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We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer’s dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.

A difficult question in autopsy practice is whether intracranial haemorrhage has resulted from or brought about a fall.To address this we undertook a retrospective study of all autopsy reports (N = 2126) complied over a 10 year period (2009-2018). Of 720 patients who underwent a comprehensive post mortem neuropathologic examination we found 226 patients who had a history of a fall.Of the 226 with a history of fall, 179 (79%) had an intrcranial haemorrhage which was classified as truamatic (n = 134, 77%) or spontaneous (n = 41, 23%. Within the traumatic group, falls from a standing height (51%) were more common than falls involving stairs (31%) or falls from a height (12%). Cerebral contusional injury (51%) and subdural haemorrhage (45%) were the most common type of haemorrhage in the traumatic group. In the spontaneous haemorrhage group cerebral amyloid angiopaty (49%) was the commonest detected cause and was typically lobar in distribution).We are of the view that a comprehensice analysis of fatal falls with intracranial haemorrhage warrants a detailed neuropathologic examination as part of the overall death analysis.

Background Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, neurodegenerative disease. In Ireland, clinical diagnostics and laboratory testing remain the responsibility of the managing clinician and the Neuropathology Department at the Beaumont Hospital, respectively. Centralized review of individual cases is not undertaken. Aims To determine how diagnostic processes for CJD could be improved in Ireland and to outline the structure and referral process for a new CJD review panel at the Beaumont Hospital. Methods We surveyed Irish neurologists’ experiences on the management of CJD in Ireland. We measured turnaround times (TAT) for CSF samples referred for diagnostic CJD testing. Finally, we retrospectively reviewed imaging of autopsy-proven CJD cases to compare with initial reports. Results Ninety-three percent of neurologists supported a national central review of suspect CJD cases. A second clinical opinion was considered to be of likely benefit by 79%. Additionally, 93% reported that a centralized review of neuroradiology would be useful. All respondents felt that expediting turnaround of CSF analysis would be of benefit. The average TAT for CSF testing was 35.4 days. In retrospective review of imaging, all patients demonstrated MRI findings consistent with CJD. However, in only one of these cases were the initial pre-autopsy radiological findings reported as being consistent with CJD. Conclusions These findings support the need for improvements to the Irish National CJD Surveillance Unit to maximize antemortem diagnostic accuracy. On foot of this, a clinical CJD Multidisciplinary Team (CJD MDT) has been established to provide a second opinion on (i) the patient’s clinical history, (ii) neuroradiology and (iii) and neurophysiology reports (where available).

While magnetic resonance imaging (MRI) is the predominant imaging modality for glioblastoma (GBM), pre-clinical MRI scanner availability is limited. As pre-clinical CT is more widely available and cost-effective, this study aimed to 1) establish preclinical-GBM CT and CT-radiomic workflows, 2) identify whether CE-CT could detect murine orthotopic GBM tumours on two CT instruments [TRIUMPHX-O-CT; IVISSPECTRUM-CT], 3) assess whether CT-radiomic features could distinguish tumour from normal tissue, and support earlier detection of tumours, 4) verify translation of pre-clinical CT-radiomic pipelines to, and assess pre-clinical CT-features in, clinical CE-CT scans.U87R-Luc2(n=25) and NFpp10a-Luc2(n=10) orthotopic GBM models were established and tumours monitored via bioluminescence imaging (BLI). Concurrently, mice underwent CE-CT (IV-iodine/300mg/mL/50kV-scan). Extracted radiomic features (PyRadiomics) underwent dimensionality reduction (Spearman correlation; >0.85). Remaining features were analysed (Recursive feature elimination (RFE)/RepeatedCV/randomforest) in normal and tumour tissue and across timepoints (TRIUMPHX-O-CT-Wk3vsWk6,Wk6vsWk9/12; IVISSPECTRUM-CT-Wk6vsWk9/12).CE-CT and radiomic pipelines were successfully established for orthotopic GBM models, using both CT-systems. On visual assessment of images, BLI was significantly more sensitive, with tumours detectable at Wk1 (BLI) vs Wk9 (CE-CT). However, RFE analysis identified CT-radiomic features (first_order&glcm) which differentiated tumour from normal tissue (TRIUMPHX-O-CT). A subsequent feature set (first_order,glcm,gldm&glzm) were identified (TRIUMPHX-O-CT/IVISSPECTRUM-CT), detecting tumours earlier (Wk3&Wk6) than possible by visual assessment of CTs. Preclinical radiomic methods were successfully applied to exploratory clinical CE-CT scans(n=10). Here, several preclinical CT-features (e.g. Zone_Entropy) showed increased intensity in tumour regions. Overall experimental BLI is the most sensitive method for pre-clinical intracranial tumour detection. However, analysis of clinically relevant CT-radiomic features may facilitate tumour identification and earlier tumour detection (Wk3/Wk6-TRIUMPHX-O-CT/Wk6-IVISSPECTRUM-CT) than possible by visual assessment of CT (Wk9). Clinically relevant CT-derived radiomic features may therefore support intracranial rodent tumour assessment. Importantly, preclinical radiomic methods successfully translate to clinical CT-radiomic analysis. Parallel trends in tumour-specific feature intensities across pre-clinical and clinical scans suggest species conservation of features.

