RESUMO
Background: Synaptic dysfunction is closely associated with cognitive function in Alzheimer's disease (AD), and is present already in an early stage of the disease. Objective: Using serial cerebrospinal fluid (CSF) sampling, we aimed to investigate slopes of CSF synaptic proteins, and their relation with cognition along the AD continuum. Methods: We included subjects with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) (nâ=â50 amyloid-ß+ [Aâ+], nâ=â50 A-) and 50 patients with AD dementia from the Amsterdam dementia cohort, with CSF at two time points (median[IQR] 2.1[1.4-2.7] years). We analyzed 17 synaptic proteins and neurofilament light (NfL). Using linear mixed models we assessed trajectories of protein levels, and associations with cognitive decline (repeated Mini-Mental State Examination). We used Cox regression models to assess predictive value of protein levels for progression to AD dementia. Results: At baseline most proteins showed increased levels in AD dementia compared to the other groups. In contrast NPTX2 levels were lower in AD dementia. Higher baseline levels of SNAP25, ß-syn, and 14-3-3 proteins were associated with faster cognitive decline (St.B[SE] -0.27[0.12] to -0.61[0.12]). Longitudinal analyses showed that SYT1 and NPTX levels decreased over time in AD dementia (st.B[SE] -0.10[0.04] to -0.15[0.05]) and SCD/MCI-A+ (St.B[SE] -0.07[0.03] to -0.12[0.03]), but not in SCD/MCI-A- (pinteractionâ<â0.05). Increase over time in NfL levels was associated with faster cognitive decline in AD dementia (St.B[SE] -1.75[0.58]), but not in the other groups (pinteractionâ<â0.05). Conclusions: CSF synaptic proteins showed different slopes over time, suggesting complex synaptic dynamics. High levels of especially SNAP-25 may have value for prediction of cognitive decline in early AD stages, while increase in NfL over time correlates better with cognitive decline in later stages.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Disfunção Cognitiva , Progressão da Doença , Proteínas de Neurofilamentos , Humanos , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Masculino , Feminino , Idoso , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/líquido cefalorraquidiano , Sinapses , Proteína 25 Associada a Sinaptossoma/líquido cefalorraquidiano , Estudos de Coortes , Proteína C-ReativaRESUMO
BACKGROUND: Soluble inflammatory factors in the cerebrospinal fluid (CSF) of patients with neurosyphilis have been investigated with low-throughput technology. This study aimed to illustrate the characteristics of soluble factor profiles in CSF of patients with neurosyphilis. METHODS: We measured the concentrations of 45 cytokines, chemokines, and growth factors in CSF from 112 untreated syphilis cases, including latent syphilis (LS), asymptomatic neurosyphilis (ANS), meningeal neurosyphilis (MNS), meningovascular neurosyphilis (MVNS), paralytic dementia (PD), and ocular syphilis (OS). RESULTS: Thirty-three differentially expressed soluble factors (DeSFs) were categorized into 3 clusters. DeSF scores of clusters 1 and 2 (DeSFS1 and DeSFS2) were positively correlated with elevated neopterin and neurofilament light subunit (NF-L) concentration, respectively. DeSF scores of cluster 3 were positively correlated with white blood cells, protein, NF-L, and neopterin. Patients with LS, ANS, and OS exhibited an overall lower abundance of DeSFs. Patients with PD exhibited significantly increased levels of clusters 1 and 3, and the highest total DeSF score, whereas patients with MNS and MVNS showed enhanced levels of cluster 2. Receiver operating characteristic analysis revealed that DeSFS1 effectively discriminated PD, and DeSFS2 discriminated MNS/MVNS with high accuracy. CONCLUSIONS: Patients with neurosyphilis at different stages have distinctive patterns of soluble factors in CSF, which are correlated with immune status and neuronal damage.
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Citocinas , Neurossífilis , Humanos , Neurossífilis/líquido cefalorraquidiano , Neurossífilis/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Citocinas/líquido cefalorraquidiano , Neopterina/líquido cefalorraquidiano , Idoso , Biomarcadores/líquido cefalorraquidiano , Peptídeos e Proteínas de Sinalização Intercelular/líquido cefalorraquidiano , Curva ROC , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Quimiocinas/líquido cefalorraquidiano , Adulto JovemRESUMO
Amyotrophic lateral sclerosis (ALS) is a neurological disease without effective treatment. No pathognomonic test can diagnose ALS in sporadic cases. Routine investigation in suspected cases includes neurological examination, imaging of the brain and spine and electromyography supported by blood and cerebrospinal fluid (CSF) analyses. The ALS diagnosis is made by clinical judgement and results from examinations. We aimed to study if the CSF biomarkers neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), YKL-40, soluble amyloid precursor protein (sAPP) α and ß, and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were associated with ALS diagnosis and could predict disease progression. Eighty-one patients with suspected ALS were included after referral to the neurological clinic at Sahlgrenska University Hospital. Fifty-nine patients were diagnosed having ALS, while 22 patients were given alternative diagnoses and labeled ALS mimics. Finally, 25 age-matched neurologically intact individuals were used as controls. ALS patients had significantly higher CSF levels of NFL than controls and mimics. Levels of YKL-40 and GFAP were significantly higher in ALS patients compared with controls. No difference was found between study groups when comparing levels of sAPPα, sAPPß and sTREM2. Further, elevated levels of NFL and YKL-40 were associated with an increased hazard of death and the annual decline in ALSFRS-R. We also found that patients with elevated levels of both NFL and YKL-40 had a particularly poor prognosis. The results demonstrate the usefulness of CSF biomarkers in the diagnosis and prognostication of ALS.
