Free Neuropathology

Northern Lights Neuroscience Symposium 2024, Meeting Abstracts, September 26–27, 2024

Scandinavian Neuropathological Society — Tue, 19 Nov 2024 00:00:00 +0100

The Northern Lights Neuroscience Symposium 2024 “Expanding Spectrum of Common Dementia Disorders” was held in Hanasaari, Helsinki (Espoo), Finland on September 26–27, 2024. The meeting was jointly organised by the Scandinavian Neuropathological Society (chair Olivera Casar-Borota) and University of Helsinki. Drs. Liisa Myllykangas (chair), Olli Tynninen, Maria Gardberg and Tuomas Rauramaa made up the organising committee.

The event brought together neuropathologists, clinicians and neuroscientists from nine different counties. In total, 91 people had registered for the meeting, and there were 29 abstracts. The keynote lectures on neuropathological and clinical aspects of new dementia entities such as LATE and PART as well as subtypes of AD and LBD, vascular and mixed patologies, were given by Irina Alafuzoff, Peter Nelson, David Wolk, Gabor Kovacs, Melissa Murray, Jacob Vogel, Liisa Myllykangas, Per Borghammer, Johannes Attems and Masafumi Ihara. The Patrick Sourander lecture “Investigating choroid plexus and cerebrospinal fluid roles and functions in neurologic disease“ was presented by Maria Lehtinen from Harvard Medical School. Seven additional oral presentations (selected from submitted abstracts) were also given.

The participants were highly appreciative of the meeting’s top level scientific content and of the networking event, which included a Finnish sauna, a cruise in the Helsinki archipelago and a dinner in the center of Helsinki.

35th Australian and New Zealand Society for Neuropathology (ANZSNP) Scientific Meeting - Meeting Abstracts, August 31st - September 1st, 2024

The Australian and New Zealand Society for Neuropathology (ANZSNP) — Mon, 18 Nov 2024 00:00:00 +0100

The ANZSNP scientific meeting 2024 was held in the scenic city of Queenstown, New Zealand on 31 August and September 1. Dr Fouzia Ziad, President of the ANZSNP and Dr Laveniya Satgunaseelan, Secretary /Treasurer of the ANZSNP were the convenors of the meeting. The meeting was co-badged with the Australasian Winter Conference on Brain Research (AWCBR) 2024. There were 55 registrants from Australia, New Zealand, USA, Europe and Asia.

The academic program covered a wide range of neuropathology topics ranging from neuro-trauma to neuro-oncology. The neuro-oncology sessions featured a series of lectures on updates in the classification and diagnosis of various CNS tumours delivered by keynote speaker Prof Arie Perry, UCSF. Dr Thomas Robertson presented an approach to frozen sections in surgical neuropathology. An interactive session on the RCPA Neuropathology Quality Assurance Program (QAP) was organised with the QAP convenor, Dr Barbara Koszyca. Prof David Capper delivered the plenary lecture on “DNA methylation profiling and its practical implications” during the combined session with AWCBR attendees. Combined sessions also featured presentations on non-neoplastic conditions such as neurotrauma and neurodegeneration, comprising of presentations from invited faculty including Prof Michael Buckland, Dr Helen Murray and Prof Glenda Halliday. Four scientific research papers and 3 interesting cases were selected for oral presentation by the scientific committee. The meeting concluded with a plenary lecture delivered by Prof Arie Perry on “Biomarkers in Neuro-oncology”.

Two of the research paper presentations were eligible for the Bill Evans Memorial award for postgraduate students or trainees. The prize was awarded to Dr Monish Maharaj for his presentation “DNA Methylation Profiling to categorise meningioma recurrence risk: optimisation of resource allocation for patient selection”.

The feedback from the participants suggested that the meeting was well organized and appreciated for its educational content.

68th Annual Meeting of the German Society of Neuropathology and Neuroanatomy (DGNN) - Meeting Abstracts, September 12–14, 2024

German Society of Neuropathology and Neuroanatomy (DGNN) — Tue, 03 Sep 2024 00:00:00 +0200

Dear colleagues,

It is my pleasure and honor to host the 68^th Annual Meeting of the German Society of Neuropathology and Neuroanatomy (DGNN) in Regensburg. Since the Magdeburg meeting in 2019 this is the first pure national meeting of our society that will be held in presence after five long years. While the meeting in 2020 was cancelled due to the Corona pandemic, the 2021 meeting (organized by the colleagues in Gießen) took place as a mere online meeting. In 2022 and 2023 our national society meetings were embedded in the “Neurowoche” and the International Congress of Neuropathology in Berlin. We are enthusiastic about this years’ reunion of our society in Regensburg.