We describe a patient with chronic progressive external ophthalmoplegia (CPEO) due to a rare mitochondrial genetic variant. Muscle biopsy revealed numerous cytochrome c oxidase (COX)-deficient fibres, prompting sequencing of the entire mitochondrial genome in muscle which revealed a rare m.12334G>A variant in the mitochondrial (mt-) tRNALeu(CUN)(MT-TL2) gene. Analysis of several tissues showed this to be a de novo mutational event. Single fibre studies confirmed the segregation of high m.12334G>A heteroplasmy levels with the COX histochemical defect, confirming pathogenicity of the m.12334G>A MT-TL2 variant. This case illustrates the importance of pursuing molecular genetic analysis in clinically-affected tissues when mitochondrial disease is suspected.

Background We describe the clinical and neuropathological features of a patient with T-cell-mediated paraneoplastic limbic encephalitis, parkinsonism, hypothermia, and narcolepsy-like presentation associated with endometrial carcinoma. Objectives This patient with prominent parkinsonism and narcolepsy broadens the phenotype of known paraneoplastic syndromes and demonstrates the importance of investigation for occult malignancy even in the absence of paraneoplastic antibodies. Methods This is a case report with diagnosis confirmed at postmortem. Results Paraneoplastic antibodies were not detected. The initial improvement with immunosuppression was short lived, and postmortem neuropathological examination demonstrated encephalitis with predominant T-cell infiltration affecting the hypothalamus and extending to the brainstem, suggestive of a paraneoplastic syndrome. Conclusions Although the possibility of a novel antibody cannot be ruled out, consideration must also be given to recent demonstration of purely T-cell-mediated neuronal destruction in the context of paraneoplastic syndromes.

Knowledge of the clinical outcome in tumefactive demyelination remains limited. This study aims to characterise the natural history of biopsy-proven, pathogen-free, cerebral demyelination in an adult Irish population. We identified all patients with biopsy-proven demyelination in a single neuropathology centre between 1999 and 2017. A baseline, and at least one follow-up MRI scan was available in each instance (mean of 3 scans per patient), together with both the presenting and most recent clinical details including disability level and disease-modifying drugs. In 21 patients, white matter biopsies showed the following: macrophages with myelin debris, myelin-axonal dissociation, reactive astrocytes and occasional lymphocytes. During a mean follow-up time of 8 years (± 4.4), 17 patients developed MS, confirmed both clinically and on MRI, using the 2010 McDonald criteria: 11 relapsing remitting (RR) MS, four secondary progressive and two primary progressive MS. Four patients had a monophasic illness with lesion regression, without clinical or radiological evidence of any further disease activity on follow-up. The patients with progressive MS had significantly higher levels of physical disability than either the RRMS or monophasic patients. Uniform white matter subacute demyelination is associated with a diverse clinical course ranging from a monophasic illness to progressive MS, suggesting that extraneous factors distinct from the basic pathology significantly influence the clinical course in MS.

This is the fourteenth case of an intracranial and dural-based osteosarcoma in the literature to date. The case involves a forty-year old woman with a previous history of a brain tumour, which was treated with surgery, chemotherapy and radiotherapy six years previously. The hypothesis is that this rare malignancy is secondary to the radiation exposure given the growth of the lesion in the previous radiation field

Introduction Metastatic breast cancer (MBC) is the main source of mortality in breast cancer patients largely due to lack of effective treatments. Our previous results suggest that tumour transcriptional heterogeneity drives therapy resistance and cancer relapse. While traditional in vitro human cancer cell line models have been widely used for disease modelling, they do not faithfully recapitulate the pathophysiology of MBC. Method In this study we developed patient-derived tumour organoid cultures from frozen patient-derived (PDX) models of MBC. Using those models we performed preclinical drug screening of investigational and FDA approved therapeutics previously uncovered by us as potentially clinically actionable in MBC. Result Our results reveal high heterogeneity in the responses to various targeted therapies among tested MBC organoids, which makes them a valuable tool for studying intra-tumor heterogeneity and drug response. Moreover, drug screening identified a divergent set of the breast to brain metastatic MBC organoids that showed high sensitivity to a new class of tyrosine kinase receptors, RET. Conclusion Taken together, our novel MBC models and methodology applied here provides an important modelling tool to assess the contribution of intra-tumour heterogeneity and microenvironment to drug response as they recapitulate the cellular, structural and biochemical complexity previously observed in our genomic characterisation of MBCs. Application of this type of translational research will enhance the development of new targeted precision medicine strategies and prelude stratification for clinical trials. Abbreviations MBC- Metastatic Breast Cancer; PDX- Patient-Derived Xenografts; FDA- Food and Drug Administration; RET- Receptor Tyrosine Kinase Take-home message Patient-derived tumour organoid cultures provide an important modelling tool to assess the contribution of intra-tumour heterogeneity and microenvironment to drug response as they recapitulate the cellular, structural and biochemical complexity previously observed in genomic characterisation of metastatic breast cancer. SURGICAL EDUCATION AND TRAINING

