Reviews

John Fonda Crary
Free Neuropathol 2: 9 (2021)
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.
 
Alfonsa Zamora-Moratalla, María Martínez de Lagrán, Mara Dierssen
Free Neuropathol 2: 6 (2021)
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 de novo 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.
 
Pieter Wesseling
Free Neuropathol 2: 5 (2021)
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.
 
Daniel P. Perl
Free Neuropathol 2: 4 (2021)
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.
 
Marta Margeta
Free Neuropathol 2: 3 (2021)
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.
 
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
Free Neuropathol 2: 2 (2021)
Coronavirus disease 2019 (COVID-19) is emerging as the greatest public health crisis in the early 21st 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.
 
Hans Lassmann
Free Neuropathol 2: 1 (2021)
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.
 
Kurt A. Jellinger
Free Neuropathol 1: 32 (2020)
Alzheimer’s disease (AD), the most common form of dementia worldwide, is a mixed proteinopathy (amyloid and tau). Originally defined as a clinicopathological entity, it is a heterogenous, multifactorial disorder, currently referred to as the Alzheimer’s continuum. Its cardinal pathological features are extracellular β-amyloid (amyloid plaques) and intraneuronal tau aggregates forming neurofibrillary tangles, which are accompanied by vascular amyloid deposits (cerebral amyloid angiopathy), synapse and neuronal loss, as well as neuroinflammation and reactive astrogliosis. In addition to “typical” AD, various subtypes with characteristic regional patterns of tau pathology have been described that show distinct clinical features, biomarker levels, and patterns of key network destructions responsible for cognitive decline. AD is frequently associated with other age-related changes including Lewy and TDP-43 pathologies, hippocampal sclerosis, argyrophilic grain disease, cerebrovascular lesions, and others. These additional pathologies influence the clinical picture of AD, may accelerate disease progression, and can cause a number of challenges in our understanding of the disease including the threshold of each individual pathology to cause dementia and the possibility of underlying common etiologies. This article provides an up-to-date overview of AD neuropathology, its heterogeneity, and additional pathologies in order to explain the difficulties in the diagnosis and the failure of clinical trials in AD patients.
 
Lary C Walker
Free Neuropathol 1: 31 (2020)
Aβ plaques are one of the two lesions in the brain that define the neuropathological diagnosis of Alzheimer’s disease. Plaques are highly diverse structures; many of them include massed, fibrillar polymers of the Aβ protein referred to as Aβ-amyloid, but some lack the defining features of amyloid. Cellular elements in ‘classical’ plaques include abnormal neuronal processes and reactive glial cells, but these are not present in all plaques. Plaques have been given various names since their discovery in 1892, including senile plaques, amyloid plaques, and neuritic plaques. However, with the identification in the 1980s of Aβ as the obligatory and universal component of plaques, the term ‘Aβ plaques’ has become a unifying term for these heterogeneous formations. Tauopathy, the second essential lesion of the Alzheimer’s disease diagnostic dyad, is downstream of Aβ-proteopathy, but it is critically important for the manifestation of dementia. The etiologic link between Aβ-proteopathy and tauopathy in Alzheimer’s disease remains largely undefined. Aβ plaques develop and propagate via the misfolding, self-assembly and spread of Aβ by the prion-like mechanism of seeded protein aggregation. Partially overlapping sets of risk factors and sequelae, including inflammation, genetic variations, and various environmental triggers have been linked to plaque development and idiopathic Alzheimer’s disease, but no single factor has emerged as a requisite cause. The value of Aβ plaques per se as therapeutic targets is uncertain; although some plaques are sites of focal gliosis and inflammation, the complexity of inflammatory biology presents challenges to glia-directed intervention. Small, soluble, oligomeric assemblies of Aβ are enriched in the vicinity of plaques, and these probably contribute to the toxic impact of Aβ aggregation on the brain. Measures designed to reduce the production or seeded self-assembly of Aβ can impede the formation of Aβ plaques and oligomers, along with their accompanying abnormalities; given the apparent long timecourse of the emergence, maturation and proliferation of Aβ plaques in humans, such therapies are likely to be most effective when begun early in the pathogenic process, before significant damage has been done to the brain. Since their discovery in the late 19th century, Aβ plaques have, time and again, illuminated fundamental mechanisms driving neurodegeneration, and they should remain at the forefront of efforts to understand, and therefore treat, Alzheimer’s disease.
 