In our Regensburg meeting, we aim to provide a comprehensive update on the major and hot topics in neuropathology. Neuropathologists address some of the currently most relevant and discussed health care issues, such as for example cancer, neuroimmunological diseases like Multiple Sclerosis, neurodegenerative diseases including Alzheimer’s and Parkinson’s, and muscle/nerve diseases. As tissue specialists, neuropathologists directly study diseases in human materials. Neuropathologists use state of-the-art methods to uncover disease processes on the molecular level. During our congress, we will hear a lot on the methodical progress made in this regard. Neuropathology is also becoming increasingly clinical as many of our scientific and diagnostic findings influence and directly guide treatment decisions.

We were able to attract renowned national and international speakers and our meeting will allow for an intensive interchange both within our society and with our neighboring disciplines. Program highlights include a Pre-Congress hands-on Workshop on Next Generation Sequencing, a session on Molecular Tumorboards and a Mini-Symposium on Quality Assurance in Neuropathology.

We are delighted about the submission of 31 abstracts covering the research fields Neurooncology, Neuroimmunology, Muscle/Nerve, Neurodegeneration, and Methods/Free Topics. The abstracts are published below in this edition of Free Neuropathology. I want to thank the scientific committee of our congress for helping in evaluating the submissions and selecting the poster talks and poster spotlight presentations. Many of the abstracts were submitted by our young researchers. They deserve our special attention! Posters will be exhibited throughout the entire congress and we will have plenty of time for poster viewing and discussions on Thursday evening at the Welcome Reception and at the main poster session on Friday at noon.

So let me again welcome you all to our beautiful city of Regensburg. I am looking forward to inspiring talks, vivid discussions and enriching encounters with like-minded people.

Yours,

Prof. Dr. Markus J. Riemenschneider

Regensburg University Hospital, Department of Neuropathology

Congress President DGNN Annual Meeting 2024

Assessment of intraepidermal nerve fiber densities in 5 µm sections from arm and leg – a search for normative age-related values

Linnéa Ekman, Lars B. Dahlin, Elisabet Englund — Fri, 11 Oct 2024 00:00:00 +0200

Background and aims: Normative values are lacking regarding intraepidermal nerve fiber density (IENFD) in thin sections of 5 µm. Thus, we aimed to assess IENFD in thin sections in a healthy adult population as well as to investigate whether IENFD is related to age, sex, and site of excision.

Methods: Archival skin biopsies or excisions at the Department of Pathology, Lund, Sweden, from arm and leg were collected, re-sectioned, and immunohistochemically stained for Protein Gene Product 9.5 during 2020–2023. Nerve fibers were manually quantified in the 5 µm thin sections, and IENFD was compared between age groups, sex, and excision sites.

Results: IENFDs were evaluated in 602 samples from 591 healthy adults aged 18 to 97 years (295 women, 296 men). Median IENFD values are presented, stratified by age groups, sex, and excision sites. Higher IENFD was observed in the arm compared to the leg, as well as in the proximal compared to the distal leg, however not across all age groups. Levels of IENFD were lower among older adults, compared to all younger groups.

Conclusion: We have presented data on IENFD in thin 5 µm sections from a healthy adult population. Despite differences in IENFD observed across age groups, sexes, and excision sites, no strong conclusions regarding affecting factors could be drawn except that individuals > 65 years present with lower IENFD. Additional research and development of the method are warranted.

Fast-track neuropathological screening for neurodegenerative diseases

Tue, 06 Aug 2024 00:00:00 +0200

Background: The postmortem diagnostic of individuals having suffered presumptive neurodegenerative disease comprises exclusion of a prion disease, extensive brain sampling and histopathological evaluation, which are resource-intensive and time consuming. To exclude prion disease and to achieve prompt accurate preliminary diagnosis, we developed a fast-track procedure for the histopathological assessment of brains from patients with suspected neurodegenerative disease.

Methods: Based on the screening of two brain regions (frontal cortex and cerebellum) with H&E and six immunohistochemical stainings in 133 brain donors, a main histopathological diagnosis was established and compared to the final diagnosis made after a full histopathological work-up according to our brain bank standard procedure.

Results: In over 96 % of cases there was a concordance between the fast-track and the final main neuropathological diagnosis. A prion disease was identified in four cases without prior clinical suspicion of a prion infection.

