Seasonally recurring hibernation-like states are exceptionally rare in humans, and their neural substrates remain unknown. We investigated the brain of a 57-year-old woman with a > 30-year history of winter-associated hypothermia, neuroendocrine instability, psychomotor suppression and circannual rhythmicity. Postmortem neuropathological analysis revealed preserved hypothalamic and basal forebrain anatomy but profound neurochemical abnormalities. Key peptidergic neuronal populations involved in circadian and neuroendocrine regulation, including arginine vasopressin (AVP), oxytocin (OXT), corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH) neurons, showed near-complete loss of immunoreactivity in the SCN, SON and PVN. Immunoreactivity for vasoactive intestinal peptide (VIP) and neurotensin (NT) in the SCN was markedly reduced. These changes were accompanied by markedly reduced synaptophysin immunoreactivity in all hypothalamic regions examined, whereas catecholaminergic neurons were relatively preserved in the PVN and SON. Beyond the hypothalamus, cholinergic neurons in the NBM showed a moderate reduction without evidence of Alzheimer-related pathology. Microglial immunoreactivity was nearly absent in the hypothalamic and extrahypothalamic regions examined, contrasting with preserved GFAP and AQP4 immunoreactivity. Moreover, myelination and microvascular architecture also remained intact. These findings identify a selective hypothalamic and microglial suppression associated with a rare human hibernation-like phenotype and indicate markedly reduced output of core neuroendocrine and circadian circuits during long-standing hypometabolic states. The case also illustrates that recurrent, profound hypothermia can be tolerated over decades without systemic organ failure, highlighting an unexpected degree of human metabolic resilience.

A child with hypereosinophilic syndrome presented with an intraventricular mass and hydrocephalus. Histopathology showed dense eosinophilic infiltration, supporting central nervous system involvement. This rare entity can mimic an intraventricular neoplasm and should be considered in the differential diagnosis.

We report a case of primary intramedullary infantile fibrosarcoma (IFS) in a 4-week-old infant with rapidly progressive cervical myelopathy. Histology showed a spindle cell tumour with diffuse S100 and pan-TRK expression. RNA sequencing identified an RBPMS::NTRK3 fusion. RNA-based clustering and DNA methylation profiling classified the tumour as IFS. Treatment with the TRK inhibitor, larotrectinib, achieved marked clinical and radiological recovery within 1 month, expanding the spectrum of NTRK-rearranged sarcomas and confirming TRK inhibition's efficacy in primary central nervous system IFS.

Two new cases of low-grade diffusely infiltrative tumour (LGDIT), SMARCB1 mutant, are described in an 18-year-old and a 50-year-old male, both with supratentorial lesions, characteristic rhabdoid histology on a myxoid-collagenous background, and complete INI1 loss. Both tumours showed homozygous SMARCB1 deletion and clustered with previously reported LGDIT on t-SNE analysis, in proximity to ATRT-MYC. These observations reinforce the distinct clinicopathological profile of LGDIT and support its consideration as a provisional CNS tumour type.

Mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) define a major subgroup of adult-type diffuse gliomas and induce accumulation of D-2-hydroxyglutarate, resulting in extensive DNA and histone methylation changes. This epigenetic reprogramming underlies the glioma CpG island methylator phenotype (G-CIMP) and contributes to tumour lineage, differentiation state and clinical behaviour. DNA methylation profiling has consequently evolved from a research tool into an important ancillary method for CNS tumour classification, molecular subclassification and copy-number analysis. This narrative review examines the biological basis, analytical platforms and clinical applications of DNA methylation profiling in IDH-mutant gliomas. Particular attention is given to the distinction between research-defined G-CIMP-high and G-CIMP-low states and classifier-defined lower-grade and high-grade methylation subclasses. High-grade signatures, including A_IDH_HG and G-CIMP-low, are associated with adverse genomic features and outcome but should not be considered interchangeable or used in isolation to assign CNS WHO grade. Their interpretation requires integration with histology and established molecular criteria, including homozygous CDKN2A/B deletion. The review also discusses array-based profiling, emerging Nanopore and long-read approaches, computational quality control, and the integration of methylation data with genomic and transcriptomic alterations. Longitudinal studies indicate that a subset of IDH-mutant astrocytomas undergoes methylation loss, copy-number accumulation and altered cell-state differentiation during progression, although these changes are not universal. The clinical relevance of MGMT promoter methylation is more context-dependent than in IDH-wildtype glioblastoma. Moreover, the INDIGO trial established the clinical activity of mutant IDH inhibition in selected Grade 2 gliomas but did not validate methylation class as a predictive biomarker or demonstrate complete epigenetic reversal. Emerging applications, including single-cell and spatial epigenomics, tumour microenvironment deconvolution and CSF methylation profiling, remain investigational. Overall, DNA methylation profiling is most valuable when used as integrated diagnostic and risk-stratification evidence within the complete histological, genomic and clinical context.

We describe the case of a 32-year-old woman with focal drug-resistant epilepsy, who underwent surgical resection of a cerebral cavernous malformation (CCM), previously treated with laser interstitial thermal therapy (LITT), after experiencing seizure recurrence. Histological findings after LITT have been rarely described. We report and discuss neuropathological findings to explain post-LITT seizure recurrence, with a focus on extensive hemosiderin deposition and a minimal residue of the original CCM. This illustrative case may aid the comprehension of histological bases underlying the LITT failure in seizure relief.

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.

We describe a unique case of papillary tumour of the pineal region (PTPR) arising in the fourth ventricle without any demonstrable anatomical continuity with the pineal region, in a 2-year-old male patient harbouring a germline PTEN pathogenic variant. This case arisen in the fourth ventricle shows epigenetic characteristics consistent with PTPR, suggesting the possibility that PTPR develops outside the pineal region. The tumour was composed of epithelioid-looking papillary structures (A, Haematoxylin and eosin [H&E]), intermingled with more densely cellular areas displaying perivascular pseudorosettes (B, H&E). Neoplastic cells resulted immunopositive for GFAP (C), CD56/NCAM (D) and focally positive for cytokeratin 18 (E) and showed dot-like immunostaining for EMA (F). DNA methylation profiling using the Bethesda Classifier version 2.0 demonstrated that the tumour clustered with PTPR-B in the UMAP analysis (G). CNV plot of the tumour showed the isolated loss of chromosome 10 (H).

We report an autopsy case of frontotemporal lobar degeneration (FTLD)-TDP type C with severe striatal involvement and annexin A11- and phosphorylated TDP-43-positive glial cytoplasmic inclusions. The patient developed progressive asymmetric rigidity accompanied by marked striatal atrophy and showed both upper and lower motor neuron involvement. These findings expand the clinicopathological spectrum of FTLD-TDP type C and may support the concept of an annexin A11-associated pathogenic continuum linking FTLD and amyotrophic lateral sclerosis.

We report the clinicopathological and biochemical findings of ALS associated with a UBQLN2 P494L mutation. Autopsy revealed widespread TDP-43 pathology and UBQLN2-positive inclusions. Immunoblot analysis demonstrated a marked reduction of soluble UBQLN2, supporting functional UBQLN2 insufficiency as a pathogenic mechanism underlying TDP-43 aggregation.