Kurt A. Jellinger
Free Neuropathol 1: 17 (2020)
Multiple system atrophy (MSA) is a fatal, adult-onset neurodegenerative disorder of uncertain etiology, clinically characterized by various combinations of Levo-dopa-unresponsive parkinsonism, and cerebellar, motor, and autonomic dysfunctions. MSA is an α-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, autonomic and peripheral nervous systems. The pathologic hallmark of this unique proteinopathy is the deposition of aberrant α-synuclein (αSyn) in both glia (mainly oligodendroglia) and neurons forming pathological inclusions that cause cell dysfunction and demise. The major variants are striatonigral degeneration (MSA with predominant parkinsonism / MSA-P) and olivopontocerebellar atrophy (MSA with prominent cerebellar ataxia / MSA-C). However, the clinical and pathological features of MSA are broader than previously considered. Studies in various mouse models and human patients have helped to better understand the molecular mechanisms that underlie the progression of the disease. The pathogenesis of MSA is characterized by propagation of disease-specific strains of αSyn from neurons to oligodendroglia and cell-to-cell spreading in a "prion-like" manner, oxidative stress, proteasomal and mitochondrial dysfunctions, myelin dysregulation, neuroinflammation, decreased neurotrophic factors, and energy failure. The combination of these mechanisms results in neurodegeneration with widespread demyelination and a multisystem involvement that is specific for MSA. Clinical diagnostic accuracy and differential diagnosis of MSA have improved by using combined biomarkers. Cognitive impairment, which has been a non-supporting feature of MSA, is not uncommon, while severe dementia is rare. Despite several pharmacological approaches in MSA models, no effective disease-modifying therapeutic strategies are currently available, although many clinical trials targeting disease modification, including immunotherapy and combined approaches, are under way. Multidisciplinary research to elucidate the genetic and molecular background of the noxious processes as the basis for development of an effective treatment of the hitherto incurable disorder are urgently needed.
 
János Bencze, Woosung Seo, Abdul Hye, Dag Aarsland, Tibor Hortobágyi
Free Neuropathol 1: 7 (2020)
Dementia is one of the major burdens of our aging society. According to certain predictions, the number of patients will double every 20 years. Although Alzheimer’s disease (AD), as the most frequent neurodegenerative dementia, has been extensively analysed, less is known about dementia with Lewy bodies (DLB). Neuropathological hallmarks of DLB are the deposition of intracellular Lewy bodies (LB) and Lewy neurites (LN). DLB belongs to the α-synucleinopathies, as the major component of these inclusions is pathologically aggregated α-synuclein. Depending on the localization of LBs and LNs in the central nervous system cognitive and motor symptoms can occur. In our work, we will systematically review the possible etiology and epidemiology, pathological (both macroscopic and microscopic) features, structural and functional imaging findings, with a special emphasis on the clinico-pathological correlations. Finally, we summarize the latest clinical symptoms-based diagnostic criteria and the novel therapeutic approaches. Since DLB is frequently accompanied with AD pathology, highlighting possible differential diagnostic approaches is an integral part of our paper. Although our present knowledge is insufficient, the rapid development of diagnostic and research methods provide hope for better diagnosis and more efficient treatment, contributing to a better quality of life.
 