Conclusion: The fast-track screening approach relying on two defined, easily accessible brain regions is sufficient to obtain a reliable tentative main diagnosis in individuals with neurodegenerative disease and thus allows for a prompt feedback to the physicians. However, a more thorough histological work-up taking into account the clinical history and the working diagnosis from fast-track screening is necessary for accurate staging and for assessment of co-pathologies.

Stem cell-associated transcription factors in non-functioning pituitary neuroendocrine tumours

Thu, 06 Jun 2024 00:00:00 +0200

Background: Cells with stem cell features have been described in pituitary neuroendocrine tumours (PitNETs). Transcription factors SOX2 and SOX9 are stem cell-associated markers while the pituitary progenitor marker PROP1 is involved in anterior pituitary development. We characterised the presence of these markers known to be present in the human pituitary in non-functioning (NF) PitNETs.

Methods: We investigated the pituitary transcription factors SOX2, SOX9 and PROP1 by immunohistochemistry (IHC) (N = 125) and RT-qPCR (N = 78) in a retrospective cohort of clinically NF-PitNETs. The markers were scored based on the percentage of immunolabeled cells. IHC staining scores were compared to reintervention rates for the whole cohort, and to expression of FSH, LH or ER in gonadotroph NF-PitNETs.

Results: Most tumours showed no or few cells positive for SOX2, SOX9 and PROP1. More patients with SOX2-negative tumours went through reintervention (40 % vs 19 %, p = 0.03).
SOX2, SOX9 and PROP1 staining correlated positively to each other (SOX2 and SOX9 r_s= 0.666, SOX2 and PROP1 r_s= 0.704, SOX9 and PROP1 r_s= 0.570, and p < 0.001 for all).
In gonadotroph NF-PitNETs, staining for SOX2 and PROP1 was positively associated to FSHβ staining (p < 0.001 for both). Staining for SOX2, SOX9 and PROP1 was positively associated with gene expression of Estrogen Receptor 1 (ESR1) (p < 0.001, p = 0.004 and p < 0.001) and IHC staining for ERα (p = 0.001, p = 0.03 and p = 0.05, respectively).

Conclusion: SOX2, SOX9 and PROP1 were present at low levels in NF-PitNETs. Absence of SOX2 staining was associated with a higher reintervention rate. The stem cell markers correlated positively with markers of gonadotroph differentiation in gonadotroph NF-PitNETs. SOX2 and SOX9 were frequently coexpressed and showed positivity in intratumoural cells with epithelial features, however without coexpression of pituitary transcription factors.

Heterogeneity of DNA methylation profiles and copy number alterations in 10782 adult-type glioblastomas, IDH-wildtype

Fri, 22 Mar 2024 00:00:00 +0100

The morphological patterns leading to the diagnosis of glioblastoma may also commonly be observed in several other distinct tumor entities, which can result in a mixed bag of tumors subsumed under this diagnosis. The 2021 WHO Classification of CNS Tumors has separated several of these entities from the diagnosis of glioblastoma, IDH-wildtype. This study determines the DNA methylation classes most likely receiving the diagnosis glioblastoma, IDH wildtype according to the definition by the WHO 2021 Classification and provides comparative copy number analyses.

We identified 10782 methylome datasets uploaded to the web page www.molecularneuropathology.org with a calibrated score of ≥0.9 by the Heidelberg Brain Tumor Classifier version v12.8. These methylation classes were characterized by the diagnosis glioblastoma being the most frequent classification encountered in each of the classes according to the WHO 2021 definition. Further, methylation classes selected for this study predominantly contained adult patients.

Unsupervised clustering confirmed the presence of nine methylation classes containing tumors most likely receiving the diagnosis glioblastoma, IDH-wildtype according to the WHO 2021 definition. Copy number analysis and a focus on genes with typical numerical alterations in glioblastoma revealed clear differences between the nine methylation classes. Although great progress in diagnostic precision has been achieved over the last decade, our data clearly demonstrate that glioblastoma, IDH-wildtype still is a heterogeneous group in need of further stratification.