Assuntos
Esclerose Lateral Amiotrófica , Biomarcadores , Proteína 1 Semelhante à Quitinase-3 , Proteínas de Neurofilamentos , Humanos , Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/sangue , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3/sangue , Feminino , Masculino , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Pessoa de Meia-Idade , Idoso , Biomarcadores/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Progressão da Doença , Adulto , Glicoproteínas de Membrana , Receptores ImunológicosRESUMO
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.
Assuntos
Doenças Autoimunes , Biomarcadores , Proteína Glial Fibrilar Ácida , Transtornos Mentais , Proteínas de Neurofilamentos , Proteínas tau , Humanos , Feminino , Masculino , Proteínas tau/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/imunologia , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Adulto , Transtornos Mentais/líquido cefalorraquidiano , Transtornos Mentais/imunologia , Doenças Autoimunes/líquido cefalorraquidiano , Doenças Autoimunes/imunologia , Imageamento por Ressonância Magnética , Estudos de Coortes , Idoso , Eletroencefalografia , Autoanticorpos/líquido cefalorraquidiano , Autoanticorpos/sangueRESUMO
BACKGROUND AND OBJECTIVES: Cerebral hemorrhages are an exclusion criterion and potential adverse effect of antiamyloid agents. It is, therefore, critical to characterize the natural history of cerebral microbleeds in populations genetically predisposed to Alzheimer disease (AD), such as Down syndrome (DS). We aimed to assess microbleed emergence in adults with DS across the AD spectrum, defining their topography and associations with clinical variables, cognitive outcomes, and fluid and neuroimaging biomarkers. METHODS: This cross-sectional study included participants aged 18 years or older from the Down-Alzheimer Barcelona Neuroimaging Initiative and Sant Pau Initiative on Neurodegeneration with T1-weighted and susceptibility-weighted images. Participants underwent comprehensive assessments, including apolipoprotein E (APOE) genotyping; fluid and plasma determinations of beta-amyloid, tau, and neurofilament light; cognitive outcomes (Cambridge Cognitive Examination and modified Cued Recall Test); and vascular risk factors (hypertension, diabetes mellitus, and dyslipidemia). We manually segmented microbleeds and characterized their topography. Associations between microbleed severity and AD biomarkers were explored using between-group comparisons (none vs 1 vs 2+) and multivariate linear models. RESULTS: We included 276 individuals with DS and 158 healthy euploid controls (mean age = 47.8 years, 50.92% female). Individuals with DS were more likely to have microbleeds than controls (20% vs 8.9%, p < 0.001), with more severe presentation (12% with 2+ vs 1.9%). Microbleeds increased with age (12% 20-30 years vs 60% > 60 years) and AD clinical stage (12.42% asymptomatic, 27.9% prodromal, 35.09% dementia) were more common in APOEε4 carriers (26% vs 18.3% noncarriers, p = 0.008), but not associated with vascular risk factors (p > 0.05). Microbleeds were predominantly posterior (cerebellum 33.66%; occipital 14.85%; temporal 21.29%) in participants with DS. Associations with microbleed severity were found for neuroimaging and fluid AD biomarkers, but only hippocampal volumes (standardized ß = -0.18 [-0.31, -0.06], p < 0.005) and CSF p-tau-181 concentrations (ß = 0.26 [0.12, 0.41], p < 0.005) survived regression controlling for age and disease stage, respectively. Microbleeds had limited effect on cognitive outcomes. DISCUSSION: In participants with DS, microbleeds present with a posterior, lobar predominance, are associated with disease severity, but do not affect cognitive performance. These results suggest an interplay between AD pathology and vascular lesions, implicating microbleeds as a risk factor limiting the use of antiamyloid agents in this population.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Hemorragia Cerebral , Síndrome de Down , Proteínas tau , Humanos , Síndrome de Down/líquido cefalorraquidiano , Síndrome de Down/complicações , Síndrome de Down/diagnóstico por imagem , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Transversais , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/líquido cefalorraquidiano , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Adulto , Imageamento por Ressonância Magnética , Idoso , Apolipoproteínas E/genética , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas de Neurofilamentos/sangueRESUMO
BACKGROUND: Increasing evidence supports the use of plasma biomarkers of amyloid, tau, neurodegeneration, and neuroinflammation for diagnosis of dementia. However, their performance for positive and differential diagnosis of dementia with Lewy bodies (DLB) in clinical settings is still uncertain. METHODS: We conducted a retrospective biomarker study in two tertiary memory centers, Paris Lariboisière and CM2RR Strasbourg, France, enrolling patients with DLB (n = 104), Alzheimer's disease (AD, n = 76), and neurological controls (NC, n = 27). Measured biomarkers included plasma Aß40/Aß42 ratio, p-tau181, NfL, and GFAP using SIMOA and plasma YKL-40 and sTREM2 using ELISA. DLB patients with available CSF analysis (n = 90) were stratified according to their CSF Aß profile. RESULTS: DLB patients displayed modified plasma Aß ratio, p-tau181, and GFAP levels compared with NC and modified plasma Aß ratio, p-tau181, GFAP, NfL, and sTREM2 levels compared with AD patients. Plasma p-tau181 best differentiated DLB from AD patients (ROC analysis, area under the curve [AUC] = 0.80) and NC (AUC = 0.78), and combining biomarkers did not improve diagnosis performance. Plasma p-tau181 was the best standalone biomarker to differentiate amyloid-positive from amyloid-negative DLB cases (AUC = 0.75) and was associated with cognitive status in the DLB group. Combining plasma Aß ratio, p-tau181 and NfL increased performance to identify amyloid copathology (AUC = 0.79). Principal component analysis identified different segregation patterns of biomarkers in the DLB and AD groups. CONCLUSIONS: Amyloid, tau, neurodegeneration and neuroinflammation plasma biomarkers are modified in DLB, albeit with moderate diagnosis performance. Plasma p-tau181 can contribute to identify Aß copathology in DLB.
Assuntos
Peptídeos beta-Amiloides , Biomarcadores , Doença por Corpos de Lewy , Proteínas tau , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Axônios/patologia , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3/sangue , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Diagnóstico Diferencial , Proteína Glial Fibrilar Ácida/sangue , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Doença por Corpos de Lewy/sangue , Doença por Corpos de Lewy/líquido cefalorraquidiano , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/patologia , Glicoproteínas de Membrana , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Doenças Neuroinflamatórias/sangue , Doenças Neuroinflamatórias/diagnóstico , Doenças Neuroinflamatórias/líquido cefalorraquidiano , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/líquido cefalorraquidiano , Receptores Imunológicos/sangue , Estudos Retrospectivos , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidianoRESUMO
INTRODUCTION: Frontotemporal lobar degeneration (FTLD) encompasses behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy, corticobasal syndrome/degeneration, and primary progressive aphasias (PPAs). We cross-validated fluid biomarkers and neuroimaging. METHODS: Seven fluid biomarkers from cerebrospinal fluid and serum were related to atrophy in 428 participants including these FTLD subtypes, logopenic variant PPA (lvPPA), Alzheimer's disease (AD), and healthy subjects. Atrophy was assessed by structural magnetic resonance imaging and atlas-based volumetry. RESULTS: FTLD subtypes, lvPPA, and AD showed specific profiles for neurofilament light chain, phosphorylated heavy chain, tau, phospho-tau, amyloid beta1-42 from serum/cerebrospinal fluid, and brain atrophy. Neurofilaments related to regional atrophy in bvFTD, whereas progranulin was associated with atrophy in semantic variant PPA. Ubiquitin showed no effects. DISCUSSION: Results specify biomarker and atrophy patterns in FTLD and AD supporting differential diagnosis. They identify neurofilaments and progranulin in interaction with structural imaging as promising candidates for monitoring disease progression and therapy. HIGHLIGHTS: Study cross-validated neuroimaging and fluid biomarkers in dementia. Five kinds of frontotemporal lobar degeneration and two variants of Alzheimer's disease. Study identifies disease-specific fluid biomarker and atrophy profiles. Fluid biomarkers and atrophy interact in a disease-specific way. Neurofilaments and progranulin are proposed as biomarkers for diagnosis and therapy.
Assuntos
Doença de Alzheimer , Atrofia , Biomarcadores , Encéfalo , Degeneração Lobar Frontotemporal , Imageamento por Ressonância Magnética , Proteínas de Neurofilamentos , Progranulinas , Proteínas tau , Humanos , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Degeneração Lobar Frontotemporal/patologia , Masculino , Feminino , Atrofia/patologia , Idoso , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas de Neurofilamentos/sangue , Proteínas tau/líquido cefalorraquidiano , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Doença de Alzheimer/patologia , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidianoRESUMO
OBJECTIVES: To longitudinally characterize disease-relevant CSF and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion. METHODS: This single-center longitudinal cohort study has followed known carriers of PRNP pathogenic variants at risk for prion disease, individuals with a close relative who died of genetic prion disease but who have not undergone predictive genetic testing, and controls. All participants were asymptomatic at first visit and returned roughly annually. We determined PRNP genotypes, measured NfL and GFAP in plasma, and RT-QuIC, total PrP, NfL, T-tau, and beta-synuclein in CSF. RESULTS: Among 41 carriers and 21 controls enrolled, 28 (68%) and 15 (71%) were female, and mean ages were 47.5 and 46.1. At baseline, all individuals were asymptomatic. We observed RT-QuIC seeding activity in the CSF of 3 asymptomatic E200K carriers who subsequently converted to symptomatic and died of prion disease. 1 P102L carrier remained RT-QuIC negative through symptom conversion. No other individuals developed symptoms. The prodromal window from detection of RT-QuIC positivity to disease onset was 1 year long in an E200K individual homozygous (V/V) at PRNP codon 129 and 2.5 and 3.1 years in 2 codon 129 heterozygotes (M/V). Changes in neurodegenerative and neuroinflammatory markers were variably observed prior to onset, with increases observed for plasma NfL in 4/4 converters, and plasma GFAP, CSF NfL, CSF T-tau, and CSF beta-synuclein each in 2/4 converters, although values relative to age and fold changes relative to individual baseline were not remarkable for any of these markers. CSF PrP was longitudinally stable with mean coefficient of variation 9.0% across all individuals over up to 6 years, including data from converting individuals at RT-QuIC-positive timepoints. DISCUSSION: CSF prion seeding activity may represent the earliest detectable prodromal sign in E200K carriers. Neuronal damage and neuroinflammation markers show limited sensitivity in the prodromal phase. CSF PrP levels remain stable even in the presence of RT-QuIC seeding activity. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT05124392 posted 2017-12-01, updated 2023-01-27.
Assuntos
Biomarcadores , Doenças Priônicas , Proteínas Priônicas , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Proteínas Priônicas/genética , Proteínas Priônicas/líquido cefalorraquidiano , Proteínas Priônicas/sangue , Doenças Priônicas/genética , Doenças Priônicas/líquido cefalorraquidiano , Doenças Priônicas/sangue , Doenças Priônicas/diagnóstico , Estudos Longitudinais , Adulto , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas de Neurofilamentos/sangue , Heterozigoto , Proteína Glial Fibrilar Ácida/sangue , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/genética , Progressão da Doença , alfa-Sinucleína/líquido cefalorraquidiano , alfa-Sinucleína/genética , alfa-Sinucleína/sangueRESUMO
BACKGROUND: Studies suggest that cerebrospinal fluid (CSF) levels of amyloid-ß (Aß)42 and Aß40 present a circadian rhythm. However sustained sampling of large volumes of CSF with indwelling intrathecal catheters used in most of these studies might have affected CSF dynamics and thereby confounded the observed fluctuations in the biomarker levels. METHODS: We included 38 individuals with either normal (N = 20) or abnormal (N = 18) CSF Aß42/Aß40 levels at baseline. CSF and plasma were collected at two visits separated by an average of 53 days with lumbar punctures and venipunctures performed either in the morning or evening. At the first visit, sample collection was performed in the morning for 17 participants and the order was reversed for the remaining 21 participants. CSF and plasma samples were analyzed for Alzheimer' disease (AD) biomarkers, including Aß42, Aß40, GFAP, NfL p-tau181, p-tau217, p-tau231 and t-tau. CSF samples were also tested using mass spectrometry for 22 synaptic and endo-lysosomal proteins. RESULTS: CSF Aß42 (mean difference [MD], 0.21 ng/mL; p = 0.038), CSF Aß40 (MD, 1.85 ng/mL; p < 0.001), plasma Aß42 (MD, 1.65 pg/mL; p = 0.002) and plasma Aß40 (MD, 0.01 ng/mL, p = 0.002) were increased by 4.2-17.0% in evening compared with morning samples. Further, CSF levels of 14 synaptic and endo-lysosomal proteins, including neurogranin and neuronal pentraxin-1, were increased by 4.5-13.3% in the evening samples (MDrange, 0.02-0.56 fmol/µl; p < 0.042). However, no significant differences were found between morning and evening levels for the Aß42/Aß40 ratio, different p-tau variants, GFAP and NfL. There were no significant interaction between sampling time and Aß status for any of the biomarkers, except that CSF t-tau was increased (by 5.74%) in the evening samples compared to the morning samples in Aß-positive (MD, 16.46 ng/ml; p = 0.009) but not Aß-negative participants (MD, 1.89 ng/ml; p = 0.47). There were no significant interactions between sampling time and order in which samples were obtained. DISCUSSION: Our findings provide evidence for diurnal fluctuations in Aß peptide levels, both in CSF and plasma, while CSF and plasma p-tau, GFAP and NfL were unaffected. Importantly, Aß42/Aß40 ratio remained unaltered, suggesting that it is more suitable for implementation in clinical workup than individual Aß peptides. Additionally, we show that CSF levels of many synaptic and endo-lysosomal proteins presented a diurnal rhythm, implying a build-up of neuronal activity markers during the day. These results will guide the development of unified sample collection procedures to avoid effects of diurnal variation for future implementation of AD biomarkers in clinical practice and drug trials.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Ritmo Circadiano , Fragmentos de Peptídeos , Proteínas tau , Humanos , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/sangue , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Feminino , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Masculino , Idoso , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/sangue , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/sangue , Pessoa de Meia-Idade , Ritmo Circadiano/fisiologia , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Idoso de 80 Anos ou mais , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/sangueRESUMO
BACKGROUND AND OBJECTIVES: Plasma ß-amyloid-1-42/1-40 (Aß42/40), phosphorylated-tau (P-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) have been widely examined in Alzheimer disease (AD), but little is known about their reflection of copathologies, clinical importance, and predictive value in dementia with Lewy bodies (DLB). We aimed to evaluate associations of these biomarkers with CSF amyloid, cognition, and core features in DLB. METHODS: This cross-sectional multicenter cohort study with prospective component included individuals with DLB, AD, and healthy controls (HCs), recruited from 2002 to 2020 with an annual follow-up of up to 5 years, from the European-Dementia With Lewy Bodies consortium. Plasma biomarkers were measured by single-molecule array (Neurology 4-Plex E kit). Amyloid status was determined by CSF Aß42 concentrations, and cognition was assessed by Mini-Mental State Examination (MMSE). Biomarker differences across groups, associations with amyloid status, and clinical core features were assessed by analysis of covariance. Associations with cognitive impairment and decline were assessed by linear regression and linear mixed-effects models. RESULTS: In our cohort consisting of 562 individuals (HC n = 89, DLB n = 342, AD n = 131; 250 women [44.5%], mean [SD] age of 71 [8] years), sex distribution did not differ between groups. Patients with DLB were significantly older, and had less years of education and worse baseline cognition than HC, but not AD. DLB participants stratified for amyloid status differed significantly in plasma Aß42/40 ratio (decreased in amyloid abnormal: ß = -0.008, 95% CI -0.016 to -0.0003, p = 0.01) and P-tau (increased in amyloid abnormal, P-tau181: ß = 0.246, 95% CI 0.011-0.481; P-tau231: ß = 0.227, 95% CI 0.035-0.419, both p < 0.05), but not in GFAP (ß = 0.068, 95% CI -0.018 to 0.153, p = 0.119), and NfL (ß = 0.004, 95% CI -0.087 to 0.096, p = 0.923) concentrations. Higher baseline GFAP, NfL, and P-tau concentrations were associated with lower MMSE scores in DLB, and GFAP and NfL were associated with a faster cognitive decline (GFAP: annual change of -2.11 MMSE points, 95% CI -2.88 to -1.35 MMSE points, p < 0.001; NfL: annual change of -2.13 MMSE points, 95% CI -2.97 to -1.29 MMSE points, p < 0.001). DLB participants with parkinsonism had higher concentrations of NfL (ß = 0.08, 95% CI 0.02-0.14, p = 0.006) than those without. DISCUSSION: Our study suggests a possible utility of plasma Aß42/40, P-tau181, and P-tau231 as a noninvasive biomarkers to assess amyloid copathology in DLB, and plasma GFAP and NfL as monitoring biomarkers for cognitive symptoms in DLB.
Assuntos
Peptídeos beta-Amiloides , Biomarcadores , Proteína Glial Fibrilar Ácida , Doença por Corpos de Lewy , Proteínas de Neurofilamentos , Proteínas tau , Humanos , Feminino , Masculino , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/sangue , Idoso , Doença por Corpos de Lewy/líquido cefalorraquidiano , Doença por Corpos de Lewy/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/sangue , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/sangue , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Estudos Transversais , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/sangue , Pessoa de Meia-Idade , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/sangue , Idoso de 80 Anos ou mais , Estudos de Coortes , Estudos Prospectivos , Cognição/fisiologia , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/sangueRESUMO
BACKGROUND: Our objective was to explore various biomarkers for predicting suboptimal responses to disease-modifying treatments (DMTs) in patients with MS (pwMS). METHODS: We conducted a longitudinal, bicentric study with pwMS stratified based on their DMTs responses. Treatment failure (TF) was defined as the onset of a second relapse, presence of two or more T2 new lesions, or disability progression independent of relapse during the follow-up period. We evaluated intrathecal synthesis (ITS) of IgG and IgM using OCB, linear indices, and Reibergrams. Free kappa light chains ITS was assessed using the linear index (FKLCi). NfL and GFAP in serum and CSF, and CHI3L1 in CSF were quantified. Quantitative variables were dichotomized based on the third quartile. Predictive efficacy was assessed through bivariate and multivariate analyses, adjusting for age, sex, EDSS, acute inflammatory activity (AI) -defined as the onset of a relapse or gadolinium-enhancing lesions within a 90-day window of lumbar puncture-, treatment modality, study center, and time from disease onset to treatment initiation. In case of collinearity, multiple models were generated or confounding variables were excluded if collinearity existed between them and the biomarker. The same methodology was used to investigate the predictive potential of various combinations of two biomarkers, based on whether any of them tested positive or exceeded the third quartile. RESULTS: A total of 137 pwMS were included. FKLCi showed no differences based on AI, no correlation with EDSS and was significantly higher in pwMS with TF (p = 0.008). FKLCi>130 was associated with TF in bivariate analysis (Log-Rank p = 0.004). Due to collinearity between age and EDSS, two different models were generated with each of them and the rest of the confounding variables, in which FKLCi>130 showed a Hazard Ratio (HR) of 2.69 (CI: 1.35-5.4) and 2.67 (CI: 1.32-5.4), respectively. The combination of either FKLC or sNfL exceeding the third quartile was also significant in bivariate (Log-Rank p = 0.04) and multivariate (HR=3.1 (CI: 1.5-6.5)) analyses. However, when analyzed independently, sNfL did not show significance, and FKLCi mirrored the pattern obtained in the previous model (HR: 3.04; CI: 1.51-6.1). Treatment with highefficacy DMTs emerged as a protective factor in all models. DISCUSSION: Our analysis and the fact that FKLCi is independent of EDSS and AI suggest that it might be a valuable parameter for discriminating aggressive phenotypes. We propose implementing high-efficacy drugs in pwMS with elevated FKLCi.
Assuntos
Biomarcadores , Humanos , Feminino , Masculino , Adulto , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Pessoa de Meia-Idade , Estudos Longitudinais , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacologia , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/sangue , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/diagnóstico , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/sangue , Imunoglobulina G/líquido cefalorraquidiano , Imunoglobulina G/sangue , Falha de Tratamento , Proteína 1 Semelhante à Quitinase-3/sangue , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Imunoglobulina M/líquido cefalorraquidiano , Imunoglobulina M/sangue , PrognósticoRESUMO
BACKGROUND: In Amyotrophic Lateral Sclerosis (ALS) patients with SOD1 mutation the intrathecal administration of tofersen slowed down the progression of disease in a controlled clinical study, but results were not statistically significant. METHODS: In this multicentre, observational study, we evaluated a cohort of 27 ALS-SOD1 patients who were treated with tofersen, focussing on 17 patients who were followed for at least 48 weeks (median period of 84 weeks, range 48-108). We compared the clinical slopes, as measured by ALSFRS-R, MRC scale and Forced Vital Capacity, during tofersen treatment with retrospective data at 1 year prior to therapy. Cerebrospinal fluid (CSF) and serum neurofilament light chains (NFL) were measured in all patients. RESULTS: Cumulative evaluation of the ALSFRS-R and MRC progression rates showed a statistically significant change during treatment with respect to the period prior to therapy (p = 0.023 and p = 0.007, respectively). The analysis of individual patients showed that nine of the seventeen patients substantially stabilized or slightly improved. Four patients deteriorated during treatment, while in the remaining patients the very slow course did not allow to identify significant changes. CSF and serum NFL concentration markedly decreased in the near totality of patients. Increased levels of white blood cells and proteins in the CSF were found in 60% of patients. Such alterations were clinically asymptomatic in all but two patients who showed an acute pure motor radiculitis, which responded to steroid therapy. CONCLUSIONS: Clinical findings and NFL analysis strongly suggest that tofersen may have a disease-modifying effect in a subset of SOD1-ALS patients.
