Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 465
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Immunity ; 51(5): 915-929.e7, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31732167

RESUMO

The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are occluded by self-N-glycan shielding, limiting B cell recognition of the underlying polypeptide surface. The exceptions to the contiguous glycan shield include the conserved receptor CD4 binding site (CD4bs) and glycoprotein (gp)41 elements proximal to the furin cleavage site. Accordingly, we performed heterologous trimer-liposome prime:boosting in rabbits to drive B cells specific for cross-conserved sites. To preferentially expose the CD4bs to B cells, we eliminated proximal N-glycans while maintaining the native-like state of the cleavage-independent NFL trimers, followed by gradual N-glycan restoration coupled with heterologous boosting. This approach successfully elicited CD4bs-directed, cross-neutralizing Abs, including one targeting a unique glycan-protein epitope and a bNAb (87% breadth) directed to the gp120:gp41 interface, both resolved by high-resolution cryoelectron microscopy. This study provides proof-of-principle immunogenicity toward eliciting bNAbs by vaccination.


Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Lipossomos , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Antígenos CD4/química , Antígenos CD4/imunologia , Antígenos CD4/metabolismo , Complemento C3/imunologia , Complemento C3/metabolismo , Apresentação Cruzada/imunologia , Epitopos/imunologia , Glicosilação , Infecções por HIV/virologia , Humanos , Imunoglobulina G/imunologia , Modelos Moleculares , Testes de Neutralização , Polissacarídeos/imunologia , Polissacarídeos/metabolismo , Ligação Proteica , Conformação Proteica , Coelhos , Produtos do Gene env do Vírus da Imunodeficiência Humana/administração & dosagem , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo
2.
Immunity ; 46(6): 1073-1088.e6, 2017 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-28636956

RESUMO

The development of stabilized recombinant HIV envelope trimers that mimic the virion surface molecule has increased enthusiasm for a neutralizing antibody (nAb)-based HIV vaccine. However, there is limited experience with recombinant trimers as immunogens in nonhuman primates, which are typically used as a model for humans. Here, we tested multiple immunogens and immunization strategies head-to-head to determine their impact on the quantity, quality, and kinetics of autologous tier 2 nAb development. A bilateral, adjuvanted, subcutaneous immunization protocol induced reproducible tier 2 nAb responses after only two immunizations 8 weeks apart, and these were further enhanced by a third immunization with BG505 SOSIP trimer. We identified immunogens that minimized non-neutralizing V3 responses and demonstrated that continuous immunogen delivery could enhance nAb responses. nAb responses were strongly associated with germinal center reactions, as assessed by lymph node fine needle aspiration. This study provides a framework for preclinical and clinical vaccine studies targeting nAb elicitation.


Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Neutralizantes/uso terapêutico , Centro Germinativo/imunologia , Anticorpos Anti-HIV/uso terapêutico , Infecções por HIV/terapia , HIV-1/imunologia , Animais , Células Cultivadas , Epitopos de Linfócito B/química , Epitopos de Linfócito B/imunologia , Centro Germinativo/virologia , Infecções por HIV/imunologia , Humanos , Imunização , Injeções Subcutâneas , Primatas , Multimerização Proteica , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia
3.
Mult Scler ; 30(10): 1278-1289, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39246289

RESUMO

BACKGROUND: Choroid plexus (ChP) enlargement is an emerging radiological biomarker in multiple sclerosis (MS). OBJECTIVES: This study aims to assess ChP volume in a large cohort of patients with radiologically isolated syndrome (RIS) versus healthy controls (HC) and explore its relationship with other brain volumes, disease activity, and biological markers. METHODS: RIS individuals were included retrospectively and compared with HC. ChPs were automatically segmented using an in-house automated algorithm and manually corrected. RESULTS: A total of 124 patients fulfilled the 2023 RIS criteria, and 55 HCs were included. We confirmed that ChPs are enlarged in RIS versus HC (mean (±SD) normalized ChP volume: 17.24 (±4.95) and 11.61 (±3.58), respectively, p < 0.001). Larger ChPs were associated with more periventricular lesions (ρ = 0.26; r2 = 0.27; p = 0.005 for the correlation with lesion volume, and ρ = 0.2; r2 = 0.21; p = 0.002 for the correlation with lesion number) and lower thalamic volume (ρ = -0.38; r2 = 0.44; p < 0.001), but not with lesions in other brain regions. Conversely, ChP volume did not correlate with biological markers. No significant difference in ChP volume was observed between subjects who presented or did not have a clinical event or between those with or without imaging disease activity. CONCLUSIONS: This study provides evidence that ChP volume is higher in RIS and is associated with measures reflecting periventricular pathology but does not correlate with biological, radiological, or clinical markers of disease activity.