Blocking TGF-β- and Epithelial-to-Mesenchymal Transition (EMT)-mediated activation of vessel-associated mural cells in glioblastoma impacts tumor angiogenesismor angiogenesis

Fri, 01 Mar 2024 00:00:00 +0100

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. GBM displays excessive and unfunctional vascularization which may, among others, be a reason for its devastating prognosis. Pericytes have been identified as the major component of the irregular vessel structure in GBM. In vitro data suggest an epithelial-to-mesenchymal transition (EMT)-like activation of glioma-associated pericytes, stimulated by GBM-secreted TGF-β, to be involved in the formation of a chaotic and dysfunctional tumor vasculature. This study investigated whether TGF-β impacts the function of vessel associated mural cells (VAMCs) in vivo via the induction of the EMT transcription factor SLUG and whether this is associated with the development of GBM-associated vascular abnormalities. Upon preventing the TGF-β-/SLUG-mediated EMT induction in VAMCs, the number of PDGFRβ and αSMA positive cells was significantly reduced, regardless of whether TGF-β secretion by GBM cells was blocked or whether SLUG was specifically knocked out in VAMCs. The reduced amount of PDGFRβ⁺ or αSMA⁺ cells observed under those conditions correlated with a lower vessel density and fewer vascular abnormalities. Our data provide evidence that the SLUG-mediated modulation of VAMC activity is induced by GBM-secreted TGF-β and that activated VAMCs are key contributors in neo-angiogenic processes. We suggest that a pathologically altered activation of GA-Peris in the tumor microenvironment is responsible for the unstructured tumor vasculature. There is emerging evidence that vessel normalization alleviates tumor hypoxia, reduces tumor-associated edema and improves drug delivery. Therefore, avoiding the generation of an unstructured and non-functional tumor vasculature during tumor recurrence might be a promising treatment approach for GBM and identifies pericytes as a potential novel therapeutic target.

Cellular activation patterns of CD10+ fibro-adipogenic progenitors across acquired disease states in human skeletal muscle biopsies

Peter W. Schutz, Simon Cheung, Lin Yi, Fabio M. V. Rossi — Fri, 09 Feb 2024 00:00:00 +0100

Background: Fibro-adipogenic progenitors (FAP) are muscle resident mesenchymal stem cells pivotal for regulation of myofiber repair. Experimental results show in addition involvement in a range of other pathological conditions and potential for pharmacological intervention. FAP histopathology in human muscle biopsies is largely unknown, but has potential to inform translational research.

Methods: CD10+ FAPs in 32 archival muscle biopsies from 8 groups (normal, dermatomyositis, inclusion body myositis (IBM), anti-synthetase syndrome, immune-mediated necrotizing myopathy (IMNM), denervation, type 2 atrophy, rhabdomyolysis) were visualized by CD10 immunohistochemistry and their histology compared. Groups are compared by semi-quantitative scoring.

Results: Histological activation of endomysial CD10+ FAPs includes prominent expansion of a network of cell processes surrounding muscle fibers, as well as endomysial cell clusters evidencing proliferation. Prominence of periarteriolar processes is a notable feature in some pathologies. FAP activation is often associated with fiber degeneration/regeneration, foci of inflammation, and denervation in keeping with experimental results. Type 2 atrophy shows no evidence of FAP activation. Dermatomyositis and anti-synthetase syndrome associated myositis demonstrate diffuse activation.

Conclusion: Assessment of CD10+ FAP activation is routinely possible using CD10 immunohistochemistry and demonstrates several patterns in keeping with preclinical results. Prominent expansion of FAP processes surrounding myofibers suggests enhanced interaction between myofiber/basement membranes and FAPs during activation. The presence of diffuse FAP activation in dermatomyositis biopsies unrelated to fiber repair raises the possibility of FAP activation as part of the autoimmune process. Future diagnostic applications, clinical significance and therapeutic potential remain to be elucidated.

Deep RNA sequencing of muscle tissue reveals absence of viral signatures in dermatomyositis

Thu, 04 Jan 2024 00:00:00 +0100

Objective: To explore a possible connection between active viral infections and manifestation of Dermatomyositis (DM).

Methods: Skeletal muscle biopsies were analyzed from patients diagnosed with juvenile (n=10) and adult (n=12) DM. Adult DM patients harbored autoantibodies against either TIF-1γ (n=7) or MDA5 (n=5). Additionally, we investigated skeletal muscle biopsies from non-diseased controls (NDC, n=5). We used an unbiased high-throughput sequencing (HTS) approach to detect viral sequences. To further increase sequencing depth, a host depletion approach was applied.

Results: In this observational study, no relevant viral sequences were detected either by native sequencing or after host depletion. The absence of detectable viral sequences makes an active viral infection of the muscle tissue unlikely to be the cause of DM in our cohorts.

Discussion: Type I interferons (IFN) play a major role in the pathogenesis of both juvenile and adult dermatomyositis (DM). The IFN response is remarkably conserved between DM subtypes classified by specific autoantibodies. Certain acute viral infections are accompanied by a prominent type I IFN response involving similar downstream mechanisms as in DM. Aiming to elucidate the pathogenesis of DM in skeletal muscle tissue, we used an untargeted high-throughput sequencing and a host depletion approach to detect possible causative viruses.

A hobby neuropathologist from Far East resides in Western Europe

Akira Hori — Tue, 16 Apr 2024 00:00:00 +0200

Glioneuronal heterotopia in the right middle cranial fossa

Tue, 12 Nov 2024 00:00:00 +0100

Infantile pilocytic astrocytoma with persisting external granular layer of the cerebellum: a potential diagnostic pitfall

Arnault Tauziède-Espariat; Lauren Hasty; Alice Métais, Pascale Varlet — Mon, 21 Oct 2024 00:00:00 +0200

YAP1 fusion-positive ependymoma presenting in an adult with a pigmented phenotype and association with superficial siderosis

Mon, 07 Oct 2024 00:00:00 +0200

Striking intraneuronal neurofilament inclusions restricted to the locus coeruleus in a patient with Creutzfeldt-Jakob disease

Felix Leitner, Sigrid Klotz, Karoline Ornig, Serge Weis, Ellen Gelpi — Wed, 02 Oct 2024 00:00:00 +0200

Cell-in-cell phenomena of intracellular neutrophils in a recurrent pleomorphic xanthoastrocytoma

Thu, 08 Aug 2024 00:00:00 +0200

We describe a case of a young patient with a recurrent pleomorphic xanthoastrocytoma (PXA) showing unusual cell-in-cell (CiC) phenomena. We observed mostly viable but also necrotic neutrophils engulfed within tumor cells. The recurrent tumor was immunopositive for BRAFV600E mutant protein and showed CDKN2 homozygous deletions typical of PXA. Both genetic alterations were also reported in the original primary tumor. Unlike the original tumor that was GFAP and Olig-2 immunopositive, the recurrent neoplasm was largely negative for GFAP and Olig-2 suggesting dedifferentiation. The large malignant cells that contained the neutrophils were negative for histiocytic and lymphohematopoietic markers. Whereas CDKN2 homozygous deletion is common in PXA, its presence is rare in histiocytic neoplasms. Both reactive astrocytes and glial neoplasms very rarely may engulf neutrophils in a process resembling emperipolesis or cellular cannibalism. Future work may clarify which type of CiC pathway is involved.

The presence of shrunken neurons with pyknotic nuclei in the dentate nucleus is a common postmortem change associated with autolysis of the cerebellar granular cell layer

Bilge Dundar, Busranur Agac, Eyas Alzayadneh, Randy Tashjian, Kyle Conway — Fri, 24 May 2024 00:00:00 +0200

Brainstem inflammation in sudden unexpected death in infancy and childhood (SIDS/SUDC)

Herbert Budka, Daniele U. Risser, Fabio C. Monticelli — Fri, 03 May 2024 00:00:00 +0200

Searching for a cut-off point for p53 immunohistochemistry as evidence of TP53 mutations

Tue, 12 Mar 2024 00:00:00 +0100

Pituitary adenoma classification: Tools to improve the current system

William C. McDonald — Wed, 10 Jan 2024 00:00:00 +0100

The World Health Organization classification of pituitary tumors provides a framework for pathologists and researchers to classify pituitary adenomas. From the perspective of a practicing pathologist, this classification can be improved by pooling immunohistochemical data in a more standardized way, and by deliberately distinguishing features that assist in classification from those that do not. This article illustrates one general workflow to examine classification features consisting of immunohistochemical stains for anterior pituitary tumors, in order to promote debate and advance an evidence-based framework for classification.

An optimized filter trap assay for detecting recombinant authentic tau fibrils

Allison R. Balaj, Thomas L. Rothstein, Hiroaki Kaku — Fri, 02 Aug 2024 00:00:00 +0200

The development and optimization of the Filter Trap Assay (FTA) for the detection of authentic tau fibrils in vitro mark a pivotal advancement in the realm of tauopathy research, particularly by addressing the limitations of using polyanion-induced tau fibrils, which structurally differ from those isolated from tauopathy patients. Recently it has been shown that truncated tau fragment (297-391), also termed dGAE, can form authentic tau fibrils in the absence of polyanions. This study introduces a refined protocol that reliably detects authentic tau fibrils in a physiologically relevant framework, utilizing nitrocellulose membranes to achieve heightened sensitivity. Our investigation highlights the superior efficacy of sarkosyl, an anionic surfactant traditionally used to prepare protein lysates from brains and cultured neurons, in preserving the aggregated state of tau dGAE fibrils in vitro, underscoring its potential for further exploratory studies. By offering a user-friendly and economically feasible approach, this technique enables a broad range of laboratories to measure the presence of authentic tau fibrils. This methodological enhancement propels our understanding of tauopathies forward and bridges the gap between basic research and advanced structural analyses, enriching the scientific community's methodologies for studying neurodegenerative disorders.

