not identify consistent sex-related patterns. Current evidence indicates that urinary symptoms have been reported in myasthenic syndromes and have been associated with reduced quality of life in the included studies, but the available data remain insufficient to define prevalence, mechanisms, or optimal management.

Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) co-occur frequently, and growing evidence, including neuropathology, supports synergistic interplay between the diseases. We tested whether a single T1-weighted MRI scan may differentiate neuropathologically confirmed comorbid AD/DLB and AD controls using heterogeneously acquired neuroimaging. We obtained structural neuroimaging, on two groups, AD with and without DLB pathology. Convolutional neural networks are trained across dimensions. We introduce a triple-ensemble strategy consisting of majority voting schemes within a variety of plane permutations. In addition, we conduct voxel-wise statistical analyses. Here we show convolutional neural networks record a classification accuracy of 0.820 and an f1 score of 0.79 in identifying comorbid DLB/AD from AD patients. Prediction accuracy is higher proximal to date of death, while the trained model largely outperforms clinical baseline diagnosis. The slice-level performance varies depending on the sampled brain location, with sensitivity highest in the temporal lobe and specificity highest in the occipital lobe. In DLB/AD, gray matter is relatively preserved though atrophy is observed in the occipital lobe, suggesting that the comorbidity differentially affects brain loss and may accelerate it in the occipital lobe. This study demonstrates how machine learning approaches can address diverse neuroimaging data from clinical sources to differentiate neurodegenerative diseases using a true gold standard of neuropathological confirmation. The frameworks utilized here can be extended to other diseases that are frequently co-occurring and feasibly extend to single scan diagnostic clinical utility of scans already being acquired. Alzheimer’s disease (AD) and lewy body dementia (LBD) are both progressive neurodegenerative diseases that result in declines in memory and other cognitive functions. AD and LBD are known to occur together, however conventional methods that image the brain are unable to accurately show the effect of these diseases. Specialized computational methods may be able to more accurately diagnose these conditions than clinical evaluation. We used brain imaging data that is commonly obtained to see whether we could identify people with suspected AD who also had LBD. Our method identified the places in the brain whether both AD and LBD are likely to occur and was able to better diagnose in patients with confirmed disease at death that usual clinical diagnosis methods. Our method could be used to better identify people with AD and LBD and thus allow earlier appropriate treatment.

Primary intracranial sarcoma, DICER1-mutant, a novel, rare entity in the 2021 WHO classification of central nervous system tumors, is characterized by spindled to pleomorphic cells with eosinophilic cytoplasmic globules, immunophenotypic evidence of myogenic differentiation and DICER1 mutations. These tumors mainly occur in children and have a distinct methylation profile. We report 5 additional cases of primary intracranial sarcoma, DICER1-mutant (age range 6 to 40 years) identified by methylation profiling and/or sequencing, including 1 in an unusual infratentorial location, 1 in an adult patient and 1 in the setting of a germline DICER1 mutation. All tumors were surgically resected and demonstrated spindle cells with fascicular growth and variable pleomorphism; 3 showed variably prominent eosinophilic cytoplasmic globules and at least focal myogenic differentiation by immunohistochemistry. All cases had a hotspot DICER1 mutation; 2 had concurrent DICER1 loss; and 1 had a known germline truncating DICER1 mutation. Three cases also demonstrated a KRAS mutation, 1 of which had a TP53 mutation. Two patients were alive with no evidence of disease after 26.7 and 39.3 months; 1 patient died of disease after 20.1 months. We demonstrate the utility of methylation profiling in combination with next generation sequencing testing in the diagnosis of this rare entity.