Funder: Breast Cancer Ireland GR 14-0883, Steroid regulated cancer cells use nuclear receptors and associated regulatory proteins to orchestrate transcriptional networks to drive disease progression. In primary breast cancer, the coactivator AIB1 promotes estrogen receptor (ER) transcriptional activity to enhance cell proliferation. The function of the coactivator in ER+ metastasis however is not established. Here we describe AIB1 as a survival factor, regulator of pro-metastatic transcriptional pathways and a promising actionable target. Genomic alterations and functional expression of AIB1 associated with reduced disease-free survival in patients and enhanced metastatic capacity in novel CDX and PDX ex-vivo models of ER+ metastatic disease. Comparative analysis of the AIB1 interactome with complementary RNAseq characterized AIB1 as a transcriptional repressor. Specifically, we report that AIB1 interacts with MTA2 to form a repressive complex, inhibiting CDH1 (encoding E-cadherin) to promote EMT and drive progression. We further report that pharmacological and genetic inhibition of AIB1 demonstrates significant anti-proliferative activity in patient-derived models establishing AIB1 as a viable strategy to target endocrine resistant metastasis. This work defines a novel role for AIB1 in the regulation of EMT through transcriptional repression in advanced cancer cells with a considerable implication for prognosis and therapeutic interventions.

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Background Central nervous system (CNS) lymphoma is rare, representing 2% of all brain tumors. The commonest subtype is diffuse large B-cell lymphoma (DLBCL), with primary T-cell lymphomas (PCNSTL) accounting for ~ 2%. Objective To determine the frequency and describe the key features of CNS lymphoma over a 10-year period in an Irish population. Materials and methods This retrospective review was carried out using the neuropathology database in Beaumont hospital, the largest of two national neurosurgical centers, to identify all cases of CNS lymphoma from 2007 to 2017. Clinical, radiological, morphological, immunophenotype, and molecular information was recorded where available. Results We identified 149 cases of CNS lymphoma from 2007 to 2017, which equated to a cumulative incidence rate of 0.4/100,000 persons. Median age at diagnosis was 66 years, and 46% were male. 86% were classified as DLBCL (n = 128), 10% immunodeficiency-associated CNS lymphoma (n = 15), 3% PCNSTL (n = 4), and 1% (n = 2) cases of intravascular large B-cell lymphoma. Location in declining frequency was as follows: supratentorial (n = 125), infratentorial (n = 22), spinal (n = 1), and orbital (n = 1). Conclusion This is the first study in an Irish population to determine a cumulative incidence rate of CNS lymphoma, which is in line with larger international population-based registries. No significant trends in incidence rate have been observed from 2007 to 2017. DLBCL is the commonest subtype encountered. Rare variants including PCNSTL can pose a significant diagnostic challenge, and in this setting, molecular studies can be useful to confirm diagnoses.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly occurring in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. SMARCB1-mutant tumors in adolescents and adults are rare and may show uncommon histopathological and clinical features. Here we report seven SMARCB1-deficient intracranial tumors sharing distinct clinical, histopathological and molecular features. Median age of the four females and three males was 40years (range 15–61years). All tumors were located in the pineal region. Histopathologically, these tumors displayed spindled and epithelioid cells embedded in a desmoplastic stroma alternating with a variable extent of a loose myxoid matrix. All cases showed loss of nuclear SMARCB1/INI1 protein expression, expression of EMA and CD34 was frequent and the Ki67/MIB1 proliferation index was low in the majority of cases (median 3%). Three cases displayed heterozygous SMARCB1 deletions and two cases a homozygous SMARCB1 deletion. On sequencing, one tumor showed a 2bp deletion in exon 4 (c.369_370del) and one a short duplication in exon 3 (c.237_276dup) both resulting in frameshift mutations. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-SNE analysis and hierarchical clustering analysis, however, all tumors grouped closely together and showed similarities with ATRT-MYC. After a median observation period of 48months, three patients were alive with stable disease, whereas one patient experienced tumor progression and three patients had succumbed to disease. In conclusion, our series represents an entity with distinct clinical, histopathological and molecular features showing epigenetic similarities with ATRT-MYC. We propose the designation desmoplastic myxoid tumor (DMT), SMARCB1-mutant, for these tumors.

Background Metastatic breast cancer is a major cause of cancer-related deaths in woman. Brain metastasis is a common and devastating site of relapse for several breast cancer molecular subtypes, including oestrogen receptor-positive disease, with life expectancy of less than a year. While efforts have been devoted to developing therapeutics for extra-cranial metastasis, drug penetration of blood–brain barrier (BBB) remains a major clinical challenge. Defining molecular alterations in breast cancer brain metastasis enables the identification of novel actionable targets. Methods Global transcriptomic analysis of matched primary and metastatic patient tumours (n = 35 patients, 70 tumour samples) identified a putative new actionable target for advanced breast cancer which was further validated in vivo and in breast cancer patient tumour tissue (n = 843 patients). A peptide mimetic of the target’s natural ligand was designed in silico and its efficacy assessed in in vitro, ex vivo and in vivo models of breast cancer metastasis. Results Bioinformatic analysis of over-represented pathways in metastatic breast cancer identified ADAM22 as a top ranked member of the ECM-related druggable genome specific to brain metastases. ADAM22 was validated as an actionable target in in vitro, ex vivo and in patient tumour tissue (n = 843 patients). A peptide mimetic of the ADAM22 ligand LGI1, LGI1MIM, was designed in silico. The efficacy of LGI1MIM and its ability to penetrate the BBB were assessed in vitro, ex vivo and in brain metastasis BBB 3D biometric biohybrid models, respectively. Treatment with LGI1MIM in vivo inhibited disease progression, in particular the development of brain metastasis. Conclusion ADAM22 expression in advanced breast cancer supports development of breast cancer brain metastasis. Targeting ADAM22 with a peptide mimetic LGI1MIM represents a new therapeutic option to treat metastatic brain disease.

The presence of oligodendroglioma-like areas in pilocytic astrocytoma may give rise to pathologic diagnostic uncertainty. This study aims to determine if the oligodendroglioma-like areas present in some pilocytic astrocytomas (PA) possess the signature 1p/19q codeletion that is characteristic of classical oligodendroglioma. Array comparative genomic hybridization was carried out on 12 PA samples, from which oligodendroglioma-like areas were microdissected and used as the template DNA source. 1p/19q codeletions were not found in any of the oligodendroglioma areas in PAs. We conclude that PAs with oligodendroglioma-like areas do not share the same molecular genetics as classic oligodendroglioma. .

The aim of this study is to identify, in our center, all cases of foreign-body reactions to hemostatic agents or other prostheses resulting in a radiological suspicion of tumor recurrence. We interrogated our internal database to identify all such cases and systematically evaluated the MRI brain scans of patients: (i) at the time of initial tumor diagnosis, (ii) postoperatively, (iii) and at the time of suspected tumor recurrence. In addition, we reviewed each patient’s operative notes and reviewed the histology of all cases following a second surgical intervention. In total, we identified 8 patients, 7 of whom had a WHO grade II glioma at initial surgery. We did not identify any distinguishing radiological abnormalities from the initial diagnostic brain scan to the suspected recurrence, and histologically all cases were characterized by extensive gliosis; with both macrophages and reactive astrocytes present throughout. The cause of gliosis was identified as being relating to hemostatic agents in 4 cases; in the other 4 cases, the foreign-body reaction was presumed to be caused be materials used in a craniotomy or cranioplasty. This study highlights the difficulty in radiologically diagnosing a foreign-body reaction and also identifies that such a gliotic reaction may occur as a consequence of exogenous materials used in a craniotomy or cranioplasty.

We report the first clinical-radiological-genetic-molecular-pathological study of a kindred with c.823-10G>T MAPT intronic variant (rs63749974) associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We describe the clinical spectrum within this family and emphasize the association between MAPT gene variants and motor neuron disease. This report of a second family with FTDP-17 associated with c.823-10G>T MAPT variant strongly supports pathogenicity of the variant and confirms it is a 4-repeat (4R) tauopathy. This intronic point mutation, probably strengthens the polypyrimidine tract and alters the splicing of exon 10 (10 nucleotides into intron 9) close to the 3' splice site.

Brain biopsy in patients presenting with subacute encephalopathy is never straightforward, and only undertaken when a ‘treatable condition’ is a realistic possibility.This 63 year old right handed, immunocompetent Caucasian woman presented with an 8 month history of rapidly progressive right-sided hearing impairment, a 4 month history of intermittent headaches, tinnitus, ‘dizziness’, dysphagia, nausea and vomiting, with the subsequent evolution of progressive gait ataxia and a subacute global encephalopathy. The possibility of CJD was raised. Brain biopsy was carried out. Western blot for prion protein was negative. She died 9 days later and autopsy brain examination confirmed widespread subacute infarction due to an EBV positive atypical NK/T-cell infiltrate with positivity for CD3, CD56, granzyme B, perforin and EBER with absence of CD4, CD5 and CD8 expression. Molecular studies for T-cell clonality were attempted but failed due to insufficient DNA quality. Serology was consistent with past EBV infection (EBV VCA and EBNA IgG Positive). There was no evidence of disease outside the CNS. Primary central nervous system NK/T-cell lymphoma is extremely rare. The rare reported cases all present with a discrete intracranial mass, unlike the diffuse infiltrative pattern in this case. Whilst the diffuse interstitial pattern is reminiscent of chronic active EBV infection (CAEBV) seen in other organ systems such as the liver and bone marrow, the clinical presentation and epidemiologic profile are not typical for CAEBV.

Definitive diagnosis of Creutzfeldt Jakob disease (CJD) remains tissue-based. Possible and probable CJD are useful clinical terms but may be used indiscriminately. The aim of this study was to assess the effectiveness of the Irish surveillance system and to ascertain how diagnostic accuracy in identifying clinically "definite" cases might be improved. We reviewed the clinical information, relevant investigations, and samples n = 100; (autopsy n = 87; biopsy n = 13) in 96 patients between January 1, 2005 and December 31, 2015. In 4 cases both a biopsy and autopsy were performed. CJD was confirmed in 50 patients (45 at autopsy and 5 at biopsy). Sporadic CJD (sCJD) accounted for 90% of cases (n = 45); variant CJD (vCJD) for 6% (n = 3) with 1 case each of familial CJD and iatrogenic CJD. CSF 14-3-3, EEG, and MRI investigations were helpful but not available on all patients. CJD mimics (n = 46) fell into the following categories: neurodegenerative (n = 22), immune mediated (n = 3), cerebrovascular disease (n = 5), tumor (n = 5), dual pathology (n = 3), and miscellaneous (n = 8). The Irish surveillance system fulfils its main objective as all clinically suspicious cases are being referred. CJD was confirmed in 52% (n = 50/96) of referrals. Based on this, we propose an algorithm for CJD referrals to reduce both infection control and diagnostic difficulties encountered in CJD surveillance. .

Objective: Pituitary adenomas that produce thyroid-stimulating hormone (TSH) are typically accompanied by hyperthyroxinemia and a non-suppressed or elevated TSH at diagnosis. Occasionally, patients with this type of tumor have normal thyroid function test results, a condition termed ‘silent’ thyrotroph adenomas. This report characterizes TSH dynamics in this rare pituitary tumor subtype.Methods: We report 2 cases of pituitary macroadenoma associated with visual failure and hypopituitarism. The patients had normal thyroid function test results but the adenoma was intensely immunopositive for β-TSH expression. The results of TSH dynamics are reported for both cases.Results: Preoperative assessment did not reveal any clinical or biochemical evidence of pituitary hormone excess save mild, asymptomatic hyperprolactinemia consistent with pituitary stalk compression. In particular, thyroid function test results were within normal ranges. In both cases, each patient's vision recovered following transsphenoidal surgery. Histological analysis confirmed pituitary adenoma with extensive immunopositivity for TSH and the complete absence of immunostaining for all other anterior pituitary hormones. Following surgery, thyroid function test results were again normal. Surveillance magnetic resonance imaging performed 6 months postoperatively showed the presence of an intrasellar tumor remnant. A postoperative thyrotropin-releasing hormone test yielded a discordant, dynamic TSH response that was normal in one patient but was abnormal and flat in the second patient.Conclusion: TSH dynamics in ‘silent’ thyrotroph adenomas are variable. It is not known whether the biochemical behavior of the tumor may be indicative of its natural history or response to treatment.Abbreviations: ACTH = adrenocorticotrophic hormone GH = growth hormone T4 = thyroxine TRH = thyrotropin-releasing hormone TSH = thyroid-stimulating hormone

Chronic traumatic encephalopathy (CTE) is a postmortem diagnosis. Consensus postmortem, but not antemortem, diagnostic criteria have been established. A key factor in these criteria is evidence of phosphorylated-tau (p-tau) around sulcal vessels in the cortex. However, this sign has been observed anecdotally in a diverse range of neurodegenerative diseases (NDD). We therefore hypothesise that this criterion may lack specificity. To test this, we assessed patients with NDD, but no documented history of brain trauma, for sulcal p-tau. Tissue was retrieved from Dublin Brain Bank (known NDD n = 17; control with no diagnosed NDD n = 6; CTE n = 1), and slides were prepared from three sites with a predilection for trauma: superior frontal gyrus, temporal pole, and superior temporal gyrus. We stained the resulting anonymised slides with both hemotoxylin and eosin (H&E) and p-tau. Three neuropathologists, blinded to the clinical history and neuropathological diagnosis in each instance, evaluated each case for sulcal p-tau. We calculated the interrater agreement, using Fleiss’s kappa, and the specificity of this neuropathological sign. Sulcal p-tau was highly specific to diagnosed CTE cases (specificity 0.98), with moderate interrater agreement (κ = 0.45). In conclusion, therefore, we observed sulcal p-tau to be a sign highly specific to CTE when compared with NDD cases in the absence of head trauma.

Intracranial collision tumors are composed of two histologically distinct but merging components, and are rare. Their genetic profile has rarely been described. Comparative genome hybridization of a combined meningioma and oligodendroglioma demonstrated deletion of chromosome 22q and of 19q in both tumors. Somatic deletion of chromosome 22q and 19q is associated with development of an intracranial collision tumor. .

Cerebral toxoplasmosis is one of the most common causes of focal brain lesions in immunocompromised patients, such as those with human immunodeficiency virus (HIV). Differentiating toxoplasmosis from other central nervous system (CNS) lesions provides a significant clinical challenge. Magnetic resonance (MR) imaging of the brain is key to prompt diagnosis and treatment of cerebral toxoplasmosis. Several specific signs on MRI of brain have been described in recent literature including the “concentric target sign” and “eccentric target sign.” We report a case of successfully treated HIV-associated cerebral toxoplasmosis in which both MRI signs were present simultaneously.

Our aim is to present a typical case of IgG4-related hypophysitis, which will offer insight into the aetiology and pathogenesis of this relatively newly described disease. IgG4 Related Disease is a protean systemic condition that mimics inflammatory, infectious, and malignant processes. Biopsy of affected organs will show a typical histopathological pattern.

Epigenetic silencing of O-6-methylguanine-DNA methyltransferase (MGMT) promoter via methylation in a glioblastoma (GBM), has been correlated with a more favourable response to alkylating chemotherapeutic agents such as temozolomide. The use of global methylation surrogates such as Long Interspersed Nucleotide Element 1 (LINE1) may also be valuable in order to fully understand these highly heterogeneous tumours. In this study, we analysed both original and recurrent GBMs in 22 patients (i.e. 44 tumours), for both MGMT and LINE1 methylation status. In the 22 patients: 14 (63.6%) displayed MGMT methylation stability in the recurrent GBM versus 8 (36.4%), with instability of methylation status. No significant differences in overall and progression free survival was evident between these two groups. LINE1 methylation status remained stable for 12 (54.5%) of recurrent GBM patients versus 9 (41%) of the patients with instability in LINE1 methylation status (p = 0.02), resulting in an increase in overall survival of the stable LINE1 group (p = 0.04). The results obtained demonstrated major epigenetic instability of GBMs treated with temozolomide as part of the STUPP protocol. GBMs appear to undergo selective evolution post-treatment, and have the ability to recur with a newly reprogrammed epigenetic status. Selective targeting of the altered epigenomes in recurrent GBMs may facilitate the future development of both prognostic biomarkers and enhanced therapeutic strategies.

Haemangiomas of the vertebrae, usually regarded as having little or no consequence, may display aggressive features, including extension into the extradural space, and cause significant neurological symptoms and signs necessitating treatment. Extraosseous haemangiomas in an extradural or intradural extramedullary location are a rare entity. Here we review our radiologic and pathologic experience of osseous haemangiomas with extradural extension and primary extradural and intradural extramedullary haemangiomas. Magnetic resonance imaging plays a pivotal role in the characterisation of spinal haemangiomas, with typical imaging features including T1 and T2 signal hyperintensity. Atypical and aggressive imaging features are also described. Spinal angiography may be required to differentiate haemangiomas from non-vascular lesions. This is a rare and unusual entity, and should be considered as a differential diagnosis for some extramedullary masses. • Osseous haemangiomas can display aggressive features and cause neurologic symptoms needing treatment. • Haemangioma extension into the extradural space is an imaging feature of aggressiveness. • Extraosseous haemangiomas are a rare but important differential diagnosis for extramedullary masses. • Extraosseous extramedullary haemangiomas most frequently present with progressive myelopathy. • MRI is pivitol in characterising spinal haemangiomas; imaging characteristics can vary.

Hypokalaemic periodic paralysis typically presents with intermittent mild-to-moderate weakness lasting hours to days. We report a case with an uncommon phenotype of late-onset myopathy without episodic paralytic attacks. Initial work-up including muscle biopsy was inconclusive. A subsequent review of the right deltoid biopsy, long exercise testing and repeated family history was helpful, followed by appropriate genetic testing. We identified a heterozygous pathogenic mutation in calcium ion channel (CACNA1S:c.1583G>A p.Arg528His) causing hypokalaemic periodic paralysis. Myopathy can present without episodic paralysis and the frequency of paralytic episodes does not correlate well with the development and progression of a fixed myopathy. Our report also highlights the intrafamilial phenotypic variation of hypokalaemic periodic paralysis secondary to a CACNA1S gene mutation.

