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The arachnoid barrier delineates the border between the central nervous system and dura mater. Although the arachnoid barrier creates a partition, communication between the central nervous system and the dura mater is crucial for waste clearance and immune surveillance1,2. How the arachnoid barrier balances separation and communication is poorly understood. Here, using transcriptomic data, we developed transgenic mice to examine specific anatomical structures that function as routes across the arachnoid barrier. Bridging veins create discontinuities where they cross the arachnoid barrier, forming structures that we termed arachnoid cuff exit (ACE) points. The openings that ACE points create allow the exchange of fluids and molecules between the subarachnoid space and the dura, enabling the drainage of cerebrospinal fluid and limited entry of molecules from the dura to the subarachnoid space. In healthy human volunteers, magnetic resonance imaging tracers transit along bridging veins in a similar manner to access the subarachnoid space. Notably, in neuroinflammatory conditions such as experimental autoimmune encephalomyelitis, ACE points also enable cellular trafficking, representing a route for immune cells to directly enter the subarachnoid space from the dura mater. Collectively, our results indicate that ACE points are a critical part of the anatomy of neuroimmune communication in both mice and humans that link the central nervous system with the dura and its immunological diversity and waste clearance systems.
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Aracnoide-Máter , Encéfalo , Dura-Máter , Animais , Humanos , Camundongos , Aracnoide-Máter/anatomia & histologia , Aracnoide-Máter/irrigação sanguínea , Aracnoide-Máter/imunologia , Aracnoide-Máter/metabolismo , Transporte Biológico , Encéfalo/anatomia & histologia , Encéfalo/irrigação sanguínea , Encéfalo/imunologia , Encéfalo/metabolismo , Dura-Máter/anatomia & histologia , Dura-Máter/irrigação sanguínea , Dura-Máter/imunologia , Dura-Máter/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Perfilação da Expressão Gênica , Imageamento por Ressonância Magnética , Camundongos Transgênicos , Espaço Subaracnóideo/anatomia & histologia , Espaço Subaracnóideo/irrigação sanguínea , Espaço Subaracnóideo/imunologia , Espaço Subaracnóideo/metabolismo , Líquido Cefalorraquidiano/metabolismo , Veias/metabolismoRESUMO
Dimension reduction tools preserving similarity and graph structure such as t-SNE and UMAP can capture complex biological patterns in high-dimensional data. However, these tools typically are not designed to separate effects of interest from unwanted effects due to confounders. We introduce the partial embedding (PARE) framework, which enables removal of confounders from any distance-based dimension reduction method. We then develop partial t-SNE and partial UMAP and apply these methods to genomic and neuroimaging data. For lower-dimensional visualization, our results show that the PARE framework can remove batch effects in single-cell sequencing data as well as separate clinical and technical variability in neuroimaging measures. We demonstrate that the PARE framework extends dimension reduction methods to highlight biological patterns of interest while effectively removing confounding effects.
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Algoritmos , Biologia Computacional , Neuroimagem , Humanos , Neuroimagem/métodos , Biologia Computacional/métodos , Genômica/métodos , Genômica/estatística & dados numéricos , Análise de Célula Única/métodos , Análise de Célula Única/estatística & dados numéricosRESUMO
Chronic active lesions (CAL) are an important manifestation of chronic inflammation in multiple sclerosis (MS) and have implications for non-relapsing biological progression. In recent years, the discovery of innovative magnetic resonance imaging (MRI) and PET derived biomarkers has made it possible to detect CAL, and to some extent quantify them, in the brain of persons with MS, in vivo. Paramagnetic rim lesions on susceptibility-sensitive MRI sequences, MRI-defined slowly expanding lesions on T1-weighted (T1-w) and T2-w scans, and 18-kDa translocator protein-positive lesions on PET are promising candidate biomarkers of CAL. While partially overlapping, these biomarkers do not have equivalent sensitivity and specificity to histopathological CAL. Standardization in the use of available imaging measures for CAL identification, quantification, and monitoring is lacking. To fast-forward clinical translation of CAL, the North American Imaging in Multiple Sclerosis Cooperative developed a Consensus Statement, which provides guidance for the radiological definition and measurement of CAL. The proposed manuscript presents this Consensus Statement, summarizes the multistep process leading to it, and identifies the remaining major gaps in knowledge.
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The intricate relationship between the central nervous system (CNS) and the immune system plays a crucial role in the pathogenesis of various neurological diseases. Understanding the interactions among the immunopathological processes at the brain borders is essential for advancing our knowledge of disease mechanisms and developing novel diagnostic and therapeutic approaches. In this review, we explore the emerging role of neuroimaging in providing valuable insights into brain barrier inflammation and brain fluid drainage in human neurological diseases. Neuroimaging techniques have enabled us not only to visualize and assess brain structures, but also to study the dynamics of the CNS in health and disease in vivo. By analyzing imaging findings, we can gain a deeper understanding of the immunopathology observed at the brain-immune interface barriers, which serve as critical gatekeepers that regulate immune cell trafficking, cytokine release, and clearance of waste products from the brain. This review explores the integration of neuroimaging data with immunopathological findings, providing valuable insights into brain barrier integrity and immune responses in neurological diseases. Such integration may lead to the development of novel diagnostic markers and targeted therapeutic approaches that can benefit patients with neurological disorders.
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Sistema Glinfático , Doenças do Sistema Nervoso , Humanos , Sistema Glinfático/patologia , Encéfalo/patologia , Sistema Nervoso Central/patologia , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/terapia , Doenças do Sistema Nervoso/patologia , Inflamação/diagnóstico por imagem , Inflamação/patologia , Barreira Hematoencefálica/diagnóstico por imagemRESUMO
Cerebral creatine deficiency syndromes (CCDS) are inherited metabolic phenotypes of creatine synthesis and transport. There are two enzyme deficiencies, guanidinoacetate methyltransferase (GAMT), encoded by GAMT and arginine-glycine amidinotransferase (AGAT), encoded by GATM, which are involved in the synthesis of creatine. After synthesis, creatine is taken up by a sodium-dependent membrane bound creatine transporter (CRTR), encoded by SLC6A8, into all organs. Creatine uptake is very important especially in high energy demanding organs such as the brain, and muscle. To classify the pathogenicity of variants in GAMT, GATM, and SLC6A8, we developed the CCDS Variant Curation Expert Panel (VCEP) in 2018, supported by The Clinical Genome Resource (ClinGen), a National Institutes of Health (NIH)-funded resource. We developed disease-specific variant classification guidelines for GAMT-, GATM-, and SLC6A8-related CCDS, adapted from the American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant interpretation guidelines. We applied specific variant classification guidelines to 30 pilot variants in each of the three genes that have variants associated with CCDS. Our CCDS VCEP was approved by the ClinGen Sequence Variant Interpretation Working Group (SVI WG) and Clinical Domain Oversight Committee in July 2022. We curated 181 variants including 72 variants in GAMT, 45 variants in GATM, and 64 variants in SLC6A8 and submitted these classifications to ClinVar, a public variant database supported by the National Center for Biotechnology Information. Missense variants were the most common variant type in all three genes. We submitted 32 new variants and reclassified 34 variants with conflicting interpretations. We report specific phenotype (PP4) using a points system based on the urine and plasma guanidinoacetate and creatine levels, brain magnetic resonance spectroscopy (MRS) creatine level, and enzyme activity or creatine uptake in fibroblasts ranging from PP4, PP4_Moderate and PP4_Strong. Our CCDS VCEP is one of the first panels applying disease specific variant classification algorithms for an X-linked disease. The availability of these guidelines and classifications can guide molecular genetics and genomic laboratories and health care providers to assess the molecular diagnosis of individuals with a CCDS phenotype.
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Amidinotransferases , Amidinotransferases/deficiência , Erros Inatos do Metabolismo dos Aminoácidos , Creatina , Creatina/deficiência , Guanidinoacetato N-Metiltransferase , Deficiência Intelectual , Transtornos do Desenvolvimento da Linguagem , Transtornos dos Movimentos/congênito , Proteínas do Tecido Nervoso , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Distúrbios da Fala , Humanos , Guanidinoacetato N-Metiltransferase/deficiência , Guanidinoacetato N-Metiltransferase/genética , Creatina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Amidinotransferases/genética , Amidinotransferases/metabolismo , Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Mutação , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/diagnóstico , Fenótipo , Curadoria de Dados , Deficiências do DesenvolvimentoRESUMO
This study aimed to determine whether choroid plexus volume (CPV) could differentiate multiple sclerosis (MS) from its mimics. A secondary analysis of two previously enrolled studies, 50 participants with MS and 64 with alternative diagnoses were included. CPV was automatically segmented from 3T magnetic resonance imaging (MRI), followed by manual review to remove misclassified tissue. Mean normalized choroid plexus volume (nCPV) to intracranial volume demonstrated relatively high specificity for MS participants in each cohort (0.80 and 0.76) with an area under the receiver-operator characteristic curve of 0.71 (95% confidence interval (CI) = 0.55-0.87) and 0.65 (95% CI = 0.52-0.77). In this preliminary study, nCPV differentiated MS from its mimics.
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Plexo Corióideo , Imageamento por Ressonância Magnética , Esclerose Múltipla , Humanos , Plexo Corióideo/diagnóstico por imagem , Plexo Corióideo/patologia , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Feminino , Adulto , Masculino , Pessoa de Meia-Idade , Diagnóstico DiferencialRESUMO
PURPOSE: Infantile hypertrophic pyloric stenosis (IHPS) is suspected to have worse outcomes when length of illness prior to presentation is prolonged. Our objective was to evaluate how social determinants of health influence medical care and outcomes for babies with IHPS. METHODS: A retrospective review was performed over 10 years. Census data were used as proxy for socioeconomic status via Geo-Identification codes and correlated with food access and social vulnerability variables. The cohort was subdivided to understand the impact of Medicaid Managed Care (MMC). RESULTS: The cohort (279 cases) was divided into two groups; early group from 2011 to 2015 and late from 2016 to 2021. Cases in the late group were older at the time of presentation (41.5 vs. 36.5 days; p = 0.022) and presented later in the disease course (12.8 vs. 8.9 days; p = 0.021). There was no difference in race (p = 0.282), gender (p = 0.874), or length of stay. CONCLUSIONS: Patients who presented with IHPS after implementation of phased MMC were older, had a longer symptomatic course, and shorter pylorus measurements. Patients with public insurance after the implementation of MMC were more likely to follow-up with an outpatient pediatrician within a month of hospitalization. These results suggest that MMC may have improved access to care for infants with IHPS.
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Cobertura do Seguro , Estenose Pilórica Hipertrófica , Humanos , Estenose Pilórica Hipertrófica/cirurgia , Estudos Retrospectivos , Feminino , Masculino , Lactente , Estados Unidos , Cobertura do Seguro/estatística & dados numéricos , Recém-Nascido , Medicaid/estatística & dados numéricos , Disparidades em Assistência à Saúde/estatística & dados numéricos , Determinantes Sociais da Saúde/estatística & dados numéricosRESUMO
Concepts of multiple sclerosis (MS) biology continue to evolve, with observations such as "progression independent of disease activity" challenging traditional phenotypic categorization. Iron-sensitive, susceptibility-based imaging techniques are emerging as highly translatable MR imaging sequences that allow for visualization of at least 2 clinically useful biomarkers: the central vein sign and the paramagnetic rim lesion (PRL). Both biomarkers demonstrate high specificity in the discrimination of MS from other mimics and can be seen at 1.5 T and 3 T field strengths. Additionally, PRLs represent a subset of chronic active lesions engaged in "smoldering" compartmentalized inflammation behind an intact blood-brain barrier.
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Imageamento por Ressonância Magnética , Esclerose Múltipla , Humanos , Esclerose Múltipla/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Biomarcadores , Inflamação/diagnóstico por imagem , Neuroimagem/métodos , Veias Cerebrais/diagnóstico por imagemRESUMO
Neurodegenerative and neuroinflammatory diseases, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis, affect millions of people globally. As aging is a major risk factor for neurodegenerative diseases, the continuous increase in the elderly population across Western societies is also associated with a rising prevalence of these debilitating conditions. The complement system, a crucial component of the innate immune response, has gained increasing attention for its multifaceted involvement in the normal development of the central nervous system (CNS) and the brain but also as a pathogenic driver in several neuroinflammatory disease states. Although complement is generally understood as a liver-derived and blood or interstitial fluid operative system protecting against bloodborne pathogens or threats, recent research, particularly on the role of complement in the healthy and diseased CNS, has demonstrated the importance of locally produced and activated complement components. Here, we provide a succinct overview over the known beneficial and pathological roles of complement in the CNS with focus on local sources of complement, including a discussion on the potential importance of the recently discovered intracellularly active complement system for CNS biology and on infection-triggered neurodegeneration.
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INTRODUCTION: We sought to identify patient understanding of urology residents and comfort with being cared for by residents. Through this pilot study, we aim to propose educational objectives to improve this knowledge gap and ultimately allow for an improved patient experience. METHODS: A prospective survey was distributed from September 2022 to October 2022. A patient knowledge about residents (KAR) score was calculated by combining correct responses to 5 questions (maximum = 5). Another score evaluating patient opinion of residents was calculated using Likert scale questions (range 3-19; higher scores correlate with positive opinion) denoting patient outlook on residents. RESULTS: A total of 88 surveys were completed. The average ± SD patient age was 62.7 ± 15.2 years. Patients previously seen by a resident had significantly higher KAR scores (3.591 ± 1.210) compared to patients never interacting with a resident or unsure (KAR = 2.381 ± 1.324; P < .0001). Additionally, those with higher levels of education had greater KAR scores (graduate-level KAR = 3.792 ± 1.179; P = .002). No variables were found to have a statistically significant impact on patients' average opinion of residents. CONCLUSIONS: Current patient understanding of the role of a urology resident is suboptimal. Given this knowledge gap, we hope to propose educational approaches to help aid in patient understanding of resident physicians, who play a critical role in their clinical care.
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Internato e Residência , Urologia , Humanos , Urologia/educação , Pessoa de Meia-Idade , Masculino , Projetos Piloto , Feminino , Estudos Prospectivos , Idoso , Competência Clínica , Inquéritos e Questionários , Adulto , Relações Médico-PacienteRESUMO
We began using the da Vinci single port (SP) robot for pediatric urologic surgeries at our institution due to limited access to the multiport robot. Availability of this technology has allowed us to schedule cases in a timelier fashion and increase access to minimally invasive urologic surgery for children in our area. Here, we report our technique for transperitoneal SP robotic pyeloplasty in the case of a 7 year-old boy with left ureteropelvic junction obstruction. Our technique was refined over a series of 10 patients under the age of 18. Highlights of the SP RALP technique include one 3 cm, concealed incision over the pubic tubercle, gentle frog leg positioning and burping of the boom to create optimal angle for robotic docking, and use of a "floating dock" to obtain 10 cm distance from target anatomy which is essential in smaller pediatric patients. SP pyeloplasty is safe and feasible in children and offers a concealed single incision alternative to the multiport approach.
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Laparoscopia , Procedimentos Cirúrgicos Robóticos , Robótica , Ureter , Obstrução Ureteral , Masculino , Humanos , Criança , Procedimentos Cirúrgicos Robóticos/métodos , Pelve Renal/cirurgia , Laparoscopia/métodos , Ureter/cirurgia , Obstrução Ureteral/cirurgia , Procedimentos Cirúrgicos Urológicos/métodos , Resultado do Tratamento , Estudos RetrospectivosRESUMO
Background: Although minimal is known about coronavirus disease 2019 (COVID-19)'s impact on patient healthcare perceptions, improved understanding can guide healthcare providers to adequately address patient concerns. This cross-sectional study investigated how fear induced by COVID-19 impacted nephrolithiasis patients' perceptions, decision-making, and preferences for care delivery. Methods: Utilizing the validated Fear of COVID-19 Scale (FCV-19S), patients were surveyed at a single stone clinic during part of the COVID-19 pandemic, 03/2021-04/2022. One-way analysis of variance (ANOVA), Chi-square tests, and multinomial logistic regression evaluated the effect of sociodemographics on responses. Results: Two hundred and four surveys were completed. Mean age was 58±16 years, and 112 (54.9%) were women. Mean FCV-19S was 14.8±5.8 points (range, 7-33). Women and non-Caucasian races were associated with higher fear scores (P<0.01 and P=0.01 respectively). Stone prevention effort was not associated with fear (P=0.38). Poorer self-assessed health status was associated with increased stone prevention efforts (P=0.04). Preference for in-person care was reported in 89% of patients. Willingness to seek care varied by age and education, with decreased likelihood to seek care for middle-aged patients (P=0.04) and increased education (P=0.01). Conclusions: Perceived fear during the COVID-19 pandemic was highly variable in nephrolithiasis patients, with higher fear scores in women and non-Caucasians. Willingness to seek care during the pandemic varied with age, education level, symptom severity, COVID-19 fear, current stone status, and health status. Stone patients greatly preferred in-person medical care over telemedicine during COVID-19. Future studies are needed to further evaluate these health disparities, discrepancies in fear, and comfort in seeking stone-related healthcare to help us better inform health policymakers and provide patient-centered care.
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Ultra-low field (ULF) magnetic resonance imaging (MRI) holds the potential to make MRI more accessible, given its cost-effectiveness, reduced power requirements, and portability. However, signal-to-noise ratio (SNR) drops with field strength, necessitating imaging with lower resolution and longer scan times. This study introduces a novel Fourier-based Super Resolution (FouSR) approach, designed to enhance the resolution of ULF MRI images with minimal increase in total scan time. FouSR combines spatial frequencies from two orthogonal ULF images of anisotropic resolution to create an isotropic T2-weighted fluid-attenuated inversion recovery (FLAIR) image. We hypothesized that FouSR could effectively recover information from under-sampled slice directions, thereby improving the delineation of multiple sclerosis (MS) lesions and other significant anatomical features. Importantly, the FouSR algorithm can be implemented on the scanner with changes to the k-space trajectory. Paired ULF (Hyperfine SWOOP, 0.064 tesla) and high field (Siemens, Skyra, 3 Tesla) FLAIR scans were collected on the same day from a phantom and a cohort of 10 participants with MS or suspected MS (6 female; mean ± SD age: 44.1 ± 4.1). ULF scans were acquired along both coronal and axial planes, featuring an in-plane resolution of 1.7 mm × 1.7 mm with a slice thickness of 5 mm. FouSR was evaluated against registered ULF coronal and axial scans, their average (ULF average) and a gold standard SR (ANTs SR). FouSR exhibited higher SNR (47.96 ± 12.6) compared to ULF coronal (36.7 ± 12.2) and higher lesion conspicuity (0.12 ± 0.06) compared to ULF axial (0.13 ± 0.07) but did not exhibit any significant differences contrast-to-noise-ratio (CNR) compared to other methods in patient scans. However, FouSR demonstrated superior image sharpness (0.025 ± 0.0040) compared to all other techniques (ULF coronal 0.021 ± 0.0037, q = 5.9, p-adj. = 0.011; ULF axial 0.018 ± 0.0026, q = 11.1, p-adj. = 0.0001; ULF average 0.019 ± 0.0034, q = 24.2, p-adj. < 0.0001) and higher lesion sharpness (-0.97 ± 0.31) when compared to the ULF average (-1.02 ± 0.37, t(543) = -10.174, p = <0.0001). Average blinded qualitative assessment by three experienced MS neurologists showed no significant difference in WML and sulci or gyri visualization between FouSR and other methods. FouSR can, in principle, be implemented on the scanner to produce clinically useful FLAIR images at higher resolution on the fly, providing a valuable tool for visualizing lesions and other anatomical structures in MS.
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Background: Previous genetic and epidemiological studies have examined subpopulations from the Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS) patient cohort, but an encompassing analysis of the study population has not yet been carried out. Objective: This study examines patterns of multiple sclerosis (MS) prevalence in 13,663 cohort members, including 4,821 patients with MS or suspected MS and 8,842 family members. Methods: We grouped participants into epidemiologic subgroups based on age of MS onset, clinical stage at diagnosis, symptom type at disease onset, sex, proband status, disability as measured by the EDSS, and ancestry based on reported ethnicity. Results: We observed a 2.7:1 MS prevalence ratio of women to men, though disease severity was greater for male patients. Variation in the age of disease onset between patients was only slightly associated with sex and strongly associated with disease type. Specific types of clinical symptoms at disease onset were associated with the prognosis. Regional residence did not correlate with disease onset, type, or severity. Conclusion: Population trends, as presented here, are not explained by environmental factors alone, highlighting the need for a comprehensive genetic analysis to understand disease variance across families.
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BACKGROUND AND OBJECTIVES: People with multiple sclerosis (MS) have a dysregulated circulating metabolome, but the metabolome of MS brain lesions has not been studied. The aims of this study were to identify differences in the brain tissue metabolome in MS compared with controls and to assess its association with the cellular profile of corresponding tissue. METHODS: MS tissues included samples from the edge and core of chronic active or inactive lesions and periplaque white matter (WM). Control specimens were obtained from normal WM. Metabolomic analysis was performed using mass-spectrometry coupled with liquid/gas chromatography and subsequently integrated with single-nucleus RNA-sequencing data by correlating metabolite abundances with relative cell counts, as well as individual genes using Multiomics Factor Analysis (MOFA). RESULTS: Seventeen samples from 5 people with secondary progressive MS and 8 samples from 6 controls underwent metabolomic profiling identifying 783 metabolites. MS lesions had higher levels of sphingosines (false discovery rate-adjusted p-value[q] = 2.88E-05) and sphingomyelins and ceramides (q = 2.15E-07), but lower nucleotide (q = 0.05), energy (q = 0.001), lysophospholipid (q = 1.86E-07), and monoacylglycerol (q = 0.04) metabolite levels compared with control WM. Periplaque WM had elevated sphingomyelins and ceramides (q = 0.05) and decreased energy metabolites (q = 0.01) and lysophospholipids (q = 0.05) compared with control WM. Sphingolipids and membrane lipid metabolites were positively correlated with astrocyte and immune cell abundances and negatively correlated with oligodendrocytes. On the other hand, long-chain fatty acid, endocannabinoid, and monoacylglycerol pathways were negatively correlated with astrocyte and immune cell populations and positively correlated with oligodendrocytes. MOFA demonstrated associations between differentially expressed metabolites and genes involved in myelination and lipid biosynthesis. DISCUSSION: MS lesions and perilesional WM demonstrated a significantly altered metabolome compared with control WM. Many of the altered metabolites were associated with altered cellular composition and gene expression, indicating an important role of lipid metabolism in chronic neuroinflammation in MS.
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Esclerose Múltipla , Humanos , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Esfingomielinas , Monoglicerídeos , Perfilação da Expressão Gênica , Metabolismo dos Lipídeos , CeramidasRESUMO
BACKGROUND AND OBJECTIVES: The diagnosis of multiple sclerosis (MS) can be challenging in clinical practice because MS presentation can be atypical and mimicked by other diseases. We evaluated the diagnostic performance, alone or in combination, of the central vein sign (CVS), paramagnetic rim lesion (PRL), and cortical lesion (CL), as well as their association with clinical outcomes. METHODS: In this multicenter observational study, we first conducted a cross-sectional analysis of the CVS (proportion of CVS-positive lesions or simplified determination of CVS in 3/6 lesions-Select3*/Select6*), PRL, and CL in MS and non-MS cases on 3T-MRI brain images, including 3D T2-FLAIR, T2*-echo-planar imaging magnitude and phase, double inversion recovery, and magnetization prepared rapid gradient echo image sequences. Then, we longitudinally analyzed the progression independent of relapse and MRI activity (PIRA) in MS cases over the 2 years after study entry. Receiver operating characteristic curves were used to test diagnostic performance and regression models to predict diagnosis and clinical outcomes. RESULTS: The presence of ≥41% CVS-positive lesions/≥1 CL/≥1 PRL (optimal cutoffs) had 96%/90%/93% specificity, 97%/84%/60% sensitivity, and 0.99/0.90/0.77 area under the curve (AUC), respectively, to distinguish MS (n = 185) from non-MS (n = 100) cases. The Select3*/Select6* algorithms showed 93%/95% specificity, 97%/89% sensitivity, and 0.95/0.92 AUC. The combination of CVS, CL, and PRL improved the diagnostic performance, especially when Select3*/Select6* were used (93%/94% specificity, 98%/96% sensitivity, 0.99/0.98 AUC; p = 0.002/p < 0.001). In MS cases (n = 185), both CL and PRL were associated with higher MS disability and severity. Longitudinal analysis (n = 61) showed that MS cases with >4 PRL at baseline were more likely to experience PIRA at 2-year follow-up (odds ratio 17.0, 95% confidence interval: 2.1-138.5; p = 0.008), whereas no association was observed between other baseline MRI measures and PIRA, including the number of CL. DISCUSSION: The combination of CVS, CL, and PRL can improve MS differential diagnosis. CL and PRL also correlated with clinical measures of poor prognosis, with PRL being a predictor of disability accrual independent of clinical/MRI activity.
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Imageamento por Ressonância Magnética , Esclerose Múltipla , Humanos , Feminino , Masculino , Adulto , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/diagnóstico , Pessoa de Meia-Idade , Estudos Transversais , Prognóstico , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Veias Cerebrais/diagnóstico por imagem , Veias Cerebrais/patologia , Progressão da Doença , Estudos LongitudinaisRESUMO
Aging is associated with structural brain changes, cognitive decline, and neurodegenerative diseases. Brain age, an imaging biomarker sensitive to deviations from healthy aging, offers insights into structural aging variations and is a potential prognostic biomarker in neurodegenerative conditions. This study introduces BrainAgeNeXt, a novel convolutional neural network inspired by the MedNeXt framework, designed to predict brain age from T1-weighted magnetic resonance imaging (MRI) scans. BrainAgeNeXt was trained and validated on 11,574 MRI scans from 33 private and publicly available datasets of healthy volunteers, aged 5 to 95 years, imaged with 3T and 7T MRI. Performance was compared against three state-of-the-art brain age prediction methods. BrainAgeNeXt achieved a mean absolute error (MAE) of 2.78 ± 3.64 years, lower than the compared methods (MAE = 3.55, 3.59, and 4.16 years, respectively). We tested all methods also across different levels of image quality, and BrainAgeNeXt performed well even with motion artifacts and less common 7T MRI data. In three longitudinal multiple sclerosis (MS) cohorts (273 individuals), brain age was, on average, 4.21 ± 6.51 years greater than chronological age. Longitudinal analysis indicated that brain age increased by 1.15 years per chronological year in individuals with MS (95% CI = [1.05, 1.26]). Moreover, in early MS, individuals with worsening disability had a higher annual increase in brain age compared to those with stable clinical assessments (1.24 vs. 0.75, p < 0.01). These findings suggest that brain age is a promising prognostic biomarker for MS progression and potentially a valuable endpoint for clinical trials.
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The role of central nervous system (CNS) glia in sustaining self-autonomous inflammation and driving clinical progression in multiple sclerosis (MS) is gaining scientific interest. We applied a single transcription factor (SOX10)-based protocol to accelerate oligodendrocyte differentiation from human induced pluripotent stem cell (hiPSC)-derived neural precursor cells, generating self-organizing forebrain organoids. These organoids include neurons, astrocytes, oligodendroglia, and hiPSC-derived microglia to achieve immunocompetence. Over 8 weeks, organoids reproducibly generated mature CNS cell types, exhibiting single-cell transcriptional profiles similar to the adult human brain. Exposed to inflamed cerebrospinal fluid (CSF) from patients with MS, organoids properly mimic macroglia-microglia neurodegenerative phenotypes and intercellular communication seen in chronic active MS. Oligodendrocyte vulnerability emerged by day 6 post-MS-CSF exposure, with nearly 50% reduction. Temporally resolved organoid data support and expand on the role of soluble CSF mediators in sustaining downstream events leading to oligodendrocyte death and inflammatory neurodegeneration. Such findings support the implementation of this organoid model for drug screening to halt inflammatory neurodegeneration.
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Cortical lesions are common in multiple sclerosis and are associated with disability and progressive disease. We asked whether cortical lesions continue to form in people with stable white matter lesions and whether the association of cortical lesions with worsening disability relates to pre-existing or new cortical lesions. Fifty adults with multiple sclerosis and no new white matter lesions in the year prior to enrolment (33 relapsing-remitting and 17 progressive) and a comparison group of nine adults who had formed at least one new white matter lesion in the year prior to enrolment (active relapsing-remitting) were evaluated annually with 7 tesla (T) brain MRI and 3T brain and spine MRI for 2 years, with clinical assessments for 3 years. Cortical lesions and paramagnetic rim lesions were identified on 7T images. Seven total cortical lesions formed in 3/30 individuals in the stable relapsing-remitting group (median 0, range 0-5), four total cortical lesions formed in 4/17 individuals in the progressive group (median 0, range 0-1), and 16 cortical lesions formed in 5/9 individuals in the active relapsing-remitting group (median 1, range 0-10, stable relapsing-remitting versus progressive versus active relapsing-remitting P = 0.006). New cortical lesions were not associated with greater change in any individual disability measure or in a composite measure of disability worsening (worsening Expanded Disability Status Scale or 9-hole peg test or 25-foot timed walk). Individuals with at least three paramagnetic rim lesions had a greater increase in cortical lesion volume over time (median 16â µl, range -61 to 215 versus median 1â µl, range -24 to 184, P = 0.007), but change in lesion volume was not associated with disability change. Baseline cortical lesion volume was higher in people with worsening disability (median 1010â µl, range 13-9888 versus median 267â µl, range 0-3539, P = 0.001, adjusted for age and sex) and in individuals with relapsing-remitting multiple sclerosis who subsequently transitioned to secondary progressive multiple sclerosis (median 2183â µl, range 270-9888 versus median 321â µl, range 0-6392 in those who remained relapsing-remitting, P = 0.01, adjusted for age and sex). Baseline white matter lesion volume was not associated with worsening disability or transition from relapsing-remitting to secondary progressive multiple sclerosis. Cortical lesion formation is rare in people with stable white matter lesions, even in those with worsening disability. Cortical but not white matter lesion burden predicts disability worsening, suggesting that disability progression is related to long-term effects of cortical lesions that form early in the disease, rather than to ongoing cortical lesion formation.