Assuntos
Plexo Corióideo , Doenças Desmielinizantes , Imageamento por Ressonância Magnética , Humanos , Feminino , Masculino , Adulto , Plexo Corióideo/patologia , Plexo Corióideo/diagnóstico por imagem , Pessoa de Meia-Idade , Doenças Desmielinizantes/diagnóstico por imagem , Doenças Desmielinizantes/patologia , Estudos Retrospectivos , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia
4.
Muscle Nerve ; 70(3): 333-345, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39031772

RESUMO

INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (SOD1-ALS), tofersen received accelerated approval in the United States and is available via expanded access programs (EAP) outside the United States. This multicenter study investigates clinical and patient-reported outcomes (PRO) and serum neurofilament light chain (sNfL) during tofersen treatment in an EAP in Germany. METHODS: Sixteen SOD1-ALS patients receiving tofersen for at least 6 months were analyzed. The ALS progression rate (ALS-PR), as measured by the monthly change of the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity (SVC), and sNfL were investigated. PRO included the Measure Yourself Medical Outcome Profile (MYMOP2), Treatment Satisfaction Questionnaire for Medication (TSQM-9), and Net Promoter Score (NPS). RESULTS: Mean tofersen treatment was 11 months (6-18 months). ALS-PR showed a mean change of -0.2 (range 0 to -1.1) and relative reduction by 25%. Seven patients demonstrated increased ALSFRS-R. SVC was stable (mean 88%, range -15% to +28%). sNfL decreased in all patients except one heterozygous D91A-SOD1 mutation carrier (mean change of sNfL -58%, range -91 to +27%, p < .01). MYMOP2 indicated improved symptom severity (n = 10) or yet perception of partial response (n = 6). TSQM-9 showed high global treatment satisfaction (mean 83, SD 16) although the convenience of drug administration was modest (mean 50, SD 27). NPS revealed a very high recommendation rate for tofersen (NPS +80). DISCUSSION: Data from this EAP supported the clinical and sNfL response to tofersen in SOD1-ALS. PRO suggested a favorable patient perception of tofersen treatment in clinical practice.


Assuntos
Esclerose Lateral Amiotrófica , Proteínas de Neurofilamentos , Medidas de Resultados Relatados pelo Paciente , Superóxido Dismutase-1 , Humanos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Superóxido Dismutase-1/genética , Proteínas de Neurofilamentos/sangue , Resultado do Tratamento , Progressão da Doença , Adulto , Oligonucleotídeos/uso terapêutico
5.
Am J Geriatr Psychiatry ; 32(8): 988-1001, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38609836

RESUMO

BACKGROUND: Symptoms of behavioral variant frontotemporal dementia (bvFTD) overlap with primary psychiatric disorders (PPD) making diagnosis challenging. Serum neurofilament light (sNfL) is a candidate biomarker to distinguish bvFTD from PPD, but large-scale studies in PPD are lacking. OBJECTIVE: Determine factors that influence sNfL from a large database of PPD patients, and test its diagnostic accuracy. DESIGN, SETTINGS, SUBJECTS, MEASUREMENTS: Clinical data of people aged 40-81 were obtained from healthy subjects (n = 69), and patients with PPD (n = 848) or bvFTD (n = 82). sNfL was measured using Simoa technology on an HD-X instrument. Data were analyzed using general linear models, and Receiver Operating Characteristic (ROC) curve analyses to determine global and age-specific sNfL cutoffs to distinguish bvFTD from PPD, using the Youden Index. RESULTS: sNfL increased with age, while sex, BMI and diabetes status were modestly associated with sNfL. sNfL was slightly higher in PPD than healthy subjects (14.1 versus 11.7 pg/mL), when controlling for covariates. sNfL was markedly lower in PPD than bvFTD (14.1 versus 44.1 pg/mL). sNfL could differentiate PPD from bvFTD with an AUC = 0.868, but the effect was driven by the younger subjects between age 40-60 years at a cutoff of 16.0 pg/mL. No valid cutoff was detected over age 60, however, values of sNfL above 38.5 pg/mL, or below 13.9 pg/mL, provided 90% diagnostic certainty of bvFTD or PPD, respectively. CONCLUSION: PPD have mildly elevated sNfL compared to healthy subjects but much lower than bvFTD. Results support the use of sNfL as a biomarker to differentiate PPD from bvFTD at age 60 or below, but accuracy decreases in older ages.


Assuntos
Biomarcadores , Demência Frontotemporal , Transtornos Mentais , Proteínas de Neurofilamentos , Humanos , Pessoa de Meia-Idade , Feminino , Masculino , Demência Frontotemporal/sangue , Demência Frontotemporal/diagnóstico , Idoso , Proteínas de Neurofilamentos/sangue , Adulto , Diagnóstico Diferencial , Biomarcadores/sangue , Idoso de 80 Anos ou mais , Transtornos Mentais/sangue , Transtornos Mentais/diagnóstico , Fatores Etários , Estudos de Casos e Controles , Curva ROC
6.
Eur J Neurol ; 31(1): e16070, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37724995

RESUMO

BACKGROUND AND PURPOSE: Hereditary transthyretin amyloidosis (ATTRv) is a life-threatening disease caused by mutations in the gene encoding transthyretin (TTR). The recent therapeutic advances have underlined the importance of easily accessible, objective biomarkers of both disease onset and progression. Preliminary evidence suggests a potential role in this respect for neurofilament light chain (NfL). In this study, the aim was to determine serum NfL (sNfL) levels in a late-onset ATTRv population and evaluate whether it might represent a reliable biomarker of disease onset (i.e., 'conversion' from the asymptomatic status to symptomatic disease in TTR mutation carriers). METHODS: In all, 111 individuals harbouring a pathogenic TTR variant (61 symptomatic ATTRv patients and 50 presymptomatic carriers) were consecutively enrolled. Fifty healthy volunteers were included as the control group. Ella™ apparatus was used to assess sNfL levels. RESULTS: Serum NfL levels were increased in ATTRv patients compared to both presymptomatic carriers and healthy controls, whilst not differing between carriers and healthy controls. An sNfL cut-off of 37.10 pg/mL could discriminate between asymptomatic and symptomatic individuals with high diagnostic accuracy (area under the curve 0.958; p < 0.001), sensitivity (81.4%) and specificity (100%). CONCLUSIONS: Serum NfL seems to be a promising biomarker of peripheral nerve involvement in ATTRv amyloidosis and might become a reliable, objective measure to detect the transition from the presymptomatic stage to the onset of symptomatic disease. Further longitudinal studies are needed to confirm such a role and determine whether it could equally represent a biomarker of disease progression and response to therapy.


Assuntos
Neuropatias Amiloides Familiares , Filamentos Intermediários , Humanos , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/patologia , Estudos Longitudinais , Biomarcadores
7.
Eur J Neurol ; 31(9): e16379, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38859579

RESUMO

OBJECTIVE: To assess the performance of serum neurofilament light chain (sNfL) in clinical phenotypes of amyotrophic lateral sclerosis (ALS). METHODS: In 2949 ALS patients at 16 ALS centers in Germany and Austria, clinical characteristics and sNfL were assessed. Phenotypes were differentiated for two anatomical determinants: (1) upper and/or lower motor involvement (typical, typMN; upper/lower motor neuron predominant, UMNp/LMNp; primary lateral sclerosis, PLS) and (2) region of onset and propagation of motor neuron dysfunction (bulbar, limb, flail-arm, flail-leg, thoracic onset). Phenotypes were correlated to sNfL, progression, and survival. RESULTS: Mean sNfL was - compared to typMN (75.7 pg/mL, n = 1791) - significantly lower in LMNp (45.1 pg/mL, n = 413), UMNp (58.7 pg/mL n = 206), and PLS (37.6 pg/mL, n = 84). Also, sNfL significantly differed in the bulbar (92.7 pg/mL, n = 669), limb (64.1 pg/mL, n = 1305), flail-arm (46.4 pg/mL, n = 283), flail-leg (53.6 pg/mL, n = 141), and thoracic (74.5 pg/mL, n = 96) phenotypes. Binary logistic regression analysis showed highest contribution to sNfL elevation for faster progression (odds ratio [OR] 3.24) and for the bulbar onset phenotype (OR 1.94). In contrast, PLS (OR 0.20), LMNp (OR 0.45), and thoracic onset (OR 0.43) showed reduced contributions to sNfL. Longitudinal sNfL (median 12 months, n = 2862) showed minor monthly changes (<0.2%) across all phenotypes. Correlation of sNfL with survival was confirmed (p < 0.001). CONCLUSIONS: This study underscored the correlation of ALS phenotypes - differentiated for motor neuron involvement and region of onset/propagation - with sNfL, progression, and survival. These phenotypes demonstrated a significant effect on sNfL and should be recognized as independent confounders of sNfL analyses in ALS trials and clinical practice.


