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The potential of combining serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels to predict disability worsening in multiple sclerosis (MS) remains underexplored. We aimed to investigate whether sNfL and sGFAP values identify distinct subgroups of patients according to the risk of disability worsening and their response to disease-modifying treatments (DMTs). This multicentre study, conducted across thirteen European hospitals, spanned from July 15, 1994, to August 18, 2022, with follow-up until September 26, 2023. We enrolled MS patients who had serum samples collected within 12 months from disease onset and before initiating DMTs. Multivariable regression models were used to estimate the risk of relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), and Expanded Disability Status Scale (EDSS) score of 3. Of the 725 patients included, median age was 34.2 years (IQR, 27.6-42.4), and 509 patients (70.2%) were female. Median follow-up duration was 6.43 years (IQR, 4.65-9.81). Higher sNfL values associated with an elevated risk of RAW (HR of 1.45; 95% CI 1.19-1.76; P < 0.001), PIRA (HR of 1.43; 95% CI 1.13-1.81; P = 0.003), and reaching an EDSS of 3 (HR of 1.55; 95% CI 1.29-1.85; P < 0.001). Moreover, higher sGFAP levels were linked to a higher risk of achieving an EDSS score of 3 (HR of 1.36; 95% CI 1.06-1.74; P = 0.02) and, in patients with low sNfL values, to PIRA (HR of 1.86; 95% CI 1.01-3.45; P = 0.04). We further examined the combined effect of sNfL and sGFAP levels. Patients with low sNfL and sGFAP values (NLGL) exhibited a low risk of all outcomes and served as reference. Untreated patients with high sNfL levels showed a higher risk of RAW, PIRA, and reaching an EDSS of 3. Injectable or oral DMTs reduced the risk of RAW in these patients but failed to mitigate the risk of PIRA and reaching an EDSS of 3. Conversely, high-efficacy DMTs counteracted the heightened risk of these outcomes, except for the risk of PIRA in patients with high sNfL and sGFAP levels. Patients with low sNfL and high sGFAP values (NLGH) showed an increased risk of PIRA and achieving an EDSS of 3, which remained unchanged with either high-efficacy or other DMTs. In conclusion, evaluating sNfL and sGFAP levels at disease onset in MS may identify distinct phenotypes associated with diverse immunological pathways of disability acquisition and therapeutic response.
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BACKGROUND: There is a need for biomarkers of disease progression and therapeutic response in multiple sclerosis (MS). This study aimed to identify cerebrospinal fluid (CSF) lipids that differentiate MS from other neuroinflammatory conditions and correlate with Expanded Disability Status Scale (EDSS) scores, gadolinium-enhancing lesions or inflammatory mediators. METHODS: Lipids and inflammatory cytokines/chemokines were quantified with liquid chromatography-tandem mass spectrometry and multiplex ELISA, respectively, in CSF from people with untreated MS, neuromyelitis optica spectrum disorder (NMOSD), other inflammatory neurological diseases and non-inflammatory neurological diseases (NIND). Analytes were compared between groups using analysis of variance, and correlations were assessed with Pearson's analysis. RESULTS: Twenty-five sphingolipids and four lysophosphatidylcholines were significantly higher in NMOSD compared with MS and NIND cases, whereas no lipids differed significantly between MS and NIND. A combination of three sphingolipids differentiated NMOSD from MS with the area under the curve of 0.92 in random forest models. Ninety-four lipids, including those that differentiated NMOSD from MS, were positively correlated with macrophage migration inhibitory factor (MIF) and 37 lipids were positively correlated with CSF protein in two independent MS cohorts. EDSS was inversely correlated with cholesterol ester CE(16:0) in both MS cohorts. In contrast, MIF and soluble triggering receptor expressed on myeloid cells 2 were positively associated with EDSS. CONCLUSIONS: CSF sphingolipids are positively correlated with markers of neuroinflammation and differentiate NMOSD from MS. The inverse correlation between EDSS and CE(16:0) levels may reflect poor clearance of cholesterol released during myelin break-down and warrants further investigation as a biomarker of therapeutic response.
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BACKGROUND: Calorie restriction (CR) ameliorates preclinical models of multiple sclerosis (MS) via multiple mechanisms. These include decreased leptin, a proinflammatory adipokine, but mechanistic studies in humans are lacking. Tests of daily and intermittent CR (iCR) in people with MS (pwMS) showed improvements in fatigue and well-being measures. This trial studied the effects of 12-week iCR on metabolic, immunological, and clinical outcomes in pwMS. METHOD: Relapsing-remitting MS participants were randomised to iCR or a control group. Study visits were conducted at baseline, 6 and 12 weeks. The primary outcome was reduction in serum leptin levels at 12 weeks. Feasibility and safety were assessed by diet adherence and adverse events (AEs). Secondary outcomes included changes in anthropometric and body composition measures, metabolic and immunologic profiling, and clinical measures. Mixed effects linear regression models were used to evaluate outcome differences between and within groups over time. RESULTS: Forty-two pwMS were randomised, 34 completed the study (17/group). Leptin serum levels at 12 weeks were significantly lower in the iCR versus the control group (mean decrease -6.98 µg/dL, 95% CI: -28.02 to 14.06; p=0.03). Adherence to iCR was 99.5% and 97.2% at 6 and 12 weeks, respectively, and no serious AEs were reported. An increase in blood CD45RO+ regulatory T-cell numbers was seen after 6 weeks of iCR. Exploratory cognitive testing demonstrated a significant improvement in the Symbol Digit Modality Test Score in the iCR group at 12 weeks. CONCLUSIONS: iCR has the potential to benefit metabolic and immunologic profiles and is safe and feasible in pwMS. TRIAL REGISTRATION NUMBER: NCT03539094 .
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BACKGROUND: Inflammation has been proposed as a crucial player in neurodegeneration, including Frontotemporal Dementia (FTD). A few studies on sporadic FTD lead to inconclusive results, whereas large studies on genetic FTD are lacking. The aim of this study is to determine cytokine and chemokine plasma circulating levels in a large cohort of genetic FTD, collected within the GENetic Frontotemporal dementia Initiative (GENFI). METHODS: Mesoscale technology was used to analyse levels of 30 inflammatory factors in 434 plasma samples, including 94 Symptomatic Mutation carriers [(SMC); 15 with mutations in Microtubule Associated Protein Tau (MAPT) 34 in Progranulin (GRN) and 45 in Chromosome 9 Open Reading Frame (C9ORF)72], 168 Presymptomatic Mutation Carriers (PMC; 34 MAPT, 70 GRN and 64 C9ORF72) and 173 Non-carrier Controls (NC)]. RESULTS: The following cytokines were significantly upregulated (P<0.05) in MAPT and GRN SMC versus NC: Tumor Necrosis Factor (TNF)α, Interleukin (IL)-7, IL-15, IL-16, IL-17A. Moreover, only in GRN SMC, additional factors were upregulated, including: IL-1ß, IL-6, IL-10, IL-12/IL-23p40, eotaxin, eotaxin-3, Interferon γ-induced Protein (IP-10), Monocyte Chemotactic Protein (MCP)4. On the contrary, IL-1α levels were decreased in SMC compared with NC. Significantly decreased levels of this cytokine were also found in PMC, independent of the type of mutation. In SMC, no correlations between disease duration and cytokine and chemokine levels were found. Considering NfL and GFAP levels, as expected, significant increases were observed in SMC as compared to NC. These differences in mean values remain significant even when stratifying symptomatic patients by the mutated gene (P<0.0001). Considering instead the levels of NfL, GFAP, and the altered inflammatory molecules, no significant correlations emerged. CONCLUSION: We showed that inflammatory proteins are upregulated in MAPT and GRN SMC, with some specific factors altered in GRN only, whereas no changes were seen in C9ORF72 carriers. Notably, only IL-1α levels were decreased in both SMC and PMC, independent of the type of causal mutation, suggesting common modifications occurring in the preclinical phase of the disease.
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Multiple sclerosis (MS) is a central nervous system (CNS) demyelinating disease. Failure to remyelinate successfully is common in MS lesions, often with consequent neuronal/axonal damage. CNS myelin is normally produced by oligodendroglial cells. Remyelination by Schwann cells (SchC) has been reported in spinal cord demyelination, in which SchCs are in close proximity to CNS myelin. We identified an MS cerebral lesion that was remyelinated by SchCs. This prompted us to query the extent of SchC remyelination in the brain and spinal cords of additional autopsied MS specimens. CNS tissues were obtained from the autopsies of 14 MS cases. Remyelinated lesions were identified by Luxol fast blue-periodic-acid Schiff and solochrome cyanine staining. Deparaffinized sections containing remyelinated lesions were stained with anti-glial fibrillary acid protein to identify reactive astrocytes. Glycoprotein P zero (P0) is a protein exclusive to peripheral but not CNS myelin. Areas of SchC remyelination were identified by staining with anti-P0. Myelinated regions in the index case cerebral lesion were confirmed to be of SchC origin using anti-P0 staining. Subsequently, 64 MS lesions from 14 autopsied MS cases were examined, and 23 lesions in 6 cases showed remyelination by SchCs. Lesions from the cerebrum, brainstem, and spinal cord were examined in each case. When present, SchC remyelination was most commonly located adjacent to the venules and associated with a lower surrounding density of glial fibrillary acid protein+ reactive astrocytes than areas of only oligodendroglial cell remyelination. The difference was significant only for spinal cord and brainstem lesions but not for lesions located in the brain. In conclusion, we demonstrated SchC remyelination in the cerebrum, brainstem, and spinal cord of 6 autopsied MS cases. To our knowledge, this is the first report of supratentorial SchC remyelination in MS.
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Esclerose Múltipla , Remielinização , Humanos , Esclerose Múltipla/patologia , Células de Schwann/metabolismo , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Medula Espinal/patologia , Proteína Glial Fibrilar Ácida/metabolismoRESUMO
TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer's disease and frontotemporal dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two NHD families: three homozygous TREM2 p.Q33X mutation carriers (termed NHD), two heterozygous mutation carriers, one related non-carrier, and two unrelated non-carriers. Transcriptomic and biochemical analyses revealed that iMGLs from NHD patients exhibited lysosomal dysfunction, downregulation of cholesterol genes, and reduced lipid droplets compared to controls. Also, NHD iMGLs displayed defective activation and HLA antigen presentation. This defective activation and lipid droplet content were restored by enhancing lysosomal biogenesis through mTOR-dependent and independent pathways. Alteration in lysosomal gene expression, such as decreased expression of genes implicated in lysosomal acidification (ATP6AP2) and chaperone mediated autophagy (LAMP2), together with reduction in lipid droplets were also observed in post-mortem brain tissues from NHD patients, thus closely recapitulating in vivo the phenotype observed in iMGLs in vitro. Our study provides the first cellular and molecular evidence that the TREM2 p.Q33X mutation in microglia leads to defects in lysosomal function and that compounds targeting lysosomal biogenesis restore a number of NHD microglial defects. A better understanding of how microglial lipid metabolism and lysosomal machinery are altered in NHD and how these defects impact microglia activation may provide new insights into mechanisms underlying NHD and other neurodegenerative diseases.
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Doença de Alzheimer , Microglia , Adulto , Humanos , Microglia/metabolismo , Metabolismo dos Lipídeos/genética , Mutação com Perda de Função , Mutação/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Lisossomos/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Receptor de Pró-ReninaRESUMO
OBJECTIVE: Over the past decades, an increasing number of women have been using hormonal contraception. The potential role of sex hormones in regulating vegetative, psychophysiological, and cognitive functions has been highlighted in several studies, and there is a need to further understand the impact of hormonal contraception on women's quality of life, especially as regards psychological health and sexuality. METHODS: We conducted a narrative review aimed at clarifying the mechanisms involved in the interaction between sex hormones and the brain, also focusing on the association between hormonal contraception and mood and sexual function. RESULTS: Our findings clarified that hormonal contraception may be associated with depressive symptoms, especially among adolescents, and with sexual dysfunction. However, the evidence included in this review was conflicting and did not support the hypothesis that hormonal contraception directly causes depressive symptoms, major depressive disorder, or sexual dysfunction. CONCLUSIONS: The optimal hormonal contraception should be identified in the context of shared decision making, considering the preferences and needs of each woman, as well as her physical and psychosexual conditions.
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Transtorno Depressivo Maior , Contracepção Hormonal , Adolescente , Anticoncepção/efeitos adversos , Depressão/induzido quimicamente , Feminino , Humanos , Qualidade de Vida , SexualidadeRESUMO
Primary progressive aphasia (PPA) damages the parts of the brain that control speech and language. There are three clinical PPA variants: nonfluent/agrammatic (nfvPPA), logopenic (lvPPA) and semantic (svPPA). The pathophysiology underlying PPA variants is not fully understood, including the role of micro (mi)RNAs which were previously shown to play a role in several neurodegenerative diseases. Using a two-step analysis (array and validation through real-time PCR), we investigated the miRNA expression pattern in serum from 54 PPA patients and 18 controls. In the svPPA cohort, we observed a generalized upregulation of miRNAs with miR-106b-5p and miR-133a-3p reaching statistical significance (miR-106b-5p: 2.69 ± 0.89 mean ± SD vs. 1.18 ± 0.28, p < 0.0001; miR-133a-3p: 2.09 ± 0.10 vs. 0.74 ± 0.11 mean ± SD, p = 0.0002). Conversely, in lvPPA, the majority of miRNAs were downregulated. GO enrichment and KEGG pathway analyses revealed that target genes of both miRNAs are involved in pathways potentially relevant for the pathogenesis of neurodegenerative diseases. This is the first study that investigates the expression profile of circulating miRNAs in PPA variant patients. We identified a specific miRNA expression profile in svPPA that could differentiate this pathological condition from other PPA variants. Nevertheless, these preliminary results need to be confirmed in a larger independent cohort.
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Afasia Primária Progressiva , MicroRNAs , Afasia Primária Progressiva/genética , Afasia Primária Progressiva/patologia , Encéfalo/patologia , Humanos , Idioma , MicroRNAs/genética , SemânticaRESUMO
BACKGROUND: Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune demyelinating disease. Its pathogenesis involves humoral and cellular immunity, with production of pro- and anti-inflammatory cytokines by T cells. OBJECTIVE: To analyze the cytokine profile of cerebrospinal fluid (CSF) T cells in patients with relapsing-remitting MS (RRMS) and non-inflammatory controls. METHODS: T cell cytokine production was analyzed by flow cytometry in CSF samples collected from 34 untreated RRMS patients and 20 age-matched controls. Immunofluorescence studies were performed in spinal cord MS active lesions. RESULTS: Percentages of CSF-derived IL-17A, IL-17A/IL-22, and IL-17A/GM-CSF producing T cells were significantly higher in RRMS patients compared to controls. Percentages of T cells producing IFN-γ were lower in RRMS patients compared to controls. Patients in relapse showed higher percentages of CD4+ T cells producing IL-13 and GM-CSF compared to patients in remission. We found a positive correlation between percentages of IL-13+ T cells and the Expanded Disability Status Scale (EDSS; ρ = 0.5; p < 0.05). Meningeal IL-13-producing T cells were detected in spinal cord MS active lesions. CONCLUSION: We observed differences in IL-17, IL-22, and IFN-γ production by CSF T cells in RRMS versus controls and a positive correlation between IL-13-producing T cells and EDSS in RRMS patients.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Humanos , Interleucina-13 , Recidiva , Linfócitos TRESUMO
PURPOSE: The disease course of multiple sclerosis (MS) is unpredictable, and reliable prognostic biomarkers are needed. Positron emission tomography (PET) with ß-amyloid tracers is a promising tool for evaluating white matter (WM) damage and repair. Our aim was to investigate amyloid uptake in damaged (DWM) and normal-appearing WM (NAWM) of MS patients, and to evaluate possible correlations between cerebrospinal fluid (CSF) ß-amyloid1-42 (Aß) levels, amyloid tracer uptake, and brain volumes. METHODS: Twelve MS patients were recruited and divided according to their disease activity into active and non-active groups. All participants underwent neurological examination, neuropsychological testing, lumbar puncture, brain magnetic resonance (MRI) imaging, and 18F-florbetapir PET. Aß levels were determined in CSF samples from all patients. MRI and PET images were co-registered, and mean standardized uptake values (SUV) were calculated for each patient in the NAWM and in the DWM. To calculate brain volumes, brain segmentation was performed using statistical parametric mapping software. Nonparametric statistical analyses for between-group comparisons and regression analyses were conducted. RESULTS: We found a lower SUV in DWM compared to NAWM (p < 0.001) in all patients. Decreased NAWM-SUV was observed in the active compared to non-active group (p < 0.05). Considering only active patients, NAWM volume correlated with NAWM-SUV (p = 0.01). Interestingly, CSF Aß concentration was a predictor of both NAWM-SUV (r = 0.79; p = 0.01) and NAWM volume (r = 0.81, p = 0.01). CONCLUSIONS: The correlation between CSF Aß levels and NAWM-SUV suggests that the predictive role of ß-amyloid may be linked to early myelin damage and may reflect disease activity and clinical progression.
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Peptídeos beta-Amiloides/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Tomografia por Emissão de Pósitrons , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismo , Tomografia por Emissão de Pósitrons/normas , Valores de Referência , Substância Branca/metabolismo , Adulto JovemRESUMO
BACKGROUND: The importance of neurodegeneration in multiple sclerosis (MS) is increasingly well recognized. OBJECTIVES: To evaluate retinal pathology using optical coherence tomography (OCT) and to investigate possible associations between retinal layers' thickness and specific patterns of gray matter volume in patients with a new diagnosis of MS. METHODS: A total of 31 patients underwent OCT scans and brain magnetic resonance imaging. In total, 30 controls underwent the same OCT procedure. The association between focal cortical volume and OCT measurements was investigated with voxel-based morphometry (VBM). RESULTS: Compared to controls, patients' macular retinal nerve fiber layer (mRNFL), macular ganglion cell layer (mGCL), macular inner plexiform layer (mIPL), and macular ganglion cell-inner plexiform layer (mGCIPL) thickness were significantly reduced ( p = 0.0009, p = 0.0003, p = 0.0049, and p = 0.0007, respectively). Peripapillary RNFL (pRNFL) and temporal sector pRNFL (T-pRNFL) did not show any significant changes, although there was a trend toward T-pRNFL thinning ( p = 0.0254). VBM analysis showed that mGCIPL and pRNFL were significantly correlated with the volume reduction of occipital-parietal cortex ( p < 0.005). CONCLUSION: mRNFL, mGCL, and mIPL are significantly reduced in MS patients without concomitant pRNFL thinning. These retinal changes show a significant association with cortical regions that are known to be important for visuospatial performance.
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Progressão da Doença , Lobo Occipital/patologia , Lobo Parietal/patologia , Células Ganglionares da Retina/patologia , Adulto , Atrofia/diagnóstico por imagem , Atrofia/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Lobo Occipital/diagnóstico por imagem , Lobo Parietal/diagnóstico por imagem , Tomografia de Coerência ÓpticaRESUMO
BACKGROUND: The importance of predicting disease progression in multiple sclerosis (MS) has increasingly been recognized, and hence reliable biomarkers are needed. OBJECTIVES: To investigate the prognostic role of cerebrospinal fluid (CSF) amyloid beta1-42 (Aß) levels by the determination of a cut-off value to classify patients in slow and fast progressors. To evaluate possible association with white matter (WM) and grey matter (GM) damage at early disease stages. METHODS: Sixty patients were recruited and followed up for 3-5 years. Patients underwent clinical assessment, brain magnetic resonance imaging (MRI; at baseline and after 1 year), and CSF analysis to determine Aß levels. T1-weighted volumes were calculated. T2-weighted scans were used to quantify WM lesion loads. RESULTS: Lower CSF Aß levels were observed in patients with a worse follow-up Expanded Disability Status Scale (EDSS; r = -0.65, p < 0.001). The multiple regression analysis confirmed CSF Aß concentration as a predictor of patients' EDSS increase (r = -0.59, p < 0.0001). Generating a receiver operating characteristic curve, a cut-off value of 813 pg/mL was determined as the threshold able to identify patients with worse prognosis (95% confidence interval (CI): 0.690-0.933, p = 0.0001). No differences in CSF tau and neurofilament light chain (NfL) levels were observed (p > 0.05). CONCLUSION: Low CSF Aß levels may represent a predictive biomarker of disease progression in MS.
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Peptídeos beta-Amiloides/líquido cefalorraquidiano , Progressão da Doença , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico por imagem , Fragmentos de Peptídeos/líquido cefalorraquidiano , Substância Branca/diagnóstico por imagem , Adulto , Biomarcadores/líquido cefalorraquidiano , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
OBJECTIVE: To assess the connection between amyloid pathology and white matter (WM) macrostructural and microstructural damage in demented patients compared with controls. METHODS: Eighty-five participants were recruited: 65 with newly diagnosed Alzheimer's disease (AD), non-AD dementia or mild cognitive impairment and 20 age-matched and sex-matched healthy controls. ß-amyloid1-42 (Aß) levels were determined in cerebrospinal fluid (CSF) samples from all patients and five controls. Among patients, 42 had pathological CSF Aß levels (Aß(+)), while 23 had normal CSF Aß levels (Aß(-)). All participants underwent neurological examination, neuropsychological testing and brain MRI. We used T2-weighted scans to quantify WM lesion loads (LLs) and diffusion-weighted images to assess their microstructural substrate. Non-parametric statistical tests were used for between-group comparisons and multiple regression analyses. RESULTS: We found an increased WM-LL in Aß(+) compared with both, healthy controls (p=0.003) and Aß(-) patients (p=0.02). Interestingly, CSF Aß concentration was the best predictor of patients' WM-LL (r=-0.30, p<0.05) when using age as a covariate. Lesion apparent diffusion coefficient value was higher in all patients than in controls (p=0.0001) and correlated with WM-LL (r=0.41, p=0.001). In Aß(+), WM-LL correlated with WM microstructural damage in the left peritrigonal WM (p<0.0001). CONCLUSIONS: WM damage is crucial in AD pathogenesis. The correlation between CSF Aß levels and WM-LL suggests a direct link between amyloid pathology and WM macrostructural and microstructural damage.
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Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Substância Branca/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Estudos de Casos e Controles , Disfunção Cognitiva/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-IdadeRESUMO
Myeloid-derived cells play important modulatory and effector roles in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells, composed of monocytic (MO) and polymorphonuclear (PMN) fractions, which can suppress T cell activities in EAE. Their role in MS remains poorly characterized. We found decreased numbers of circulating MDSCs, driven by lower frequencies of the MO-MDSCs, and higher MDSC expression of microRNA miR-223 in MS versus healthy subjects. To gain mechanistic insights, we interrogated the EAE model. MiR-223 knock out (miR-223-/-) mice developed less severe EAE with increased MDSC numbers in the spleen and spinal cord compared to littermate controls. MiR-223-/- MO-MDSCs suppressed T cell proliferation and cytokine production in vitro and EAE in vivo more than wild-type MO-MDSCs. They also displayed an increased expression of critical mediators of MDSC suppressive function, Arginase-1(Arg1), and the signal transducer and activator of transcription 3 (Stat3), which herein, we demonstrate being an miR-223 target gene. Consistently, MDSCs from MS patients displayed decreased STAT3 and ARG1 expression compared with healthy controls, suggesting that circulating MDSCs in MS are not only reduced in numbers but also less suppressive. These results support a critical role for miR-223 in modulating MDSC biology in EAE and in MS and suggest potential novel therapeutic applications.
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Encefalomielite Autoimune Experimental/metabolismo , MicroRNAs/metabolismo , Esclerose Múltipla Recidivante-Remitente/metabolismo , Células Supressoras Mieloides/metabolismo , Animais , Arginase/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Contagem de Células , Encefalomielite Autoimune Experimental/patologia , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Esclerose Múltipla Recidivante-Remitente/patologia , Células Supressoras Mieloides/patologia , Fator de Transcrição STAT3/metabolismo , Medula Espinal/metabolismo , Medula Espinal/patologia , Baço/metabolismo , Baço/patologia , Linfócitos T/metabolismo , Linfócitos T/patologiaRESUMO
Low frequency coding variants in TREM2 are associated with increased Alzheimer disease (AD) risk, while loss of functions mutations in the gene lead to an autosomal recessive early-onset dementia, named Nasu-Hakola disease (NHD). TREM2 can be detected as a soluble protein in cerebrospinal fluid (CSF) and plasma, and its CSF levels are elevated in inflammatory CNS diseases. We measured soluble TREM2 (sTREM2) in the CSF of a large AD case-control dataset (n = 180) and 40 TREM2 risk variant carriers to determine whether CSF sTREM2 levels are associated with AD status or mutation status. We also performed genetic studies to identify genetic variants associated with CSF sTREM2 levels. CSF, but not plasma, sTREM2 was highly correlated with CSF total tau and phosphorylated-tau levels (r = 0.35, P < 1×10(-4); r = 0.40, P < 1×10(-4), respectively), but not with CSF Aß42. AD cases presented higher CSF sTREM2 levels than controls (P = 0.01). Carriers of NHD-associated TREM2 variants presented significantly lower CSF sTREM2 levels, supporting the hypothesis that these mutations lead to reduced protein production/function (R136Q, D87N, Q33X or T66M; P = 1×10(-3)). In contrast, CSF sTREM2 levels were significantly higher in R47H carriers compared to non-carriers (P = 6×10(-3)), suggesting that this variant does not impact protein expression and increases AD risk through a different pathogenic mechanism than NHD variants. In GWAS analyses for CSF sTREM2 levels the most significant signal was located on the MS4A gene locus (P = 5.45 × 10(-07)) corresponding to one of the SNPs reported to be associated with AD risk in this locus. Furthermore, SNPs involved in pathways related to virus cellular entry and vesicular trafficking were overrepresented, suggesting that CSF sTREM2 levels could be an informative phenotype for AD.
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Doença de Alzheimer/patologia , Variação Genética/genética , Glicoproteínas de Membrana/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/genética , Mutação/genética , Fenótipo , Receptores Imunológicos/genética , RiscoRESUMO
INTRODUCTION: Lumbar puncture (LP) is increasingly performed in memory clinics. We investigated patient-acceptance of LP, incidence of and risk factors for post-LP complications in memory clinic populations. METHODS: We prospectively enrolled 3868 patients (50% women, age 66 ± 11 years, mini mental state examination 25 ± 5) at 23 memory clinics. We used logistic regression analysis using generalized estimated equations to investigate risk factors for post-LP complications, such as typical postlumbar puncture headache (PLPH) and back pain. RESULTS: A total of 1065 patients (31%) reported post-LP complaints; 589 patients (17%) reported back pain, 649 (19%) headache, of which 296 (9%) reported typical PLPH. Only few patients needed medical intervention: 11 (0.3%) received a blood patch, 23 (0.7%) were hospitalized. The most important risk factor for PLPH was medical history of headache. An atraumatic needle and age >65 years were preventive. Gender, rest after LP, or volume of cerebrospinal fluid had no effect. DISCUSSIONS: The overall risk of complications is relatively low. If risk factors shown in this study are taken into account, LPs can be safely performed in memory clinics.
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Instituições de Assistência Ambulatorial , Memória/fisiologia , Punção Espinal/efeitos adversos , Idoso , Transtornos Cognitivos/líquido cefalorraquidiano , Demência/líquido cefalorraquidiano , Estudos de Viabilidade , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Cefaleia Pós-Punção Dural/epidemiologia , Cefaleia Pós-Punção Dural/etiologia , Estudos Prospectivos , Fatores de Risco , Punção Espinal/métodosRESUMO
Balò's concentric sclerosis (BCS) is considered a rare demyelinating disease and regarded as an aggressive variant of multiple sclerosis (MS). We describe three cases (one male and two females) with neuroimaging features suggestive of BCS and heterogeneous symptoms, with benign long-term clinical course upon treatment with natalizumab and fingolimod. Neurological examination, blood and cerebrospinal fluid analyses, brain and spinal cord magnetic resonance imaging (MRI) and brain proton magnetic resonance spectroscopy were performed. At onset, patient #1 showed predominant cognitive impairment with consciousness disturbances; patient #2 presented with left hemiparesis; patient #3 demonstrated hesitance in speech and in written word production, along with right central facial palsy. All patients showed the typical MRI changes associated with BCS, such as concentric rings or a whorled appearance on T2-weighted and contrast-enhanced T1-weighted images. They were treated with high dosage i.v. steroid with clinical improvement and followed-up for 3 years with different clinical course. Two patients fulfilled the revised McDonald criteria for MS and received preventive therapy, natalizumab and fingolimod, respectively, whereas the third patient is still stable without clinical and radiological evolution. All of them did not have new exacerbations or MRI lesions over 2-4 year follow-up. Our descriptions demonstrate the heterogeneity of clinical presentation of BCS. Moreover, these case reports suggest that BCS may neither be rapidly progressive nor fatal and may be considered part of the MS spectrum. In line with this hypothesis, current treatments for MS were effective in our patients.
Assuntos
Doenças Desmielinizantes/patologia , Esclerose Cerebral Difusa de Schilder/diagnóstico , Esclerose Cerebral Difusa de Schilder/tratamento farmacológico , Esclerose Múltipla/diagnóstico , Esteroides/uso terapêutico , Adulto , Encéfalo/patologia , Doenças Desmielinizantes/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/tratamento farmacológico , Exame Neurológico/métodos , Medula Espinal/patologiaRESUMO
We analysed the expression levels of 84 key genes involved in the regulated degradation of cellular protein by the ubiquitin-proteasome system in peripheral cells from patients with frontotemporal dementia (FTD) due to C9ORF72 and GRN mutations, as compared with sporadic FTD and age-matched controls. A SABiosciences PCR array was used to investigate the transcription profile in a discovery population consisting of six patients each in C9ORF72, GRN, sporadic FTD and age-matched control groups. A generalized down-regulation of gene expression compared with controls was observed in C9ORF72 expansion carriers and sporadic FTD patients. In particular, in both groups, four genes, UBE2I, UBE2Q1, UBE2E1 and UBE2N, were down-regulated at a statistically significant (p < 0.05) level. All of them encode for members of the E2 ubiquitin-conjugating enzyme family. In GRN mutation carriers, no statistically significant deregulation of ubiquitination pathway genes was observed, except for the UBE2Z gene, which displays E2 ubiquitin conjugating enzyme activity, and was found to be statistically significant up-regulated (p = 0.006). These preliminary results suggest that the proteasomal degradation pathway plays a role in the pathogenesis of FTD associated with TDP-43 pathology, although different proteins are altered in carriers of GRN mutations as compared with carriers of the C9ORF72 expansion.
Assuntos
Demência Frontotemporal/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas/genética , Idoso , Proteína C9orf72 , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo , Feminino , Demência Frontotemporal/patologia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Progranulinas , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , UbiquitinaçãoRESUMO
Inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), are characterized by humoral immune abnormalities. Anti-MOG antibodies are not specific to MOGAD, with their presence described in MS. Autoantibodies may also be present and play a role in various neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease driven by motor neuron dysfunction. While immune involvement in ALS has been recognized, the presence of antibodies targeting CNS myelin antigens has not been established. We aimed to establish a live cell-based assay for quantification of serum anti-MOG IgG1 in patients with CNS diseases, including MS and ALS. In total, 771 serum samples from the John L. Trotter MS Center and the Northeast ALS Consortium were examined using a live cell-based assay for detection of anti-MOG IgG1. Samples from three cohorts were tested in blinded fashion: healthy control (HC) subjects, patients with clinically diagnosed MOGAD, and an experimental group of ALS and MS patients. All samples from established MOGAD cases were positive for anti-MOG antibodies, while all HC samples were negative. Anti-MOG IgG1 was detected in 65 of 658 samples (9.9%) from MS subjects and 4 of 108 (3.7%) samples from ALS subjects. The presence of serum anti-MOG IgG1 in MS and ALS patients raises questions about the contribution of these antibodies to disease pathophysiology as well as accuracy of diagnostic approaches for CNS inflammatory diseases.
Assuntos
Esclerose Lateral Amiotrófica , Autoanticorpos , Imunoglobulina G , Glicoproteína Mielina-Oligodendrócito , Glicoproteína Mielina-Oligodendrócito/imunologia , Humanos , Autoanticorpos/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/imunologia , Esclerose Lateral Amiotrófica/diagnóstico , Imunoglobulina G/sangue , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/diagnóstico , Idoso , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/sangue , Adulto , Esclerose Múltipla/imunologia , Esclerose Múltipla/sangue , AnimaisRESUMO
BACKGROUND: Pilot trials indicate that both a low glycemic load (GL) diet and calorie restriction (CR) can be implemented successfully in people with multiple sclerosis (pMS) and may improve MS symptoms and physical function, but large randomized clinical trials (RCTs) have not yet been conducted. The purpose of this study is to test these interventions alone and in combination to determine their efficacy for improving clinical and patient reported outcomes (PROs) in pMS. METHODS: This 32-week, two-arm, RCT at two centers will randomly assign 100 adults with relapsing-remitting or secondary progressive MS to a low GL diet (nâ¯=â¯50) or a standard GL diet (nâ¯=â¯50). Both diet groups will complete two study phases: a eucaloric phase (16â¯weeks) and a CR phase (16â¯weeks). Groceries for the study meal plans will be delivered to participants' homes weekly. The primary outcome is physical function, measured by timed 25-ft walk test. Secondary outcomes are pain, fatigue, mood, and anxiety. DISCUSSION: This will be the most rigorous intervention trial to date of a low GL diet and CR in adults with MS, and among the first to assess the impact of intentional weight loss on MS symptoms. Results will provide valuable insight for recommending dietary change, weight loss, or both to adults with MS. These non-drug interventions pose few risks and have potential to yield significant improvements in MS symptoms. TRIAL REGISTRATION ID: NCT05327322.