Microglia, the resident immune cells of the central nervous system, are key regulators of synaptic plasticity and neural circuit homeostasis. This review summarizes the mechanisms by which microglia shape synaptic structure and function, including dynamic synaptic interactions, selective pruning, epigenetic regulation, extracellular matrix remodeling, metabolic adaptation, and communication with other glial cells. Under physiological conditions, these processes support circuit refinement, synaptic stability, and cognition, which are modulated by circadian rhythms and the microbiota-gut-brain axis. In Alzheimer's disease, schizophrenia, and related disorders, microglial dysfunction can shift synaptic pruning from a controlled homeostatic process to pathological synapse loss. Excessive complement-mediated pruning, disrupted excitation-inhibition balance, neuroinflammation, and metabolic dysregulation may jointly impair synaptic integrity and circuit function. This review highlights microglial heterogeneity, state transitions, and targeted modulation as important directions for understanding synaptic remodeling and developing therapeutic strategies for neurological diseases.

Creutzfeldt-Jakob disease (CJD) is a rare, rapidly progressive prion disease with established zoonotic transmission only in its variant form. Chronic wasting disease (CWD), a prion disease affecting cervid populations in North America, continues to expand geographically, raising public health concerns regarding potential interspecies transmission. We describe the clinical course, diagnostic evaluation, and public health investigation of a patient with confirmed sporadic CJD and long-term venison exposure from CWD-endemic regions in Louisiana. Clinical data, neuroimaging, electroencephalography, cerebrospinal fluid (CSF) biomarkers, neuropathology, and epidemiologic findings were reviewed. A 72-year-old lifelong hunter developed rapidly progressive dementia with startle myoclonus and characteristic MRI findings of cortical ribboning and basal ganglia diffusion restriction. CSF biomarkers (RT-QuIC, total tau, 14-3-3) and postmortem neuropathology confirmed sporadic CJD, MM1 subtype. During hospitalization, the patient developed posterior reversible encephalopathy syndrome (PRES), complicating radiographic interpretation. Given extensive cervid exposure and reports of similar illness among hunting peers from the same lodge, the case was reported to public health authorities. Given extensive cervid exposure and reports of similar illness among hunting peers from the same lodge, the apparent clustering of suspected prion disease prompted epidemiologic investigation and public health review. This case highlights diagnostic and public health challenges posed by prion disease in individuals with relevant zoonotic exposure histories. Although no evidence supporting confirmed CWD-to-human transmission was identified, the apparent clustering of suspected prion disease within a shared exposure network appropriately prompted epidemiologic investigation, structured exposure assessment, and public health review.

The clonal glioma driver mutation IDH1R132H gives rise to a major histocompatibility class II-restricted neoepitope. A multicenter, first-in-human phase 1 trial met its prespecified primary endpoints by demonstrating safety and immunogenicity of an IDH1-R132H peptide vaccine (IDH1-vac) integrated into standard of care in 33 participants with newly diagnosed grade III and IV (World Health Organization classification 2007) IDH1-R132H+ astrocytomas (NOA16). Here we report on the clinical and immunological long-term follow-up of this trial as secondary and translational endpoints. The 8-year progression-free and overall survival (OS) rates were 0.42 months (confidence interval (CI): 0.24-0.59) and 0.66 months (CI: 0.46-0.79), respectively. For participants with grade IV astrocytoma, median OS was 106.1 months (CI: 39.6-not estimable (NE)), comparing favorably to the published median OS in this population ranging from 31.6-56.4 months. Within the responder group, sustained antibody responses to IDH1-R132H were associated with a favorable long-term clinical course. IDH1-vac-induced T cell responses were detected in the inflamed brain lesion of an IDH1-vac-associated pseudoprogression, whereas no IDH1-vac-induced T cells were found in participants with early progressive disease. The favorable long-term outcome of the NOA16 cohort supports investigating IDH1-vac in persons with newly diagnosed grade 3 and 4 (World Health Organization classification 2021) IDH-mutant astrocytomas in a randomized phase 2 trial (ClinicalTrials.gov identifier: NCT02454634 ).

