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Background: It has been argued that the use of artificial turf football fields in the National Football League (NFL) increases player injury risk compared with natural grass surfaces. Purpose/Hypothesis: The purpose of this study was to quantify the rate of lower extremity injuries occurring in NFL players on artificial turf compared with natural grass surfaces and characterize the time missed due to injury and proportion of injuries requiring surgery. It was hypothesized that lower extremity injuries requiring surgical intervention would occur at a higher rate on artificial turf than on natural grass. Study Design: Descriptive epidemiology study. Methods: Lower extremity injury data for the 2021 and 2022 NFL seasons were obtained using publicly available records. Data collected included injury type, player position, player age, playing surface, weeks missed due to injury, and whether the patient underwent season-ending or minor surgery. Multivariable logistic regression was performed to determine the risk of season-ending surgery according to playing surface. Results: When combining injuries for the 2021 and 2022 seasons (N = 718 injuries), the incidence rate of lower extremity injury was 1.22 injuries/game for natural grass and 1.42 injuries/game for artificial turf. The odds of a season-ending surgery were found to be significantly higher on artificial turf compared with natural grass (odds ratio = 1.60; 95% CI, 1.28-1.99; P < .05), while additional variables, including weather, age, position, week of injury occurrence, and history of prior injury, did not influence the odds of season-ending surgery. Conclusion: The 2021 and 2022 NFL seasons of our analysis demonstrated a higher incidence rate of injuries on artificial turf surfaces compared with natural grass surfaces. In addition, the odds of injury requiring season-ending surgery were found to be significantly higher on artificial turf compared with natural grass.
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Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative condition affecting upper and/or lower motor neurons and characterized neuropathologically by TDP-43 proteinopathy. Given its role in ALS pathobiology, it is currently under debate whether TDP-43 might represent a suitable ALS biomarker to be measured in patients' biofluids. The rs12608932 A > C single nucleotide polymorphism in the UNC13A gene is a risk factor for ALS and patients homozygous for the high-risk C allele display a higher burden of TDP-43 neuropathology than homozygotes for the low-risk A allele, although the association with TDP-43 levels in biofluids has never been evaluated. In this study, we measured serum levels of TDP-43 and neurofilament light chain (NFL) by Simoa technology in a cohort of 69 ALS patients stratified according to the UNC13A rs12608932 genotype compared to 43 neurologically healthy controls. By multiple linear regression analysis, serum TDP-43 was significantly elevated in ALS patients compared to controls, with UNC13A AA and AC, but not CC, ALS patients showing higher serum TDP-43 levels than controls. We also confirmed that serum NFL concentration was increased in ALS patients, without any correlation with the UNC13A genotype. Our results indicate that serum TDP-43 is higher in ALS patients compared to controls and that, in contrast to NFL, this increase is specifically associated with the UNC13A rs12608932 AA and AC genotypes, but not with the high-risk CC genotype. Studies in larger cohorts will be needed to confirm these findings and to elucidate the biological link between serum TDP-43 levels and UNC13A genotype.
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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.
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The G4C2 hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. Despite displaying key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis, the AAV-(G4C2)66 mouse model in this study exhibits negligible neuronal loss, no motor deficits, and functionally unimpaired TAR DNA-binding protein-43 (TDP-43). While our findings indicate and support that this is a robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease associated neurodegeneration, TDP-43 dysfunction, gliosis, and motor performance. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.
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Blood-based biomarkers of neurodegeneration demonstrate great promise for the diagnosis and prognosis of Alzheimer's disease. Ultra-sensitive plasma assays now allow for quantification of the lower concentrations in cognitively unimpaired older adults, making it possible to investigate whether these markers can provide insight also into the early neurodegenerative processes that affect cognitive function and whether the markers are influenced by modifiable risk factors. Adopting an exploratory approach in 93 healthy older adults (65-75 years), we used structural equation modelling to investigate cross-sectional associations between multiple latent cognitive abilities (working memory, episodic memory, spatial and verbal reasoning) and plasma amyloid beta (Aß42/Aß40 ratio), phosphorylated-tau 181 (ptau-181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL), as well as the influence of device-measured habitual physical activity on these associations. The results showed that NfL was negatively associated with working memory, and that NfL interacted with moderate-to-vigorous physical activity in its association with episodic memory. The study has thereby demonstrated the potential of neurodegenerative plasma markers for improving understanding of normative cognitive aging and encourages future research to test the hypothesis that high levels of NfL, indicative of white matter pathology, limit the beneficial effect of physical activity on episodic memory in healthy aging.
