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 <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> (Werner Paulus) (Ralf Mersmann) Tue, 11 Jan 2022 00:00:00 +0100 OJS 60 Amygdala granular fuzzy astrocytes as lesions preceding development of argyrophilic grains: data from 239 autopsy cases Osamu Yokota, Tomoko Miki, Chikako Ikeda, Hideki Ishizu, Takashi Haraguchi, Akinori Miyashita, Takeshi Ikeuchi, Shintaro Takenoshita, Seishi Terada Copyright (c) 2022 Osamu Yokota, Tomoko Miki, Chikako Ikeda, Hideki Ishizu, Takashi Haraguchi, Akinori Miyashita, Takeshi Ikeuchi, Shintaro Takenoshita, Seishi Terada Wed, 27 Jul 2022 00:00:00 +0200 A potential diagnostic pitfall: Primary synovial sarcoma of the central nervous system <p> </p> Arnault Tauziede-Espariat, Nicolas Macagno, Daniel Pissaloux, Dominique Figarella-Branger, Romain Appay, Dorian Bochaton, Sanaa Tazi, Paul Kauv, Lauren Hasty, Alice Métais, Fabrice Chrétien, Pascale Varlet Copyright (c) 2022 Arnault Tauziede-Espariat, Nicolas Macagno, Daniel Pissaloux, Dominique Figarella-Branger, Romain Appay, Dorian Bochaton, Sanaa Tazi, Paul Kauv, Lauren Hasty, Alice Métais, Fabrice Chrétien, Pascale Varlet Tue, 26 Apr 2022 00:00:00 +0200 From Research to Diagnostic Application of Raman Spectroscopy in Neurosciences: Past and Perspectives <p>In recent years, Raman spectroscopy has been more and more frequently applied to address research questions in neuroscience. As a non-destructive technique based on inelastic scattering of photons, it can be used for a wide spectrum of applications including neurooncological tumor diagnostics or analysis of misfolded protein aggregates involved in neurodegenerative diseases. Progress in the technical development of this method allows for an increasingly detailed analysis of biological samples and may therefore open new fields of applications. The goal of our review is to provide an introduction into Raman scattering, its practical usage and also commonly associated pitfalls. Furthermore, intraoperative assessment of tumor recurrence using Raman based histology images as well as the search for non-invasive ways of diagnosis in neurodegenerative diseases are discussed. Some of the applications mentioned here may serve as a basis and possibly set the course for a future use of the technique in clinical practice. Covering a broad range of content, this overview can serve not only as a quick and accessible reference tool but also provide more in-depth information on a specific subtopic of interest.</p> Gilbert Georg Klamminger, Katrin Frauenknecht, Michel Mittelbronn, Felix Bruno Kleine Borgmann Copyright (c) 2022 Gilbert Georg Klamminger, Katrin Frauenknecht, Michel Mittelbronn, Felix Bruno Kleine Borgmann Fri, 05 Aug 2022 00:00:00 +0200 Alzheimer’s disease is an inherent, natural part of human brain aging: an integrated perspective <p>Alzheimer disease is one of the most challenging demons in our society due to its very high prevalence and its clinical manifestations which cause deterioration of cognition, intelligence, and emotions – the very capacities that distinguish <em>Homo sapiens</em> from other animal species. Besides the personal, social, and economical costs, late stages of AD are vivid experiences for the family, relatives, friends, and general observers of the progressive ruin of an individual who turns into a being with lower mental and physical capacities than less evolved species. A human brain with healthy cognition, conscience, and emotions can succeed in dealing with most difficulties that life may pose. Without these capacities, the same person probably cannot. Due, in part, to this emotional impact, the absorbing study of AD has generated, over the years, a fascinating and complex story of theories, hypotheses, controversies, fashion swings, and passionate clashes, together with tremendous efforts and achievements geared to improve understanding of the pathogenesis and treatment of the disorder. Familal AD is rare and linked to altered genetic information associated with three genes. Sporadic AD (sAD) is much more common and multifactorial. A major point of clinical discussion has been, and still is, establishing the differences between brain aging and sAD. This is not a trivial question, as the neuropathological and molecular characteristics of normal brain aging and the first appearance of early stages of sAD-related pathology are not easily distinguishable in most individuals. Another important point is confidence in assigning responsibility for the beginning of sAD to a few triggering molecules, without considering the wide number of alterations that converge in the pathogenesis