Assuntos
Esclerose Lateral Amiotrófica , Proteínas de Neurofilamentos , Fenótipo , Humanos , Esclerose Lateral Amiotrófica/sangue , Proteínas de Neurofilamentos/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Longitudinais , Progressão da Doença , Biomarcadores/sangue , Adulto , Alemanha/epidemiologia
8.
Eur J Neurol ; 31(9): e16371, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38937912

RESUMO

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/sangue
9.
Clin Chem Lab Med ; 62(4): 698-705, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-37882772

RESUMO

OBJECTIVES: Blood biomarkers have the potential to transform diagnosis and prognosis for multiple neurological indications. Establishing normative data is a critical benchmark in the analytical validation process. Normative data are important in children as little is known about how brain development may impact potential biomarkers. The objective of this study is to generate pediatric reference intervals (RIs) for serum neurofilament light (NfL), an axonal marker, and glial fibrillary acidic protein (GFAP), an astrocytic marker. METHODS: Serum from healthy children and adolescents aged 1 to <19 years were obtained from the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort. Serum NfL (n=300) and GFAP (n=316) were quantified using Simoa technology, and discrete RI (2.5th and 97.5th percentiles) and continuous RI (5th and 95th percentiles) were generated. RESULTS: While there was no association with sex, there was a statistically significant (p<0.0001) negative association between age and serum NfL (Rho -0.400) and GFAP (Rho -0.749). Two statistically significant age partitions were generated for NfL: age 1 to <10 years (lower, upper limit; 3.13, 20.6 pg/mL) and 10 to <19 years (1.82, 7.44 pg/mL). For GFAP, three statistically significant age partitions were generated: age 1 to <3.5 years (80.4, 601 pg/mL); 3.5 to <11 years (50.7, 224 pg/mL); and 11 to <19 years (26.2, 119 pg/mL). CONCLUSIONS: Taken together with the literature on adults, NfL and GFAP display U-shaped curves with high levels in infants, decreasing levels during childhood, a plateau during adolescence and early adulthood and increasing levels in seniors. These normative data are expected to inform future pediatric studies on the importance of age on neurological blood biomarkers.


Assuntos
Filamentos Intermediários , Soro , Adulto , Adolescente , Humanos , Criança , Proteína Glial Fibrilar Ácida , Prognóstico , Biomarcadores , Proteínas de Neurofilamentos
10.
Clin Chem Lab Med ; 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39297506

RESUMO

OBJECTIVES: To assess the variations and diagnostic performance of serum biomarkers of neurodegenerative diseases. METHODS: In this monocentric prospective study, neurofilament light (NFL), T-tau, p-tau181, p-tau217, Aß40, and Aß42 were measured in serum collected from orthopedic patients (control group, n=114) and patients in the neurology department (n=69) previously diagnosed with Alzheimer's disease (AD, n=52), parkinsonian syndromes (n=10), and other etiologies of neurodegeneration (non-AD, n=7). RESULTS: In the control group, serum NFL, T-tau, p-tau181, p-tau217, and Aß40 significantly increased with age, independently of sex. NFL (p=0.0078), p-tau217 (p<0.001) were significantly increased with neurodegeneration when compared to controls, with only p-tau217 significant in the multivariate analysis (p<0.001). Multivariate regression analysis accounting for age highlighted a significant increase of p-tau217 (p<0.001) in the AD subgroup. NFL was significantly increased in the non-AD patients (p<0.001), and in the parkinsonian syndromes subgroup (p=0.016) when compared to negative controls. Serum p-tau181 and p-tau217 were significantly correlated with CSF p-tau181 (Spearman's coefficients of 0.43 and 0.48 respectively, n=40). Areas under the ROC curves for the identification of patients with neurodegenerative diseases were 0.62 (0.54-0.70) for NFL, 0.62 (0.54-0.71) for T-tau, 0.83 (0.76-0.89) for p-tau217, and 0.66 (0.58-0.74) for Aß40. CONCLUSIONS: Serum biomarkers can help identify patients with neurodegenerative disease and may be a valuable tool for care and orientation. Phosphorylated tau p-tau217 is a promising blood biomarker for AD and NFL for other etiologies.

11.
J Peripher Nerv Syst ; 29(1): 17-27, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38066727

RESUMO

Neurofilament light protein (NfL) is a part of the neuronal skeleton, primarily expressed in axons, and is released when nerves are damaged. NfL has been found to be a potential diagnostic biomarker in different types of polyneuropathies. However, whether NfL levels can be used as a predictor for the risk of disease progression is currently less understood. We searched MEDLINE (PubMed), Embase, Cochrane Library, and Web of Science Searches and included longitudinal studies with a baseline and follow-up examination of adult patients with polyneuropathy and NfL measured in blood. Twenty studies investigating NfL as a predictor of disease progression were identified, examining eight polyneuropathy subtypes. The results from studies in Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) patients were divergent, with two out of five studies finding a significant association between NfL levels and clinical outcomes. Meta-analysis of the three Guillian-Barré Syndrome (GBS) studies found higher odds for the inability to run after 1 year in patients with high levels of NfL (odds ratio 2.18, 95% confidence interval 1.04-4.56). Results from studies examining other subacute or chronic polyneuropathies like Charcot-Marie-Tooth (CMT) varied in study design and results. Our findings suggest NfL can be used as a predictor of disease progression, particularly in polyneuropathies such as CIDP and GBS. However, NfL may not serve as a reliable and cost-effective biomarker for slowly progressive polyneuropathies like CMT. Future standardized studies considering NfL as a prognostic blood biomarker in patients with different types of polyneuropathies are warranted.


Assuntos
Doença de Charcot-Marie-Tooth , Polineuropatias , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Adulto , Humanos , Prognóstico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Filamentos Intermediários/metabolismo , Polineuropatias/diagnóstico , Biomarcadores , Proteínas de Neurofilamentos , Síndrome , Progressão da Doença
12.
Brain ; 146(6): 2570-2583, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-36975162

RESUMO

Human prion diseases are remarkable for long incubation times followed typically by rapid clinical decline. Seed amplification assays and neurodegeneration biofluid biomarkers are remarkably useful in the clinical phase, but their potential to predict clinical onset in healthy people remains unclear. This is relevant not only to the design of preventive strategies in those at-risk of prion diseases, but more broadly, because prion-like mechanisms are thought to underpin many neurodegenerative disorders. Here, we report the accrual of a longitudinal biofluid resource in patients, controls and healthy people at risk of prion diseases, to which ultrasensitive techniques such as real-time quaking-induced conversion (RT-QuIC) and single molecule array (Simoa) digital immunoassays were applied for preclinical biomarker discovery. We studied 648 CSF and plasma samples, including 16 people who had samples taken when healthy but later developed inherited prion disease (IPD) ('converters'; range from 9.9 prior to, and 7.4 years after onset). Symptomatic IPD CSF samples were screened by RT-QuIC assay variations, before testing the entire collection of at-risk samples using the most sensitive assay. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), tau and UCH-L1 levels were measured in plasma and CSF. Second generation (IQ-CSF) RT-QuIC proved 100% sensitive and specific for sporadic Creutzfeldt-Jakob disease (CJD), iatrogenic and familial CJD phenotypes, and subsequently detected seeding activity in four presymptomatic CSF samples from three E200K carriers; one converted in under 2 months while two remain asymptomatic after at least 3 years' follow-up. A bespoke HuPrP P102L RT-QuIC showed partial sensitivity for P102L disease. No compatible RT-QuIC assay was discovered for classical 6-OPRI, A117V and D178N, and these at-risk samples tested negative with bank vole RT-QuIC. Plasma GFAP and NfL, and CSF NfL levels emerged as proximity markers of neurodegeneration in the typically slow IPDs (e.g. P102L), with significant differences in mean values segregating healthy control from IPD carriers (within 2 years to onset) and symptomatic IPD cohorts; plasma GFAP appears to change before NfL, and before clinical conversion. In conclusion, we show distinct biomarker trajectories in fast and slow IPDs. Specifically, we identify several years of presymptomatic seeding positivity in E200K, a new proximity marker (plasma GFAP) and sequential neurodegenerative marker evolution (plasma GFAP followed by NfL) in slow IPDs. We suggest a new preclinical staging system featuring clinical, seeding and neurodegeneration aspects, for validation with larger prion at-risk cohorts, and with potential application to other neurodegenerative proteopathies.


Assuntos
Síndrome de Creutzfeldt-Jakob , Doenças Priônicas , Príons , Humanos , Proteínas tau/metabolismo , Biomarcadores
13.
Brain ; 146(3): 1093-1102, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35472722

RESUMO

This cohort study aimed to characterize the prodromal phase of hereditary spastic paraplegia type 4 (SPG4) using biomarkers and clinical signs and symptoms that develop before manifest gait abnormalities. Fifty-six first-degree relatives at risk of developing SPG4 underwent blinded genotyping and standardized phenotyping, including the Spastic Paraplegia Rating Scale (SPRS), complicating symptoms, non-motor affection, Three-Minute Walk, and neurophysiological assessment. Automated MR image analysis was used to compare volumetric properties. CSF of 33 probands was analysed for neurofilament light chain (NfL), tau, and amyloid-ß (Aß). Thirty participants turned out to be SPAST mutation carriers, whereas 26 did not inherit a SPAST mutation. Increased reflexes, ankle clonus, and hip abduction weakness were more frequent in prodromal mutation carriers but were also observed in non-mutation carriers. Only Babinski's sign differentiated reliably between the two groups. Timed walk and non-motor symptoms did not differ between groups. Whereas most mutation carriers had total SPRS scores of 2 points or more, only two non-mutation carriers reached more than 1 point. Motor evoked potentials revealed no differences between mutation and non-mutation carriers. We found NfL but not tau or Aß to rise in CSF of mutation carriers when approaching the time point of predicted disease manifestation. Serum NfL did not differ between groups. Volumetric MRI analyses did not reveal group differences apart from a smaller cingulate gyrus in mutation carriers. This study depicts subtle clinical signs which develop before gait abnormalities in SPG4. Long-term follow-up is needed to study the evolution of SPG4 in the prodromal stage and conversion into manifest disease. NfL in CSF is a promising fluid biomarker that may indicate disease activity in prodromal SPG4 but needs further evaluation in longitudinal studies.


Assuntos
Paraplegia Espástica Hereditária , Humanos , Paraplegia Espástica Hereditária/genética , Estudos de Coortes , Paraplegia/genética , Mutação/genética , Peptídeos beta-Amiloides/genética , Espastina/genética
14.
Brain ; 146(7): 2928-2943, 2023 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-36625756

RESUMO

Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer's disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer's disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer's disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer's disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer's disease.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Conectoma , Humanos , Estudos Transversais , Filamentos Intermediários , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Cognição , Rede Nervosa/diagnóstico por imagem
15.
Alzheimers Dement ; 20(1): 437-446, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37671801

RESUMO

INTRODUCTION: Alzheimer's disease studies often lack ethnic diversity. METHODS: We evaluated associations between plasma biomarkers commonly studied in Alzheimer's (p-tau181, GFAP, and NfL), clinical diagnosis (clinically normal, amnestic MCI, amnestic dementia, or non-amnestic MCI/dementia), and Aß-PET in Hispanic and non-Hispanic older adults. Hispanics were predominantly of Cuban or South American ancestry. RESULTS: Three-hundred seventy nine participants underwent blood draw (71.9 ± 7.8 years old, 60.2% female, 57% Hispanic of which 88% were Cuban or South American) and 240 completed Aß-PET. P-tau181 was higher in amnestic MCI (p = 0.004, d = 0.53) and dementia (p < 0.001, d = 0.97) than in clinically normal participants and discriminated Aß-PET[+] and Aß-PET[-] (AUC = 0.86). P-tau181 outperformed GFAP and NfL. There were no significant interactions with ethnicity. Among amnestic MCI, Hispanics had lower odds of elevated p-tau181 than non-Hispanic (OR = 0.41, p = 0.006). DISCUSSION: Plasma p-tau181 informs etiological diagnosis of cognitively impaired Hispanic and non-Hispanic older adults. Hispanic ethnicity may relate to greater likelihood of non-Alzheimer's contributions to memory loss. HIGHLIGHTS: Alzheimer's biomarkers were measured in Hispanic and non-Hispanic older adults. Plasma p-tau181 related to amnestic cognitive decline and brain amyloid burden. AD biomarker associations did not differ between Hispanic and non-Hispanic ethnicity. Hispanic individuals may be more likely to have non-Alzheimer causes of memory loss.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Feminino , Humanos , Idoso , Pessoa de Meia-Idade , Masculino , Proteínas Amiloidogênicas , Encéfalo/diagnóstico por imagem , Amnésia , Biomarcadores , Peptídeos beta-Amiloides , Proteínas tau
16.
Alzheimers Dement ; 20(1): 356-365, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37622539

RESUMO

INTRODUCTION: Despite their increased application, the heritability of Alzheimer's disease (AD)-related blood-based biomarkers remains unexplored. METHODS: Plasma amyloid beta 40 (Aß40), Aß42, the Aß42/40 ratio, total tau (t-tau), and neurofilament light (NfL) data came from 1035 men 60 to 73 years of age (µ = 67.0, SD = 2.6). Twin models were used to calculate heritability and the genetic and environmental correlations between them. RESULTS: Additive genetics explained 44% to 52% of Aß42, Aß40, t-tau, and NfL. The Aß42/40 ratio was not heritable. Aß40 and Aß42 were genetically near identical (rg  = 0.94). Both Aß40 and Aß42 were genetically correlated with NfL (rg  = 0.35 to 0.38), but genetically unrelated to t-tau. DISCUSSION: Except for Aß42/40, plasma biomarkers are heritable. Aß40 and Aß42 share mostly the same genetic influences, whereas genetic influences on plasma t-tau and NfL are largely unique in early old-age men. The absence of genetic associations between the Aßs and t-tau is not consistent with the amyloid cascade hypothesis.


Assuntos
Doença de Alzheimer , Masculino , Humanos , Doença de Alzheimer/genética , Peptídeos beta-Amiloides , Proteínas tau/genética , Biomarcadores , Fragmentos de Peptídeos
17.
Alzheimers Dement ; 20(6): 3889-3905, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38644682

RESUMO

INTRODUCTION: We investigate pathological correlates of plasma phosphorylated tau 181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) across a clinically diverse spectrum of neurodegenerative disease, including normal cognition (NormCog) and impaired cognition (ImpCog). METHODS: Participants were NormCog (n = 132) and ImpCog (n = 461), with confirmed ß-amyloid (Aß+/-) status (cerebrospinal fluid, positron emission tomography, autopsy) and single molecule array plasma measurements. Logistic regression and receiver operating characteristic (ROC) area under the curve (AUC) tested how combining plasma analytes discriminated Aß+ from Aß-. Survival analyses tested time to clinical dementia rating (global CDR) progression. RESULTS: Multivariable models (p-tau+GFAP+NfL) had the best performance to detect Aß+ in NormCog (ROCAUC = 0.87) and ImpCog (ROCAUC = 0.87). Survival analyses demonstrated that higher NfL best predicted faster CDR progression for both Aß+ (hazard ratio [HR] = 2.94; p = 8.1e-06) and Aß- individuals (HR = 3.11; p = 2.6e-09). DISCUSSION: Combining plasma biomarkers can optimize detection of Alzheimer's disease (AD) pathology across cognitively normal and clinically diverse neurodegenerative disease. HIGHLIGHTS: Participants were clinically heterogeneous, with autopsy- or biomarker-confirmed Aß. Combining plasma p-tau181, GFAP, and NfL improved diagnostic accuracy for Aß status. Diagnosis by plasma biomarkers is more accurate in amnestic AD than nonamnestic AD. Plasma analytes show independent associations with tau PET and post mortem Aß/tau. Plasma NfL predicted longitudinal cognitive decline in both Aß+ and Aß- individuals.