Fetal hypoxaemia during pregnancy is not uncommon, arising from chronic placental insufficiency or acute stressors. In the case of placental insufficiency and chronic fetal hypoxia, fetal growth is reduced, resulting in fetal growth restriction (FGR). Fetal hypoxaemia initiates an immediate adaptive strategy to preserve brain oxygen delivery - the brain sparing response. Asymmetric FGR, in which head size is relatively larger than body size, is evidence of prolonged brain sparing. The acute physiology of the brain sparing response is well-defined in preclinical studies, involving peripheral vasoconstriction and reduced cerebral resistance to promote cerebral vasodilatation. Yet, the mechanisms that maintain fetal brain sparing during sustained hypoxaemia remain incompletely understood. Furthermore, although brain sparing has historically been interpreted as protective, this concept is being challenged, with its presence linked to increased risk of death or neonatal morbidity and neuropathology. This contradiction reflects that brain sparing is not static but evolves with the severity of fetal hypoxaemia; clinical evidence points to a front-to-back pattern of brain vasodilatation that initially prioritises cortical perfusion for higher-order function, whereas prolonged or severe hypoxaemia drives a shift towards brainstem preservation and survival. Thus, the brain sparing response is initiated by fetal hypoxaemia and is a unique indicator of fetal compromise, but it progresses from a compensatory to a maladaptive response. The mechanisms, multisystem physiology and ontogeny of sustained brain sparing in severe FGR are not well characterised, but advancing this knowledge affords new opportunities to diagnose and manage FGR, and to intervene to prevent adverse consequences.

Human herpesvirus-6 consists of a pair of viral species, HHV-6A and HHV-6B, which are neurotropic with the ability to invade, persist, and reactivate within the nervous system. Accumulating evidence links HHV-6 to epilepsy and other neuropathologies, including: multiple sclerosis, chronic fatigue syndrome, and neurodegeneration. Yet, mechanisms by which these viruses induce neurological disorders, including their role in epileptogenesis, remain unknown. It has been demonstrated that HHV-6 exhibits tropism for astrocytes, oligodendrocytes, and neurons. Thus, HHV-6 can perturb cellular homeostasis, neuronal signaling, and immune regulation, astrocytic glutamate clearance, GABAergic inhibition, and cholinergic or monoaminergic neurotransmission yielding network hyperexcitability. It is also reported that HHV-6 can activate neuroinflammation through Toll-Like Receptor (TLR), cytokine, and/or NF-κB activation, which facilitates neuronal injury and network instability. Indeed, a suite of converging processes suggest a multifactorial nature for HHV-6 related neuropathology. Despite robust experimental and clinical data, definitive causal relationships between HHV-6 and epilepsy (or induction of neurodegeneration) remain elusive. This review discusses evidence for roseolovirus-induced neurological dysfunction and disorders commonly associated with HHV-6A and HHV-6B infections. A preponderance of clinical and experimental evidence suggests that differential tropism for distinct neuronal neurotransmitter chemotypes and glia as well as systemic effects are involved in roseolovirus-mediated neurological disease.