of aging and sAD. Genetic risk factors covering multiple molecular signals are increasing in number. In the same line, molecular pathways are altered at early stages of sAD pathology, currently grouped under the aegis of normal brain aging, only to increase massively at advanced stages of the process. Sporadic AD is here considered an inherent, natural part of human brain aging, which is prevalent in all humans, and variably present or not in a few individuals in other species. The progression of the process has devastating effects in a relatively low percentage of human beings eventually evolving to dementia. The continuum of brain aging and sAD implies the search for a different approach in the study of human brain aging at the first stages of the biological process, and advances in the use of new technologies aimed at slowing down the molecular defects underlying human brain aging and sAD at the outset, and transfering information and tasks to AI and coordinated devices.</p> Isidro Ferrer Copyright (c) 2022 Isidro Ferrer Fri, 08 Jul 2022 00:00:00 +0200 Neurovascular disease: 2022 update <p>In this update we present a series of papers focused on topics that have emerged in vascular disease over the prior year. The first two papers focus on the pathogenesis of vascular malformations, the first on brain arteriovenous malformations, and the second on cerebral cavernous malformations. These disorders can lead to significant brain injuries from intracerebral hemorrhage (if they rupture) or other neurological complications, including seizures. The next set of papers reflects work that has advanced our understanding of how the brain and the immune system “communicate” after brain injury, including stroke (papers 3-6). The first of these shows that T cells are involved in white matter repair after ischemic injury, an effect dependent on microglia, demonstrating the important cross-talk between innate and adaptive immunity. The next two papers focus on B cells, which have been relatively understudied in the context of brain injury. The contribution of antigen-experienced B cells from the meninges and skull bone marrow, rather than blood-derived B cells in neuroinflammation opens up a very novel area of investigation. The possibility that antibody secreting B cells may contribute to vascular dementia will certainly be an active area for future investigations. Similarly, in paper 6, investigators found that CNS-infiltrating myeloid cells can originate from brain borders tissues. These cells have unique transcriptional signatures that are distinct from their blood-derived counterparts, and likely contribute to myeloid cell infiltration from bone-marrow niches in close proximity to the brain. The contribution of microglia, the primary innate immune cell of the brain, to amyloid deposition and propagation is then discussed, followed by work on how perivascular Aβ is potentially cleared along the cerebral vessels in patients with cerebral amyloid angiopathy. The final two papers focus on the contribution of senescent endothelial cells and pericytes. The first used a model of accelerated senescence (Hutchinson-Gilford progeria syndrome; HGPS) and shows the translational potential of an approach to reduce telomere shortening to slow aging. The final paper demonstrates how capillary pericytes contribute to basal blood flow resistance and slow modulation of blood flow throughout the brain. Interestingly, several of the papers identified therapeutic strategies that could be potentially translated into clinical populations.</p> Louise D. McCullough Copyright (c) 2022 Louise D. McCullough Tue, 14 Jun 2022 00:00:00 +0200 Neurodegeneration: 2022 update <p>Here, we review a collection of recent manuscripts and research trends on the neuropathology of neurodegeneration that are considered by the author to be among the potentially most impactful. To the greatest extent possible, we chose to focus on histopathological studies that are most relevant to experimental and diagnostic neuropathology. While there has been an abundance of important recent discoveries and developments in neurodegenerative disease research, there was a deliberate effort here to provide balance to prevent disease categories and experimental approaches from overshadowing the others. The result is a diverse series of outstanding studies, together showing the landscape of progress across neurodegenerative disorders. One is a stereological study examining dystrophic microglia in aging. We highlight the first large genetic study of primary age-related tauopathy, showing convergence and divergence from classical Alzheimer’s disease. There were further