Assuntos
Peptídeos beta-Amiloides , Biomarcadores , Doenças Neurodegenerativas , Proteínas de Neurofilamentos , Tomografia por Emissão de Pósitrons , Proteínas tau , Humanos , Biomarcadores/sangue , Feminino , Masculino , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidiano , Idoso , Proteínas de Neurofilamentos/sangue , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/diagnóstico , Peptídeos beta-Amiloides/sangue , Proteína Glial Fibrilar Ácida/sangue , Progressão da Doença , Disfunção Cognitiva/sangue , Disfunção Cognitiva/diagnóstico , Pessoa de Meia-Idade , Fosforilação , Cognição/fisiologia
18.
Alzheimers Dement ; 2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39193893

RESUMO

INTRODUCTION: We investigated blood DNA methylation patterns associated with 15 well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration. METHODS: We assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF-AD) study using the EPIC array. RESULTS: We identified Bonferroni-significant differential methylation associated with CSF YKL-40 (five loci) and neurofilament light chain (NfL; seven loci) levels, with two of the loci associated with CSF YKL-40 levels correlating with plasma YKL-40 levels. A co-localization analysis showed shared genetic variants underlying YKL-40 DNA methylation and CSF protein levels, with evidence that DNA methylation mediates the association between genotype and protein levels. Weighted gene correlation network analysis identified two modules of co-methylated loci correlated with several amyloid measures and enriched in pathways associated with lipoproteins and development. DISCUSSION: We conducted the most comprehensive epigenome-wide association study (EWAS) of AD-relevant CSF biomarkers to date. Future work should explore the relationship between YKL-40 genotype, DNA methylation, and protein levels in the brain. HIGHLIGHTS: Blood DNA methylation was assessed in the EMIF-AD MBD study. Epigenome-wide association studies (EWASs) were performed for 15 Alzheimer's disease (AD)-relevant cerebrospinal fluid (CSF) biomarker measures. Five Bonferroni-significant loci were associated with YKL-40 levels and seven with neurofilament light chain (NfL). DNA methylation in YKL-40 co-localized with previously reported genetic variation. DNA methylation potentially mediates the effect of single-nucleotide polymorphisms (SNPs) in YKL-40 on CSF protein levels.

19.
Int J Mol Sci ; 25(15)2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39125924

RESUMO

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two major neurodegenerative diseases causing dementia. Due to similar clinical phenotypes, differential diagnosis is challenging without specific biomarkers. Beta-site Amyloid Precursor Protein cleaving enzyme 1 (BACE1) is a ß-secretase pivotal in AD pathogenesis. In AD and mild cognitive impairment subjects, BACE1 activity is increased in brain/cerebrospinal fluid, and plasma levels appear to reflect those in the brain. In this study, we aim to evaluate serum BACE1 activity in FTD, since, to date, there is no evidence about its role. The serum of 30 FTD patients and 30 controls was analyzed to evaluate (i) BACE1 activity, using a fluorescent assay, and (ii) Glial Fibrillary Acid Protein (GFAP) and Neurofilament Light chain (NfL) levels, using a Simoa kit. As expected, a significant increase in GFAP and NfL levels was observed in FTD patients compared to controls. Serum BACE1 activity was not altered in FTD patients. A significant increase in serum BACE1 activity was shown in AD vs. FTD and controls. Our results support the hypothesis that serum BACE1 activity is a potential biomarker for the differential diagnosis between AD and FTD.


Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Biomarcadores , Demência Frontotemporal , Proteína Glial Fibrilar Ácida , Humanos , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Demência Frontotemporal/sangue , Demência Frontotemporal/diagnóstico , Secretases da Proteína Precursora do Amiloide/sangue , Secretases da Proteína Precursora do Amiloide/metabolismo , Diagnóstico Diferencial , Feminino , Masculino , Biomarcadores/sangue , Idoso , Projetos Piloto , Ácido Aspártico Endopeptidases/sangue , Pessoa de Meia-Idade , Proteína Glial Fibrilar Ácida/sangue , Proteínas de Neurofilamentos/sangue , Estudos de Casos e Controles
20.
Int J Mol Sci ; 25(12)2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38928000

RESUMO

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/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA