AIMS:Homozygous deletion (HD) of CDKN2A/B represents an adverse prognostic biomarker in meningiomas and a diagnostic criterion for CNS WHO grade 3 assignment. However, fluorescence in situ hybridisation (FISH) thresholds and the role of immunohistochemistry (IHC) surrogates remain uncertain. This study evaluated multiple CDKN2A/B FISH cutoffs and assessed the diagnostic and prognostic performance of MTAP and p16 IHC. METHODS AND RESULTS:Ninety-two meningiomas (CNS WHO grades 1-3) were analysed by FISH evaluating ≥ 10%, ≥ 20% and ≥ 30% CDKN2A/B HD thresholds. CDKN2A/B HD was identified in 18.5%, 6.5% and 4.3% of cases using the respective cutoffs and was significantly associated with shorter disease-specific survival across all thresholds (HD ≥ 10% p = 0.001; HD ≥ 20% p = 0.0001; HD ≥ 30% p = 0.043). Patients with HD ≥ 20% and ≥ 30% experienced universal disease-specific mortality within a median survival time of approximately 2 years. MTAP and p16 IHC were performed in matched areas. MTAP IHC showed high specificity (90%-92%) but limited sensitivity (30%-50%), while p16 IHC displayed variable sensitivity (41%-75%) and lower specificity (63%). Combined MTAP/p16 negativity improved sensitivity (up to 100%) but reduced specificity (57%). Neither MTAP nor p16 loss correlated significantly with survival. Spatially heterogeneous IHC patterns corresponded to regional variability in CDKN2A/B deletion by FISH. CONCLUSIONS:CDKN2A/B HD detected by FISH, particularly using thresholds equal or greater than 20%, is strongly associated with poor outcome in meningiomas. MTAP and p16 IHC, alone or combined, lack sufficient accuracy as independent surrogates but may guide tissue selection for molecular testing in heterogeneous tumours.
TAR DNA-binding protein 43 (TDP-43) inclusions are defining pathological features of frontotemporal lobar degeneration (FTLD) but are also often observed in Alzheimer's disease (AD) and primary age-related tauopathy (PART). TDP-43 in AD is either associated with cognitive impairment or a protective-life prolonging impact, and yet the localization, cellular and fragment characteristics of TDP-43 need to be determined. We investigated the relationships between TDP-43 volumetric inclusion burden in low likelihood AD (lAD) and definite PART by immunostaining against phosphorylated TDP-43 (pTDP-43), TDP-43 C terminal (TDP-C) and TDP-43 N-terminal (TDP-N) fragments combined with 3D confocal imaging taken from eight regions: amygdala (basolateral [amygdala-BL] and centromedial amygdala [amygdala-CM]), the hippocampus (Cornu Ammonis [CA]-1, CA2/3, CA4, dentate gyrus [DG] and subiculum [SUB]) and entorhinal cortex (ERC) and artificial intelligence (AI)-based segmentation via object recognition, reconstruction and quantification. We found amygdala-CM in lAD and PART to have the overall greatest burden of pTDP-43 whereas TDP-N burden in amygdala-BL of PART cases was greater than other TDP-43 fragments. There was no difference in TDP-43 burden in hippocampal subfields in PART. However, CA2/3 region showed greater pTDP-43 burden while TDP-N stood out in DG and SUB. Multiple comparisons among the groups revealed that TDP-C was the only fragment showing differences among PART and lAD in CA2/3, DG and SUB regions. Overall, unbiased AI-based volumetric burden analysis pipeline demonstrated unique fragment aggregation patterns in the neurodegenerative processes of PART and AD.
Choroid plexus tumours are rare epithelial neoplasms arising from the choroid plexus, accounting for approximately 0.2% of all central nervous system tumours but up to 20% of brain tumours diagnosed during the first year of life. CPTs exhibit marked clinical and biological heterogeneity and are classified into three entities according to the World Health Organization (WHO): choroid plexus papilloma (CPP, WHO grade 1), atypical choroid plexus papilloma (aCPP, WHO grade 2) and choroid plexus carcinoma (CPC, WHO grade 3). Although CPP is a benign tumour with excellent prognosis following complete surgical resection, aCPP is defined by increased mitotic activity and carries a higher risk of recurrence in children older than 3 years and in adults. In addition, a subset of adult (a)CPPs harbours TERT promoter mutations, which have been associated with an increased risk of tumour recurrence. CPC is a highly malignant tumour characterised by frank signs of malignancy and aggressive clinical behaviour, with particularly poor outcomes in TP53-mutant cases, frequently associated with Li-Fraumeni syndrome. Accurate grading and distinction from histological mimics may be difficult, especially in small biopsy specimens or tumours with atypical features. In addition, the integration of molecular findings, including DNA methylation analysis and copy-number assessment, has become an important adjunct in the diagnostic evaluation of CPTs by improving diagnostic accuracy and providing additional prognostic information. In this review, we outline the histological and molecular characteristics of CPTs and highlight common diagnostic pitfalls and relevant differential diagnoses across different age groups.
This case provides clinicopathological evidence supporting the association between FBDS and basal ganglia involvement in anti-LGI1 encephalitis. It highlights the diagnostic challenge posed by tumour-like unilateral basal ganglia lesions on MRI and underscores the importance of neuronal autoantibody testing before invasive procedures. In addition, this report contributes the first neuropathological description of basal ganglia involvement in anti-LGI1 encephalitis and summarises previously reported pathological findings.
INTRODUCTION:Genomic instability is common in cancer, driven by different mechanisms and often linked to disease stage and progression. Optical genome mapping (OGM) enables the detection of genome-wide balanced and unbalanced structural rearrangements (SRs), providing an overview of genomic complexity. AIMS:To explore the utility of OGM in brain tumour characterisation, we conducted a pilot study on a well-characterised series of 43, mostly paediatric, cases encompassing different histotypes and enriched for gene fusion-positive neoplasms (30 cases). RESULTS:SRs were observed in 37/43 samples and defined three genomic patterns based on their number and distribution across the chromosomes: SR-chromothripsis (11 cases), high SR-complexity (11 cases) and low SR-complexity (21 cases). Genomic complexity was also assessed according to the number of copy number alterations (CNA) and, to this end, in SR-chromothripsis samples, only CNAs affecting chromosomes not involved in chromothripsis were considered: absence of CNAs was found in 15 cases, 1-9 CNAs in 19 cases, 10-49 CNAs in three cases and ≥ 50 CNAs in six cases. When examining the relationship between SR and CNA, a positive correlation emerged between CNA burden and the number of chromosomes harbouring SR (Spearman's r = 0.588, p = 0.0001), while breakpoint number was weakly associated; chromothripsis occurred exclusively within low CNA-complexity groups (p = 0.0836). Genome complexity patterns correlated with tumour types, with diffuse high-grade gliomas exhibiting high complexity, whereas infant-type hemispheric gliomas, most low-grade gliomas and embryonal tumours showed low complexity profiles. Importantly, SR-chromothripsis cases corresponded to low/intermediate-grade fusion-driven tumours, with balanced/nearly balanced CNA profiles. OGM allowed the detection of gene fusions in 24/30 cases, failing in six. When integrated with RNA sequencing, OGM unveiled the mechanisms underlying gene fusion formation in all cases: chromothripsis (11 cases), isolated chromosomal abnormalities (12 cases) and genome-wide alterations (seven cases). CONCLUSIONS:OGM reveals distinct genomic complexity patterns and refines the definition of chromothripsis, improving insights into tumourigenic mechanisms.
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a fatal neurodegenerative disease primarily affecting motor neurons. Two key protein inclusions found in lower motor neurons serve as neuropathological hallmarks of the disease in human tissue: the TDP43-positive inclusion and the cystatin C-positive Bunina body. Despite their diagnostic specificity and presence in most sporadic and familial ALS cases, Bunina bodies remain poorly understood, and their true prevalence is likely underestimated. The co-occurrence of the Bunina body and the TDP43 inclusion may provide valuable insights into the development of TDP43 pathology in ALS. Thorough characterisation of the Bunina body is needed to understand this interplay and the broader pathomechanisms of disease. This review examines our current knowledge of Bunina bodies and the biochemical properties of cystatin C that may promote its aggregation. Sequestration and aggregation of cystatin C into Bunina bodies may diminish its neuroprotective functions, including cysteine protease inhibition, autophagy induction and anti-amyloidogenic activity, thereby contributing to ALS pathogenesis. This review also evaluates findings from human post-mortem tissue and ALS disease models, discussing the value and limitations of these models in the context of Bunina bodies and TDP43 pathology. Finally, we discuss cystatin C's use as a biomarker and its therapeutic potential. A deeper understanding of cystatin C biology, its relationship with TDP43 pathology and improved ALS models will be essential for determining whether targeting cystatin C could provide a viable avenue for future ALS therapies.
AIMS:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with unclear molecular mechanisms. Heterozygous protein-truncating variants of DNAJC7, which encode a cochaperone involved in Hsp70/90-mediated protein quality control, are potential risk factors for ALS. However, the neuropathological consequences of heterozygous DNAJC7 mutations are unclear. We aimed to clarify the molecular and neuropathological features associated with a heterozygous DNAJC7 mutation in ALS. METHODS:We genetically screened 39 Japanese patients with ALS and identified a novel heterozygous frameshift mutation in DNAJC7 (c.157_163del, p.Lys53Ter) in one patient that was neuropathologically diagnosed with Kii ALS. We performed biochemical and neuropathological analyses using postmortem tissues from this patient, from cases of ALS without the mutation and from control cases. RESULTS:In the cases of ALS without DNAJC7 mutation, there was elevation of both DNAJC7 mRNA and protein levels compared with controls. The patient with DNAJC7 mutation showed relatively lower DNAJC7 mRNA and protein levels compared with the nonmutated cases of ALS, although mRNA expression remained relatively higher. DNAJC7 may be upregulated as a protective response against ALS pathogenesis, whereas a heterozygous mutation may attenuate this response. Immunohistochemistry and double immunofluorescence demonstrated partial colocalization of DNAJC7 with phospho-TDP-43-positive neuronal cytoplasmic inclusions, which supports a direct role for DNAJC7 in modulating pathological TDP-43 aggregation. CONCLUSIONS:These findings provide neuropathological evidence linking heterozygous DNAJC7 mutation to ALS, demonstrating impaired protein expression and suggesting a loss-of-function mechanism that compromises protective responses to TDP-43 pathology. DNAJC7 may represent a key modulator of ALS pathogenesis and potential therapeutic target.
Central nervous system embryonal tumour with PLAGL amplification, a methylation-defined tumour entity, may lack typical embryonal morphology. In this paediatric case, the diagnosis was established by DNA methylation profiling and confirmed by fluorescence in situ hybridisation demonstrating PLAGL1 amplification. Recognition of this morphology-molecular discordance may help avoid diagnostic pitfalls.
AIMS:The misfolding and accumulation of the protein α-synuclein (αSyn) into cytoplasmic inclusions termed Lewy bodies (LBs) and Lewy neurites is the defining neuropathological feature of LB diseases, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The loss of neurons and/or synapses has been postulated to underlie the clinical syndrome of DLB. The present study sought to elucidate the relationship between LB burden and neuronal and synaptic loss in DLB. METHODS:Post-mortem brain tissue from the cingulate gyrus and inferior temporal gyrus, two regions vulnerable to LB pathology, was obtained from DLB (N = 20) and control cases (N = 20). Formalin-fixed paraffin-embedded tissue was stained to quantify LB, Alzheimer-type pathology and a neuronal marker. Frozen tissue from the contralateral hemisphere was processed for immunoblotting to compare the abundance of synaptic markers across cases. RESULTS:Across both regions, no evidence of reduced total neuronal density was observed, but a modest reduction in parvalbumin interneurons was observed in the cingulate gyrus, and there were only modest reductions in some synaptic markers in DLB. LB burden was markedly variable across DLB cases but was not associated with any synaptic marker abundance or neuronal density. CONCLUSIONS:Taken together, these findings do not support an association between LB density and neuronal or synaptic loss in DLB, even in regions with particularly high burdens of LBs, such as the cingulate gyrus. These findings suggest that the link between αSyn proteinopathy and disease requires further investigation.
Muscle-specific antibodies against signal recognition particle (SRP) and 3‑hydroxy-3-methylglutaryl-CoA reductase (HMGCR) are established pathogenic factors in immune-mediated necrotizing myopathy (IMNM), and their titers are generally considered to correlate with disease activity. In contrast, the relevance of anti-Ku antibodies, which are myositis-associated autoantibodies typically detected in overlap syndromes and also found in a subset of IMNM patients lacking anti-SRP and anti-HMGCR antibodies, remains unclear. We report a 13-year-old girl with steroid-resistant Ku-positive myositis with necrotizing myopathy-like pathology who was exclusively positive for anti-Ku antibodies. Rituximab was introduced after failure of multiple immunosuppressive therapies and resulted in marked clinical improvement, accompanied by normalization of serum creatine kinase levels, improvement on muscle magnetic resonance imaging, and recovery of Childhood Myositis Assessment Scale scores. Immunostaining showed relatively enhanced nuclear Ku expression in the sarcolemmal region of the patient's muscle fibers compared with control muscle. However, anti-Ku antibody titers remained persistently elevated despite sustained clinical remission. These findings suggest that anti-Ku antibody titers did not correlate with disease activity in this patient, indicating that anti-Ku-associated myositis may differ from anti-SRP- or anti-HMGCR-associated myopathies.
Recreational nitrous oxide (N₂O) use is an emerging cause of severe neurotoxicity due to vitamin B12 inactivation. This study analyzes the relationship between initial clinical, biochemical and neuroimaging findings and functional disability at discharge in a cohort of 10 patients recruited between 2024 and 2025. All patients presented with hyperhomocysteinemia, while only 40% showed vitamin B12 hypovitaminosis, confirming hyperhomocysteinemia as a more sensitive diagnostic marker. The most common clinical manifestations were acroparesthesia (90%) and unstable gait (80%). Electrodiagnostic testing revealed pure motor axonal or mixed polyneuropathy in the lower limbs in all analyzed cases. Spinal Magnetic Resonance Imaging (MRI) showed posterior column hyperintensity in 60% of patients. In this series, patients with a poor functional status at discharge (mRS ≥ 2), tended to present with radiological signs of myelopathy, a higher number of affected spinal segments on MRIand combined cervical and thoracic involvement. These findings suggest that the anatomical extent of spinal cord damage on MRI is the primary predictor of functional outcome in N₂O-induced myeloneuropathy after discharge.
The first descriptions of perinatal white matter injury and its proposed relationship to adverse neurological outcomes were published over 150 years ago. Initial studies highlighted the significance of prematurity in the development of this pathology. Although prematurity remains a significant risk factor in the development of perinatal white matter injury today, it can be seen in many clinical settings and is associated with hypoxic/ischaemic insults and inflammation. White matter injury is typically divided into the focal form, white matter necrosis (or periventricular leukomalacia) and the diffuse form, often referred to as diffuse white matter gliosis. Diffuse white matter gliosis is characterised by a proliferation of reactive astrocytes throughout the cerebral white matter and is associated with injury to pre-oligodendrocytes that results in the arrest of maturation and delayed myelination in surviving infants. White matter necrosis causes focal injury to the cellular components of the affected white matter as well as axons. However, axonal injury is also present in the diffuse form of white matter injury, even in the absence of necrosis, and the location of pre-oligodendrocytes correlates with sites of white matter injury, suggesting that the diffuse and focal forms of perinatal white matter injury may exist on a spectrum rather than as completely distinct entities. This review focuses on the macroscopic and microscopic features of white matter injury and how these relate to the proposed pathophysiology of this disease and adverse neurodevelopmental outcomes. Areas of uncertainty and future challenges are also discussed.