advances in the neuropathological criteria and staging of chronic traumatic encephalopathy. Links suggesting a causal role for <em>TMEM106B</em> in TDP-43 proteinopathy emerged. Attempts to subtype Alzheimer’s disease on the molecular level were made. Evidence for a role for the <em>VEGF</em> family in cognitive impairment was advanced. Comparison of gene expression profiles from myeloid cells in peripheral blood and brain tissues from Parkinson’s disease patients revealed pathways that may lead to new mechanistic insights and biomarkers. A large autopsy series identified an increased frequency of central nervous system developmental malformations in Huntington’s disease. A robust and reliable system for assessing Lewy body pathology was proposed. Finally, we continue to be plagued by the COVID-19 pandemic, with lingering concerns of a long-term link with neurodegeneration.</p> John Fonda Crary Copyright (c) 2022 John Fonda Crary Tue, 10 May 2022 00:00:00 +0200 Neuropathology and epilepsy surgery: 2022 update <p>The impact of a precise histopathology diagnosis and molecular workup for surgical patient management remains a controversial issue in epileptology with a lack of diagnostic agreement as root cause. Very recent advances in genotype-phenotype characterization of epilepsy-associated developmental brain lesions, including the first diagnostically useful DNA methylation studies, opened new avenues and will help to finally resolve these issues. A series of most recent articles were decisively selected by the author to exemplify the areas of improvement in neuropathology and epilepsy surgery. These topics include the progress in genotype-phenotype association studies of Focal Cortical Dysplasia (FCD) leading to the discovery of new molecularly defined entities, i.e. mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE), <em>SLC35A2</em> altered. These studies also triggered the first update of the international FCD consensus classification scheme from 2011, which will hopefully support diagnostic agreement in clinical practice and research. The dilemma of new tumor entities proposed by the 5<sup>th</sup> edition of the WHO classification primarily associated with early seizure onset yet not well introduced to the epileptology community will also be discussed in the light of emerging experimental evidence when transfecting the developing murine brain with the single most important genetic alteration for both carcino- and epileptogenesis, i.e. <em>BRAF V600E</em>.</p> Ingmar Blümcke Copyright (c) 2022 Ingmar Blümcke Tue, 03 May 2022 00:00:00 +0200 Neurodevelopmental disorders: 2022 update <p>With a prevalence of 2-4% of the worldwide population, neurodevelopmental disorders (NDDs) comprise a heterogeneous group of disorders associated with neurodevelopmental dysfunction, including intellectual disability (ID), autism spectrum disorder (ASD), Down syndrome (DS) and attention-deficit/hyperactivity disorder (ADHD) among others. Last year, important steps in the mechanistic understanding of several NDDs have been achieved. New preclinical models demonstrated causality between <em>PAK3</em> mutations and disorders associated with social deficiencies. <em>ARID1B</em> mutations have been linked to neuroectoderm specification in Coffin-Siris syndrome and DNA damage was established as an important pathologic mechanism in Aicardi- Goutières syndrome. Moreover, alterations in basic molecular processes including translation and histone acetylation have been established as major traits in the pathology of X-linked ID and Rett syndrome, revealing new pathogenetic mechanisms. Advances in bioinformatics have begun to shed light on the human repeatome, a largely unexplored part of our genome, and how alterations in these sequences have a central role in ASD. The role of mitochondria in neuropathology also advanced last year with the discovery of previously unknown vesicles derived from mitochondria, mitovesicles, with a putative role in ASD, DS and Alzheimer disease. An interesting discovery in the field is that during postnatal brain development, changes in genome architecture and transcriptional dynamics progress independently of sensory experience, a finding that will definitely impact the research in NDDs in the near future. Finally, our neurocentric views of NDDs is changing as new players such as astrocytes are revealed to be crucial in neuropathology. The role of astrocytes has started to be clarified for some pathologies such as ASD and DS, linking well-known genetic mutations to impaired astrocyte function.