System Pathology Research Articles

Metabolic Reprogramming of Astrocytes in Pathological Conditions: Implications for Neurodegenerative Diseases.

Astrocytes play a pivotal role in maintaining brain energy homeostasis, supporting neuronal function through glycolysis and lipid metabolism. This review explores the metabolic intricacies of astrocytes in both physiological and pathological conditions, highlighting their adaptive plasticity and diverse functions. Under normal conditions, astrocytes modulate synaptic activity, recycle neurotransmitters, and maintain the blood-brain barrier, ensuring a balanced energy supply and protection against oxidative stress. However, in response to central nervous system pathologies such as neurotrauma, stroke, infections, and neurodegenerative diseases like Alzheimer's and Huntington's disease, astrocytes undergo significant morphological, molecular, and metabolic changes. Reactive astrocytes upregulate glycolysis and fatty acid oxidation to meet increased energy demands, which can be protective in acute settings but may exacerbate chronic inflammation and disease progression. This review emphasizes the need for advanced molecular, genetic, and physiological tools to further understand astrocyte heterogeneity and their metabolic reprogramming in disease states.

Tumefactive Multiple Sclerosis: The Lethal Chameleon.

Tumefactive multiple sclerosis is an uncommon variant of multiple sclerosis that presents a substantial diagnostic challenge due to its potential to resemble the clinical and radiological characteristics of other central nervous system (CNS) pathologies, including neoplasms, granulomatous diseases, abscesses and vasculitis.Despite the fact that multimodal imaging studies may help narrow the differential diagnosis, a biopsy is often required to reach a definitive diagnosis and should not be delayed.Awareness of this condition among non-neurologists is critical since a timely and accurate diagnosis prompts aggressive immunomodulatory treatments that may delay a second demyelinating event or progression to clinically definite multiple sclerosis.

Effect of pseudorabies virus infection on NMDA receptor expression in mice and its role in immunosuppression

Pseudorabies virus (PRV), an α-herpesvirus, induces immunosuppression and can lead to severe neurological diseases. N-methyl-D-aspartate receptor (NMDAR), an important excitatory nerve receptor in the central nervous system, is linked to various nervous system pathologies. The link between NMDAR and PRV-induced neurological diseases has not been studied. In vivo studies revealed that PRV infection triggers a reduction in hippocampal NMDAR expression, mediated by inflammatory processes. Extensive hippocampal neuronal degeneration was found in mice on the 6th day by hematoxylin-eosin staining, which was strongly correlated with increased NMDAR protein expression. In vitro studies utilizing the CCK-8 assay demonstrated that treatment with an NMDAR antagonist significantly heightened the cytotoxic effects of PRV on T lymphocytes. Notably, NMDAR inhibition did not affect the replication ability of PRV. However, it facilitated the accumulation of pro-inflammatory cytokines in PRV-infected T cells and enhanced the transcription of the CD25 gene through the secretion of interleukin-2 (IL-2), consequently exacerbating immunosuppression. In this study, we found that NMDAR has functional activity in T lymphocytes and is crucial for the inflammatory and immune responses triggered by PRV infection. These discoveries highlight the significant role of NMDAR in PRV-induced neurological disease pathogenesis.