Autoantibodies (ABs) against intracellular proteins, including glutamate-decarboxylase 65 (anti-GAD65), are increasingly recognized in autoimmune and limbic encephalitis (AE/LE). Anti-GAD65 LE frequently progresses to severe temporal lobe epilepsy (TLE), neuropathologically characterized by hippocampal sclerosis (HS) and variable infiltration of cytotoxic T lymphocytes (CTLs). Recently, we have identified Drebrin (DBN) as a new intracellular target protein of ABs in index patients with suspected AE. Here, we aim to characterize key molecular and cellular signatures of hippocampal tissue from anti-GAD65- (GAD65-TLE) versus anti-DBN-positive TLE (DBN-TLE) patients correlated to clinical parameters. We examined hippocampal neuropathology and performed exploratory single-nucleus RNA sequencing (snRNA-seq) of hippocampal tissue from DBN- and GAD65-TLE patients, integrated with key clinical data from a large patient cohort. Although the hippocampi of the two patient groups were neuropathologically virtually indistinguishable, exploratory snRNA-seq revealed distinct transcriptional programs. DBN-TLE patients (n = 2) showed transcriptional signatures enriched for forkhead box (Fox) transcription factor family, whereas GAD65-TLE patients (n = 2) displayed transcriptional signatures enriched for transcripts related to NF-κB- signaling. In a larger cohort, DBN-TLE patients (n = 22) showed significantly more favorable pharmacological responsiveness than GAD65-TLE patients (n = 35), who were largely pharmacoresistant. Notably, in a T cell-mediated mouse model for LE, similar inflammatory programs were dynamically regulated. These findings provide a discovery-based transcriptomic signatures of rare autoimmune hippocampal tissue, revealing distinct immune-associated transcriptional states in anti-DBN- versus anti-GAD65-positive AE/TLE patients despite virtually indistinguishable hippocampal pathology in both groups and support further investigations of disease-specific therapeutic strategies.

Background and Objectives: Among CNS malignancies arising in infancy, ATRT stands out as the most frequently diagnosed in children younger than six months. Disruption of the SMARCB1 gene underlies the overwhelming majority of cases. Progress toward effective treatment has been hampered by two persistent challenges. Current mouse models, while informative, fall short of reproducing the full clinical and biological picture of human ATRT, and their ability to predict therapeutic outcomes in patients remains uncertain. Compounding this, the rarity of the disease makes it difficult to assemble patient cohorts of sufficient size for meaningful clinical trials. At the molecular level, germline loss of SMARCB1 exons 4 and 5 has emerged as a particularly penetrant predisposing event, with affected individuals presenting at an earlier age than those harboring other mutation types. The porcine SMARCB1 gene offers a compelling basis for translational modeling as its protein product is identical to the human ortholog at every amino acid position across isoforms, a degree of conservation that exceeds what is seen in the mouse. Methods: Thus, we hypothesized that germline deletion of exons 4 and 5 would predispose heterozygote swine to ATRT development. In this manuscript, we describe the creation of an ATRT porcine model through a CRISPR/Cas9 mediated gene-editing approach. Results: 15 piglets were produced, two of which had confirmed SMARCB1 targeted excisions. However, none developed tumors. To induce further tumorigenicity, one pig with confirmed exons 4 and 5 excision was crossed with a pig with TP53 exon 2 truncation. In total, 11 piglets were born, of which one contained the original excision without a TP53 mutation. This piglet developed a spinal mass at the T1 level. Conclusion: To our knowledge, this is the first ATRT porcine model ever developed and provides proof-of-concept feasibility for large animal modeling of SMARCB1-deficient rhabdoid tumors. These findings support the continued development of porcine RTPS-1 models toward preclinical application.

Peritumoral brain edema (PTBE) is a major contributor to neurological morbidity in patients with melanoma brain metastases (BM). While serum lactate dehydrogenase (LDH) is an established systemic biomarker in metastatic melanoma, its relationship with local radiological characteristics such as PTBE remains insufficiently understood. This study aimed to investigate the association between serum LDH levels and PTBE, as well as its relationship with clinical and tumor-related parameters. We performed a retrospective analysis of 56 consecutive patients who underwent surgical resection for melanoma BM between 2012 and 2024. Preoperative MRI was used to assess the presence and volumetric extent of PTBE. Clinical, radiological, and laboratory parameters, including serum LDH levels, MIB-1 proliferation index, tumor volume and preoperative seizures were analyzed. Associations were evaluated using univariate analyses and Spearman rank correlation. Receiver operating characteristic (ROC) curve analyses were performed to assess the discriminative ability of the variables. Preoperative PTBE was present in 71.4% of patients. Serum LDH levels were significantly higher in patients with PTBE (p&#x2009;<&#x2009;0.001) and demonstrated a strong positive correlation with edema volume (r&#x2009;=&#x2009;0.822, p&#x2009;<&#x2009;0.001). In addition, LDH levels were significantly correlated with the MIB-1 proliferation index (r&#x2009;=&#x2009;0.601, p&#x2009;<&#x2009;0.001) and tumor volume (r&#x2009;=&#x2009;0.584, p&#x2009;<&#x2009;0.001) and were significantly elevated in patients presenting with preoperative seizures (p&#x2009;<&#x2009;0.001). ROC analysis demonstrated that LDH had the highest discriminative performance (AUC 0.802, p&#x2009;<&#x2009;0.001), with an optimal cut-off value of 179.4 U/L. In this exploratory study, serum LDH was associated with both the presence and extent of PTBE and may serve as a surrogate of tumor-related biological activity. These hypothesis-generating findings warrant prospective validation before clinical implications can be drawn.