</p> Miguel Sabariego-Navarro, Alvaro Fernández-Blanco, César Sierra, Mara Dierssen Copyright (c) 2022 Miguel Sabariego-Navarro, Alvaro Fernández-Blanco, César Sierra, Mara Dierssen Mon, 21 Mar 2022 00:00:00 +0100 Neuropathology studies of dementia in US persons other than non-Hispanic whites <p class="AbstractText">Alzheimer’s disease (AD) and vascular dementia are two of the most prevalent dementias that afflict the aging population in the United States (US). Studies have made great strides in understanding the neuropathology of these diseases; however, many studies are conducted in the context of non-Hispanic whites (NHWs), and few include the rapidly growing underrepresented populations that reside in the US. We sought to characterize current knowledge of the neuropathologic landscape of AD and vascular dementia of the largest growing US minority groups, namely Latinos/Hispanics, Black Americans, and Asian Americans, compared with NHWs being the majority group. It is vital to note these historic categories are social constructs and cultural and social associations may underlie differences. We conducted a literature search utilizing specific criteria to yield neuropathology papers that addressed the demographics and neuropathologies of relevance, then collated the findings into this review. We reveal that while there has been much progress in neuropathological research involving Latinos/Hispanics and Black Americans in the past decade, no cohesive conclusions could be extrapolated from the existing data due to the dearth of minority participants and even smaller amount of information related to the heterogeneity within each minority group, especially Latinos/Hispanics. Furthermore, we reveal an even greater scarcity in neuropathological studies involving Asian Americans, also a very heterogeneous group. We hope the presented findings will illuminate the paucity of minority representation in not just neuropathological research but the field of clinical research overall and serve to inspire clinicians and researchers to help reduce the health disparities underrepresented groups in the US face.</p> My-Le Nguyen, Emily Huie, Rachel Whitmer, Kristen George, Brittany Dugger Copyright (c) 2022 My-Le Nguyen, Emily Huie, Rachel Whitmer, Kristen George, Brittany Dugger Thu, 10 Mar 2022 00:00:00 +0100 Neuromuscular disease: 2022 update <p>This review highlights ten important advances in the neuromuscular disease field that were reported in 2021. As with prior updates in this article series, 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; (iii) diagnostic advances; and (iv) therapeutic advances. Within this general framework, the individual disease entities that are discussed in more detail include neuromuscular complications of COVID-19 (another look at the topic first covered in the 2021 review), autosomal recessive myopathy caused by MLIP mutations, autosomal recessive neuromuscular disease caused by VWA1 mutations, Leber’s hereditary optic neuropathy, myopathies with autophagic defects, tRNA synthetase-associated Charcot-Marie-Tooth disease, systemic sclerosis-associated myopathy, humoral immune endoneurial microvasculopathy, and late-onset Pompe disease. In addition, the review highlights a few other advances (including new insights into mechanisms of muscle and nerve regeneration and the use of gene expression profiling to better characterize different subtypes of immune-mediated myopathies) that will be of significant interest for clinicians and researchers who specialize in neuromuscular disease.</p> Marta Margeta Copyright (c) 2022 Marta Margeta Fri, 04 Mar 2022 00:00:00 +0100 Neurooncology: 2022 update <p><strong>Abstract</strong></p> <p>This ‘Neurooncology: 2022 update’ presents topics that were selected by the authors as top ten discoveries published in 2021 in the broader field of neurooncological pathology. This time, the spectrum of topics includes: papers with a direct impact on daily diagnostic practice of CNS tumors in general and with information on how to improve grading of meningiomas; studies shedding new light on the oncogenesis of gliomas (in particular ‘optic gliomas’ and H3-mutant gliomas); several ‘multi-omic’ investigations unraveling the intra-tumoral heterogeneity of especially glioblastomas further; a study indicating the potential of ‘repurposing’ Prozac®; for the treatment of glioblastomas; liquid biopsy using CSF for assessment of residual medulloblastoma. In the last part of this review some other papers are mentioned that didn’t make it to this (quite subjective) top ten list.