(196) VAGINAL REJUVENATION BY LASER OR RADIOFREQUENCY: A SYSTEMATIC REVIEW OF THE LITERATURE

Abstract Introduction Vaginal rejuvenation refers to a variety of procedures that aim to improve genitourinary function or cosmetics. Local estrogen is the current standard of care to address complaints of vulvovaginal atrophy and vaginal laxity. However, energy-based treatments have become an emerging treatment option. Following an FDA statement in 2018 expressing concern over alleged lack of supporting evidence, laser and radiofrequency treatment of the vagina remains somewhat controversial. Objective Provide an updated review of the literature in order to summarize the efficacy and safety of laser and radiofrequency vaginal rejuvenation procedures. Methods The PubMed, EMBASE, and CENTRAL databases were queried for English-language studies published between November 2018 and June 17th, 2024 with a variety of terms associated with vaginal rejuvenation, including but not limited to, “vaginal” or “vagina” and “genitourinary syndrome of menopause” or “rejuvenation” or “vulvovaginal atrophy” or “vaginal atrophy”. Searches also included “laser” or “erbium-doped yttrium aluminum garnet” or “diode” or “carbon dioxide” or “CO2” or “radiofrequency” or “thermal”. Studies were included if they included at least one patient 18 years of age and older undergoing laser or radiofrequency therapy of the vagina for a specific vaginal or lower urinary complaint. Studies with purely cosmetic indications were excluded, as were studies with combined therapies, animal or cadaver models, or participants with active infectious or neoplastic pathology of the genitourinary system. Additionally, studies must have been available in full text and reported clinical outcome data, including standardized measures of patient reported outcomes and qualitative symptom data. Studies that did not explicitly report the presence or absence of adverse effects were excluded. Results A total of 1374 studies were identified (EMBASE = 792, PubMed = 376, CENTRAL = 206). 337 duplicates were excluded and 1059 studies were ultimately screened. 77 studies were included with a total number of 5,143 patients. 27 of these were randomized controlled trials, 40 were prospective interventional studies, and 10 were retrospective studies. A majority (79.2%) used laser treatment for vaginal rejuvenation. Indication for rejuvenation was stress urinary incontinence in 18 studies and genitourinary syndrome of menopause or its related symptoms in the remaining 59. 93.5% (N = 72/77) of the studies reported improvements in patient-reported outcomes. Just under half (49.4%) of the studies reported at least minor or transient adverse effects of the treatment. These included vaginitis, leukorrhea, vaginal pain, dysuria, and urinary tract infection among others. Conclusions Laser and radiofrequency treatment of the vagina has demonstrated improvement in patient-reported outcomes for genitourinary symptoms associated with vaginal atrophy and urinary incontinence. Adverse effects of vaginal rejuvenation in the literature are minor, suggesting that this is a safe and effective option with post-menopausal complaints requiring vaginal rejuvenation. Disclosure No.

Late diagnosis of chronic inflammatory demyelinating polyneuropathy on the background of misdiagnosed alcoholic polyneuropathy: a clinical case

Chronic inflammatory demyelinating polyneuropathy is a rare immune-mediated polyneuropathy pathology of the peripheral nervous system. The presence of etiological factors in the patient, such as type 1 and 2 diabetes mellitus, alcohol intoxication in the anamnesis or other causes of polyneuropathy, which are often found in practice, can disguise chronic inflammatory demyelinating polyneuropathy and lead to delayed diagnosis of potentially curable polyneuropathy, which further increases the likelihood of disability of the patient and a significant decrease in the quality of his life. The clinical case under consideration is a demonstration of such diagnostic difficulties, which led to a delayed diagnosis of chronic inflammatory demyelinating polyneuropathy against the background of alcohol abuse in the debut of neurological disorders.

Surfactant system of the lungs in antiphospholipid syndrome under the conditions of administration of the immunosuppressive agent FTY-720

Antiphospholipid syndrome (APS) is a thrombophilic disease in the pathogenesis of which the leading role belongs to antibodies reacting with antigenic determinants of phospholipids. APS is a systemic autoimmune pathology that involves many organs and systems in the pathological process, including the respiratory system. Given the fact that the lung surfactant is mainly represented by phospholipids, it can be presented that the surfactant is damaged and its functioning is impaired in APS. The results of our experiments showed that in antiphospholipid syndrome, there was a decline in the functional activity of the surfactant and a change in its biochemical composition. The introduction of FTY-720 normalized the parameters of the lung surfactant system, which were changed during the modeling of antiphospholipid syndrome. The work shows the effectiveness of the therapy of this autoimmune pathology with immunosuppressor FTY-720, which is a structural analogue of endogenous sphingosine. The effect of the drug is based on the modulation of sphingosine-1 phosphate receptors of lymphocytes. The main effect of the immunosuppressor FTY-720 as a result of receptor interaction is a decrease in the number of circulating lymphocytes. The research involved 85 white random bred male rats: Group 1 (APS modeling) consisted of 30 rats who were intravenously injected with cardiolipin antigen at a total dose of 0.2-0.4 mg per rat every other day for three weeks; Group 2 (control) consisted of 25 rats who were injected with 0.9% NaCl solution according to the same scheme; and Group 3 including 30 rats in which APS was combined with the administration of the immunosuppressive agent FTY-720 (intraperitoneally 1 mg/kg of animal weight). Three weeks later, there was an operation conducted with the purpose of extraction of the bronchopulmonary complex. After extraction of the bronchopulmonary complex, its triple lavage was carried out with 0.9% NaCl solution. The material of the experimental study was a lavage liquid, in which the biophysical and biochemical parameters of the surfactant were studied. Langmuir–Blodgett method was used to identify static, minimal and maximal surface tension. These figures were used to identify integrative indicator reflecting surfactant characteristics – the Clements stability index. The fractional composition of surfactant phospholipids was determined by thin-layer chromatography. The results of our experiments showed that in antiphospholipid syndrome, there was a decline in the functional activity of the surfactant and a change in its biochemical composition. The introduction of FTY-720 normalized the parameters of the lung surfactant system, which were changed during the modeling of antiphospholipid syndrome.