Regression of multiple intracranial meningiomas after cessation of long-term synthetic progesterone (megestrol) medication: case report and autopsy

Tamadar A. AlDoheyan, Marc R. Del Bigio — Tue, 29 Oct 2024 00:00:00 +0100

We report the history of a woman who developed four intracranial meningiomas during 11 years of therapy with the synthetic progesterone agonist megestrol. After discontinuation of the drug at age 75 years, she improved clinically and a CT scan showed near complete regression of the meningiomas by 78 years. Autopsy was performed at 83 years of age following an accidental death. At the tumor sites, we found both collagenous tissue with small islands of low grade meningioma having strong nuclear immunoreactivity for progesterone receptor and lipomatous tissue. A literature review showed similar cases of radiologic meningioma regression following discontinuance of progestins. Our case is the first one with histopathologic characterization of the end point.

Mesial temporal lobe epilepsy and hippocampal sclerosis associated with BRAFV600E mutant neurons in the Cornu Ammonis: an uncertain pathogenesis and a diagnostic challenge

Wed, 21 Aug 2024 00:00:00 +0200

Mesial temporal lobe epilepsy (MTLE) is a common cause of seizures, and hippocampal sclerosis (HS) is the predominant subtype. BRAFV600E mutations in MTLE-HS have only been reported infrequently. Herein, we illustrate the neurologic, radiological, and histopathological details of a patient with MTLE-HS and BRAFV600E mutant neurons. A 31-year-old male with medically refractory epilepsy presented with magnetic resonance imaging (MRI) and electroencephalography (EEG) findings typical of mesial temporal sclerosis without a mass lesion. The surgical specimens showed ILAE Type 1 HS with neurons immunopositive for BRAFV600E mutant protein distributed along the Cornu Ammonis (CA) curvature. Instead of the normal mostly perpendicular orientation of pyramidal neurons relative to the hippocampal surface, the BRAF mutant neurons were often oriented in a parallel manner. On CD34 immunostaining, sparse clusters or nodules of CD34+ stellate cells and single immunopositive stellate cells were identified. BRAFV600E or CD34 immunopositive cells were less than 1 % of total cells. The patient responded well to surgery with no further seizures after 2 years and occasional auras. Hippocampal BRAF mutant non-expansive lesion (HBNL) has been used to describe such lesions with preserved cytoarchitecture and without overt tumor mass. Others may argue for the dual pathology of HS with early ganglioglioma. Whether pre-neoplastic lesions or early tumors, these cases are important for understanding early glioneuronal tumorigenesis and suggest that BRAFV600E studies should be routinely performed on MTLE-HS cases in the setting of clinical trials. With next-generation sequencing, a FANCL deletion was detected in almost half of the alleles in our case, suggesting that many of the histologically normal-appearing cells of the hippocampus contain this alteration. FANCL mutations can result in cytogenetic anomalies and defective DNA repair and therefore may underlie the development of a low frequency BRAF alteration.

Malignant glioma in L-2-Hydroxy Glutaric Aciduria: thorough molecular characterization of a case and literature review

Fri, 03 May 2024 00:00:00 +0200

L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare neurometabolic disorder characterized by accumulation of L2-hydroxyglutarate (L-2-HG) due to mutations in the L2HGDH gene. L-2-HGA patients have a significantly increased lifetime risk of central nervous system (CNS) tumors. Here, we present a 16-year-old girl with L-2-HGA who developed a tumor in the right cerebral hemisphere, which was discovered after left-sided neurological deficits of the patient. Histologically, the tumor had a high-grade diffuse glioma phenotype. DNA sequencing revealed the inactivating homozygous germline L2HGDH mutation as well as inactivating mutations in TP53, BCOR and NF1. Genome-wide DNA-methylation analysis was unable to classify the tumor with high confidence. More detailed analysis revealed that this tumor clustered amongst IDH-wildtype gliomas by methylation profiling and did not show the glioma CpG island methylator phenotype (G-CIMP) in contrast to IDH-mutant diffuse gliomas with accumulated levels of D-2-HG, the stereoisomer of L-2-HD. These findings were against all our expectations given the inhibitory potential of 2-HG on DNA-demethylation enzymes. Our final integrated histomolecular diagnosis of the tumor was diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype. Due to rapid tumor progression the patient died nine months after initial diagnosis. In this manuscript, we provide extensive molecular characterization of the tumor as well as a literature review focusing on oncogenetic considerations of L-2-HGA-associated CNS tumors.