</p> Pieter Wesseling, Jacob S. Rozowsky Copyright (c) 2022 Pieter Wesseling, Jacob S. Rozowsky Thu, 24 Feb 2022 00:00:00 +0100 Neuroinflammation: 2022 update <p>Besides important progress in the understanding of the pathological substrate of COVID-19-associated brain disease, major insights into mechanisms of neurodegeneration in human disease have been provided in neuropathological studies published in 2021. Recently developed techniques, which allow the simultaneous detection of a large battery of different molecules within single cells, have proven useful in the analysis of disease mechanisms in experimental and human neuroinflammatory conditions. They have elucidated protective and detrimental effects of activated microglia, which act in a stage and context-dependent manner in the induction and propagation of neurodegeneration. In addition, they emphasize the importance of synaptic damage and of selective neuronal vulnerability in the respective diseases. The results provide important new insights with high clinical relevance.</p> Hans Lassmann Copyright (c) 2022 Hans Lassmann Thu, 10 Feb 2022 00:00:00 +0100 66th Annual Meeting of the German Society of Neuropathology and Neuroanatomy (DGNN) - Meeting Abstracts, November 1–5, 2022 <p>Liebe Kolleginnen und Kollegen,</p> <p>&nbsp;</p> <p>zur 66. Jahrestagung der Deutschen Gesellschaft für Neuropathologie und Neuroanatomie im Rahmen der Neurowoche vom 1. bis zum 5. November 2022 begrüße ich Sie herzlich in Berlin.</p> <p>Die letzten Jahre haben eine enorme Erweiterung der analytischen Methodik mit Schwerpunkt auf molekularen Untersuchungen gebracht. Ein großer Teil dieser Untersuchungen wurde in unseren Einrichtungen entwickelt und wird dort erbracht. In der Tat hat sich die Neuropathologie zu einem Motor der neuroonkologischen und neurowissenschaftlichen Forschung entwickelt und deutschsprachige neuropathologische Institutionen haben wesentlich dazu beigetragen. Ganz neue Therapien bauen auf diese Erkenntnisse auf. Dadurch sind wir für die Versorgung unserer Patienten wichtiger denn jeher. Deswegen sehe ich einen großen und zunehmenden Bedarf dem wir Neuropathologen nachkommen müssen. Alle Schwerpunkte unseres Faches sind hiervon betroffen, die Gehirntumordiagnostik, die neurodegenerativen Erkrankungen, Entzündung und Erkrankungen der Muskeln und der Nerven. Wir arbeiten eng mit unseren Kollegen aus der Neuroonkologie, Neuropädiatrie, Neurologie Neurochirurgie und Neuroradiologie zusammen. Der interdisziplinäre Austausch hat einen hohen Stellenwert und wir freuen uns deshalb besonders, dass unsere Jahrestagung in diesem Jahr wieder im Rahmen der Neurowoche stattfindet, was die Kommunikation und den Wissenstransfer über die Fächergrenzen beflügelt.</p> <p>Dieses Jahr wollen wir besonders die jungen Neuropathologen und Neuropathologinnen in den Vordergrund stellen. Sie sollen unser Fach als lebendig und besonders zukunftsfähig erleben. Von ihnen erwarten wir die Dynamik, den Einsatz und den Ideenreichtum, der die Neuropathologie in den nächsten Jahren noch weiter zu einer zentralen Querschnittsplattform für die Neurofächer machen wird.</p> <p>Wir haben einen Kongressstrang mit wissenschaftlichen Sitzungen am Donnerstag, Freitag und Samstag ausgerichtet. Sie dürfen Vorträge mit jungen neuropathologischen Expertinnen und Experten sowie von jungen Nachwuchswissenschaftlerinnen und Nachwuchswissenschaftlern erwarten. Ich freue mich auf lebhafte Diskussionen und spannende interdisziplinäre Debatten!</p> <p>&nbsp;</p> <p>Ihr</p> <p>Prof. Dr. Andreas von Deimling</p> <p>Universitätsklinikum Heidelberg,<br>Neuropathologie</p> German Society of Neuropathology and Neuroanatomy (DGNN) Copyright (c) 2022 German Society of Neuropathology and Neuroanatomy (DGNN) Wed, 10 Aug 2022 00:00:00 +0200 5th Asian Oceanian Congress of Neuropathology along with the 5th Annual Conference of the Neuropathology Society of India - Meeting Abstracts, September 24–26, 2021 <p>The <strong>5<sup>th</sup> </strong><strong>Asian Oceanian Congress of Neuropathology along with the 5</strong><strong><sup> th</sup> Annual Conference of the Neuropathology Society of India (AOCN-NPSICON)</strong> was held in virtual mode on September 24–26, 2021, at National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India, hosted by the Department of Neuropathology. It had 361 attendees from 20 countries from Asia and Oceania including India.