AIMS:Microglia undergo profound structural and functional changes during Alzheimer's disease, yet the earliest stages of morphological remodelling that occur prior to amyloid deposition remain poorly defined. We hypothesised that microglia in the hippocampus of AppNL-G-F mice would exhibit early, region-specific structural adaptations before local plaque formation, reflecting an initial phase of disease-associated structural remodelling. METHODS:Two-month-old AppNL-G-F and wildtype mice were examined using high-resolution confocal microscopy of Iba1-labelled microglia in the dorsal CA1 apical field. Automated three-dimensional reconstructions were generated in Imaris, and quantitative morphometric analyses quantified cell density, Iba1 coverage, process topology and Sholl-based arbor complexity. Statistical analyses were performed using linear mixed-effects models incorporating sex as a fixed factor in all analyses. RESULTS:Microglial density and total Iba1 coverage were unaffected in AppNL-G-F mice at this age. In contrast, Sholl analysis revealed significant genotype-dependent reductions in process intersections and total process length, accompanied by reduced individual-cell territorial coverage, indicating an early contraction of the surveillance arbor independent of cell number. CONCLUSIONS:These findings demonstrate that hippocampal microglia in AppNL-G-F mice undergo an early, coordinated structural remodelling before local amyloid deposition becomes apparent. This preplaque adaptation defines an early structural remodelling of hippocampal microglia prior to evident local amyloid deposition, providing new insight into the earliest structural adaptations associated with neuroimmune engagement in AD pathogenesis.
INTRODUCTION:Vascular disease is associated with late-life dementia and other morbidities during life and commonly coexists with neurodegenerative pathologies. A complex variety of lesions can be documented, which has made development of standardised operationalised criteria difficult. A semiquantitative approach, vascular cognitive impairment neuropathology guidelines (VCING), has been developed that provides a score based on assessment of occipital white matter arteriolosclerosis, occipital leptomeningeal cerebral amyloid angiopathy (CAA) and the presence of any macroscopic infarct. METHODS:We applied VCING assessment to an ageing population-derived neuropathology cohort derived from two subcentres of the cognitive function and ageing study (n = 158, 63.7% female and 36.3% male). RESULTS:Vascular pathology using this method was common in this UK ageing population sample with 75% of individuals having a score of 1 or more. VCING score was associated with the presence of dementia at death, even accounting for Alzheimer's disease neuropathological change (ADNC). Of the VCING components, white matter arteriolosclerosis, but not CAA or infarcts, was associated with dementia (after adjustment for ADNC). VCING score was not associated with vascular risk factors during life, but males were at greater risk of a higher VCING score than females. VCING and arteriolosclerosis were associated with white matter pallor and perivascular space widening as markers of white matter damage. Venous collagenosis was also associated with white matter pallor. There was an association between VCING score and ADNC in regression analysis, and the association was particularly strong for the CAA component. CONCLUSIONS:VCING is a straightforward method to assess vascular pathology in neuropathology cohorts and retains its association with dementia. The arteriolosclerosis component, in particular, is related to dementia and to white matter damage, whereas venous-side effects may also be important for the latter. The strong association of the CAA component with ADNC measures, however, raises the question of whether the VCING approach may have some confounding effects with ADNC.
Tumours historically classified as extraventricular neurocytoma (EVN), initially in comparison with central neurocytoma, are defined by location and morphology; however, emerging molecular data demonstrate that this term is outdated. We report 14 previously unpublished tumours with a robust EVN DNA methylation profile, independent of original histopathologic diagnosis or anatomic location. Integrated molecular analyses identified FGFR1 alterations, particularly FGFR1::TACC1 fusions, as the predominant molecular driver of this tumour class. A smaller number of tumours harboured FGFR1 hotspot mutations (p.N546K and p.K656E). Among these, two cases additionally showed NF1 variants, and one tumour carried a PIK3CA mutation (p.H1047L). In addition, a single case exhibited an NTRK2 fusion. Histologically, tumours exhibited neurocytic differentiation with neuropil islands and a minor glial component, while immunohistochemistry showed frequent OLIG2 expression, contrasting with the typical immunophenotype of central neurocytoma. Notably, tumours with an EVN DNA methylation profile were identified in both extraventricular and intraventricular locations, demonstrating that anatomy-based definitions are inadequate for this tumour type. Clinical follow-up (median 33.2 months) showed predominantly lower grade behaviour, with occasional recurrence. Collectively, these findings support the view that tumours previously labelled as EVN do not represent a direct counterpart of central neurocytoma but instead constitute a molecularly and epigenetically distinct glioneuronal tumour type. We propose the designation glioneuronal tumour with neurocytic differentiation (GNTN) to reflect its biological identity and to align the terminology with contemporary molecular neuropathology, and recommend DNA methylation profiling as an essential diagnostic criterion.
KIF1A-associated neurological disorder (KAND) is a rare hereditary condition caused by KIF1A variants, affecting axonal transport and presenting with a wide clinical spectrum, including hereditary spastic paraplegia. This case of childhood-onset KAND reveals FTLD-TDP43 with motor neuron disease pathology emerging late in the disease course, suggesting that HSP and FTLD-MND share a pathological continuum through a TDP-43-related pathway and expanding the clinicopathological spectrum of KAND.
Spinal muscular atrophy type 1 (SMA type 1) is a severe neuromuscular disorder characterized by early-onset muscle weakness and bulbar dysfunction. Although disease-modifying therapies (DMTs) have markedly improved motor outcomes, swallowing function in treated children with SMA type 1 remains poorly characterized. This study aimed to retrospectively describe the common features of dysphagia in this population, explore associations with motor function and clinical features, and conduct a preliminary comparison of swallowing abilities among children treated with different DMTs. We included 53 patients, assessed between September 2021 and December 2025, using the Mealtime Assessment Scale (MAS), the Oral and Swallowing Abilities Tool (OrSAT), the Food Intake LEVEL Scale (FILS), and the paediatric Functional Oral Intake Scale (p-FOIS). Motor function was assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) and the Hammersmith Infant Neurological Examination motor milestone module (HINE-2). A distinctive dysphagia profile emerged. All swallowing scales showed strong correlations (r = 0.733-0.964, p < 0.001). Safety and efficiency were positively correlated with motor scores (p < 0.05); swallowing function was higher in sitters than in non-sitters; and differences were observed among DMTs. Based on our findings, routine swallowing assessment should be implemented in all patients with SMA type 1.
The MV1 subtype of sporadic Creutzfeldt-Jakob disease (sCJD) is one of the least studied. Cases are defined by the presence of the methionine/valine (MV) polymorphism at codon 129 of the PRNP gene and a type 1 immunoblot pattern of pathological prion protein (PrPD), where the unglycosylated PrPD fragment migrates at ~21 kDa (T21). Because the originally described MV1 cases had T21 plus brain pathology indistinguishable from MM1 cases (small vacuoles), the MV1 subtype has historically been grouped with MM1. However, the recent identification of MV1 cases with immunoblot and pathological features similar to the VV1 subtype (T21-20 doublet, larger vacuoles, ballooned neurons) has raised the possibility that the MV1 subtype is more heterogeneous than originally proposed. Here, we report three MV1 cases that further reveal the heterogeneity of this subtype. All cases were atypical in that they had persistent T20 fragments, in isolation or combination with T21 or T19, when typed at pH 6.9, a finding that would have been missed if typing were undertaken at pH 8.0 only. Fragment proportions differed in different brain regions, and further examination found that the cases had mixed MM1/VV1 features, predominant VV1-like characteristics or features of the MV2C subtype. Two cases had small to intermediate-sized vacuoles and synaptic PrP staining. The third case had intermediate vacuolation, weak synaptic staining and coarse PrP deposits. We also describe, for the first time, the application of asymmetric-flow field-flow fractionation as a novel tool to discriminate sCJD subtypes based on size distributions of protease-resistant and protease-sensitive PrPD. Overall, we propose that MV1 is a more heterogeneous subtype than previously appreciated, potentially existing along a spectrum from MM1-like to VV1-like phenotypes. Importantly, this biochemical heterogeneity may be underrepresented when subtyping is done at pH 8.0, so we recommend CJD subtyping be performed at pH 6.9 to avoid missing atypical or mixed cases.