Neurotrauma: 2024 update

David S. Priemer, Daniel P. Perl — Wed, 23 Oct 2024 00:00:00 +0200

2023 was an important year for research in traumatic brain injury (TBI), particularly as it concerned interests in neuropathology. After reviewing the literature, we present the advancements that we felt were of particular importance to the neuropathology community. Highlighted are articles that report upon: (1) the first large-cohort assessment for the neuropathology of intimate partner violence, (2) the assessment of chronic traumatic encephalopathy (CTE) in young athletes, (3) the observation of cortical sulcal depth vascular changes in CTE, (4) a proposal for a tau immunohistochemical panel to evaluate complex cases of CTE in the context of multiple tauopathies, (5) the relationship of TBI and/or CTE with TDP-43 pathology, (6) repetitive TBI inducing pathology in C9orf72-transgenic mice, (7) radiologic patterns of head and neck injury following vehicular underbody blast exposure, (8) chronic alterations in brain metal content following repetitive impact TBI, (9) neurovascular unit injury following low-level blast exposure, and finally (10) an assessment of Muhammad Ali’s clinical history leading to the conclusion that he suffered from young-onset, idiopathic Parkinson Disease. We close our writing with in memoriam to Dr. Byron A. Kakulas, a renowned figure in the neuropathology of spinal cord injury who we lost in 2023.

Neurodevelopmental disorders: 2024 update

María Martínez de Lagrán, Karen Bascón-Cardozo , Mara Dierssen — Thu, 05 Sep 2024 00:00:00 +0200

Neurodevelopmental disorders encompass a range of conditions such as intellectual disability, autism spectrum disorder, rare genetic disorders and developmental and epileptic encephalopathies, all manifesting during childhood. Over 1,500 genes involved in various signaling pathways, including numerous transcriptional regulators, spliceosome elements, chromatin-modifying complexes and de novo variants have been recognized for their substantial role in these disorders. Along with new machine learning tools applied to neuroimaging, these discoveries facilitate genetic diagnoses, providing critical insights into neuropathological mechanisms and aiding in prognosis, and precision medicine. Also, new findings underscore the importance of understanding genetic contributions beyond protein-coding genes and emphasize the role of RNA and non-coding DNA molecules but also new players, such as transposable elements, whose dysregulation generates gene function disruption, epigenetic alteration, and genomic instability. Finally, recent developments in analyzing neuroimaging now offer the possibility of characterizing neuronal cytoarchitecture in vivo, presenting a viable alternative to traditional post-mortem studies. With a recently launched digital atlas of human fetal brain development, these new approaches will allow answering complex biological questions about fetal origins of cognitive function in childhood. In this review, we present ten fascinating topics where major progress has been made in the last year.

Neurooncology: 2024 update

Michel Mittelbronn — Fri, 27 Sep 2024 00:00:00 +0200

As in previous years, including 2023, a major focus in the neurooncological area of neuropathology was put on more precise and constantly faster diagnostic procedures, even reaching the level of ultra-fast intraoperative diagnostics based on methylation profiling. Neuropathological diagnostic precision and clinical follow-up treatment has been further increased by combining DNA methylation profiling with targeted panel sequencing. A few new, molecularly defined tumor subtypes have been proposed, among others, a glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (in its abbreviated form named GTAKA) and the de novo replication repair deficient glioblastoma, IDH-wildtype both having either distinct prognostic or therapeutic implications. Regarding the understanding of brain tumor development and progression, several novel mechanisms have been presented which might also be considered as treatment targets in the future, such as a) autonomous rhythmical Ca²⁺ oscillations in interconnected glioma cell networks driving tumor growth; b) transfer of mitochondria from normal astrocytes to glioma cells enhancing proliferation and self-renewal; c) brain endothelial cell remodeling upon matrix-metalloprotease 9 secretion by tumor cells metastasizing into the CNS and d) anti-tumor activity of microglia in CNS metastasis of breast cancer. Finally, in contrast to previous years, several very promising neurooncological treatment studies have been conducted, focusing on specific targets such as H3K27M or IDH1/2 mutations for which a proper neuropathological assessment is key. The continuous translation of potential new treatment targets using faster and precise diagnostic procedures will further pave the way for better individualized clinical care of neurooncological patients.

Fluid preservation in brain banking: a review

Tue, 23 Apr 2024 00:00:00 +0200

Fluid preservation is nearly universally used in brain banking to store fixed tissue specimens for future research applications. However, the effects of long-term immersion on neural circuitry and biomolecules are not well characterized. As a result, there is a need to synthesize studies investigating fluid preservation of brain tissue. We searched PubMed and other databases to identify studies measuring the effects of fluid preservation in nervous system tissue. We categorized studies based on the fluid preservative used: formaldehyde solutions, buffer solutions, alcohol solutions, storage after tissue clearing, and cryoprotectant solutions. We identified 91 studies containing 197 independent observations of the effects of long-term storage on cellular morphology. Most studies did not report any significant alterations due to long-term storage. When present, the most frequent alteration was decreased antigenicity, commonly attributed to progressive crosslinking by aldehydes that renders biomolecules increasingly inaccessible over time. To build a mechanistic understanding, we discuss biochemical aspects of long-term fluid preservation. A subset of lipids appears to be chemical altered or extracted over time due to incomplete retention in the crosslinked gel. Alternative storage fluids mitigate the problem of antigen masking but have not been extensively characterized and may have other downsides. We also compare fluid preservation to cryopreservation, paraffin embedding, and resin embedding. Overall, existing evidence suggests that fluid preservation provides maintenance of neural architecture for decades, including precise structural details. However, to avoid the well-established problem of overfixation caused by storage in high concentration formaldehyde solutions, fluid preservation procedures can use an initial fixation step followed by an alternative long-term storage fluid. Further research is warranted on optimizing protocols and characterizing the generalizability of the storage artifacts that have been identified.

Neuropathology and epilepsy surgery – 2024 update

Ingmar Blümcke — Fri, 22 Mar 2024 00:00:00 +0100

Neuropathology-based studies in neurosurgically resected brain tissue obtained from carefully examined patients with focal epilepsies remain a treasure box for excellent insights into human neuroscience, including avenues to better understand the neurobiology of human brain organization and neuronal hyperexcitability at the cellular level including glio-neuronal interaction. It also allows to translate results from animal models in order to develop personalized treatment strategies in the near future. A nice example of this is the discovery of a new disease entity in 2017, termed mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy or MOGHE, in the frontal lobe of young children with intractable seizures. In 2021, a brain somatic missense mutation of the galactose transporter SLC35A2 leading to altered glycosylation of lipoproteins in the Golgi apparatus was detected in 50 % of MOGHE samples. In 2023, the first clinical trial evaluated galactose supplementation in patients with histopathologically confirmed MOGHE carrying brain somatic SLC35A2 mutations that were not seizure free after surgery. The promising results of this pilot trial are an example of personalized medicine in the arena of epileptology. Besides this, neuropathological studies of epilepsy samples have revealed many other fascinating results for the main disease categories in focal epilepsies, such as the first deep-learning based classifier for Focal Cortical Dysplasia, or the genomic landscape of cortical malformations showing new candidate genes such as PTPN11, which is associated with ganglioglioma and adverse clinical outcome. This update will also ask why common pathogenic variants accumulate in certain brain regions, e.g., MTOR in the frontal lobe, and BRAF in the temporal lobe. Finally, I will highlight the ongoing discussion addressing commonalities between temporal lobe epilepsy and Alzheimer's disease, the impact of adult neurogenesis and gliogenesis for the initiation and progression of temporal lobe seizures in the human brain as well as the immunopathogenesis of glutamic acid decarboxylase antibody associated temporal lobe epilepsy as a meaningful disease entity. This review will update the reader on some of these fascinating publications from 2022 and 2023 which were selected carefully, yet subjectively, by the author.

HIV and COVID-19: two pandemics with significant (but different) central nervous system complications

Tue, 05 Mar 2024 00:00:00 +0100

Human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause significant neurologic disease. Central nervous system (CNS) involvement of HIV has been extensively studied, with well-documented invasion of HIV into the brain in the initial stage of infection, while the acute effects of SARS-CoV-2 in the brain are unclear. Neuropathologic features of active HIV infection in the brain are well characterized whereas neuropathologic findings in acute COVID-19 are largely non-specific. On the other hand, neuropathologic substrates of chronic dysfunction in both infections, as HIV-associated neurocognitive disorders (HAND) and post-COVID conditions (PCC)/long COVID are unknown. Thus far, neuropathologic studies on patients with HAND in the era of combined antiretroviral therapy have been inconclusive, and autopsy studies on patients diagnosed with PCC have yet to be published. Further longitudinal, multidisciplinary studies on patients with HAND and PCC and neuropathologic studies in comparison to controls are warranted to help elucidate the mechanisms of CNS dysfunction in both conditions.