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Modelling of human diseases is an essential component of biomedical research, to understand their pathogenesis and ultimately, develop therapeutic approaches. Here, we will describe models of tumours of the central nervous system, with focus on intrinsic CNS tumours. Model systems for brain tumours were established as early as the 1920s, using chemical carcinogenesis, and a systematic analysis of different carcinogens, with a more refined histological analysis followed in the 1950s and 1960s. Alternative approaches at the time used retroviral carcinogenesis, allowing a more topical, organ‐centred delivery. Most of the neoplasms arising from this approach were high‐grade gliomas. Whilst these experimental approaches did not directly demonstrate a cell of origin, the localisation and growth pattern of the tumours already pointed to an origin in the neurogenic zones of the brain. In the 1980s, expression of oncogenes in transgenic models allowed a more targeted approach by expressing the transgene under tissue‐specific promoters, whilst the constitutive inactivation of tumour suppressor genes (‘knock out’)‐often resulted in embryonic lethality. This limitation was elegantly solved by engineering the Cre‐lox system, allowing for a promoter‐specific, and often also time‐controlled gene inactivation. More recently, the use of the CRISPR Cas9 technology has significantly increased experimental flexibility of gene expression or gene inactivation and thus added increased value of rodent models for the study of pathogenesis and establishing preclinical models. We describe the evolution of experimental systems, illustrated here in a timeline to show changing popularity over time. Starting with chemical and viral carcinogenesis, systems then developed into increasingly sophisticated genetically modified animal models. The literature cited in this article corresponds to the arrows in this illustration and the schematics illustrate the mechanism of action described in this article.

Many of the molecular and pathological features associated with human Alzheimer disease (AD) are mirrored in the naturally occurring age-associated neuropathology in the canine species. In aged dogs with declining learned behavior and memory the severity of cognitive dysfunction parallels the progressive build up and location of Aβ in the brain. The main aim of this work was to study the biological behavior of soluble oligomers isolated from an aged dog with cognitive dysfunction through investigating their interaction with a human cell line and synthetic Aβ peptides. We report that soluble oligomers were specifically detected in the dog's blood and cerebrospinal fluid (CSF) via anti-oligomer- and anti-Aβ specific binders. Importantly, our results reveal the potent neurotoxic effects of the dog's CSF on cell viability and the seeding efficiency of the CSF-borne soluble oligomers on the thermodynamic activity and the aggregation kinetics of synthetic human Aβ. The value of further characterizing the naturally occurring Alzheimer-like neuropathology in dogs using genetic and molecular tools is discussed.

In the last 6 years, following the first pathological description of presumed amyloid-beta (Aβ) transmission in humans (in 2015) and subsequent experimental confirmation (in 2018), clinical cases of iatrogenic cerebral amyloid angiopathy (CAA)—attributed to the transmission of Aβ seeds—have been increasingly recognised and reported. This newly described form of CAA is associated with early disease onset (typically in the third to fifth decade), and often presents with intracerebral haemorrhage, but also seizures and cognitive impairment. Although assumed to be rare, it is important that clinicians remain vigilant for potential cases, particularly as the optimal management, prognosis, true incidence and public health implications remain unknown. This review summarises our current understanding of the clinical spectrum of iatrogenic CAA and provides a diagnostic framework for clinicians. We provide clinical details for three patients with pathological evidence of iatrogenic CAA and present a summary of the published cases to date (n=20), identified following a systematic review. Our aims are: (1) To describe the clinical features of iatrogenic CAA, highlighting important similarities and differences between iatrogenic and sporadic CAA; and (2) To discuss potential approaches for investigation and diagnosis, including suggested diagnostic criteria for iatrogenic CAA.

Glioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma stem cells are maintained in specialised microenvironments, but whether, or how, they undergo lineage progression outside of these niches remains unclear. Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte lineage competency. Tumour cells in contact with white matter acquire pre-oligodendrocyte fate, resulting in decreased proliferation and invasion. Differentiation is a response to white matter injury, which is caused by tumour infiltration itself in a tumoursuppressive feedback loop. Mechanistically, tumour cell differentiation is driven by selective white matter upregulation of SOX10, a master regulator of normal oligodendrogenesis. SOX10 overexpression or treatment with myelination-promoting agents that upregulate endogenous SOX10, mimic this response, leading to niche-independent pre-oligodendrocyte differentiation and tumour suppression in vivo. Thus, glioblastoma recapitulates an injury response and exploiting this latent programme may offer treatment opportunities for a subset of patients. Glioma stem cells (GSCs) retain the ability to partially differentiate, but it is unclear how the brain microenvironment may influence this response. Here the authors show that glioblastoma cells infiltrating into the white matter acquire pre-oligodendrocyte-like fate in a process that mimics myelin repair and results in tumour suppression

This study looks at a polymorphism of the human prion protein gene, which results in a G-to-V substitution at residue 127, in transgenic mice expressing different human prion proteins, finding that mice heterozygous for the G127V polymorphism are resistant to both kuru and classical CJD prions, but there is some transmission of variant CJD prions; most remarkable, however, is that mice homozygous for V127 are completely resistant to all prion strains. Disease-resistant human prion protein Long-term studies in Papua New Guinea, where the prion disease kuru has been endemic, identified a polymorphism of the human prion protein (PrP) gene — a glycine to valine substitution at residue 127 — that provided a high degree of protection from kuru and was positively selected for during the kuru epidemic. Here John Collinge and colleagues study this G127V polymorphism in detail in transgenic mice expressing different human prion proteins. Mice heterozygous for the G127V polymorphism, which mirrors the human genotype found in Papua New Guinea, are resistant to both kuru and classical Creutzfeldt–Jakob disease (CJD) prions, but there was some transmission of variant CJD, a bovine spongiform encephalopathy (BSE)-derived strain that the humans in Papua New Guinea were never exposed to. Most remarkably, however, mice homozygous for 127V were completely resistant to all prion strains. This represents a previously unknown mechanism of protection against prions; the more common polymorphism M129V is protective only in the heterozygous state. How a single amino acid change can offer such protection awaits further studies. Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP) 1 . A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru—an acquired prion disease epidemic of the Fore population in Papua New Guinea—and appeared to provide strong protection against disease in the heterozygous state 2 . Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt–Jakob disease (CJD) prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G→V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation.

We sought to investigate, whether texture analysis of diffusional kurtosis imaging (DKI) enhanced by support vector machine (SVM) analysis may provide biomarkers for gliomas staging and detection of the IDH mutation. First-order statistics and texture feature extraction were performed in 37 patients on both conventional (FLAIR) and mean diffusional kurtosis (MDK) images and recursive feature elimination (RFE) methodology based on SVM was employed to select the most discriminative diagnostic biomarkers. The first-order statistics demonstrated significantly lower MDK values in the IDH-mutant tumors. This resulted in 81.1% accuracy (sensitivity = 0.96, specificity = 0.45, AUC 0.59) for IDH mutation diagnosis. There were non-significant differences in average MDK and skewness among the different tumour grades. When texture analysis and SVM were utilized, the grading accuracy achieved by DKI biomarkers was 78.1% (sensitivity 0.77, specificity 0.79, AUC 0.79); the prediction accuracy for IDH mutation reached 83.8% (sensitivity 0.96, specificity 0.55, AUC 0.87). For the IDH mutation task, DKI outperformed significantly the FLAIR imaging. When using selected biomarkers after RFE, the prediction accuracy achieved 83.8% (sensitivity 0.92, specificity 0.64, AUC 0.88). These findings demonstrate the superiority of DKI enhanced by texture analysis and SVM, compared to conventional imaging, for gliomas staging and prediction of IDH mutational status.