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Péptidos beta-Amiloides , Biomarcadores , Cognición , Ejercicio Físico , Envejecimiento Saludable , Proteínas de Neurofilamentos , Proteínas tau , Humanos , Anciano , Biomarcadores/sangre , Masculino , Femenino , Péptidos beta-Amiloides/sangre , Cognición/fisiología , Ejercicio Físico/fisiología , Envejecimiento Saludable/sangre , Proteínas de Neurofilamentos/sangre , Proteínas tau/sangre , Estudios Transversales , Proteína Ácida Fibrilar de la Glía/sangre , Memoria a Corto Plazo/fisiología , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnósticoRESUMEN
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.
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Background: The global incidence of neurological diseases has been on the rise, creating an urgent need for a validated marker. Neurofilament Light Chain (NfL) holds promise as such a marker and has garnered significant attention in the field of neurological diseases over the past decades. Methods: Corresponding articles from 2013 to 2023 were collected from the Web of Science database, and data were analyzed by CiteSpace and VOSviewer software. Results: A total of 1350 articles were collected from 296 countries/regions, involving 7246 research organizations. Since 2013, among the top ten institutions and authors with the highest number of published papers, the most are from the US and the UK. The United States leads in the number of published papers, but England holds a more momentous position, because it has higher IF. Henrik Zetterberg is the most influential scholar in the field. Conclusions: The output of papers mainly relies on researchers from developed countries, and scholars from the United States and England have contributed the largest number of papers. Until now, the importance of NfL in neurological diseases has attracted global attention. In addition, NfL contributes to the potential diagnosis of various neurological disorders and can be used to improve the accuracy of differential diagnosis and prognostic assessment as well as predict the response to treatments. More and more in-depth studies are highly needed in the future.
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The HIV-1 envelope glycoprotein (Env) is the sole neutralizing determinant on the surface of the virus. The Env gp120 and gp41 subunits mediate receptor binding and membrane fusion and are generated from the gp160 precursor by cellular furins. This cleavage event is required for viral entry. One approach to generate HIV-1 neutralizing antibodies following immunization is to express membrane-bound Env anchored on the cell-surface by genetic means using the natural HIV gp41 transmembrane (TM) spanning domain. To simplify the process of Env trimer membrane expression we sought to remove the need for Env precursor cleavage while maintaining native-like conformation following genetic expression. To accomplish these objectives, we selected our previously developed 'native flexibly linked' (NFL) stabilized soluble trimers that are both near-native in conformation and cleavage-independent. We genetically fused the NFL construct to the HIV TM domain by using a short linker or by restoring the native membrane external proximal region, absent in soluble trimers, to express the full HIV Env ectodomain on the plasma membrane. Both forms of cell-surface NFL trimers, without and with the MPER, displayed favorable antigenic profiles by flow cytometry when expressed from plasmid DNA or mRNA. These results were consistent with the presence of well-ordered cell surface native-like trimeric Env, a necessary requirement to generate neutralizing antibodies by vaccination. Inoculation of rabbits with mRNA lipid nanoparticles (LNP) expressing membrane-bound stabilized HIV Env NFL trimers generated tier 2 neutralizing antibody serum titers in immunized animals. Multiple inoculations of mRNA LNPs generated similar neutralizing antibody titers compared to immunizations of matched NFL soluble proteins in adjuvant. Given the recent success of mRNA vaccines to prevent severe COVID, these are important developments for genetic expression of native-like HIV Env trimers in animals and potentially in humans.
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Vacunas contra el SIDA , Anticuerpos Neutralizantes , Anticuerpos Anti-VIH , VIH-1 , Nanopartículas , ARN Mensajero , Productos del Gen env del Virus de la Inmunodeficiencia Humana , Animales , Anticuerpos Anti-VIH/inmunología , VIH-1/inmunología , Anticuerpos Neutralizantes/inmunología , Humanos , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Vacunas contra el SIDA/inmunología , Conejos , ARN Mensajero/inmunología , ARN Mensajero/genética , Lípidos/inmunología , Multimerización de Proteína , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Infecciones por VIH/prevención & control , Femenino , LiposomasRESUMEN
PURPOSE: To detect possible neuronal damage due to recurrent isolated seizures in patients with epilepsy in a clinical routine setting. METHODS: We measured the serum concentrations of neurofilament light chain (sNfL) in 46 outpatients with an at least monthly occurrence (self-reported) of generalized tonic-clonic seizures in the six months prior to the study and in 49 patients who had been seizure free (self-reported) for at least one year. We assigned the patients with seizure activity into groups with moderate and high seizure frequency. We measured sNfL with a highly sensitive single molecule array (Simoa). RESULTS: The majority (94 %) of all patients with epilepsy had sNfL values within the age adjusted reference ranges of our laboratory. Three patients with and three patients without seizure activity (each 3 %) showed elevated sNfL concentrations. Age adjusted sNfL concentrations did not differ significantly between patients with and without seizure activity in the total sample or in the female subgroup. In contrast, NfL concentrations were significantly higher in male patients with seizure activity and highest in the subgroup of those with high seizure activity, but were only above the reference range in two patients. sNfL concentrations did not differ between focal and generalized epilepsies and between genetic and structural etiologies. CONCLUSIONS: The sNfL concentrations in patients with epilepsy and healthy patients did not differ significantly. The finding of higher sNfL concentrations in males with self-reported seizure activity should be viewed with utmost caution because the difference was small and only two male patients showed sNfL concentrations above the reference range.
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Glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) are putative non-amyloid biomarkers indicative of ongoing inflammatory and neurodegenerative disease processes. Hence, this study aimed to demonstrate the relationship between plasma biomarkers (GFAP and NfL) and 18F-AV-1451 tau PET images, and to explore their effects on cognitive function. Ninety-one participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and 20 participants from the Shanghai Action of Prevention Dementia for the Elderly (SHAPE) cohort underwent plasma biomarker testing, 18F-AV-1451 tau PET scans and cognitive function assessments. Within the ADNI, there were 42 cognitively normal (CN) individuals and 49 with mild cognitive impairment (MCI). Similarly, in the SHAPE, we had 10 CN and 10 MCI participants. We calculated the standardized uptake value ratios (SUVRs) for the regions of interest (ROIs) in the 18F-AV-1451 PET scans. Using plasma biomarkers and regional SUVRs, we trained machine learning models to differentiate between MCI and CN subjects with ADNI database and validated in SHAPE. Results showed that eight selected variables (including left amygdala SUVR, right amygdala SUVR, left entorhinal cortex SUVR, age, education, plasma NfL, plasma GFAP, plasma GFAP/ NfL) identified by LASSO could differentiate between the MCI and CN individuals, with AUC ranging from 0.783 to 0.926. Additionally, cognitive function was negatively associated with the plasma biomarkers and tau deposition in amygdala and left entorhinal cortex. Increased tau deposition in amygdala and left entorhinal cortex were related to increased plasma biomarkers. Moreover, tau pathology mediated the effect of plasma biomarkers level on the cognitive decline. The present study provides valuable insights into the association among plasma markers (GFAP and NfL), regional tau deposition and cognitive function. This study reports the mediation effect of brain regions tau deposition on the plasma biomarkers level and cognitive function, indicating the significance of tau pathology in the MCI patients.
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Biomarcadores , Cognición , Disfunción Cognitiva , Proteína Ácida Fibrilar de la Glía , Proteínas de Neurofilamentos , Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Disfunción Cognitiva/sangre , Masculino , Proteínas tau/sangre , Femenino , Biomarcadores/sangre , Anciano , Proteínas de Neurofilamentos/sangre , Proteína Ácida Fibrilar de la Glía/sangre , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Persona de Mediana Edad , Pruebas Neuropsicológicas , CarbolinasRESUMEN
BACKGROUND: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury. METHODS: Exposure-response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24 h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates. FINDINGS: Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13-15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13-15 and positive CT (1.21-2.81), GCS 9-12 (1.16-2.02), GCS 3-8 (1.09-1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51-1.80) percentages of unfavourable outcome were 37-51% in the lowest quintiles of biomarker levels and reached 90-94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83-3.79), the percentages were 2-4% and 19-28% in the lowest and highest biomarker quintiles, respectively. INTERPRETATION: Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity. FUNDING: European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust.
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Biomarcadores , Lesiones Traumáticas del Encéfalo , Humanos , Lesiones Traumáticas del Encéfalo/sangre , Lesiones Traumáticas del Encéfalo/diagnóstico , Biomarcadores/sangre , Femenino , Masculino , Adulto , Persona de Mediana Edad , Ubiquitina Tiolesterasa/sangre , Escala de Coma de Glasgow , Proteína Ácida Fibrilar de la Glía/sangre , Pronóstico , Anciano , Índice de Severidad de la Enfermedad , Estudios Prospectivos , Proteínas de Neurofilamentos/sangre , Adolescente , Adulto JovenRESUMEN
BACKGROUND: Hamstring strain injuries (HSIs) are prevalent in US National Football League (NFL) players, but there is a paucity of information regarding imaging characteristics, injury severity, and player factors associated with time missed and risk of recurrent injury. PURPOSE: To describe player, football activity, clinical, and imaging characteristics of NFL players with HSIs, as well as determine player characteristics, clinical examination results, and magnetic resonance imaging (MRI) findings associated with injury occurrence, severity, and missed time. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A retrospective cohort of NFL players with acute HSI (n = 180) during the 2018-2019 season was identified. Injury data were collected prospectively through a league-wide electronic health record system. Three musculoskeletal radiologists graded MRI muscle injury parameters using the British Athletics Muscle Injury Classification (BAMIC) system. Player, football, clinical, and imaging characteristics were correlated with HSI incidence and severity and with missed time from sport. RESULTS: Of the 1098 HSIs identified during the 2018-2019 season, 416 (37.9%) were randomly sampled, and 180 (43.3%) had diagnostic imaging available. Game activity, preseason period, and wide receiver and defensive secondary positions disproportionately contributed to HSI. The biceps femoris was the most commonly injured muscle (n = 132, 73.3%), followed by the semimembranosus (n = 24, 13.3%) and semitendinosus (n = 17, 9.4%) muscles. The most common injury site was the distal third of the biceps femoris and semitendinosus muscles (n = 60, 45.5% and n = 10, 58.8%, respectively) and central part of the semimembranosus muscle (n = 17, 70.8%). Nearly half of the injuries (n = 83, 46.1%) were BAMIC grade 2; 25.6% (n = 46), grade 3; and 17.8% (n = 32), grade 4. MRI showed sciatic nerve abnormality in 30.6% (n = 55) of all HSIs and 81.3% (n = 26) of complete tendon injuries. BAMIC grade correlated with both median days and games missed. Combined biceps femoris and semitendinosus injuries resulted in the highest median days missed (27 days). CONCLUSION: Among NFL players with acute HSIs, the most common injury was a moderate-severity injury of the distal biceps femoris. BAMIC grade was associated with missed time.
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Traumatismos en Atletas , Fútbol Americano , Músculos Isquiosurales , Imagen por Resonancia Magnética , Esguinces y Distensiones , Humanos , Estudios Retrospectivos , Fútbol Americano/lesiones , Músculos Isquiosurales/lesiones , Músculos Isquiosurales/diagnóstico por imagen , Estudios Transversales , Masculino , Adulto , Esguinces y Distensiones/diagnóstico por imagen , Esguinces y Distensiones/epidemiología , Traumatismos en Atletas/diagnóstico por imagen , Traumatismos en Atletas/epidemiología , Adulto Joven , Estados Unidos/epidemiologíaRESUMEN
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.
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Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Ácido Aspártico Endopeptidasas , Biomarcadores , Demencia Frontotemporal , Proteína Ácida Fibrilar de la Glía , Humanos , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico , Demencia Frontotemporal/sangre , Demencia Frontotemporal/diagnóstico , Secretasas de la Proteína Precursora del Amiloide/sangre , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Diagnóstico Diferencial , Femenino , Masculino , Biomarcadores/sangre , Anciano , Proyectos Piloto , Ácido Aspártico Endopeptidasas/sangre , Persona de Mediana Edad , Proteína Ácida Fibrilar de la Glía/sangre , Proteínas de Neurofilamentos/sangre , Estudios de Casos y ControlesRESUMEN
Convenient and effective biomarkers are essential for the early diagnosis and treatment of Alzheimer's disease (AD). In the cross-sectional study, 103 patients with AD, 82 patients with aMCI and 508 normal controls (NC) were enrolled. The single-molecule array (Simoa) technique was used to assess the levels of plasma proteins, including NfL, T-tau, P-tau-181, Aß40, Aß42. Montreal Cognitive Assessment (MoCA) was used to assess the overall cognitive function of all subjects. Moreover, Amyloid PET and structural head MRI were also performed in a subset of the population. In the follow-up, the previous 508 normal older adults were followed up for two years, then COX regression analysis was used to investigate the association between baseline plasma proteins and future cognitive outcomes. NfL, T-tau, P-tau-181, Aß40, Aß42 and Aß42/40 were altered in AD dementia, and NfL, Aß42 and Aß42/40 significantly outperformed all plasma proteins in differentiating AD dementia from NC, while NfL and Aß42/40 could effectively distinguish between aMCI and NC. However, only plasma NfL was associated with future cognitive decline, and it was negatively correlated with MoCA (r = - 0.298, p < 0.001) and the volume of the left globus pallidus (r = - 0.278, p = 0.033). Plasma NfL can help distinguish between cognitively normal and cognitively impaired individuals (MCI/dementia) at the syndrome level. However, since we have not introduced other biomarkers for AD, such as PET CT or cerebrospinal fluid, and have not verified in other neurodegenerative diseases, whether plasma NFL can be used as a biomarker for AD needs to be further studied and explored.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Proteínas Sanguíneas , Proteínas tau , Humanos , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico , Masculino , Femenino , Anciano , Estudios Transversales , Estudios Longitudinales , Biomarcadores/sangre , China , Proteínas Sanguíneas/análisis , Proteínas Sanguíneas/metabolismo , Proteínas tau/sangre , Proteínas tau/líquido cefalorraquídeo , Péptidos beta-Amiloides/sangre , Persona de Mediana Edad , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico , Tomografía de Emisión de Positrones , Imagen por Resonancia Magnética , Proteínas de Neurofilamentos/sangre , Anciano de 80 o más Años , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
BACKGROUND: Neuropsychiatric symptoms (NPS) are common in older people, may occur early in the development of dementia disorders, and have been associated with faster cognitive decline. Here, our objectives were to investigate whether plasma levels of neurofilament light chain (NfL), glial fibrillary acid protein (GFAP), and tau phosphorylated at threonine 181 (pTau181) are associated with current NPS and predict future NPS in non-demented older people. Furthermore, we tested whether the presence of NPS combined with plasma biomarkers are useful to predict Alzheimer's disease (AD) pathology and cognitive decline. METHODS: One hundred and fifty-one participants with normal cognition (n = 76) or mild cognitive impairment (n = 75) were examined in a longitudinal brain aging study at the Memory Centers, University Hospital of Lausanne, Switzerland. Plasma levels of NfL, GFAP, and pTau181 along with CSF biomarkers of AD pathology were measured at baseline. NPS were assessed through the Neuropsychiatric Inventory Questionnaire (NPI-Q), along with the cognitive and functional performance at baseline and follow-up (mean: 20 months). Different regression and ROC analyses were used to address the associations of interest. RESULTS: None of the three plasma biomarker was associated with NPS at baseline. Higher GFAP levels were associated with the presence of NPS at follow-up (OR = 2.8, p = .002) and both, higher NfL and higher GFAP with an increase in the NPI-Q severity score over time (ß = 0.25, p = .034 and ß = 0.30, p = .013, respectively). Adding NPS and the plasma biomarkers to a reference model improved the prediction of future NPS (AUC 0.72 to 0.88, p = .002) and AD pathology (AUC 0.78 to 0.87, p = .010), but not of cognitive decline (AUC 0.79 to 0.85, p = .081). CONCLUSION: Plasma NfL and GFAP are both associated with future NPS and NPS severity change. Considering the presence of NPS along with blood-based AD-biomarkers may improve the prediction of clinical progression of NPS over time and inform clinical decision-making in non-demented older people.
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Enfermedad de Alzheimer , Biomarcadores , Disfunción Cognitiva , Progresión de la Enfermedad , Proteína Ácida Fibrilar de la Glía , Proteínas de Neurofilamentos , Proteínas tau , Humanos , Proteínas tau/sangre , Proteínas tau/líquido cefalorraquídeo , Femenino , Masculino , Proteína Ácida Fibrilar de la Glía/sangre , Biomarcadores/sangre , Proteínas de Neurofilamentos/sangre , Anciano , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico , Fosforilación , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico , Anciano de 80 o más Años , Estudios Longitudinales , Pruebas Neuropsicológicas , Persona de Mediana EdadRESUMEN
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.
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Esclerosis Amiotrófica Lateral , Proteínas de Neurofilamentos , Medición de Resultados Informados por el Paciente , Superóxido Dismutasa-1 , Humanos , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/genética , Masculino , Femenino , Persona de Mediana Edad , Anciano , Superóxido Dismutasa-1/genética , Proteínas de Neurofilamentos/sangre , Resultado del Tratamiento , Progresión de la Enfermedad , Adulto , Oligonucleótidos/uso terapéuticoRESUMEN
Increased choroid plexus (CP) volume has been recently implicated as a potential predictor of worse multiple sclerosis (MS) outcomes. The biomarker signature of CP changes in MS are currently unknown. To determine the blood-based biomarker characteristics of the cross-sectional and longitudinal MRI-based CP changes in a heterogeneous group of people with MS (pwMS), a total of 202 pwMS (148 pwRRMS and 54 pwPMS) underwent MRI examination at baseline and at a 5-year follow-up. The CP was automatically segmented and subsequently refined manually in order to obtain a normalized CP volume. Serum samples were collected at both timepoints, and the concentration of 21 protein measures relevant to MS pathophysiology were determined using the Olink™ platform. Age-, sex-, and BMI-adjusted linear regression models explored the cross-sectional and longitudinal relationships between MRI CP outcomes and blood-based biomarkers. At baseline, there were no significant proteomic predictors of CP volume, while at follow-up, greater CP volume was significantly associated with higher neurofilament light chain levels, NfL (standardized ß = 0.373, p = 0.001), and lower osteopontin levels (standardized ß = -0.23, p = 0.02). Higher baseline GFAP and lower FLRT2 levels were associated with future 5-year CP % volume expansion (standardized ß = 0.277, p = 0.004 and standardized ß = -0.226, p = 0.014, respectively). The CP volume in pwMS is associated with inflammatory blood-based biomarkers of neuronal injury (neurofilament light chain; NfL) and glial activation such as GFAP, osteopontin, and FLRT2. The expansion of the CP may play a central role in chronic and compartmentalized inflammation and may be driven by glial changes.
Asunto(s)
Biomarcadores , Plexo Coroideo , Imagen por Resonancia Magnética , Esclerosis Múltiple , Humanos , Femenino , Masculino , Biomarcadores/sangre , Esclerosis Múltiple/sangre , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Plexo Coroideo/diagnóstico por imagen , Plexo Coroideo/patología , Adulto , Persona de Mediana Edad , Estudios Transversales , Proteínas de Neurofilamentos/sangre , Osteopontina/sangre , Proteómica , Proteína Ácida Fibrilar de la Glía/sangreRESUMEN
INTRODUCTION: The "A/T/N" (amyloid/tau/neurodegeneration) framework provides a biological basis for Alzheimer's disease (AD) diagnosis and can encompass additional changes such as inflammation ("I"). A spectrum of T/N/I imaging and plasma biomarkers was acquired in a phase 2 clinical trial of rasagiline in mild to moderate AD patients. We evaluated these to understand biomarker distributions and relationships within this population. METHODS: Plasma biomarkers of pTau-181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), other inflammation-related proteins, imaging measures including fluorodeoxyglucose (FDG) positron emission tomography (PET), flortaucipir PET, and volumetric magnetic resonance imaging (MRI), and cognitive endpoints were analyzed to assess characteristics and relationships for the overall population (N = 47 at baseline and N = 21 for longitudinal cognitive comparisons) and within age-decade subgroups (57-69, 70-79, 80-90 years). RESULTS: Data demonstrate wide clinical and biomarker heterogeneity in this population influenced by age and sex. Plasma pTau-181 and GFAP correlate with tau PET, most strongly in left inferior temporal cortex (p = 0.0002, p = 0.0006, respectively). In regions beyond temporal cortex, tau PET uptake decreased with age for the same pTau-181 or GFAP concentrations. FDG PET and brain volumes correlate with tau PET in numerous regions (such as inferior temporal: p = 0.0007, p = 0.00001, respectively). NfL, GFAP, and all imaging modalities correlate with baseline MMSE; subsequent MMSE decline is predicted by baseline parahippocampal and lateral temporal tau PET (p = 0.0007) and volume (p = 0.0006). Lateral temporal FDG PET (p = 0.006) and volume (p = 0.0001) are most strongly associated with subsequent ADAS-cog decline. NfL correlates with FDG PET and baseline MMSE but not tau PET. Inflammation biomarkers are intercorrelated but correlated with other biomarkers in only the youngest group. DISCUSSION: Associations between plasma biomarkers, imaging biomarkers, and cognitive status observed in this study provide insight into relationships among biological processes in mild to moderate AD. Findings show the potential to characterize AD patients regarding likely tau pathology, neurodegeneration, prospective clinical decline, and the importance of covariates such as age. Highlights: Plasma pTau-181 and GFAP correlated with regional and global tau PET in mild to moderate AD.NfL correlated with FDG PET and cognitive endpoints but not plasma pTau-181 or tau PET.Volume and FDG PET showed strong relationships to tau PET, one another, and cognitive status.Temporal volumes most strongly predicted decline in both MMSE and ADAS-cog.Volume and plasma biomarkers can enrich for elevated tau PET with age a significant covariate.
RESUMEN
BACKGROUND: In the field of research for new validated surrogate biomarkers of treatment efficacy, disease activity and progression in Multiple Sclerosis (MS), serum neurofilament light-chain (sNFL) are actually the best candidate for MS patient monitoring. However, before they can be implemented in clinical practice, their usefulness as additional red flag routine measure must be demonstrated. To tackle the problem, this real-life cross-sectional study at the Regional Referring Center for Multiple Sclerosis (CRESM) aims to characterize sNFL levels and prevalence of elevated sNFL, according to our age-dependent cut-off values, in a large group of patients with different types of MS and treatment conditions. METHODS: 908 serum samples from as many MS patients being admitted at CRESM for diagnostic definition and/or during routinary treatment monitoring were consecutively collected between January 2019 and January 2020. sNFL levels were measured by single molecule array (Simoa™) technology on SR-X instrument using NF-light assays (Quanterix); results were interpreted using previously published cut-off values. RESULTS: Primary and Secondary Progressive MS (PPMS, SPMS) forms demonstrate higher levels and prevalence of elevated sNFL (PPMS= 32 %, SPMS= 21 %) compared to the Relapse and Remitting one (RRMS = 12 %). Besides, naïve samples of RRMS and PPMS subtypes showed higher prevalence of elevated sNFL (RRMS naïve= 31 %, PPMS naïve=67 %) compared to samples from patients treated for more than 12 months (RRMS treat>12m= 9 %, PPMS treat>12m= 19 %); treated SPMS patients demonstrated higher sNFL levels and a prevalence (22 %) of elevated sNFL compared to RRMS treated patients. Focusing on RRMS, no statistical difference was found between groups of patients treated for whatever time (up to or more than 60 months) and with either DMT type (high or low-efficacy DMT). Finally, RRMS patients treated with all DMTs for more than 12 months, with the exception of teriflunomide and alemtuzumab showed a prevalence of elevated sNFL in the range of 5-10 %. CONCLUSION: in a real-world setting comprising about 1000 MS patients, sNFL quantification was elevated in 5-to-67 % of patients, in different MS forms and treatment conditions. Elevated levels of sNFL must be considered a red-flag suggesting the need of a further clinical monitoring in any circumstance, as it can be indicative of new inflammation, ongoing degeneration or co-morbidities. This study supports the introduction of sNFL quantification in everyday patient management.
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Esclerosis Múltiple Crónica Progresiva , Proteínas de Neurofilamentos , Humanos , Femenino , Masculino , Adulto , Estudios Transversales , Persona de Mediana Edad , Prevalencia , Proteínas de Neurofilamentos/sangre , Esclerosis Múltiple Crónica Progresiva/sangre , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Esclerosis Múltiple Crónica Progresiva/epidemiología , Biomarcadores/sangre , Adulto Joven , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/epidemiología , Esclerosis Múltiple/sangre , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/epidemiología , Anciano , Inmunosupresores/uso terapéutico , Toluidinas/uso terapéutico , Crotonatos/uso terapéutico , AdolescenteRESUMEN
Virus-associated chronic inflammation may contribute to autoimmunity in a number of diseases. In the brain, autoimmune encephalitis appears related to fluctuating reactivation states of neurotropic viruses. In addition, viral miRNAs and proteins can be transmitted via exosomes, which constitute novel but highly relevant mediators of cellular communication. The current study questioned the role of HSV-1-encoded and host-derived miRNAs in cerebrospinal fluid (CSF)-derived exosomes, enriched from stress-induced neuroinflammatory diseases, mainly subarachnoid hemorrhage (SAH), psychiatric disorders (AF and SZ), and various other neuroinflammatory diseases. The results were compared with CSF exosomes from control donors devoid of any neuroinflammatory pathology. Serology proved positive, but variable immunity against herpesviruses in the majority of patients, except controls. Selective ultrastructural examinations identified distinct, herpesvirus-like particles in CSF-derived lymphocytes and monocytes. The likely release of extracellular vesicles and exosomes was most frequently observed from CSF monocytes. The exosomes released were structurally similar to highly purified stem-cell-derived exosomes. Exosomal RNA was quantified for HSV-1-derived miR-H2-3p, miR-H3-3p, miR-H4-3p, miR-H4-5p, miR-H6-3p, miR-H27 and host-derived miR-21-5p, miR-146a-5p, miR-155-5p, and miR-138-5p and correlated with the oxidative stress chemokine IL-8 and the axonal damage marker neurofilament light chain (NfL). Replication-associated miR-H27 correlated with neuronal damage marker NfL, and cell-derived miR-155-5p correlated with oxidative stress marker IL-8. Elevated miR-138-5p targeting HSV-1 latency-associated ICP0 inversely correlated with lower HSV-1 antibodies in CSF. In summary, miR-H27 and miR-155-5p may constitute neuroinflammatory markers for delineating frequent and fluctuating HSV-1 replication and NfL-related axonal damage in addition to the oxidative stress cytokine IL-8 in the brain. Tentatively, HSV-1 remains a relevant pathogen conditioning autoimmune processes and a psychiatric clinical phenotype.