Free Neuropathology <p><em>Free Neuropathology</em> is a non-commercial journal that is run by Neuropathologists and other Neuroscientists and publishes papers on Human and Experimental Neuropathology. It is free for authors, free for readers, free from publishers, free from excessive formalities, and it encourages exchange of free opinions.</p> <p><em>Free Neuropathology</em> is not just another open-access online journal. It is a new type of journal edited and published by scientists working in the field. We do not have any financial interests, and we strongly feel that the huge amount of money currently spent for increasing the profit of publishers should be better invested into science. We believe that the usual activities of publishers such as copyediting, layout, hosting of articles, maintenance of the website and promotion could and should be overtaken by scientists in order to restitute scientific freedom. There is no article processing fee and no paywall -- the journal is free for everyone ("Diamond Open Access"). We try to reduce technicalities to a minimum. This grassroots development is managed by enthusiastic neuroscientists and it may be the future of publishing.</p> en-US Free Neuropathology 2699-4445 <p>Papers are published open access under the Creative Commons BY 4.0 license.&nbsp;This license lets others distribute, remix, adapt, and build upon your work, even commercially, as long as they credit you for the original creation. Data included in the article are made available under the CC0 1.0 Public Domain Dedication waiver, unless otherwise stated, meaning that all copyrights are waived.</p> An atypical teratoid/rhabdoid tumor (AT/RT) with molecular features of pleomorphic xanthoastrocytoma (PXA) in a 62-year-old patient <p>Atypical teratoid/rhabdoid tumors (AT/RT) are aggressively growing malignant embryonal neoplasms of the central nervous system (CNS), which mainly affect young children. Loss of SMARCB1/INI1 (or SMARCA4 in rare cases) is recognized as the genetic hallmark of AT/RTs and these tumors can be distinguished into three distinct DNA-methylation based molecular subgroups (i.e. -MYC, -SHH and -TYR). While most AT/RTs are considered to occur de novo, previous studies have recognized secondary SMARCB1/INI1-deficient rhabdoid tumors arising from other low grade CNS tumors in young patients. Three AT/RTs, which harbor epigenetic and mutational characteristics of pleomorphic xanthoastrocytoma (PXA), while being entirely void of nuclear SMARCB1/INI1 expression, were recently described in older children. We here report the first case of an AT/RT with molecular features of PXA in a senior patient. </p> Matthias Dottermusch Ali Alomari Nesrin Uksul Ulrich J. Knappe Julia E. Neumann Copyright (c) 2021 Matthias Dottermusch, Ali Alomari, Nesrin Uksul, Ulrich J. Knappe, Julia E. Neumann 2021-11-15 2021-11-15 2 31 31 10.17879/freeneuropathology-2021-3640 The Multifaceted Appearance of Supratentorial Ependymoma with ZFTA-MAML2 Fusion <p>Ependymomas are glial neoplasms with a wide morphological spectrum. The majority of supratentorial ependymomas are known to harbor <em>ZFTA </em>fusions, most commonly to <em>RELA</em>. We present an unusual case of a 9-year-old boy with a supratentorial ependymoma harboring a noncanonical <em>ZFTA-MAML2 </em>fusion. This case had unusual histomorphological features lacking typical findings of ependymoma and bearing resemblance to a primitive neoplasm with focal, previously undescribed myogenic differentiation. We discuss the diagnostic pitfalls in this case and briefly review the histological features of ependymoma with noncanonical gene fusions. Our report underscores the importance of molecular testing in such cases to arrive at the correct diagnosis. Supratentorial ependymomas with noncanonical fusions are rare, and more studies are necessary for better risk stratification and identification of potential treatment targets.</p> Ming Liang Oon Lutfi Hendriansyah Patricia Diana Pratiseyo Eka Wahjoepramono Jian Yuan Goh Chik Hong Kuick Kenneth TE Chang Arie Perry Char Loo Tan Copyright (c) 2021 Ming Liang Oon, Lutfi Hendriansyah, Patricia Diana Pratiseyo, Eka Wahjoepramono, Jian Yuan Goh, Chik Hong Kuick, Kenneth TE Chang, Arie Perry, Char Loo Tan 2021-09-20 2021-09-20 2 24 24 10.17879/freeneuropathology-2021-3397 Hydrophilic polymer embolism identified in brain tumor specimens following Wada testing: A report of 2 cases <p>Hydrophilic polymers are commonly used as coatings on intravascular medical devices. As intravascular pro-cedures continue to increase in frequency, the risk of embolization of this material throughout the body has become evident. These emboli may be discovered incidentally but can result in serious complications includ-ing death. Here, we report the first two cases of hydrophilic polymer embolism (HPE) identified on brain tu-mor resection following Wada testing. One patient experienced multifocal vascular complications and diffuse cerebral edema, while the other had an uneventful postoperative course. Wada testing is frequently per-formed during preoperative planning prior to epilepsy surgery or the resection of tumors in eloquent brain regions. These cases demonstrate the need for increased recognition of this histologic finding to enable fur-ther correlation with clinical outcomes.</p> Vanessa S. Goodwill Michael G. Brandel Jeffrey A. Steinberg Thomas L. Beaumont Lawrence A. Hansen Copyright (c) 2021 Vanessa S. Goodwill, Michael G. Brandel, Jeffrey A. Steinberg, Thomas L. Beaumont, Lawrence A. Hansen 2021-09-02 2021-09-02 2 23 23 10.17879/freeneuropathology-2021-3457 Association of acute disseminated encephalomyelitis (ADEM) and COVID-19 in a pediatric patient <p>Cases of acute disseminated encephalomyelitis (ADEM) and its hyperacute form, acute hemorrhagic leukoencephalitis (AHLE), have been reported in coronavirus disease 2019 (COVID-19) patients as rare, but most severe neurological complications. However, histopathologic evaluations of ADEM/AHLE pathology in COVID patients are extremely limited, so far having only been reported in a few adult autopsy cases. Here we compare the findings with an ADEM-like pathology in a pediatric patient taken through a biopsy procedure. Understanding the neuropathology may shed informative light on the autoimmune process affecting COVID-19 patients and provide critical information to guide the clinical management.</p> Liam Chen Copyright (c) 2021 Liam Chen 2021-07-12 2021-07-12 2 19 19 10.17879/freeneuropathology-2021-3388 Molecular clarification of brainstem astroblastoma with EWSR1-BEND2 fusion in a 38-year-old man <p>The majority of astroblastoma occur in a cerebral location in children and young adults. Here we describe the unusual case of a 38-year-old man found to have a rapidly growing cystic enhancing circumscribed brainstem tumor with high grade histopathology classified as astroblastoma, <em>MN1</em>-altered by methylome profiling. He was treated with chemoradiation and temozolomide followed by adjuvant temozolomide without progression to date over one year from treatment initiation. Astroblastoma most frequently contain a <em>MN1-BEND2 </em>fusion, while in this case a rare <em>EWSR1-BEND2</em> fusion was identified. Only a few such fusions have been reported, mostly in the brainstem and spinal cord, and they suggest that <em>BEND2</em>, rather than <em>MN1</em>, may have a more critical functional role, at least in these regions. This unusual clinical scenario exemplifies the utility of methylome profiling and assessment of gene fusions in tumors of the central nervous system.</p> Matthew A. Smith-Cohn Zied Abdullaev Kenneth D. Aldape Martha Quezado Marc K. Rosenblum Chad M. Vanderbilt Fausto J. Rodriguez John Laterra Charles G. Eberhart Copyright (c) 2021 Matthew A Smith-Cohn, Zied Abdullaev, Kenneth D. Aldape, Martha Quezado, Marc K. Rosenblum, Chad M. Vanderbilt, Fausto J. Rodriguez, John Laterra, Charles G. Eberhart 2021-06-21 2021-06-21 2 16 16 10.17879/freeneuropathology-2021-3334 Desmoplastic myxoid tumor of pineal region, SMARCB1-mutant, in young adult <p>We present a young adult woman who developed a myxoid tumor of the pineal region having a <em>SMARCB1</em> mutation, which was phenotypically similar to the recently described desmoplastic myxoid, <em>SMARCB1</em>-mutant tumor of the pineal region (DMT-SMARCB1). The 24-year-old woman presented with headaches, nausea, and emesis. Neuroimaging identified a hypodense lesion in CT scans that was T<sub>1</sub>-hypointense, hyperintense in both T<sub>2</sub>-weighted and FLAIR MRI scans, and displayed gadolinium enhancement. The resected tumor had an abundant, Alcian-blue positive myxoid matrix with interspersed, non-neoplastic neuropil-glial-vascular elements. It immunoreacted with CD34 and individual cells for EMA. Immunohistochemistry revealed loss of nuclear INI1 expression by the myxoid component but its retention in the vascular elements. Molecular analyses identified a <em>SMARCB1</em> deletion and DNA methylation studies showed that this tumor grouped together with the recently described DMT-SMARCB1. A cerebrospinal fluid cytologic preparation had several cells morphologically similar to those in routine and electron microscopy. We briefly discuss the correlation of the pathology with the radiology and how this tumor compares with other <em>SMARCB1</em>-mutant tumors of the nervous system.</p> Branavan Manoranjan Yves P. Starreveld Robert A. Nordal Christopher Dunham Susanne Bens Christian Thomas Martin Hasselblatt Jeffrey T. Joseph Copyright (c) 2021 Branavan Manoranjan, MD, PhD, Yves P. Starreveld, MD, PhD, Robert A. Nordal, MSC, MD, FRCPC, Christopher Dunham, MD, FRCPC, Susanne Bens, MD, Christian Thomas, MD, Martin Hasselblatt, MD, Jeffrey T Joseph, MD, PhD 2021-06-01 2021-06-01 2 14 14 10.17879/freeneuropathology-2021-3340 Detailed neuropathologic report of COVID-19 complicated by large intracerebral hemorrhage and periventricular lesions with macrophagic infiltrates <p>Infection with the SARS-CoV-2 virus affects a wide range of systems. Significant involvement of the central nervous system has been described, including ischemic and hemorrhagic strokes. Thus far, neuropathologic reports of patients who passed away from COVID-19 have generally described non-specific findings, such as variable reactive gliosis and meningeal chronic inflammatory infiltrates, as well as the consequences of the infection’s systemic complications on the brain, including ischemic infarcts and hypoxic/ischemic encephalopathy. The neuropathological changes in patients with COVID-19 and large hemorrhagic strokes have not been described in detail. We report the case of an elderly male who had a long course of COVID-19 and ultimately passed away from a large intracerebral hemorrhage. In addition to acute hemorrhage, neuropathologic examination demonstrated non-specific reactive changes and chronic periventricular lesions with macrophagic and perivascular lymphocytic infiltrates without evidence of demyelination or presence of SARS-CoV-2 by PCR test. This manuscript expands the spectrum of reported neuropathological changes in patients with COVID-19.</p> Adrian Levine Carol Lee Craig Fava Frankie Tsang Kelly McNeil Stephen T. Yip Veronica Hirsch-Reinshagen Copyright (c) 2021 Adrian Levine, Carol Lee, Craig Fava, Frankie Tsang, Kelly McNeil, Stephen T. Yip, Veronica Hirsch-Reinshagen 2021-03-25 2021-03-25 2 7 7 10.17879/freeneuropathology-2021-3266 63rd Meeting of the French Society of Neuropathology - Meeting Abstracts , December 3rd. 2021 The French Society of Neuropathology Copyright (c) 2021 The French Society of Neuropathology 2021-11-23 2021-11-23 2 32 32 10.17879/freeneuropathology-2021-3682 61st Annual Meeting of the Canadian Association of Neuropathologists Association canadienne des neuropathologistes (CANP-ACNP) - Meeting Abstracts Peter Gould Copyright (c) 2021 Peter Gould 2021-10-29 2021-10-29 2 29 29 10.17879/freeneuropathology-2021-3671 65th Annual Meeting of the German Society of Neuropathology and Neuroanatomy (DGNN) - Meeting Abstracts, September 1–3, 2021 <p>Dear participants, dear colleagues,</p> <p>It is our great pleasure to welcome you to the <strong>65th Annual Meeting of the German Society of Neuropathology and Neuroanatomy</strong> - the brain and nerve microenvironment in health and disease - which will be held as a virtual meeting from <strong>September 1–3, 2021</strong>.</p> <p>The meeting will bring together basic and clinical researchers, physicians as well as junior scientists and PhD students from different disciplines of basic and clinical neuroscience. We will have outstanding lectures by and with some of the most renowned international experts in the field of neuro-oncology, neuroinflammation, neurodegeneration and muscle and nerve diseases and look forward to exciting scientific discussions. There will also be a special and timely section on the effects of COVID-19 on the central and peripheral nervous system.</p> <p>The three days will offer exciting insights into different areas of basic and clinical neuroscience. We have also encouraged early career scientists to present their scientific findings in short talks and poster presentations. We are therefore particularly thankful that the abstracts of the meeting, which in their sum provide the best overview of the high scientific standing of the field, will be published in Free Neuropathology.</p> <p>Finally, we would like to thank you all for your active contribution to this conference in these difficult times. We also thank all supporters for their financial help.</p> <p>We wish you a stimulating and exciting conference.</p> <p>Yours sincerely,</p> <p><strong>Prof. Dr. med. Till Acker</strong><br> Conference Chair (Justus Liebig University Giessen</p> <p><strong>Dr. med. Anne Schänzer</strong></p> <p><strong>Dr. med. Hildegard Dohmen</strong></p> German Soc Neuropathol Neuroanat Copyright (c) 2021 German Soc Neuropathol Neuroanat 2021-08-25 2021-08-25 2 22 22 10.17879/freeneuropathology-2021-3500 Charcot identifies and illustrates amyotrophic lateral sclerosis <p>Jean-Martin Charcot described what he called amyotrophic lateral sclerosis in his 12<sup>th</sup> and 13<sup>th</sup> lessons published in 1873 by Bourneville. He distinguished the symptoms that were related to the lesion of the anterior horn of the spinal cord and those that were due to the degeneration (that he named “sclerosis”) of its lateral column. He thought that “inflammation” progressed from the lateral column to the anterior horn (but the term inflammation is not to be taken in the current meaning): the lesion of the anterior horn was thus “deuteropathic”. An album containing drawings made by Charcot is kept in La Salpêtrière Neuropathology Department. Four drawings are pasted on one of its pages, showing the degeneration of the pyramidal tract. They constitute the original of the engravings illustrating Charcot’s 12<sup>th</sup> lesson. The illustration of the fascicular atrophy of the <em>adductor pollicis</em> presented in the album does not appear in the lessons, even though this alteration is widely discussed and linked to the lesion of the anterior horn, which was supposed to ensure the “nutrition” of the muscle. The technique used by Charcot and his interpretation of the microscopic pictures, as exposed in his lessons, are discussed.</p> Charles Duyckaerts Thierry Maisonobe Jean-Jacques Hauw Danielle Seilhean Copyright (c) 2021 Charles Duyckaerts, Thierry Maisonobe, Jean-Jacques Hauw, Danielle Seilhean 2021-05-18 2021-05-18 2 12 12 10.17879/freeneuropathology-2021-3323 Taylor’s focal cortical dysplasia revisited: History, original specimens and impact <p>50 years ago back in 1971, David C. Taylor and colleagues from England reported on a small series of surgical epilepsy cases proposing a new type of tissue lesion as a cause of difficult-to-treat focal epilepsy: a localized malformation of cerebral cortex. The lesion is now known as focal cortical dysplasia (FCD) Type II or Taylor’s cortical dysplasia. FCD II is not rare, and today is a frequent finding in neurosurgical epilepsy specimens. Medical progress has been achieved in that the majority of FCD II is diagnosed non-invasively by magnetic resonance imaging today. Detailed studies on FCD revealed that the lesion belongs to a spectrum of mTOR-o-pathies, thereby confirming the authors´ initial hypothesis of a relationship to tuberous sclerosis. Here, selected original materials from Taylor´s series are presented as virtual slides, supplemented by original clinical records, in order to give a first-hand impression of this milestone finding in neuropathology of epilepsy.</p> Burkhard S. Kasper Copyright (c) 2021 Burkhard S. Kasper 2021-04-23 2021-04-23 2 11 11 10.17879/freeneuropathology-2021-3324 Differentiation of primary CNS lymphoma and glioblastoma using Raman spectroscopy and machine learning algorithms <p><strong>Objective and Methods:</strong></p> <p>Timely discrimination between primary CNS lymphoma (PCNSL) and glioblastoma is crucial for diagnostics and therapy, but most importantly also determines the intraoperative surgical course. Advanced radiological methods allow this to a certain extent but ultimately, biopsy is still necessary for final diagnosis. As an upcoming method that enables tissue analysis by tracking changes in the vibrational state of molecules via inelastic scattered photons, we used Raman Spectroscopy (RS) as a label free method to examine specimens of both tumor entities intraoperatively, as well as postoperatively in formalin fixed paraffin embedded (FFPE) samples.</p> <p><strong>Results:</strong></p> <p>We applied and compared statistical performance of linear and nonlinear machine learning algorithms (Logistic Regression, Random Forest and XGBoost), and found that Random Forest classification distinguished the two tumor entities with a balanced accuracy of 82,4% in intraoperative tissue condition and with 94% using measurements of distinct tumor areas on FFPE tissue. Taking a deeper insight into the spectral properties of the tumor entities, we describe different tumor-specific Raman shifts of interest for classification.</p> <p><strong>Conclusions:</strong></p> <p>Due to our findings, we propose RS as an additional tool for fast and non-destructive, perioperative tumor tissue discrimination, which may augment treatment options at an early stage. RS may further serve as a useful additional tool for neuropathological diagnostics with little requirements for tissue integrity.</p> Gilbert Georg Klamminger Karoline Klein Laurent Mombaerts Finn Jelke Giulia Mirizzi Rédouane Slimani Andreas Husch Michel Mittelbronn Frank Hertel Felix Bruno Kleine Borgmann Copyright (c) 2021 Gilbert Georg Klamminger, Karoline Klein, Laurent Mombaerts, Finn Jelke, Giulia Mirizzi, Rédouane Slimani, Andreas Husch, Michel Mittelbronn, Frank Hertel, Felix Bruno Kleine Borgmann 2021-10-04 2021-10-04 2 26 26 10.17879/freeneuropathology-2021-3458 Differential gene expression in the cortical sulcus compared to the gyral crest within the early stages of chronic traumatic encephalopathy <p>Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative tauopathy found in individuals with a history of repetitive head impacts (RHI). Previous work has demonstrated that neuroinflammation is involved in CTE pathogenesis, however, the specific inflammatory mechanisms are still unclear. Here, using RNA-sequencing and gene set enrichment analysis (GSEA), we investigated the genetic changes found in tissue taken from the region CTE pathology is first found, the cortical sulcus, and compared it to neighboring gryal crest tissue to identify what pathways were directly related to initial hyperphosphorylated tau (p-tau) deposition. 21 cases were chosen for analysis: 6 cases had no exposure to RHI or presence of neurodegenerative disease (Control), 5 cases had exposure to RHI but no presence of neurodegenerative disease (RHI), and 10 cases had exposure to RHI and low stage CTE (CTE). Two sets of genes were identified: genes that changed in both the sulcus and crest and genes that changed specifically in the sulcus relative to the crest. When examining genes that changed in both the sulcus and crest, GSEA demonstrated an increase in immune related processes and a decrease in neuronal processes in RHI and CTE groups. Sulcal specific alterations were observed to be driven by three mechanisms: anatomy, RHI, or p-tau. First, we observed consistent sulcal specific alterations in immune, extracellular matrix, vascular, neuronal, and endocytosis/exocytosis categories across all groups, suggesting the sulcus has a unique molecular signature compared to the neighboring crest independent of pathology. Second, individuals with a history of RHI demonstrated impairment in metabolic and mitochondrial related processes. Finally, in individuals with CTE, we observed impairment of immune and phagocytic related processes. Overall, this work provides the first observation of biological processes specifically altered in the sulcus that could be directly implicated in CTE pathogenesis and provide novel targets for biomarkers and therapies.</p> Jonathan D. Cherry Filisia Agus Erin Dixon Bertrand Huber Victor E. Alvarez Jesse Mez Ann C. McKee Adam Labadorf Thor D. Stein Copyright (c) 2021 Jonathan D. Cherry, Filisia Agus, Erin Dixon, Bertrand Huber, Victor E. Alvarez, Jesse Mez, Ann C. McKee, Adam Labadorf, Thor D. Stein 2021-08-17 2021-08-17 2 21 21 10.17879/freeneuropathology-2021-3453 The neurovascular unit in diffuse intrinsic pontine gliomas <p><strong>Aims:</strong> Diffuse intrinsic pontine glioma (DIPG) is a childhood brainstem tumor with a median overall survival of eleven months. Lack of chemotherapy efficacy may be related to an intact blood-brain barrier (BBB). In this study we aim to investigate the neurovascular unit (NVU) in DIPG patients.</p> <p><strong>Methods:</strong> DIPG biopsy (n = 4) and autopsy samples (n = 6) and age-matched healthy pons samples (n = 20) were immunohistochemically investigated for plasma protein extravasation, and the expression of tight junction proteins claudin-5 and zonula occludens-1 (ZO-1), basement membrane component laminin, pericyte marker PDGFR-β, and efflux transporters P-gp and BCRP. The mean vascular density and diameter were also assessed.</p> <p><strong>Results:</strong> DIPGs show a heterogeneity in cell morphology and evidence of BBB leakage. Both in tumor biopsy and autopsy samples, expression of claudin-5, ZO-1, laminin, PDGFR-β and P-gp was reduced compared to healthy pontine tissues. In DIPG autopsy samples, vascular density was lower compared to healthy pons. The density of small vessels (&lt;10 µm) was significantly lower (<em>P</em>&lt;0.001), whereas the density of large vessels (≥10 µm) did not differ between groups (<em>P</em> = 0.404). The median vascular diameter was not significantly different: 6.21 µm in DIPG autopsy samples (range 2.25-94.85 µm), and 6.26 µm in controls (range 1.17-264.77 µm).</p> <p><strong>Conclusion:</strong> Our study demonstrates evidence of structural changes in the NVU in DIPG patients, both in biopsy and autopsy samples, as well as a reduced vascular density in end-stage disease. Adding such a biological perspective may help to better direct future treatment choices for DIPG patients.</p> Fatma E. El-Khouly Rianne Haumann Marjolein Breur Sophie E.M. Veldhuijzen van Zanten Gertjan J.L. Kaspers N. Harry Hendrikse Esther Hulleman Dannis G. van Vuurden Marianna Bugiani Copyright (c) 2021 Fatma E. El-Khouly, Rianne Haumann, Marjolein Breur, Sophie E.M. Veldhuijzen van Zanten, Gertjan J.L. Kaspers, N. Harry Hendrikse, Esther Hulleman, Dannis G. van Vuurden, Marianna Bugiani 2021-07-05 2021-07-05 2 17 17 10.17879/freeneuropathology-2021-3341 Specific immune modulation of experimental colitis drives enteric alpha-synuclein accumulation and triggers age-related Parkinson-like brain pathology <p><strong>Background</strong>: In some people with Parkinson’s disease (PD), a-synuclein (αSyn) accumulation may begin in the enteric nervous system (ENS) decades before development of brain pathology and disease diagnosis.</p> <p><strong>Objective: </strong>To determine how different types and severity of intestinal inflammation could trigger αSyn accumulation in the ENS and the subsequent development of αSyn brain pathology.</p> <p><strong>Methods</strong>: We assessed the effects of modulating short- and long-term experimental colitis on αSyn accumulation in the gut of αSyn transgenic and wild type mice by immunostaining and gene expression analysis. To determine the long-term effect on the brain, we induced dextran sulfate sodium (DSS) colitis in young αSyn transgenic mice and aged them under normal conditions up to 9 or 21 months before tissue analyses.</p> <p><strong>Results</strong>: A single strong or sustained mild DSS colitis triggered αSyn accumulation in the submucosal plexus of wild type and αSyn transgenic mice, while short-term mild DSS colitis or inflammation induced by lipopolysaccharide did not have such an effect. Genetic and pharmacological modulation of macrophage-associated pathways modulated the severity of enteric αSyn. Remarkably, experimental colitis at three months of age exacerbated the accumulation of aggregated phospho-Serine 129 αSyn in the midbrain (including the substantia nigra), in 21- but not 9-month-old αSyn transgenic mice. This increase in midbrain αSyn accumulation is accompanied by the loss of tyrosine hydroxylase-immunoreactive nigral neurons.</p> <p><strong>Conclusions</strong>: Our data suggest that specific types and severity of intestinal inflammation, mediated by monocyte/macrophage signaling, could play a critical role in the initiation and progression of PD.</p> Stefan Grathwohl Emmanuel Quansah Nazia Maroof Jennifer A. Steiner Liz Spycher Fethalla Benmansour Gonzalo Duran-Pacheco Juliane Siebourg-Polster Krisztina Oroszlan-Szovik Helga Remy Markus Haenggi Marc Stawiski Matthias Selhausen Pierre Mailver Andreas Wolfert Thomas Emrich Zachary Madaj Arel Su Martha L. Escobar Galvis Christoph Mueller Annika Herrmann Patrik Brundin Markus Britschgi Copyright (c) 2021 Stefan Grathwohl, Emmanuel Quansah, Nazia Maroof, Jennifer A. Steiner, Liz Spycher, Fethalla Benmansour, Gonzalo Duran-Pacheco, Juliane Siebourg-Polster, Krisztina Oroszlan-Szovik, Helga Remy, Markus Haenggi, Marc Stawiski, Matthias Selhausen, Pierre Mailver, Andreas Wolfert, Thomas Emrich, Zachary Madaj, Arel Su, Martha L. Escobar Galvis, Christoph Mueller, Annika Herrmann, Patrik Brundin, Markus Britschgi 2021-05-18 2021-05-18 2 13 13 10.17879/freeneuropathology-2021-3326 Neurodegeneration: 2021 update <p>This article reviews a collection of manuscripts in the field of neurodegenerative disease chosen from what are considered by the author to be among the 10 most important and potentially impactful topics or research trends of 2020 relevant to the field of experimental and diagnostic neuropathology. A deliberate effort was made to provide balance among disease categories covered. The result is a varied selection that includes not just individual papers but also research topics and trends. The association of COVID-19 with longer-term neurological symptoms has launched a research trend fueled by speculation that the SARS-CoV-2 might trigger neurodegenerative changes. The onslaught of transcriptomic studies has begun to give way to proteomics, with three transformative studies published examining glial contributions to Alzheimer disease, cerebral atherosclerosis in cognitive decline, and the complex sequence of post-translational modifications of the tau protein. Plasma biomarkers for Alzheimer disease have continued to make rapid advances, especially around highly sensitive assays capable of detecting different forms of abnormal hyperphosphorylated tau in peripheral blood. Two studies using cryo-electron microscopy showed the power of the approach by continuing to elucidate the diversity of filamentous tau inclusions, and a third study gave the first glimpse of α-synuclein aggregates at near atomic resolution. Another study continued to delineate how different α-synuclein conformers (“strains”) target specific brain regions and lead to neurodegeneration. In Huntington’s disease, we saw compelling molecular data showing how cells adapt to endoplasmic reticulum stress through the unfolded protein response. Finally, the role of astrocytes in chronic traumatic encephalopathy has emerged as a critical area of interest.</p> John Fonda Crary Copyright (c) 2021 John Fonda Crary 2021-04-21 2021-04-21 2 9 9 10.17879/freeneuropathology-2021-3317 Neurodevelopmental disorders: 2021 update <p>One of the current challenges in the field of neurodevelopmental disorders (NDDs) is still to determine their underlying aetiology and risk factors. NDDs comprise a diverse group of disorders primarily related to neuro-developmental dysfunction including autism spectrum disorder (ASD), developmental delay, intellectual dis-ability (ID), and attention-deficit/hyperactivity disorder (ADHD) that may present with a certain degree of cognitive dysfunction and high prevalence of neuropsychiatric outcomes. Last year, advances in human ge-nomics have begun to shed light on the genetic architecture of these disorders and large-scale sequencing studies are starting to reveal mechanisms that range from unique genomic DNA methylation patterns (i.e. “episignatures”) to highly polygenic conditions. In addition, the contribution of <em>de novo</em> somatic mutations to neurodevelopmental diseases is being recognized. However, progressing from genetic findings to underlying neuropathological mechanisms has proved challenging, due to the increased resolution of the molecular and genetic assays. Advancement in modelling tools is likely to improve our understanding of the origin of neuro-developmental disorders and provide insight into their developmental mechanisms. Also, combined in vivo editing of multiple genes and single-cell RNA-sequencing (scRNA-seq) are bringing us into a new era of un-derstanding the molecular neuropathology of NDDs.</p> Alfonsa Zamora-Moratalla María Martínez de Lagrán Mara Dierssen Copyright (c) 2021 Alfonsa Zamora-Moratalla, María Martínez de Lagrán, Mara Dierssen 2021-03-24 2021-03-24 2 6 6 10.17879/freeneuropathology-2021-3268 Neurooncology: 2021 update <p>This article briefly presents 10 topics that were selected by the author as ‘top 10 discoveries’ published in 2020 in the broader field of neurooncological pathology including neurosciences as well as clinical neurooncology of interest for neurooncological pathology. The selected topics concern new information on the molecular characteristics of gliomas (infratentorial IDH-mutant diffuse astrocytomas, pediatric low-grade gliomas, infant-type high-grade gliomas, hypermutation in gliomas), the immunological aspects of the brain tumor microenvironment (TME), the impact of the TME on preclinical glioma models, and the importance of lymphatic drainage on brain tumor surveillance. Furthermore, important papers were published on two ‘new’ genetic syndromes predisposing to medulloblastoma, on liquid biopsy-based diagnosis of central nervous system (CNS) tumors, and on the ‘microbiome’ in glioblastomas (and other cancers). In the last part of this review, a dozen of papers are given as examples of papers that did not make it to the top 10 list of the author, underscoring the subjective component in the selection process. Acknowledging that 2020 will be remembered as the year in which the world changed because of the COVID-19 pandemic, some of the consequences of this pandemic for neurooncological pathology are briefly discussed as well. Hopefully, this review forms an incentive to appreciate the wealth of information provided by the papers that were used as building blocks for the present manuscript.</p> Pieter Wesseling Copyright (c) 2021 Pieter Wesseling 2021-03-17 2021-03-17 2 5 5 10.17879/freeneuropathology-2021-3271 Neurotrauma: 2021 update <p>Despite the interruptions and restrictions to the progress of science that the COVID-19 pandemic has introduced, 2020 was marked by a number of important advances in the field of neurotrauma. Here, I will highlight what I believe are among the most important contributions. This year there were notable advances towards providing clinically useful information on neurotrauma outcome through the use of fluid biomarkers. I also introduce fascinating approaches to studying the role of microglia in nervous system repair and neuroinflammatory mechanisms leading to dysfunction through the use of colony-stimulating factor 1 receptor inhibitors, especially Plexxikon 5622 (PLX5622). Oral administration of this compound is able to deplete microglial elements and then, following withdrawal from the drug, a new population of microglia then repopulates the brain. Use of this approach in traumatic brain injury experimental models has produced important insights into the pathogenetic role of microglia in responding to this process. Important new data on the nature and distribution of tau involvement of neurons and astrocytes in cases of chronic traumatic encephalopathy (CTE) also appeared suggesting differences and similarities to Alzheimer’s disease. Additionally, the use of tau-specific PET scan ligands in at-risk populations has suggested that this approach may be able to identify cases with CTE. Lastly, we note the death in the past year of a major contributor to the field of neurotrauma neuropathology, Professor J. Hume Adams.</p> Daniel P. Perl Copyright (c) 2021 Daniel P. Perl 2021-03-15 2021-03-15 2 4 4 10.17879/freeneuropathology-2021-3264 Neuromuscular disease: 2021 update <p>This review highlights ten important advances in the neuromuscular disease field that were first reported in 2020. The overarching topics include (i) advances in understanding of fundamental neuromuscular biology; (ii) new / emerging diseases; (iii) advances in understanding of disease etiology and pathogenesis; (iv) diagnostic advances; and (v) therapeutic advances. Within this broad framework, the individual disease entities that are discussed in more detail include neuromuscular complications of COVID-19, supervillin-deficient myopathy, 19p13.3-linked distal myopathy, vasculitic neuropathy due to eosinophilic granulomatosis with polyangiitis, spinal muscular atrophy, idiopathic inflammatory myopathies, and transthyretin neuropathy/myopathy. In addition, the review highlights several other advances (such as the revised view of the myofibrillar architecture, new insights into molecular and cellular mechanisms of muscle regeneration, and development of new electron microscopy tools) that will likely have a significant impact on the overall neuromuscular disease field going forward.</p> Marta Margeta Copyright (c) 2021 Marta Margeta 2021-02-23 2021-02-23 2 3 3 10.17879/freeneuropathology-2021-3236 Neuropathology of COVID-19 (neuro-COVID): clinicopathological update <p>Coronavirus disease 2019 (COVID-19) is emerging as the greatest public health crisis in the early 21<sup>st</sup> century. Its causative agent, Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), is an enveloped single-stranded positive-sense ribonucleic acid virus that enters cells via the angiotensin converting enzyme 2 receptor or several other receptors. While COVID-19 primarily affects the respiratory system, other organs including the brain can be involved. In Western clinical studies, relatively mild neurological dysfunction such as anosmia and dysgeusia is frequent (~70-84%) while severe neurologic disorders such as stroke (~1-6%) and meningoencephalitis are less common. It is unclear how much SARS-CoV-2 infection contributes to the incidence of stroke given co-morbidities in the affected patient population. Rarely, clinically-defined cases of acute disseminated encephalomyelitis, Guillain-Barré syndrome and acute necrotizing encephalopathy have been reported in COVID-19 patients. Common neuropathological findings in the 184 patients reviewed include microglial activation (42.9%) with microglial nodules in a subset (33.3%), lymphoid inflammation (37.5%), acute hypoxic-ischemic changes (29.9%), astrogliosis (27.7%), acute/subacute brain infarcts (21.2%), spontaneous hemorrhage (15.8%), and microthrombi (15.2%). In our institutional cases, we also note occasional anterior pituitary infarcts. COVID-19 coagulopathy, sepsis, and acute respiratory distress likely contribute to a number of these findings. When present, central nervous system lymphoid inflammation is often minimal to mild, is detected best by immunohistochemistry and, in one study, indistinguishable from control sepsis cases. Some cases evince microglial nodules or neuronophagy, strongly supporting viral meningoencephalitis, with a proclivity for involvement of the medulla oblongata. The virus is detectable by reverse transcriptase polymerase chain reaction, immunohistochemistry, or electron microscopy in human cerebrum, cerebellum, cranial nerves, olfactory bulb, as well as in the olfactory epithelium; neurons and endothelium can also be infected. Review of the extant cases has limitations including selection bias and limited clinical information in some cases. Much remains to be learned about the effects of direct viral infection of brain cells and whether SARS-CoV-2 persists long-term contributing to chronic symptomatology.</p> Jerry J. Lou Mehrnaz Movassaghi Dominique Gordy Madeline G. Olson Ting Zhang Maya S. Khurana Zesheng Chen Mari Perez-Rosendahl Samasuk Thammachantha Elyse J. Singer Shino D. Magaki Harry V. Vinters William H. Yong Copyright (c) 2021 Jerry Jierui Lou, Mehrnaz Movassaghi, Dominique Gordy, Madeline G Olson, Ting Zhang, Maya S Khurana, Zesheng Chen, Mari Perez-Rosendahl, Samasuk Thammachantha, Elyse J Singer, Shino D Magaki, Harry V Vinters, William H Yong 2021-01-18 2021-01-18 2 2 2 10.17879/freeneuropathology-2021-2993 Neuroinflammation: 2021 update <p>Key requirements for the validity of a neuropathological study are the inclusion of large numbers of biopsy or autopsy cases and proper controls, the rigorous classification of the basic neuropathology and the selection of the most suitable technologies for investigation. Whether the studies are performed with the fanciest, new, and state of the art technology or with rather conventional methodology is of minor importance. Fol-lowing these criteria, a spectrum of neuropathological studies has been published in 2020, which provides new insights on important questions related to neurological disease. They include the pathological substrate of brain disease in COVID-19 infected patients, the nature of the adaptive and innate inflammatory response, or the type and mechanisms of tissue injury and repair in multiple sclerosis, and diagnostically relevant or mechanistic new insights into antibody-mediated diseases of the central nervous system. Other studies de-scribe in detail the dynamic changes of brain inflammation in patients with trisomy 21 as a disease model for Alzheimer’s disease, or the presence and consequences of vascular comorbidities in a chronic inflammatory disease, such as multiple sclerosis. All these contributions have provided important, highly relevant clues for basic and translational neuroscience.</p> Hans Lassmann Copyright (c) 2021 Hans Lassmann 2021-01-12 2021-01-12 2 1 1 10.17879/freeneuropathology-2021-3166 Hypothesis: Entrapment of lipoprotein particles in the brain causes Alzheimer’s disease <p>We present for consideration a hypothesis that impaired movement of lipoprotein particles in the extracellular space in the brain in ageing is central to and causes all the key pathophysiological features of Alzheimer’s disease (AD). The role of lipoprotein particles is to transport cholesterol from glial cells, where it is synthesised, to neurons, which require cholesterol for synaptic plasticity. The lipoprotein particles have a cholesterol-containing hydrophobic core, in which amyloid-β (Aβ) can be solubilised. The core is surrounded by a hydrophilic surface containing apolipoprotein E (APOE) which, as neurons bear receptors for APOE, determines the destination of the particles. The problem arises because the extracellular space is a narrow cleft, barely wider than the lipoprotein particles themselves, which they have to navigate in order to perform their crucial cholesterol-transporting function. We explain how lipoprotein particles could become trapped in the ageing extracellular matrix and that this primary abnormality results in reduced delivery of cholesterol to neurons leading to impaired synaptic plasticity, crucial for learning and memory. It can also explain extracellular Aβ accumulation, to which a microglial response generates a neurotoxic reaction, and intraneuronal tau aggregation, each of which exacerbate the problem. All these players have been known for many years to be important in Alzheimer’s pathogenesis but a single unifying mechanism to explain how they are linked has been lacking. This proposed mechanism, with entrapment of lipoproteins particles as key to the development of AD, can explain the failure of so many clinical trials and points out new directions to be taken.</p> Delphine Boche James AR Nicoll Copyright (c) 2021 Delphine Boche, James AR Nicoll 2021-11-02 2021-11-02 2 30 30 10.17879/freeneuropathology-2021-3459 SARS-CoV-2 vaccination induced cerebral venous sinus thrombosis: Do megakaryocytes, platelets and lipid mediators make up the orchestra? <p>The COVID-19 vaccines comprised of adenoviral vectors encoding the Spike (S) glycoprotein of SARS-CoV-2 are highly effective but associated with rare thrombotic complications. The adenovirus vector infects epithelial cells expressing the coxsackievirus and adenovirus receptor (CAR). The S glycoprotein expressed locally stimulates neutralizing antibody and cellular immune responses. These vaccines have been associated with thromboembolic events including cerebral venous sinus thrombosis (CVST). S glycoprotein stimulates the expression of cyclooxygenase-2 (COX-2) and leads to massive generation of thromboxane A<sub>2</sub> in COVID-19. Megakaryocytes express CAR and we postulate that S glycoprotein stimulated generation of thromboxane A<sub>2</sub> leads to megakaryocyte activation, biogenesis of activated platelets and thereby increased thrombogenicity. Cerebral vein sinuses express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses could be further activated by thromboxane A<sub>2</sub>-dependent podoplanin-CLEC2 signaling, leading to CVST. A prothrombotic hormonal milieu, and increased generation of thromboxane A<sub>2</sub> and platelet activation in healthy females compared to males is consistent with increased risk for CVST observed in women. We propose that antiplatelet agents targeting thromboxane A<sub>2</sub> receptor signaling such as low-dose aspirin merit consideration for chemoprophylaxis when administering the adenovirus based COVID-19 vaccines to young adults at risk of thrombosis provided there are no contraindications.</p> Kate Chander Chiang Ravi Raghavan Ajay Gupta Copyright (c) 2021 Kate Chander Chiang, Ravi Raghavan, Ajay Gupta 2021-07-07 2021-07-07 2 18 18 10.17879/freeneuropathology-2021-3395 Viral infection and dementia: A brief synthesis <p>For the past 400 years, the most common cause of dementia was tertiary syphilis [1]. Its prevalence declined dramatically with the advent of potent antibiotics in the 20<sup>th</sup> century, but these same antibiotics also helped increase our average lifespan, leading to dramatic increases in the prevalence of age-related dementias. Abundant progress has been made connecting early onset dementias with mutations in neural genes. Late onset dementias have been linked to a more enigmatic set of genes, some of which have been connected to neuroinflammation, begging the question: Are age-related dementias linked to infection? Numerous studies have reported an association between dementia and infections in general and viral infections in particular. While these associations have been subject to extensive reviews, the purpose of this synthesis is to examine the hypothesized link of viral infections and dementia from the opposite perspective: What do we know about acute and chronic encephalitides that could forge a link with dementias? There appears to be little support for the concept that viral infections are a major contributor to today’s common dementias. However, the emergence of new central nervous system (CNS) viral infections, coupled with senescent immune and nervous systems in our aged population, create new opportunities for infections to contribute to dementia.</p> Clayton A. Wiley Copyright (c) 2021 Clayton A. Wiley 2021-06-08 2021-06-08 2 15 15 10.17879/freeneuropathology-2021-3347 The definition and role of brain invasion in meningioma grading: Still controversial after all these years Arie Perry Copyright (c) 2021 Arie Perry 2021-03-24 2021-03-24 2 8 8 10.17879/freeneuropathology-2021-3276 50 years of surgical pathology / 36 years of neuropathology Sverre J. Mørk Copyright (c) 2021 Sverre J. Mørk 2021-11-08 2021-11-08 2 28 28 10.17879/freeneuropathology-2021-3639 Notes on the career of Jacqueline Mikol Jacqueline Mikol Copyright (c) 2021 Jacqueline Mikol 2021-09-20 2021-09-20 2 25 25 10.17879/freeneuropathology-2021-3532 Lessons learned from a career in neuropathology Roy O. Weller Copyright (c) 2021 Henry Robbert; Roy O. Weller 2021-10-25 2021-10-25 2 27 27 10.17879/freeneuropathology-2021-3634 A varied neuropathology career - turning west and east Ralf Schober Copyright (c) 2021 Ralf Schober 2021-07-29 2021-07-29 2 20 20 10.17879/freeneuropathology-2021-3448 From neurology to neuropathology and back Arnulf H. Koeppen Copyright (c) 2021 Arnulf H. Koeppen 2021-04-21 2021-04-21 2 10 10 10.17879/freeneuropathology-2021-3333