•Prognostic value of S100B in TBI, SAH and meningitis at 6 months following treatment.•Significant correlation between serum S100B and GOS in overall cohort, TBI and SAH (p<0.05).•Significant correlation between CSF S100B and GOS in SAH (p<0.05).•Serum S100B >0.7μg/l correlated with 100% mortality.•CSF S100B sensitive to small influences with EVD exchange causing significant increase (p<0.005). S100B has been proposed as a putative biochemical marker in determining the extent of brain injury and corresponding prognosis in neurotrauma. The aim of this study was to evaluate the prognostic value of S100B early concentrations in serum and cerebrospinal fluid (CSF) in traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH), to determine prognostically relevant threshold values and to evaluate fluctuation following EVD placement. In 102 patients (45 SAH and 57 TBI) under intensive care unit (ICU) treated between January 2011 and December 2012 with external ventricular drain (EVD) S100B measurements were performed simultaneously in serum and CSF during the first 5 days and before and after EVD exchange. Glasgow coma scale (GCS) was assessed on admission and Glasgow outcome scale (GOS) 6 months later. Peak S100B levels in CSF and serum were measured on the first day after admission and concentrations decreased during the ensuing days post injury gradually. CSF and serum S100B concentrations in TBI patients were significantly higher than in SAH (p<0.005). Both in TBI and SAH patients S100B concentrations in CSF and serum were significantly higher in patients with an unfavorable outcome (GOS 1–3) in comparison to patients with a good outcome (GOS 4–5). Correlation of S100B concentrations in serum and GOS score at 6 months was significant both in TBI and SAH (p<0.05). Serum S100B concentrations >0.7μg/l correlated with 100% mortality. Correlation between S100B in CSF and GOS was significant in SAH (p<0.05), whereas it was not significant in TBI. After EVD exchange (n=53) we found a significant increase of S100B concentration in CSF (p<0.005). Initial S100B levels have a limited prognostic value in neurotrauma with CSF concentrations being highly sensitive to smallest influences like EVD placement. However, high initial S100B levels of >0.7μg/dl in serum are associated with 100% mortality, which might help to guide therapy strategies in severe neurotrauma.

The introduction of the classification of brain tumours based on their DNA methylation profile has significantly changed the diagnostic approach for cases with ambiguous histology, non-informative or contradictory molecular profiles or for entities where methylation profiling provides useful information for patient risk stratification, for example in medulloblastoma and ependymoma. We present our experience that combines a conventional molecular diagnostic approach with the complementary use of a DNA methylation-based classification tool, for adult brain tumours originating from local as well as national referrals. We report the frequency of IDH mutations in a large cohort of nearly 1550 patients, EGFR amplifications in almost 1900 IDH-wildtype glioblastomas, and histone mutations in 70 adult gliomas. We demonstrate how additional methylation-based classification has changed and improved our diagnostic approach. Of the 325 cases referred for methylome testing, 179 (56%) had a calibrated score of 0.84 and higher and were included in the evaluation. In these 179 samples, the diagnosis was changed in 45 (25%), refined in 86 (48%) and confirmed in 44 cases (25%). In addition, the methylation arrays contain copy number information that usefully complements the methylation profile. For example, EGFR amplification which is 95% concordant with our Real-Time PCR-based copy number assays. We propose here a diagnostic algorithm that integrates histology, conventional molecular tests and methylation arrays.

IntroductionIntraneural perineurioma (IP) classically causes a progressive, painless mononeuropathy, usually in young adults, and most frequently affecting the sciatic nerve or its branches. Pathological features are pathognomonic, but the radiological findings are also diagnostic; focal fusiform hypertro- phy and high signal on T2 MRI, with avid homogeneous enhancement. We present two cases of diffuse disease causing upper-limb plexopathy.MethodsPatients were evaluated at two specialist neuromuscular centres.ResultsPatient 1, a 20 year-old male, presented with a 12-year history of progressive distal then proximal, bilateral upper limb amyotrophy and sensory loss. Neurophysiology suggested an axonal process without evidence of conduction block or dispersion. MRI showed bilateral brachial plexus hypertrophy with avid enhancement. Dorsal ulnar nerve biopsy confirmed IP. Patient 2, a 41 year-old male, presented with more than a 20-year history of right lower cranial nerve palsies and right shoulder girdle amyotrophy, with distal left upper limb amyotrophy. Imaging was near identical to Patient 1, and brachial plexus biopsy confirmed IP, which in this case extended to the cranial nerves.ConclusionsDiffuse IP is extremely rare. We report cases of progressive upper-limb disease confirmed on distal and proximal biopsy. The phenotype and radiological findings should prompt consideration of the diagnosis.