Mara Dierssen
Free Neuropathol 1: 13 (2020)
Developmental brain disorders, a highly heterogeneous group of disorders with a prevalence of around 3% of worldwide population, represent a growing medical challenge. They are characterized by impaired neurodevelopmental processes leading to deficits in cognition, social interaction, behavior and motor functioning as a result of abnormal development of brain. This can include developmental brain dysfunction, which can manifest as neuropsychiatric problems or impaired motor function, learning, language or non-verbal communication. Several of these phenotypes can often co-exist in the same patient and characterize the same disorder. Here I discuss some contributions in 2019 that are shaking our basic understanding of the pathogenesis of neurodevelopmental disorders. Recent developments in sophisticated in-utero imaging diagnostic tools have raised the possibility of imaging the fetal human brain growth, providing insights into the developing anatomy and improving diagnostics but also allowing a better understanding of antenatal pathology. On the other hand, advances in our understanding of the pathogenetic mechanisms reveal a remarkably complex molecular neuropathology involving a myriad of genetic architectures and regulatory elements that will help establish more rigorous genotype-phenotype correlations.
 
John Fonda Crary
Free Neuropathol 1: 12 (2020)
As we embark on a new year of scientific inquiry in neurodegenerative disease research, it is helpful to take a look back and consider the contributions in the field with the potential to be the most impactful. The purpose of this review is to highlight recent advances in 2019 which have the potential to be transformative in the field of neurodegenerative neuropathology. Substantive scientific progress rarely occurs as a “eureka moment”, and when possible, we opted to highlight collaborative efforts and research trends. We also included groundbreaking methodologies and tools. The generous increases in federal funding in the United States and elsewhere have massively expanded the total number of active programs researching Alzheimer’s disease. This exacerbates an imbalance, and an effort was made to highlight innovations across disease categories, and not to permit dementia to crowd out movement disorders, motor neuron disease, ataxias, etc. Thus, our overall goal was to highlight some of the most important discoveries, tools or methods that we feel will most likely directly enhance our ability to understand and diagnose neurodegenerative brain diseases. Given space limitations and the targeted readership of this journal, we selected ten topics most relevant to neuropathologists and clinical neuroscientists: 1. A new neurodegenerative disease category, 2. A new approach to probing gene expression on the single cell level, 3. A new approach merging histology and gene expression profiling, 4. A new computational approach using deep machine learning and computer vision, 5. A neuropathological substrate for sleep disturbance in Alzheimer’s disease, 6. A candidate pathogenic agent for Alzheimer’s disease, 7. A comprehensive approach to morphometric analysis of cerebellar neurodegeneration, 8. The strongest evidence yet linking neurodegeneration to contact sports, 9. Mounting evidence for gut to central nervous system transmission in Parkinson’s disease, and 10. A spotlight on glia in Huntington’s disease.
 
Daniel P Perl
Free Neuropathol 1: 10 (2020)
Neurotrauma represents a major public health problem and is one of the leading causes of death and disability worldwide. Despite its high prevalence, there are major gaps in our understanding of the underlying patho-physiology leading to the substantial morbidity and mortality associated with this problem. Here, ten studies published in 2019 are reviewed that addressed issues related to the acute and long-term effects of neurotrau-ma. These studies can be broken down into three separate categories, namely, the importance of neurotrau-ma-based damage to the cerebrovascular unit, white matter damage following neurotrauma, and research related to the long-term neurodegenerative consequences of repeated head trauma, especially chronic trau-matic encephalopathy. The advances highlighted here indicate that progress has been made. However, major gaps in knowledge remain which will require additional neuropathologic studies of clinical specimens, as well as the development and investigation of a wide range of relevant pre-clinical models. Further efforts in this field are clearly needed if there are to emerge better clinical outcomes for the numerous patients that suffer neuro-trauma each year as well as those currently suffering from its long-term effects.
 
Pieter Wesseling
Free Neuropathol 1: 8 (2020)
This article briefly discusses 10 topics that were selected by the author as top 10 discoveries published in 2019 in the broader field of neuro-oncological pathology (so including neurosciences as well as clinical neuro-oncology but with implications for neuro-oncological pathology). Some topics concern new information on immunohistochemical and molecular markers that enable improved diagnosis of particular tumors of the central nervous system (CNS) and information on a refined classification of medulloblastomas. Subsequently, several papers are discussed that further elucidate some pathobiological aspects of especially medulloblastomas (histogenesis, molecular evolution) and diffuse gliomas (mechanisms involved in CNS infiltration, role of cancer stem(-like) cells, longitudinal molecular evolution). The remaining topics concern progress made in vaccination therapy for glioblastomas and in using cerebrospinal fluid for liquid biopsy diagnosis of gliomas. Clearly, substantial, and sometimes even amazing progress has been made in increasing our understanding in several areas of neuro-oncological pathology. At the same time, almost every finding raises new questions, and translation of new insights in improving the outcome for patients suffering from CNS tumors remains a huge challenge.
 