Prognosis in low-grade gliomas (LGGs) remains highly variable, and treatment-related late toxicity is a concern. This trial was comparing single-modality therapies in patients who often survive for years or decades and investigating differential responses according to molecular markers. Four hundred seventy-eight patients with clinical high-risk LGG (WHO grade 2) were randomly assigned to standard radiotherapy (RT; 28 &#xd7; 1.8 Gy) or dose-dense temozolomide (TMZ; 75 mg/m2 once daily &#xd7; 21/28 days, up to 12 cycles). There was no significant difference in progression-free survival or overall survival (OS) between study arms. Analyzable tumor tissue in 73% (351/478) of patients allowed for post hoc reclassification according to the 2021 WHO pathologic criteria. In astrocytoma, IDHmt/1p/19q noncodeleted (n = 178), median OS was similar, 6.6-6.7 years irrespective of arm (0.67-1.44, P = .93). In oligodendroglioma, IDHmt/1p/19q codeleted (n = 109), median OS was 12.9 years (9.4-not reached) with RT and 14.9 years (10.1-number of events not reached) with TMZ (hazard ratio [HR], 0.88 [0.52-1.49], P = .63). In 64 tumors without isocitrate dehydrogenase (IDH) mutations, survival favored the TMZ arm: OS 2.5 (1.8-3.3) versus 4.7 (2.2-7.2) years (HR, 0.47 [0.27-0.82], P = .0068). Patients age 40 years and older fared better than patients younger than 40 years, challenging the current notion of age alone as a negative prognostic factor. The assigned initial treatment modality did not affect progression-free survival or OS, regardless of the molecular subtype. Combined-modality therapy was not tested in this trial but has since become a standard of care for IDH-mutant astrocytoma. With emerging novel therapeutic options, rational treatment strategies tailored at the individual clinical and pathologic recurrence risk profiles will be needed. The validity of an age cutoff as prognostic factor is challenged when tumors are molecularly classified.

Severe cardiomyopathies in children may often demand a treatment with inclusion of mechanical circulatory support (MCS) or heart transplantation (HTx). Although these cardiomyopathies are not always hereditary, myocarditis may be regarded as a likely cause, if clinical course is not chronic. The aims of the study were to determine the genetic profile and prevalence of myocarditis in a pediatric population with clinical signs of severe cardiomyopathy. We retrospectively included 106 pediatric and adolescent cardiomyopathy (CMPY) patients requiring HTx, MCS, or any in-hospital treatment. DNA-sequencing was done and sequence variants were classified based on ACMG guidelines. Myocarditis was diagnosed according to the clinical protocol.We overall genotyped 106 index patients; 92 (87%) patients receiving HTx or MCS, 14 (13%) received in hospital treatment. 87 patients (82%) had dilated cardiomyopathy and 54 (51%) carried a (likely) pathogenic (P/LP) variant with TNNI3 as one of the leading affected genes. In 84 genotyped patients (80%) myocarditis was examined. 57 (68%) of the 84 had myocarditis, with chronic lymphocytic myocarditis in 34 (40%) cases. In 28 (49%) of 57 patients with and 14 (52%) of 27 patients without myocarditis P/LP-variants were found. In 41 cases (39%) genotyping of the parents suggests de novo P/LP-variants (34%). In severe CMPY, genetic causes and myocarditis because of infection are common. About 50% of childhood cardiomyopathies are linked to pathogenic genetic variants. Myocarditis signatures commonly observed in severe pediatric cardiomyopathies, are not necessarily specific and the only reason for early presentation of heart failure. Genotyping in severe CMPY is essential to identify the causes of myocarditis. Providing genetic counseling may support families facing challenging psychosocial situations.

Muscle-specific kinase myasthenia gravis (MuSK-MG) is an autoimmune neuromuscular disorder predominantly mediated by IgG4 autoantibodies disrupting MuSK signaling. The contribution of other isotypes remains incompletely defined. We characterized the serological profile of a Greek cohort of MuSK-MG patients. Baseline (n&#x2009;=&#x2009;140) and longitudinal (available n&#x2009;=&#x2009;99) samples from 140 patients, positive for anti-MuSK by radioimmunoprecipitation (RIPA) were analyzed using a live cell-based assay (L-CBA) to detect total IgG, IgG1-4 subclasses, IgM, and IgA. Also, disease and healthy controls (n&#x2009;=&#x2009;102) were included. Selected samples were additionally analyzed by flow cytometry. Clinical data were available for specific patients. Our analysis revealed 15 distinct immunoglobulin combinations and provided insights into the presence of IgA isotype. IgG4 was the most common subclass in 120/140 of patients, followed by IgG1 in 79/140, IgG3 in 59/140, and IgG2 in 42/140 patients, while IgM positivity was detected in selected patients. Anti-MuSK IgA(1) immunoreactivity was detected in 54/140 patients, frequently co-occurring with IgG, and in four patients at baseline with only-IgA positivity. IgA was detected both near disease onset and at later stages, and persisted over time in rituximab-treated patients. Controls tested largely negative for IgA, although low-intensity signals were observed in six samples and were considered non-specific. L-CBA detected anti-MuSK IgA more frequently than flow cytometry. Our findings expand the serology of MuSK-MG beyond IgG subclasses, identifying IgA as an additional component of the anti-MuSK response. These results enhance further investigation into the clinical significance, pathogenic potential, and treatment-associated fluctuations of anti-MuSK IgA antibodies.