</p> <p>The event brought together pathologists, clinicians and neuroscientists from all over Asia and Oceania with invited speakers from the USA, Germany and Canada. The program was very comprehensive and covered advances in the fields of neurooncology with emphasis on the upcoming WHO 2021 classification of CNS tumors, neuromuscular disorders, epilepsy and neurodegenerative disorders through key note addresses and symposia that featured 78 distinguished international and national faculty sharing their expertise. In addition, there were case-based learning modules, opportunities for paper presentations and poster sessions for young faculty and postgraduates with several awards for young investigators, best papers and posters. A highlight of the conference was a unique debate on the hot topic of the decade: Methylation-based classification of CNS tumors and a panel discussion on COVID-19. The participants were highly appreciative of the academic content.</p> Neuropathology Society of India Copyright (c) 2022 Neuropathology Society of India Thu, 19 May 2022 00:00:00 +0200 Soluble brain homogenates from diverse human and mouse sources preferentially seed diffuse Aβ plaque pathology when injected into newborn mouse hosts <p><strong>Background: </strong>Seeding of pathology related to Alzheimer’s disease (AD) and Lewy body disease (LBD) by tissue homogenates or purified protein aggregates in various model systems has revealed prion-like properties of these disorders. Typically, these homogenates are injected into adult mice stereotaxically. Injection of brain lysates into newborn mice represents an alternative approach of delivering seeds that could direct the evolution of amyloid-β (Aβ) pathology co-mixed with either tau or α-synuclein (αSyn) pathology in susceptible mouse models.</p> <p><strong>Methods: </strong>Homogenates of human pre-frontal cortex were injected into the lateral ventricles of newborn (P0) mice expressing a mutant humanized amyloid precursor protein (APP), human P301L tau, human wild type αSyn, or combinations thereof. The homogenates were prepared from AD and AD/LBD cases displaying variable degrees of Aβ pathology and co-existing tau and αSyn deposits. Behavioral assessments of APP transgenic mice injected with AD brain lysates were conducted. For comparison, homogenates of aged APP transgenic mice that preferentially exhibit diffuse or cored deposits were similarly injected into the brains of newborn APP mice.</p> <p><strong>Results: </strong>We observed that lysates from the brains with AD (Aβ+, tau+), AD/LBD (Aβ+, tau+, αSyn+), or Pathological Aging (Aβ+, tau-, αSyn-) efficiently seeded diffuse Aβ deposits. Moderate seeding of cerebral amyloid angiopathy (CAA) was also observed. No animal of any genotype developed discernable tau or αSyn pathology. Performance in fear-conditioning cognitive tasks was not significantly altered in APP transgenic animals injected with AD brain lysates compared to nontransgenic controls. Homogenates prepared from aged APP transgenic mice with diffuse Aβ deposits induced similar deposits in APP host mice; whereas homogenates from APP mice with cored deposits induced similar cored deposits, albeit at a lower level.</p> <p><strong>Conclusions: </strong>These findings are consistent with the idea that diffuse Aβ pathology, which is a common feature of human AD, AD/LBD, and PA brains, may arise from a distinct strain of misfolded Aβ that is highly transmissible to newborn transgenic APP mice. Seeding of tau or αSyn comorbidities was inefficient in the models we used, indicating that additional methodological refinement will be needed to efficiently seed AD or AD/LBD mixed pathologies by injecting newborn mice.</p> Brenda D. Moore, Yona Levites, Guilian Xu, Hailey Hampton, Munir F. Adamo, Cara L. Croft, Hunter S. Futch, Corey Moran, Susan Fromholt, Christopher Janus, Stefan Prokop, Dennis Dickson, Jada Lewis, Benoit I. Giasson, Todd E. Golde, David R. Borchelt Copyright (c) 2022 Brenda D. Moore, Yona Levites, Guilian Xu, Hailey Hampton, Munir F. Adamo, Cara L. Croft, Hunter S. Futch, Corey Moran, Susan Fromholt, Christopher Janus, Stefan Prokop, Dennis Dickson, Jada Lewis, Benoit I. Giasson, Todd E. Golde, David R. Borchelt Wed, 23 Mar 2022 00:00:00 +0100 Cerebrovascular disease lesions are additive and tied to vascular risk factors and cognitive impairment <p>Cerebrovascular lesions are prevalent in late life and frequently co-occur but the relationship to cognitive impairment is complicated by the lack of consensus around which lesions represent hallmark pathologies for vascular impairment, particularly in the presence of Alzheimer’s disease (AD). We developed an easily applicable model of cerebrovascular disease (CVD), defined as the presence of two or more lesions: moderate to severe cerebral amyloid angiopathy, moderate to severe arteriolosclerosis, infarcts (large, lacunar, or micro), and/or hemorrhages. AD was defined as intermediate or high AD neuropathologic change. The contribution of vascular risk factors such as atherosclerosis and/or a health history of heart disease, hyperlipidemia, stroke events, diabetes, or hypertension was also assessed. Logistic regression analysis reported the association of CVD with increasing age, vascular risk factors, AD, and cognitive impairment in this study of 1,485 autopsied individuals. Cerebrovascular lesions were present in 48% and 16% had CVD. Increasing age associated with all lesions (p&lt;0.001), except hemorrhages (p=0.41). CVD was more likely in individuals with vascular risk factors or AD (p&lt;0.01). CVD, but not individual cerebrovascular lesions, associated with impairment in cases without AD (p&lt;0.01), but not in cases with AD (p&gt;0.61). From this, we conclude that a simple, additive model of CVD is 1) age and AD-associated, 2) is associated with vascular risk factors, and 3) clinically correlates with cognitive decline independent of AD.</p> John L Robinson, Hayley Richardson, Sharon X Xie, Brian Alfaro, Nicholas Loh, Virginia M-Y Lee, Edward B Lee, John Q Trojanowski Copyright (c) 2022 John L Robinson, Hayley Richardson, Sharon X Xie, Brian Alfaro, Nicholas Loh, Virginia M-Y Lee, Edward B Lee, John Q Trojanowski Mon, 14 Mar 2022 00:00:00 +0100 Neuropathological findings in possible normal pressure hydrocephalus: A post-mortem study of 29 cases with lifelines <p><strong>Aims:</strong> There are very few detailed post-mortem studies on idiopathic normal-pressure hydrocephalus (iNPH) and there is a lack of proper neuropathological criteria for iNPH. This study aims to update the knowledge on the neuropathology of iNPH and to develop the neuropathological diagnostic criteria of iNPH.<br /><strong>Methods:</strong> We evaluated the clinical lifelines and post-mortem findings of 29 patients with possible NPH. Pre-mortem cortical brain biopsies were taken from all patients during an intracranial pressure measurement or a cerebrospinal fluid (CSF) shunt surgery.<br /><strong>Results:</strong> The mean age at the time of the biopsy was 70±8 SD years and 74±7 SD years at the time of death. At the time of death, 11/29 patients (38%) displayed normal cognition or mild cognitive impairment (MCI), 9/29 (31%) moderate dementia and 9/29 (31%) severe dementia. Two of the demented patients had only scarce neuropathological findings indicating a probable hydrocephalic origin for the dementia. Amyloid-β (Aβ) and hyperphosphorylated τ (HPτ) in the biopsies predicted the neurodegenerative diseases so that there were 4 Aβ positive/low Alzheimer’s disease neuropathological change (ADNC) cases, 4 Aβ positive/intermediate ADNC cases, 1 Aβ positive case with both low ADNC and progressive supranuclear palsy (PSP), 1 HPτ/PSP and primary age-related tauopathy (PART) case, 1 Aβ/HPτ and low ADNC/synucleinopathy case and 1 case with Aβ/HPτ and high ADNC. The most common cause of death was due to cardiovascular diseases (10/29, 34%), followed by cerebrovascular diseases or subdural hematoma (SDH) (8/29, 28%). Three patients died of a postoperative intracerebral hematoma (ICH). Vascular lesions were common (19/29, 65%).<br /><strong>Conclusions:</strong> We update the suggested neuropathological diagnostic criteria of iNPH, which emphasize the rigorous exclusion of all other known possible neuropathological causes of dementia. Despite the first 2 probable cases reported here, the issue of “hydrocephalic dementia” as an independent entity still requires further confirmation. Extensive sampling (with fresh frozen tissue including meninges) with age-matched neurologically healthy controls is highly encouraged. </p> Joni J. Hänninen, Madoka Nakajima, Aleksi Vanninen, Santtu Hytönen, Jaana Rummukainen, Anne Maria Koivisto, Juha E. Jääskeläinen, Hilkka Soininen, Anna Sutela, Ritva Vanninen, Mikko Hiltunen, Ville Leinonen, Tuomas Rauramaa Copyright (c) 2022 Joni J. Hänninen, Madoka Nakajima, Aleksi Vanninen, Santtu Hytönen, Jaana Rummukainen, Anne Maria Koivisto, Juha E. Jääskeläinen, Hilkka Soininen, Anna Sutela, Ritva Vanninen, Mikko Hiltunen, Ville Leinonen, Tuomas Rauramaa Wed, 26 Jan 2022 00:00:00 +0100 My pathway to a career in neuropathology Clive Harper Copyright (c) 2022 Henry Robbert; Clive Harper Tue, 12 Apr 2022 00:00:00 +0200 Pigmented ependymoma, a tumor with predilection for the middle-aged adult: case report with methylation classification and review of 16 literature cases <p>Ependymomas have rarely been described to contain pigment other than melanin, neuromelanin, lipofuscin or a combination. In this case report, we present a pigmented ependymoma in the fourth ventricle of an adult patient and review 16 additional cases of pigmented ependymoma from the literature. A 46-year-old female showed