Assuntos
Esclerose Lateral Amiotrófica , Superóxido Dismutase-1 , Humanos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Superóxido Dismutase-1/genética , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Progressão da Doença , Adulto , Estudos Retrospectivos , Resultado do Tratamento , Estudos de CoortesRESUMO
Neurological damage is the pathological substrate of permanent disability in various neurodegenerative disorders. Early detection of this damage, including its identification and quantification, is critical to preventing the disease's progression in the brain. Tau, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), as brain protein biomarkers, have the potential to improve diagnostic accuracy, disease monitoring, prognostic assessment, and treatment efficacy. These biomarkers are released into the cerebrospinal fluid (CSF) and blood proportionally to the degree of neuron and astrocyte damage in different neurological disorders, including stroke, traumatic brain injury, multiple sclerosis, neurodegenerative dementia, and Parkinson's disease. Here, we review how Tau, GFAP, and NfL biomarkers are detected in CSF and blood as crucial diagnostic tools, as well as the levels of these biomarkers used for differentiating a range of neurological diseases and monitoring disease progression. We also discuss a biosensor approach that allows for the real-time detection of multiple biomarkers in various neurodegenerative diseases. This combined detection system of brain protein biomarkers holds significant promise for developing more specific and accurate clinical tools that can identify the type and stage of human neurological diseases with greater precision.
Assuntos
Biomarcadores , Proteína Glial Fibrilar Ácida , Doenças Neurodegenerativas , Proteínas de Neurofilamentos , Proteínas tau , Humanos , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas de Neurofilamentos/sangue , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/sangue , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/sangue , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/sangue , Encéfalo/metabolismo , Encéfalo/patologiaRESUMO
Traumatic brain injury (TBI) and Alzheimer's disease (AD) have overlapping mechanisms but it remains unknown if pathophysiological characteristics and cognitive trajectories in AD patients are influenced by TBI history. Here, we studied AD patients (stage MCI or dementia) with TBI history (ADTBI+, n=110), or without (ADTBI-, n=110) and compared baseline CSF concentrations of amyloid beta 1-42 (Aß42), phosphorylated tau181 (pTau181), total tau, neurofilament light chain (NfL), synaptosomal associated protein-25kDa (SNAP25), neurogranin (Ng), neuronal pentraxin-2 (NPTX2) and glutamate receptor-4 (GluR4), as well as differences in cognitive trajectories using linear mixed models. Explorative, analyses were repeated within stratified TBI groups by TBI characteristics (timing, severity, number). We found no differences in baseline CSF biomarker concentrations nor in cognitive trajectories between ADTBI+ and ADTBI- patients. TBI >5 years ago was associated with higher NPTX2 and a tendency for higher SNAP25 concentrations compared to TBI ≤ 5 years ago, suggesting that TBI may be associated with long-term synaptic dysfunction only when occurring before onset or in a pre-clinical disease stage of AD.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Lesões Encefálicas Traumáticas , Cognição , Proteínas tau , Humanos , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Lesões Encefálicas Traumáticas/líquido cefalorraquidiano , Lesões Encefálicas Traumáticas/complicações , Biomarcadores/líquido cefalorraquidiano , Masculino , Feminino , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Neurogranina/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Pessoa de Meia-Idade , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/diagnóstico , Idoso de 80 Anos ou mais , Proteína 25 Associada a Sinaptossoma/líquido cefalorraquidiano , Proteína C-Reativa/líquido cefalorraquidiano , Proteínas do Tecido NervosoRESUMO
BACKGROUND AND PURPOSE: Neurofilament light chain (NFL) has been shown to be increased in amyotrophic lateral sclerosis (ALS) and, to a lesser extent, in frontotemporal dementia (FTD). A meta-analysis of NFL in ALS and FTD was performed. METHODS: Available studies comparing cerebrospinal fluid and blood NFL levels in ALS versus neurologically healthy controls (NHCs), other neurological diseases (ONDs) and ALS mimics, as well as in FTD and related entities (behavioural variant of FTD and frontotemporal lobar degeneration syndromes) versus NHCs, ONDs and other dementias were evaluated. RESULTS: In ALS, both cerebrospinal fluid and blood levels of NFL were higher compared to other categories. In FTD, behavioural variant of FTD and frontotemporal lobar degeneration syndromes, NFL levels were consistently higher compared to NHCs; however, several comparisons with ONDs and other dementias did not demonstrate significant differences. DISCUSSION: Amyotrophic lateral sclerosis is characterized by higher NFL levels compared to most other conditions. In contrast, NFL is not as good at discriminating FTD from other dementias.
Assuntos
Esclerose Lateral Amiotrófica , Degeneração Lobar Frontotemporal , Proteínas de Neurofilamentos , Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Esclerose Lateral Amiotrófica/sangue , Humanos , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Degeneração Lobar Frontotemporal/sangue , Degeneração Lobar Frontotemporal/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Demência Frontotemporal/líquido cefalorraquidiano , Demência Frontotemporal/sangueRESUMO
Cerebrospinal fluid total-tau (t-tau) and neurofilament light chain (NfL) are biomarkers of neurodegeneration and are increased in Alzheimer's disease (AD). In order to adjust for age-related increases in t-tau and NfL, cross-sectional age-adjusted norms were developed based on amyloid negative cognitively normal (CN) adults aged 41-78 years (CN, n = 137). The age-adjusted norms for t-tau and NfL did not improve receiver operating curve based diagnostic accuracies in individuals with mild cognitive impairment (MCI) due to AD (AD-MCI, n = 144). Furthermore, while NfL was correlated with higher age in AD-MCI, no significant correlation was found for t-tau. The cox proportional hazard models, applied in 429 participants with baseline t-tau and NfL, showed higher hazard ratio of progression to MCI or dementia without age-adjustments (HR = 3.39 for t-tau and HR = 3.17 for NfL), as compared to using our norms (HR = 2.29 for t-tau and HR = 1.89 for NfL). Our results indicate that utilizing normative reference data could obscure significant age-related increases in these markers associated with neurodegeneration and AD leading to a potential loss of overall diagnostic accuracy.
Assuntos
Doença de Alzheimer , Biomarcadores , Disfunção Cognitiva , Proteínas de Neurofilamentos , Proteínas tau , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Masculino , Idoso , Feminino , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/líquido cefalorraquidiano , Adulto , Progressão da Doença , Modelos de Riscos Proporcionais , Estudos Transversais , Envelhecimento/líquido cefalorraquidiano , Sintomas ProdrômicosRESUMO
Alzheimer disease (AD) and Alzheimer Disease and Related Dementias (AD/ADRD) are growing public health challenges globally affecting millions of older adults, necessitating concerted efforts to advance our understanding and management of these conditions. AD is a progressive neurodegenerative disorder characterized pathologically by amyloid plaques and tau neurofibrillary tangles that are the primary cause of dementia in older individuals. Early and accurate diagnosis of AD dementia is crucial for effective intervention and treatment but has proven challenging to accomplish. Although testing for AD brain pathology with cerebrospinal fluid (CSF) or positron emission tomography (PET) has been available for over 2 decades, most patients never underwent this testing because of inaccessibility, high out-of-pocket costs, perceived risks, and the lack of AD-specific treatments. However, in recent years, rapid progress has been made in developing blood biomarkers for AD/ADRD. Consequently, blood biomarkers have emerged as promising tools for non-invasive and cost-effective diagnosis, prognosis, and monitoring of AD progression. This review presents the evolving landscape of blood biomarkers in AD/ADRD and explores their potential applications in clinical practice for early detection, prognosis, and therapeutic interventions. It covers recent advances in blood biomarkers, including amyloid beta (Aß) peptides, tau protein, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). It also discusses their diagnostic and prognostic utility while addressing associated challenges and limitations. Future research directions in this rapidly evolving field are also proposed.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Proteínas tau , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/sangue , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/sangue , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons/métodosRESUMO
BACKGROUND: Idiopathic intracranial hypertension is a secondary headache disorder potentially causing visual loss. Neurofilament light chain is a candidate, prognostic biomarker, but further studies of neuronal biomarkers are needed. Our objective was to investigate neurofilament light chain in cerebrospinal fluid (cNfL) and plasma (pNfL), amyloid-beta 42 (Aß-42), total-tau and phosphorylated-tau in cerebrospinal fluid in new-onset idiopathic intracranial hypertension. METHODS: Prospective case-control study including new-onset idiopathic intracranial hypertension and age, sex and BMI matched controls. Biomarkers were compared between patients and controls and related to papilledema, visual fields and opening pressure. RESULTS: We included 37 patients and 35 controls. Patients had higher age-adjusted cNfL (1.4 vs. 0.6 pg/mL, p-adjusted < 0.001), pNfL (0.5 vs. 0.3 pg/mL, p-adjusted < 0.001) and total-tau/Aß-42 (0.12 vs. 0.11, p-adjusted = 0.039). Significant, positive linear correlations were found between cNfL, pNfL, total-tau/Aß-42 and opening pressure. Patients with severe papilledema had elevated cNfL compared to mild-moderate papilledema (median cNfL: 4.3 pg/mL (3.7) versus 1.0 pg/mL (1.4), p-adjusted = 0.009). cNFL was inversely associated with perimetric mean deviation (r = -0.47, p-adjusted < 0.001). CONCLUSIONS: cNfL, pNfL and total-tau/Aß-42 were elevated in new-onset idiopathic intracranial hypertension. cNfL was associated with severity of papilledema and visual field defects at diagnosis. This indicates early axonal damage. Neurofilament light chain is a candidate biomarker for disease severity.
Assuntos
Biomarcadores , Proteínas de Neurofilamentos , Pseudotumor Cerebral , Humanos , Feminino , Masculino , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas de Neurofilamentos/sangue , Adulto , Pseudotumor Cerebral/diagnóstico , Pseudotumor Cerebral/líquido cefalorraquidiano , Pseudotumor Cerebral/sangue , Pseudotumor Cerebral/complicações , Estudos Prospectivos , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Pessoa de Meia-Idade , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/sangue , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/sangueRESUMO
Background and purpose: Myelin oligodendrocyte glycoprotein (MOG) IgG is frequently elevated in pediatric patients with acquired demyelinating syndrome (ADS). However, no specific biomarkers exist for phenotype classification, symptom severity, prognosis, and treatment guidance of MOG-IgG-associated disease (MOGAD). This study evaluated neurofilament light chain (NfL) and endothelial growth factor receptor (EGFR) mRNA expression levels in serum and cerebrospinal fluid (CSF) as potential biomarkers for MOGAD in Chinese children. Methods: This was a cross-sectional and single-center study. We enrolled 22 consecutive pediatric patients hospitalized with MOGAD and 20 control pediatric patients hospitalized for noninflammatory neurological diseases in Hebei Children's Hospital. Serum and CSF were collected from MOGAD patients within 3 days before immunotherapy. The mRNA levels of NfL and EGFR in serum and CSF were measured by real-time polymerase chain reaction (qPCR), and the EGFR/NfL ratio mRNA was calculated. These measurement values were then compared between disease groups and among MOGAD phenotypes. In addition, the correlations between the mRNAs of three markers (NfL, EGFR, EGFR/NfL ratio), extended disability status scale (EDSS) scores, and clinical phenotypes were analyzed. Results: Serum and CSF NfL mRNA levels were significantly higher of acute-stage MOGAD patients than those of control patients (p< 0.05 and p< 0.01, respectively), while the mRNA levels of serum EGFR and EGFR/NfL ratio were significantly lower of MOGAD patients than those of controls (p < 0.05, p < 0.0001). Serum NfL mRNA was significantly correlated with mRNA of serum EGFR (r =0.480, p < 0.05). Serum and CSF NfL mRNA levels in MOGAD patients with the ADEM-like phenotype were also significantly higher than those in control patients (p < 0.01, p < 0.01) and optic neuritis (ON) phenotype (p < 0.05, p < 0.05). Both mRNAs of NfL in CSF and EGFR/NfL ratio in serum were correlated with EDSS scores (p < 0.05, r = 0.424; p < 0.05, r= -0.521). Conclusion: The mRNA levels of elevated NfL in serum and CSF as well as lower EGFR and EGFR/NfL ratio in serum could help distinguish acute-phase MOGAD. Higher mRNA levels of NfL in serum and CSF of MOGAD patients help distinguish ADEM-like phenotype. In addition, serum EGFR/NfL mRNA ratio is indicative of disease severity in pediatric patients with MOGAD. Further investigations are warranted to elucidate the pathological mechanisms underlying these associations.
Assuntos
Biomarcadores , Receptores ErbB , Glicoproteína Mielina-Oligodendrócito , Proteínas de Neurofilamentos , Fenótipo , RNA Mensageiro , Índice de Gravidade de Doença , Humanos , Masculino , Feminino , Biomarcadores/sangue , Criança , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas de Neurofilamentos/genética , Glicoproteína Mielina-Oligodendrócito/imunologia , RNA Mensageiro/genética , RNA Mensageiro/sangue , Receptores ErbB/genética , Receptores ErbB/sangue , Estudos Transversais , Pré-Escolar , Imunoglobulina G/sangue , Imunoglobulina G/líquido cefalorraquidiano , Adolescente , Autoanticorpos/sangue , Autoanticorpos/líquido cefalorraquidianoRESUMO
BACKGROUND: This study aimed to evaluate the utility of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCHL1) and total tau (tTAU) serum concentrations as approximation for cerebrospinal fluid (CSF) concentrations of the respective biomarkers in the context of neuroinflammation and multiple sclerosis (MS). METHODS: NfL, GFAP, UCHL1 and tTAU concentrations in serum and CSF were measured in 183 patients (122 with neuroinflammatory disease and 61 neurological or somatoform disease controls) using the single molecule array HD-1 analyzer (Quanterix, Boston, MA). Spearman's rank correlations were computed between serum and CSF concentrations. In a second step, the effects of age, BMI, gadolinium-enhancing lesions in MRI, integrity of the blood-brain barrier (BBB) and presence of acute relapse were accounted for by computing partial correlations. The analyses were repeated for a subsample consisting of MS phenotype patients only (n = 118). EDSS, MS disease activity and acute relapse were considered as additional covariates. Receiver operating characteristic (ROC) analysis was performed for each serum/CSF biomarker concentration to assess how well the particular biomarker concentration differentiates MS patients from somatoform disease controls. Correlations between serum and CSF levels as well as area under the curve (AUC) values were compared for the different biomarkers using z-test statistics. RESULTS: Serum concentrations correlated positively with CSF levels for NfL (r = 0.705, p < 0.01) as well as for GFAP (r = 0.259, p < 0.01). Correlation coefficients were significantly higher for NfL than for GFAP (z = 5.492, p < 0.01). We found no significant serum-CSF correlations for UCHL1 or tTAU. After adjusting for covariates, the results remained unchanged. In the analysis focusing only on MS patients, the results were replicated. ROC analysis demonstrated similarly acceptable performance of serum and CSF NfL values in differentiating MS phenotype patients from somatoform disease controls. AUC values were significantly higher for serum and CSF NfL compared to other biomarkers. CONCLUSION: NfL and GFAP but not UCHL1 or tTAU serum concentrations are associated with CSF levels of the respective biomarker. NfL exhibits more robust correlations between its serum and CSF concentrations as compared to GFAP independently from BBB integrity, clinical and radiological covariates. Both serum and CSF NfL values differentiate between MS and controls.