Creutzfeldt-Jakob disease (CJD) risk precautions are required when performing brain biopsies on patients with a dementing illness and in ‘risk’ groups. The impact on a diagnostic neuropathology service is considerable. We sought to determine if better case selection might reduce the necessity for application of CJD risk precautions. We reviewed the clinical information, contributory investigations and final neuropathologic diagnosis in a cohort of patients (n = 21), referred to the National CJD Surveillance Centre between January 1, 2005, and December 31, 2016. Of this 21-patient cohort, five were positive for CJD, four belonged to the ‘at risk of CJD’ category requiring brain surgery, while the remaining 12 were referred to the National CJD Surveillance Unit with CJD as part of their differential diagnosis. CJD was confirmed in 5/21 (three sporadic [s]CJD, one variant [v]CJD and one iatrogenic [i] CJD). CJD was clinically probable in 4/5 proven CJD patients (80%). The patients (n = 4) in the ‘at risk of CJD’ group were diagnosed with tumour (n = 2), inflammation (n = 1) and non-specific changes (n = 1). Of the remaining 12 patients (in whom CJD was included in the differential diagnosis), the final neuropathologic diagnoses included tumour (n = 2), neurodegenerative (n = 2), inflammatory (n = 1), metabolic (n = 2), vascular (n = 2) and non-specific gliosis (n = 3). More often than not, the clinical suspicion of CJD was not borne out by the final neuropathological diagnosis. Failure by clinicians to adhere to the recommended CJD investigation algorithm impacts adversely on the neuropathology workload and causes unnecessary concern among operating theatre, laboratory and nursing personnel.

In patients presenting with rapidly progressive dementia, prion disease may enter the differential diagnosis. The commonest malignancies masquerading as prion disease are primary CNS lymphoma and intravascular large B-cell lymphoma, both rare and difficult to diagnose without brain biopsy. This 82-year-old lady with a past history of hypertension, presented with rapidly progressive cognitive impairment and ataxia. The possibility of sCJD was raised. Brain biopsy was carried out. Western blot for prion protein was negative. Brain biopsy showed intravascular large B-cell lymphoma. She died shortly afterwards. The clinical presentation of intravascular large B-cell lymphoma is diverse. Patients may present as in this case with dementia, seizures, and myoclonus leading to a clinical diagnosis of sCJD. The diagnosis here was made at biopsy but is made at autopsy in over 50% of cases.

Mitochondrial DNA (mtDNA) analysis is centralized in the Department of Neuropathology, Beaumont Hospital. Services offered include analysis of common mtDNA point mutations, large scale mtDNA deletions/rearrangements, and sequencing of the nuclear gene POLG. The aims of this study were to audit the mtDNA diagnostic service over a 10-year period, to determine appropriate use of the service, and to improve efficient use of the service by devising a requisition form that includes diagnostic algorithms. Between July 2002 and October 2013, 716 samples were received for analysis. Overall, the number of confirmed mutations was low. Lack of diagnostic algorithms may result in expansive, unrefined requests, leading to costly investigations. We introduced a requisition form that extracts clinical, biochemical, and pathological data prior to analysis. With this information, diagnostic algorithms can be applied to select the most relevant mutations for initial analysis and also to increase the incidence of mutation detection.

Developing targeted therapies for high grade gliomas (HGG), the most common primary brain tumor in adults, relies largely on glioma cultures. However, it is unclear if HGG tumorigenic signaling pathways are retained under in-vitro conditions. Using array comparative genomic hybridization and immunohistochemical profiling, we contrasted the epidermal and platelet-derived growth factor receptor (EGFR/PDGFR) in-vitro pathway status of twenty-six primary HGG cultures with the pathway status of their original HGG biopsies. Genomic gains or amplifications were lost during culturing while genomic losses were more likely to be retained. Loss of EGFR amplification was further verified immunohistochemically when EGFR over expression was decreased in the majority of cultures. Conversely, PDGFRα and PDGFRβ were more abundantly expressed in primary cultures than in the original tumor (p0.05). Despite these genomic and proteomic differences, primary HGG cultures retained key aspects of dysregulated tumorigenic signaling. Both in-vivo and in-vitro the presence of EGFR resulted in downstream activation of P70s6K while reduced downstream activation was associated with the presence of PDGFR and the tumor suppressor, PTEN. The preserved pathway dysregulation make this glioma model suitable for further studies of glioma tumorigenesis, however individual culture related differences must be taken into consideration when testing responsiveness to chemotherapeutic agents.

Mutations in the lamin protein(found in the nuclear envelope) known to cause different allelic disorders including limb girdle muscular dystrophies (LGMD) and Emery-Dreifuss muscular dystrophy (EDMD). LGMDs are a heterogeneous group of disorders with progressive proximal muscle weakness in an autosomal inheritance pattern. LGMD type 1B is a disorder secondary to a mutation in the gene encoding Lamin A/C protein in the nuclear envelope. We report a heterozygous mutation (c.148C>T mutation) in the lamin A/C gene causing LGMD type 1B in a family. This mutation was previously reported to cause EDMD. Repeated muscle biopsies and using ever advancing molecular genetics assisted in establishing the diagnosis. Our case demonstrates the need for pursing investigations as cardiac involvement and sudden death is common in this group.

We report two brothers from a non-consanguineous Irish family presenting with a novel syndrome characterised by intellectual disability, facial dysmorphism, scoliosis and long QT. Their mother has a milder phenotype including long QT. X-linked inheritance was suspected. Whole exome sequencing identified a novel missense variant (c.128 A > C; p.Tyr43Ser) in NAA10 (X chromosome) as the cause of the family’s disorder. Sanger sequencing confirmed that the mutation arose de novo in the carrier mother. NAA10 encodes the catalytic subunit of the major human N-terminal acetylation complex NatA. In vitro assays for the p.Tyr43Ser mutant enzyme showed a significant decrease in catalytic activity and reduced stability compared to wild-type Naa10 protein. NAA10 has previously been associated with Ogden syndrome, Lenz microphthalmia syndrome and non-syndromic developmental delay. Our findings expand the clinical spectrum of NAA10 and suggest that the proposed correlation between mutant Naa10 enzyme activity and phenotype severity is more complex than anticipated; the p.Tyr43Ser mutant enzyme has less catalytic activity than the p.Ser37Pro mutant associated with lethal Ogden syndrome but results in a milder phenotype. Importantly, we highlight the need for cardiac assessment in males and females with NAA10 variants as both patients and carriers can have long QT.

A 47-year-old caucasian man presented with a new visual field defect. He had been diagnosed with pulmonary sarcoidosis 15 years previously on the basis of mediastinal lymph node biopsy and chest imaging consistent with stage three disease. Other than an eruption of cutaneous sarcoidosis 5 years after initial diagnosis, his disease had been quiescent on maintenance medication of prednisolone 15 mg per day and hydroxychloroquine 200 mg per day. Several attempts to wean his steroids were unsuccessful. He had a documented long-standing T-cell lymphopenia, and at the time of presentation, his lymphocyte count was 488 × 106/l (T-cells 394 × 106/l, CD4 cells 131 × 106/l). The patient was a hotel manager, had no other significant medical conditions and was a life-long non-smoker with moderate alcohol consumption. On routine annual ophthalmologic follow-up, perimetry demonstrated a new partial left superior quadrantanopia. On further questioning, the patient admitted to recent visual field problems, particularly during playing golf when he had a tendency to ‘lose’ the ball out to the left. Pre- and post-contrast magnetic resonance imaging (MRI) of brain at this time demonstrated numerous high signal foci throughout both cerebral hemispheres including a lesion of the right geniculate-striate pathway as well as the right midbrain and upper pons. There was one isolated focus of enhancement in the left cerebellar peduncle. There was no meningeal thickening or enhancement (Figure 1). Analysis of cerebrospinal fluid including oligoclonal bands was within normal limits. Visual evoked responses were also normal. Figure 1. ( a ) Axial FLAIR sequence at the level of the ventricles demonstrated punctate high signal in the deep white matter lesions of the left parietal lobe. ( b ) Axial FLAIR sequence at a higher level demonstrated further punctate high signal lesions in the right fronto-parietal deep white matter. The consensus opinion from ophthalmology, pulmonology, neurology and radiology specialities was that …

This is the case of a 42-year-old female who presented with transient dizziness. Her symptoms and signs progressed to include dysarthria, ataxia and cognitive decline over 2 years, such that she was unable to care for herself. She died 4 years after first presentation without a diagnosis. Investigations revealed a normochromic normocytic anaemia. Cerebrospinal fluid was normal. Serial computed tomography brain showed a wedge-shaped frontal infarct but no progressive changes. Examination at autopsy showed discoloration of the gray and white matter of the brain and spinal cord.Microscopy of leptomeningeal and parenchymal vessels showed they were filled with atypical B lymphocytes confined to the intravascular space with multiple infarcts in the brain, cerebellum and spinal cord. A diagnosis of intravascular B cell lymphoma was made and is discussed.

Loss of chromosome 1p/19q in oligodendrogliomas represents a powerful predictor of good prognosis. Expression of internexin (INA), a neuronal specific intermediate filament protein, has recently been proposed as a surrogate marker for 1p/19q deletion based on the high degree of correlation between both parameters in oligodendrogliomas. The aim of this study was to assess further the diagnostic utility of INA expression in a set of genetically well-characterized oligodendrogliomas. On the basis of a conservative approach for copy number determination, using both comparative genomic hybridization and fluorescent in situ hybridization, INA expression as a surrogate marker for 1p/19q loss had both reduced specificity (80%) and sensitivity (79%) compared with respective values of 86% and 96% reported in the previous report. The histologic interpretation and diagnostic value of INA expression in oligodendrogliomas should therefore be assessed with greater caution when compared with 1p/19q DNA copy number analysis. In addition, DNA copy number aberrations of chromosomes 10, 16, and 17 were detected exclusively in 1p/19q codeleted samples, suggesting that other regions of the genome may contribute to the 1p/19q-deleted tumor phenotype inthese samples.