up with hearing loss, headaches, and nausea. Magnetic resonance imaging revealed a 2.5 cm contrast-enhancing cystic mass in the fourth ventricle, which was resected. Intraoperatively, the tumor appeared grey-brown, cystic, and was adherent to the brainstem. Routine histology revealed a tumor with true rosettes, perivascular pseudorosettes and ependymal canals consistent with ependymoma, but also showed chronic inflammation and abundant distended pigmented tumor cells that mimicked macrophages in frozen and permanent sections. The pigmented cells were positive for GFAP and negative for CD163 consonant with glial tumor cells. The pigment was negative for Fontana-Masson, positive for Periodic-acid Schiff and autofluorescent, which coincide with characteristics of lipofuscin. Proliferation indices were low and H3K27me3 showed partial loss. H3K27me 3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates the tri-methylation of lysine 27 on histone H3 protein. This methylation classification was compatible with a posterior fossa group B ependymoma (EPN_PFB). The patient was clinically well without recurrence at three-month post-operative follow-up appointment. Our analysis of all 17 cases, including the one presented, shows that pigmented ependymomas are most common in the middle-aged with a median age of 42 years and most have a favorable outcome. However, one patient that also developed secondary leptomeningeal melanin accumulations died. Most (58.8%) arise in the 4th ventricle, while spinal cord (17.6%) and supratentorial locations (17.6%) were less common. The age of presentation and generally good prognosis raise the question of whether most other posterior fossa pigmented ependymomas may also fall into the EPN_PFB group, but additional study is required to address that question.</p> Alexander Himstead, Mari Perez-Rosendahl, Gianna Fote, Angie Zhang, Michael Kim, David Floriolli, Martha Quezado, Kenneth Aldape, Drew Pratt, Zied Abdullaev, Edwin Monuki, Frank Hsu, William Yong Copyright (c) 2022 Alexander Himstead, Mari Perez-Rosendahl, Gianna Fote, Angie Zhang, Michael Kim, David Floriolli, Martha Quezado, Kenneth Aldape, Drew Pratt, Zied Abdullaev, Edwin Monuki, Frank Hsu, William Yong Fri, 08 Jul 2022 00:00:00 +0200 Medulloblastoma and Cowden Syndrome: Further Evidence of an Association <p>Cowden syndrome (CS) is an autosomal dominant hamartoma and tumor predisposition syndrome caused by heterozygous pathogenic germline variants in <em>PTEN</em> in most affected individuals. Major features include macrocrania, multiple facial tricholemmomas, acral and oral keratoses and papillomas, as well as mammary, non-medullary thyroid, renal, and endometrial carcinomas. Lhermitte-Duclos disease (LDD), or dysplastic gangliocytoma of the cerebellum, is the typical brain tumor associated with CS; the lifetime risk for LDD in CS patients has been estimated to be as high as 30%. In contrast, medulloblastoma is much rarer in CS, with only 4 reported cases in the literature. We report a 5th such patient. All 5 patients were diagnosed between 1 and 2 years of age and not all showed the pathognomonic clinical stigmata of CS at the time of their medulloblastoma diagnosis. Where detailed information was available, the medulloblastoma was of the SHH-subtype, in keeping with the observation that in sporadic medulloblastomas, <em>PTEN</em>-alterations are usually encountered in the SHH-subtype. Medulloblastomas can be associated with several tumor-predisposition syndromes and of the 4 medulloblastoma subtypes, SHH-medulloblastomas in children have the highest prevalence of predisposing germline variants (approx. 40%). CS should be added to the list of SHH-medulloblastoma-associated syndromes. Germline analysis of <em>PTEN </em>should be performed in infants with SHH-medulloblastomas, regardless of their clinical phenotype, especially if they do not carry pathogenic germline variants in <em>PTCH1 </em>or <em>SUFU, </em>the most commonly altered predisposing genes in this age-group. In addition, these cases show that CS has a biphasic brain tumor distribution, both in regards to the age of onset and the tumor type: a small number of CS patients develop a medulloblastoma in infancy while many more develop LDD in adulthood.</p> Steffen Albrecht, Barbara Miedzybrodzki, Laura Palma, Van Hung Nguyen, Roy W.R. Dudley, Torsten Pietsch, Tobias Goschzik, Nada Jabado, Catherine Goudie, William D. Foulkes Copyright (c) 2022 Steffen Albrecht, Barbara Miedzybrodzki, Laura Palma, Van Hung Nguyen, Roy W.R. Dudley, Torsten Pietsch, Tobias Goschzik, Nada Jabado, Catherine Goudie, William D. Foulkes Tue, 11 Jan 2022 00:00:00 +0100