Medulloblastoma in infants (iMB; aged < 5 years) presents the challenge of achieving cure while minimising deleterious cranio-spinal irradiation (CSI)-associated late-effects. Non-randomised phase 2 studies have examined upfront CSI omission and chemotherapy intensification for favourable-risk desmoplastic/nodular (DN) tumours associated with the sonic hedgehog (SHH) molecular group (iMBSHH). Comparison of these therapies in large molecularly defined iMBSHH cohorts, alongside investigations of prognostic biomarkers in therapy-specific context, is urgently required to define future therapeutic strategies. In this international retrospective cohort study, a multi-national cohort of molecularly and clinically annotated iMBSHH was assembled from patient datasets in nine countries. Inclusion criteria was a principal iMBSHH group classification using DNA methylation array-based classification. Patient cohorts were assigned into upfront treatment groups based on the receipt of radiotherapy (RTx) or chemotherapy (CTx)-only. Upfront RTx treatment groups were assigned as those receiving focal-RTx or CSI. Upfront CTx only regimens used were classified into three groups to reflect disease treatment conventions: standard-dose, high-dose (intensified regimens of sufficient dosage to require stem cell support) and those including intraventricular methotrexate (IVT-MTX). We investigated molecular pathology, upfront treatments, and relationships to outcome, in this real-world setting. Outcomes of interest were progression-free survival (PFS), overall survival (OS), and post-relapse survival (PRS). Between January 20, 2018 and October 6, 2021, patient data from 267 infants with SHH medulloblastoma were collected from Canada (n = 74), Germany/USA (n = 67), and the UK (n = 54), alongside national cohorts collected from France (n = 26), Italy (n = 4), Japan (n = 20), the Netherlands (n = 11), and Spain (n = 33). 226 patients with PFS and OS data comprised the iMB survival cohort and were split into upfront treatment groups based on the receipt of RTx (n = 74, 33%) or CTx-only (n = 132, 58%). Among iMBSHH patients treated upfront with CTx-only regimens, IVT-MTX therapy (5-year PFS, 72.6%; n = 72) or high-dose therapy (73.0%; n = 29) achieved PFS outcomes comparable to upfront CSI-based regimens (n = 49; 74.0%; p = 0.51); whereas lower-intensity, standard-dose, chemotherapy-only regimens (n = 31) were inferior (48.4% PFS; p = 0.006). Rescue was common post-relapse after IVT-MTX/high-dose protocols and translated into 5-year OS of 85.6% and 88.6%, respectively. However, information on pattern of relapse and treatments received at recurrence was only available for a small proportion of our cohort (n = 43). The 5-year PFS of patients receiving focal-RTx was (58.2%; n = 25). iMBSHH encompassed SHH-1 (38%), SHH-2 (47%) and SHH-3 (14%) WHO subgroups. In CSI-na&#xef;ve iMBSHH, standard-dose chemotherapy was associated with worse PFS in SHH-1 (p = 0.001), but not SHH-2. Non-DN/MBEN histology (21.2% of iMBSHH) conferred worse PFS in the upfront CSI-treated and standard-dose (p < 0.001 and p = 0.003, respectively) groups. Metastatic disease only associated with prognosis with upfront IVT-MTX-only therapies (p = 0.013), while established high-risk features of non-infant MBSHH (TP53-mutation, LCA-histology, MYCN-amplification) only associated with poor prognosis in older SHH-3 (7/7 relapsed). Finally, CSI-na&#xef;ve PFS findings were validated in a re-evaluation of smaller historical trials cohorts. Our findings show that iMBSHH outcomes and prognostic biomarkers are therapy dependent. In our retrospective patient group, non-metastatic iMBSHH treated with high-dose or IVT-MTX chemotherapy-only had equivalent favourable outcomes, independent of histology and subgroup. With outcomes established, clinical trials are now encouraged to focus on quality-of-life following different intensified approaches to identify the kindest curative strategies. Cancer Research UK, Children with Cancer UK, Children's Cancer North, Star for Harris, JGW Patterson Foundation, Little Hero and Blue Skye Thinking.

Chronic infection with the neurotropic pathogen Toxoplasma gondii has been epidemiologically associated with a risk of neurodegeneration; however, the mechanisms driving infection-associated cognitive decline remain unclear. We investigated the role of microglial protein-tyrosine phosphatase 1B (PTP1B) as a potential driver of neuropathology in chronic toxoplasmosis. Using a murine model, we demonstrate that PTP1B expression is elevated in the hippocampus following infection. Global genetic ablation or pharmacological inhibition of PTP1B rescued infection-induced cognitive deficits and mitigated neuroinflammation. Crucially, microglia-specific deletion of Ptp1b prevented synaptic loss and cognitive impairment. Mechanistically, we show that microglial PTP1B potentiates the nuclear factor-kappa B (NF-&#x3ba;B) pathway, promoting complement component 1q (C1q)-mediated synaptic tagging and subsequent neuronal structural damage. Validating the clinical relevance of these findings, we observed significantly elevated PTP1B levels in peripheral blood mononuclear cells from T. gondii-seropositive individuals, which correlated with inflammatory markers. Overall, our findings identify microglial PTP1B as a pivotal mediator of T. gondii-associated neurodegeneration.