Anna Maria Planas
Free Neuropathol 1: 5 (2020)
The aim of this review is to highlight novel findings in 2019 in the area of neurovascular disease. Experimental studies have provided insight into disease development, molecular determinants of pathology, and putative novel therapeutic targets. Studies in genetic experimental models as well as monogenic forms of human cere-brovascular diseases identified pathogenic molecules that may also be relevant to sporadic cases. There have been advances in understanding the development of cerebral cavernous angiomas and arteriovenous malfor-mations, and putative curative treatments have been suggested from experimental models. Key pathogenic pathways involved in vessel calcification and stiffness have also been identified. At the cellular level, studies showed that proper function of endothelial and mural cells, particularly pericytes, is crucial to ensure full endo-thelial differentiation and blood-brain barrier integrity. Moreover, recent discoveries support the existence of a homeostatic crosstalk between vascular cells and other neural cells, including neurons. Cerebrovascular diseas-es are strongly associated with inflammation. Beyond pathogenic roles of specific components of the inflam-matory response, new discoveries showed interesting interactions between inflammatory molecules and regu-lators of vascular function. Clinical investigation on cerebrovascular diseases has progressed by combining ad-vanced imaging and genome-wide association studies. Finally, vascular cognitive impairment and dementia are receiving increasing attention. Recent findings suggest that high-salt intake may cause cerebrovascular dys-function and cognitive impairment independent of hypoperfusion and hypertension. These and other recent reports will surely inspire further research in the field of cerebrovascular disease that will hopefully contribute to improved prevention and treatment.
 
Marta Margeta
Free Neuropathol 1: 4 (2020)
This review highlights ten important advances in the neuromuscular disease field that either were first reported in 2019, or have reached a broad consensus during that year. The overarching topics include (i) new / emerging diseases; (ii) advances in understanding of disease etiology and pathogenesis; (iii) diagnostic advances; and (iv) therapeutic advances. Within this broad framework, the individual disease entities that are discussed in more detail include myoglobinopathy, POPDC3-mutated limb-girdle muscular dystrophy, neuromuscular adverse events associated with the immune checkpoint inhibition therapy, neuroglial stem cell-derived inflammatory pseudotumor of the spinal cord and spinal cord roots, acute flaccid myelitis, congenital myopathies, idiopathic inflammatory myopathies (with particular emphasis on immune-mediated necrotizing myopathies and sporadic inclusion body myositis), spinal muscular atrophy, and Duchenne muscular dystrophy. In addition, the review highlights several diagnostic advances (such as diagnostic RNA sequencing and development of digital diagnostic tools) that will likely have a significant impact on the overall neuromuscular disease field going forward.
 
Hans Lassmann
Free Neuropathol 1: 3 (2020)
Ten neuropathological studies, published in 2019, are discussed, which address important aspects of neuroimmunology and inflammatory brain disease. They include topics related to new mechanisms of inflammation and immune mediated neurodegeneration, which are relevant for multiple sclerosis (publications 1 to 4) and discuss the role of specific autoantibodies against myelin oligodendrocyte glycoprotein or aquaporin 4 in neuromyelitis optica spectrum disorders (publications 5 and 6). Other studies highlight the discovery of new virus induced diseases of the nervous system and their relevance for clinical neurology and diagnostic neuropathology (publications 7 and 8). Finally, very interesting studies are discussed dealing with microglia and immune mechanisms in neurodegeneration (publication 9) and the neuropathological long-term outcome of Aß vaccination in Alzheimer’s disease (publication 10). All these studies highlight the central role of neuropathology in neurological disease research.