Hypoparathyroidism: A dark horse differential in young age cataracts

In India, cataracts account for the lion’s share of cases of blindness. Age is still the single most important risk factor for cataracts. Cataracts in the young adult age group are less common and are usually secondary to various local and systemic conditions. The aetiology may be a challenging one to ascertain in certain cases of young-age cataracts. A rapidly developing cataract in a young age individual may further add to the diagnostic dilemma especially when the patient presents with multi-system affection necessitating the widening of the horizons of suspected local and systemic pathologies at play. Therefore, we report a case of a 25-year-old lady who presented with a history of seizures, headache, disc oedema and progressive bilateral blurring of vision due to rapidly developing cataracts over 4 months in a case of primary hypoparathyroidism. Correction of the underlying abnormalities resulted in the resolution of disc oedema and headache. Furthermore, the patient had no episodes of seizures in the 1½ years of follow-up. In addition, full visual recovery was achieved after bilateral cataract surgery. Awareness of this rare presentation can help in the early diagnosis and evaluation of cataracts, besides correction of the systemic pathologies for an overall better patient outcome.

Urolithiasis in children and adults. Pathogenetic mechanisms of development and modern approaches to its prevention

Urolithiasis and crystalluria rank first in the structure of pathology of the uri nary system in children and adults. Despite a significant number of publications on urolithiasis, many issues of pathogenesis, the peculiarities of the course of its various types, and, especially, the prevention of the occurrence and metaphylaxis of its relaps es require further study. The analysis of modern literary sources presented in leading search engines, Russian and European clinical recommendations on this problem, as well as the results of our own research allowed us to identify the main pathogenetic links of the most common types of crystalluria and urolithiasis. Dietary and metabolic approaches and herbal therapy are proposed for the prevention and metaphylaxis of urolithiasis in children and adults.

Visual Field Defects and Retinal Nerve Fiber Layer Thickness in Migraine Patients: A Study From a Tertiary Care Center in India.

Background This study aimed to analyze the visual field changes and retinal nerve fiber layer (RNFL) thickness during the headache phase of migraine attacks among migraine patients compared with controls. Methodology A prospective, case-control study was conducted at a tertiary care center in Palakkad, Kerala from January 2022 to August 2023. This study included 50 migraine patients and 50 age/gender-matched controls. Adults aged 20-40 years with a more than three-year history of migraine were included in this study and those who had systemic or ocular pathologies were excluded. All 100 subjects underwent complete ocular examination, including full threshold 24-2 automated perimetry for visual field analysis and optical coherence tomography for analyzing RNFL thickness. Statistical analysis was done using SPSS Statistics Version 25 (IBM Corp., Armonk, NY, USA). Results In this study, the average age for cases was 29.24 ± 5.10 years, and for controls was 30.12 ± 6.20 years. Gender distribution was identical between cases and controls with 29 (58%) females and 21 (42%) males. Among the 50 migraine patients, 22 (44%) had generalized, while 28 (56%) had localized field defects during the headache phase of migraine attacks. There was a statistically significant (p < 0.001) difference in superior quadrant RNFL thickness between cases (114.08 ± 12.25) and controls. Conclusions We found that RNFL thinning in the superior quadrant and non-specific localized visual field changes occur during migraine attacks. We conducted this study in a tertiary care center as very few studies in our country have revealed visual field changes during migraine headache attacks.

Diet outperforms microbial transplant to drive microbiome recovery post-antibiotics.

High-fat, low-fiber Western-style diets (WD) induce microbiome dysbiosis characterized by reduced taxonomic diversity and metabolic breadth, which in turn increases risk for a wide array of metabolic, immune and systemic pathologies. Recent work has established that WD can impair microbiome resilience to acute perturbations like antibiotic treatment, although we know little about the mechanism of impairment and the specific host consequences of prolonged post-antibiotic dysbiosis. Here, we characterize the trajectory by which the gut microbiome recovers its taxonomic and functional profile after antibiotic treatment in mice on regular chow (RC) and WD, and find that only mice on RC undergo a rapid successional process of recovery. Metabolic modeling indicates that RC diet promotes the development of syntrophic cross-feeding interactions, while on WD, a dominant taxon monopolizes readily available resources without releasing syntrophic byproducts. Intervention experiments reveal that an appropriate dietary resource environment is both necessary and sufficient for rapid and robust microbiome recovery, whereas microbial transplant is neither. Furthermore, prolonged post-antibiotic dysbiosis in mice on WD renders them susceptible to infection by the intestinal pathogen Salmonella enterica serovar Typhimurium. Our data challenge widespread enthusiasm for fecal microbiota transplant (FMT) as a strategy to address dysbiosis and demonstrate that specific dietary interventions are, at minimum, an essential prerequisite for effective FMT, and may afford a safer, more natural, and less invasive alternative to FMT.

Evaluation and Significance of Nonvisualization of the Cavum Septum Pellucidum on Prenatal Ultrasonography.

The identification of the cavum septum pellucidum (CSP) is an integral part of the routine second trimester fetal anatomy scan. The absence or nonvisualization of the CSP has significant clinical implications and requires further evaluation and counseling for the pregnant patient. The aim of this review is to review the importance of accurate sonographic identification of the CSP and the underlying pathologies that can be associated with nonvisualization of this structure. A literature review was performed with PubMed using key words including CSP, fetal anatomy ultrasound, and fetal anomalies. The absence of the CSP is associated with several central nervous system pathologies, all with a wide range of phenotypic outcomes, ranging from normal to very severe or lethal. Most obstetrician-gynecologists will have a patient in whom a CSP is not identified on fetal ultrasound. Thus, it is imperative to have a general understanding of this relatively common entity.

Evaluation and Significance of Nonvisualization of the Cavum Septum Pellucidum on Prenatal Ultrasonography

ABSTRACT Importance The identification of the cavum septum pellucidum (CSP) is an integral part of the routine second trimester fetal anatomy scan. The absence or nonvisualization of the CSP has significant clinical implications and requires further evaluation and counseling for the pregnant patient. Objective The aim of this review is to review the importance of accurate sonographic identification of the CSP and the underlying pathologies that can be associated with nonvisualization of this structure. Evidence Acquisition A literature review was performed with PubMed using key words including CSP, fetal anatomy ultrasound, and fetal anomalies. Results The absence of the CSP is associated with several central nervous system pathologies, all with a wide range of phenotypic outcomes, ranging from normal to very severe or lethal. Relevance Most obstetrician-gynecologists will have a patient in whom a CSP is not identified on fetal ultrasound. Thus, it is imperative to have a general understanding of this relatively common entity. Target Audience Obstetricians and gynecologists, family physicians Learning Objectives After completing this activity, the learner will be able to describe the CSP, the importance of accurate identification on ultrasonography, and the pitfalls to avoid/be aware of; explain the additional workup required in the setting of absent CSP including utility of antenatal ultrasound, fetal magnetic resonance imaging, and genetic counseling; and discuss the various pathologies that have an association with the absence of the CSP and patient counseling regarding the absence of the CSP.

Diversity of microglial transcriptional responses during opioid exposure and neuropathic pain.

Microglia take on an altered morphology during chronic opioid treatment. This morphological change is broadly used to identify the activated microglial state associated with opioid side effects, including tolerance and opioid-induced hyperalgesia (OIH). Microglia display similar morphological responses in the spinal cord after peripheral nerve injury (PNI). Consistent with this observation, functional studies have suggested that microglia activated by opioids or PNI engage common molecular mechanisms to induce hypersensitivity. In this article, we conducted deep RNA sequencing (RNA-seq) and morphological analysis of spinal cord microglia in male mice to comprehensively interrogate transcriptional states and mechanistic commonality between multiple models of OIH and PNI. After PNI, we identify an early proliferative transcriptional event across models that precedes the upregulation of histological markers of microglial activation. However, we found no proliferative transcriptional response associated with opioid-induced microglial activation, consistent with histological data, indicating that the number of microglia remains stable during morphine treatment, whereas their morphological response differs from PNI models. Collectively, these results establish the diversity of pain-associated microglial transcriptomic responses and point towards the targeting of distinct insult-specific microglial responses to treat OIH, PNI, or other central nervous system pathologies.

An exploratory study of the damage markers NfL, GFAP, and t-Tau, in cerebrospinal fluid and other findings from a patient cohort enriched for suspected autoimmune psychiatric disease

There is growing evidence suggesting that immunological mechanisms play a significant role in the development of psychiatric symptoms in certain patient subgroups. However, the relationship between clinical red flags for suspected autoimmune psychiatric disease and signs of central nervous system (CNS) pathology (e.g., routine cerebrospinal fluid (CSF) alterations, CNS damage markers, neurophysiological or neuroimaging findings) has received limited attention. Here, we aimed to describe the prevalence and distribution of potential CNS pathologies in psychiatric patients in relation to clinical red flags for autoimmune psychiatric disease and psychiatric symptoms. CSF routine findings and CNS damage markers; neurofilament light chain protein (NfL), glial fibrillary acidic protein (GFAP) and total Tau (t-Tau), in CSF from 127 patients with psychiatric disease preselected for suspected immunological involvement were related to recently proposed clinical red flags, psychiatric features, and MRI and EEG findings. Twenty-one percent had abnormal routine CSF findings and 27% had elevated levels of CNS damage markers. Six percent had anti-neuronal antibodies in serum and 2% had these antibodies in the CSF. Sixty-six percent of patients examined with MRI (n = 88) had alterations, mostly atrophy or nonspecific white matter lesions. Twenty-seven percent of patients with EEG recordings (n = 70) had abnormal findings. Elevated NfL levels were associated with comorbid autoimmunity and affective dysregulation symptoms. Elevated t-Tau was associated with catatonia and higher ratings of agitation/hyperactivity. Elevated GFAP was associated with acute onset, atypical presentation, infectious prodrome, tics, depressive/anxiety symptom ratings and overall greater psychiatric symptom burden. In conclusion, preselection based on suspected autoimmune psychiatric disease identifies a population with a high prevalence of CSF alterations suggesting CNS pathology. Future studies should examine the value of these markers in predicting treatment responses.

Immune landscape of the enteric nervous system differentiates Parkinson's disease patients from controls: The PADUA-CESNE cohort

BackgroundGastrointestinal dysfunction has emerged as a prominent early feature of Parkinson's Disease, shedding new light on the pivotal role of the enteric nervous system in its pathophysiology. However, the role of immune-cell clusters and inflammatory and glial markers in the gut pathogenetic process needs further elucidation. ObjectivesWe aimed to study duodenum tissue samples to characterize PD's enteric nervous system pathology further. Twenty patients with advanced PD, six with early PD, and 18 matched controls were included in the PADUA-CESNE cohort. MethodsDuodenal biopsies from 26 patients with early to advanced stage PD and 18 age-matched HCs were evaluated for the presence of surface markers (CD3+, CD4+, CD8+, CD20+, CD68+, HLA-DR), presence of misfolded alpha-synuclein and enteric glial alteration (GFAP). Correlation of immulogic pattern and clinical characteristic were analyzed. ResultsThe findings validate that in patients with Parkinson's Disease, the activation and reactive gliosis are linked to the neurodegeneration triggered by the presence of misfolded alpha-synuclein in the enteric nervous system. This process intensifies from the initial to the advanced stages of the disease. The clusters of T- and B-lymphocytes in the enteric system, along with the overall expression of HLA-DR in antigen-presenting cells, exceeded those in the control group. Conversely, no differences in terms of macrophage populations were found. ConclusionsThese findings broaden our understanding of the mechanisms underlying the enteric nervous system's involvement in PD and point to the gastrointestinal system as a potential therapeutic target, especially in the early stages of the disease. Moreover, our results propose a role of T- and B-lymphocytes in maintaining inflammation and ultimately influencing alpha-synuclein misfolding and aggregation.

Adherence to Guidelines for Diagnosis, Staging, and Treatment for Gastric Cancer in Italy According to the View of Surgeons and Patients.

Background: Despite the strong declining trends in incidence and mortality over the last decades, gastric cancer (GC) is still burdened with high mortality, even in high-income countries. To improve GC prognosis, several guidelines have been increasingly published with indications about the most appropriate GC management. The Italian Society of Digestive System Pathology (SIPAD) and Gastric Cancer Italian Research Group (GIRCG) designed a survey for both surgeons and patients with the purpose of evaluating the degree of application and adherence to guidelines in GC management in Italy. Materials and Methods: Between January and May 2022, a questionnaire has been administered to a sample of Italian surgeons and, in a simplified version, to members of the Patient Association "Vivere Senza Stomaco" (patients surgically treated for GC between 2008 and 2021) to investigate the diagnosis, staging, and treatment issues. Results: The survey has been completed by 125 surgeons and 125 patients. Abdominal CT with gastric hydro-distension before treatment was not widespread in both groups (47% and 42%, respectively). The rate of surgeons stating that they do not usually perform minimally invasive gastrectomy was 15%, but the rate of patients who underwent a minimally invasive approach was 22% (between 2011 and 2022). The percentage of surgeons declaring to perform extended lymphadenectomy (>D2) was 97%, although a limited lymph node dissection rate was observed in about 35% of patients. Conclusions: This survey shows several important discrepancies from surgical attitudes declared by surgeons and real data derived from the reports available to the patients, suggesting heterogeneous management in clinical practice and, thus, a not rigorous adherence to the guidelines.

Concurrent Onset of Central Retinal Vein Occlusion and Inflammation of a Large Maxillary Odontogenic Cyst: Case Report and Analysis

Central retinal vein occlusion typically manifests in older individuals with underlying systemic pathology, leading to a spectrum of symptoms ranging from blurred vision to complete vision loss. While odontogenic infections are recognized for causing complications affecting the eye and vision, their potential role as an etiological factor in cases of sudden vision impairment merits consideration. This article presents a case involving central retinal vein thrombosis, wherein resolution was achieved through a combination of ophthalmic therapy and the surgical removal of a concurrently existing large inflamed odontogenic cyst located in the ipsilateral hemimaxilla. This case underscores the importance of recognizing odontogenic factors in the assessment of sudden vision impairment and the efficacy of a multidisciplinary therapeutic approach.

SWI/SNF Complex Connects Signaling and Epigenetic State in Cells of Nervous System.

SWI/SNF protein complexes are evolutionarily conserved epigenetic regulators described in all eukaryotes. In metameric animals, the complexes are involved in all processes occurring in the nervous system, from neurogenesis to higher brain functions. On the one hand, the range of roles is wide because the SWI/SNF complexes act universally by mobilizing the nucleosomes in a chromatin template at multiple loci throughout the genome. On the other hand, the complexes mediate the action of multiple signaling pathways that control most aspects of neural tissue development and function. The issues are discussed to provide insight into the molecular basis of the multifaceted role of SWI/SNFs in cell cycle regulation, DNA repair, activation of immediate-early genes, neurogenesis, and brain and connectome formation. An overview is additionally provided for the molecular basis of nervous system pathologies associated with the SWI/SNF complexes and their contribution to neuroinflammation and neurodegeneration. Finally, we discuss the idea that SWI/SNFs act as an integration platform to connect multiple signaling and genetic programs.

Lost in translation: How neurons cope with tRNA decoding.

Post-transcriptional tRNA modifications contribute to the decoding efficiency of tRNAs by supporting codon recognition and tRNA stability. Recent work shows that the molecular and cellular functions of tRNA modifications and tRNA-modifying-enzymes are linked to brain development and neurological disorders. Lack of these modifications affects codon recognition and decoding rate, promoting protein aggregation and translational stress response pathways with toxic consequences to the cell. In this review, we discuss the peculiarity of local translation in neurons, suggesting a role for fine-tuning of translation performed by tRNA modifications. We provide several examples of tRNA modifications involved in physiology and pathology of the nervous system, highlighting their effects on protein translation and discussing underlying mechanisms, like the unfolded protein response (UPR), ribosome quality control (RQC), and no-go mRNA decay (NGD), which could affect neuronal functions. We aim to deepen the understanding of the roles of tRNA modifications and the coordination of these modifications with the protein translation machinery in the nervous system.

Single-cell atlas of the human brain vasculature across development, adulthood and disease

A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains incompletely understood1. Here we performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells and other tissue-derived cells from 117 samples, from 68 human fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated genes and pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell–cell interaction analyses predict substantial endothelial-to-perivascular cell ligand–receptor cross-talk, including immune-related and angiogenic pathways, thereby revealing a central role for the endothelium within brain neurovascular unit signalling networks. Our single-cell brain atlas provides insights into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies.