Neurofilament Light Research Articles

Quantification of serum TDP-43 and neurofilament light chain in patients with amyotrophic lateral sclerosis stratified by UNC13A genotype

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.

Cerebrovascular disease is associated with Alzheimer's plasma biomarker concentrations in adults with Down syndrome.

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

Serum neurofilament light release levels as marker of neurotoxicity in general anesthesia versus hypnosis: A prospective non-randomized trial

Background: Whether general anesthetics induce neurotoxicity is unclear. Objectives: We hypothesized that serum neurofilament light (NfL) release, a marker of neural injury, would not be different in patients receiving general anesthesia (GA) compared to hypnosis. Design: Prospective, non-randomized. Setting: Tertiary university hospital. Methods: Patients undergoing breast cancer or thyroid/parathyroid surgery were enrolled. Propofol and remifentanil were used for GA. For hypnosis, only low dose remifentanil was allowed. Main outcome measures: NfL was measured at baseline, at day 1 and at postoperative visit. At preoperative and postoperative visit, patients performed a Montreal Cognitive Assessment (MoCA) test. Primary outcome was absolute change in NfL at day 1 between groups. Results: Among 100 included patients, 51 were in GA and 49 in hypnosis group. There were 26/49 (53%) breast cancer patients in hypnosis group and 13/51 (26%) in GA arm, p = 0.005. Baseline NfL was higher in the hypnosis group (p = 0.050). We subtracted log-transformed baseline NfL from postoperative NfL to analyze normalized values as absolute change. The mean normalized value at day 1 (primary endpoint) was 0.02 (± 0.11) in the GA and 0.03 (± 0.20) in the hypnosis group; p = 0.979 [d = 0.16, 95% CI: -0.40 to 0.39]. In a linear mixed-effects model including variables that influenced baseline NfL (advanced age, higher creatinine values, breast cancer), mean difference (95 % CI) in absolute change of log NfL at day 1 between both groups was 0.007 (- 0.04 to 0.06); p = 0.791. A change in MoCA as compared to baseline was not different between groups (p = 0.761). Conclusions: Our results show that there was no statistical or clinical difference in postoperative NfL release between GA and hypnosis. GA with propofol was not associated with a different risk of neural injury compared to hypnosis. Trial registration: NCT04500236.

Biomarkers and genotypes in patients with Central nervous system infection caused by enterovirus

Purpose Enteroviruses (EV) comprises many different types and are the most common cause of aseptic meningitis. How the virus affects the brain including potential differences between types are largely unknown. Measuring biomarkers in CSF is a tool to estimate brain damage caused by CNS infections. Methods A retrospective study was performed in samples from 38 patients with acute neurological manifestations and positive CSF-EV RNA (n = 37) or serum-IgM (n = 1). The EV in 17 samples were typed by sequencing. The biomarkers neurofilament light (NFL), glial fibrillary acidic protein (GFAP), S-100B protein, amyloid-β (Aβ) 40 and Aβ42, total-tau (T-tau) and phosphorylated tau (P-tau) were measured and compared with data derived from a control group (n = 19). Results There were no increased levels of GFAP (p ≤ 0.1) nor NFL (p ≤ 0.1) in the CSF of patients with EV meningitis (n = 38) compared with controls. However, we found decreased levels of Aβ42 (p < 0.001), Aβ40 (p < 0.001), T-tau (p ≥ 0.01), P-tau (p ≤ 0.001) and S-100B (p ≤ 0.001). E30 (n = 9) and CVB5 (n = 6) were the most frequent EV-types identified, but no differences in biomarker levels or other clinical parameters were found between the infecting virus type. Seven patients who were followed for longer than one month reported remaining cognitive impairment, although no correlations with biomarker concentrations were observed. Conclusion There are no indication of neuronal or astrocyte damage in patients with EV meningitis. Yet, decreased concentrations of Aβ40, Aβ42, P-tau and T-tau were shown, a finding of unknown importance. Cognitive impairment after acute disease occurs, but with only a limited number of patients analysed, no conclusion can be drawn concerning any association with biomarker levels or EV types.

Association of hemoglobin with plasma neurofilament light and white matter hyperintensities in Alzheimer's disease continuum

ObjectiveThis study aimed to investigate the association of hemoglobin (Hb) with axonal injury marker plasma neurofilament light (PNFL) and brain structure measurements in the Alzheimer's disease (AD) continuum. MethodsThe data used in this study were collected from the Alzheimer's Disease Neuroimaging Initiative database. Participants with cognitively normal, mild cognitive impairment, and mild dementia were included in the data analyses. All participants had available data on blood tests, PNFL levels, neuropsychological assessments, brain structure measurements (including volumes of white matter hyperintensities [WMH], hippocampus, gray matter, and total brain), and Aβ positron emission tomography standardized uptake value ratio (SUVR) at baseline. Aβ-positive was defined as SUVR threshold value > 1.11. Linear regression, restricted cubic spline, and causal mediation analyses were conducted to investigate the association of Hb concentration with PNFL levels and brain structure measurements. Stratified analyses were also employed to evaluate the association between Hb concentration and PNFL levels across different APOE genotypes and sex. ResultsIn the Aβ-positive group, Hb concentration was associated with PNFL levels (β = −0.022, p = 0.002). Stratified analyses suggested an association between Hb concentration and PNFL in APOE ɛ4 carriers (β = −0.031, p < 0.001) and males (β = −0.030, p < 0.001) but not in non-carriers and females (p > 0.05). Hb concentration was also associated with WMH volume (β = −0.04, p = 0.028), especially in APOE ɛ4 carriers, with mediation analysis revealing that PNFL mediated the association between Hb concentration and WMH volume. The association of Hb concentration with other brain structure measurements was minimal. ConclusionIn the AD continuum, Hb was associated with axonal injury marker PNFL and WMH volume, particularly in APOE ɛ4 carriers.

Investigating Alzheimer’s Disease Resistance in Okinawan Centenarians’ Offspring: A Population Study in a Blue Zone

Alzheimer’s disease (AD) is a neurodegenerative condition characterized by cognitive decline and the accumulation of amyloid-β plaques and neurofibrillary tangles in the brain. Although developing the disease becomes increasingly common as people age, centenarians — individuals who reach the age of 100 — have shown an unexpected resilience to AD, and these individuals are more prevalent in regions known as blue zones, where people experience exceptional longevity and health. This study focuses on the offspring of centenarians in one of these blue zones, Okinawa, Japan, to investigate what potential protective factors they may possess against AD. By screening this unique population using a questionnaire and the Mini-Mental State Examination (MMSE) and tracking AD pathology through advanced biomarker assays following the A/T/N criteria, A: Aβ40/42 ratio, T: phosphorylated tau (pT217-tau), and N: neurofilament light chain (NfL) levels, we aim to uncover genetic, environmental, or lifestyle-related factors that contribute to the decreased incidence of AD in these populations. This study seeks to identify key factors contributing to their resilience by comparing the results of centenarian offspring with age-matched non-centenarians. The spouses of these offspring of centenarians will also be included in the study, acting as a control group of individuals who are likely to share many of the lifestyle and environmental factors with the centenarian offspring but with different genetics. These findings could provide valuable insights for the future development of public health strategies and approaches to mitigate AD risk in the broader population.

Autoimmune astrocytopathy double negative for AQP4-IgG and GFAP-IgG: Retrospective research of clinical practice, biomarkers, and pathology.

The objective of this study is to investigate the presence of astrocyte antibodies in patients, excluding aquaporin-4 or glial fibrillary acidic protein (GFAP) antibodies, while evaluating associated biomarkers and pathologies. Patient serum and cerebrospinal fluid (CSF) were tested for antibodies using tissue- and cell-based assays. Neurofilament light chain (NFL) and GFAP in the CSF were detected using single-molecule array (SIMOA). 116 patients accepted SIMOA. Fifteen functional neurological disorders patients without antibodies were designated as controls. Thirty-five patients were positive for astrocyte antibodies (Anti-GFAP: 7; Anti-AQP4: 7; unknown antibodies: 21, designed as the double-negative group, DNAP). The most frequent phenotype of DNAP was encephalitis (42.9%), followed by myelitis (23.8%), movement disorders (19.0%), and amyotrophic lateral sclerosis-like (ALS-like) disease (14.2%). The levels of CSF GFAP and NFL in DNAP were higher than in the control (GFAP: 1967.29 [776.60-13214.47] vs 475.38 [16.80-943.60] pg/mL, p < 0.001; NFL: 549.11 [162.08-2462.61] vs 214.18 [81.60-349.60] pg/mL, p = 0.002). GFAP levels decreased in DNAP (n = 5) after immunotherapy (2446.75 [1583.45-6277.33] vs 1380.46 [272.16-2005.80] pg/mL, p = 0.043), while there was no difference in NFL levels (2273.78 [162.08-2462.61] vs 890.42 [645.06-3168.06] pg/mL, p = 0.893). Two brain biopsy patterns were observed: one exhibited prominent tissue proliferation and hypertrophic astrocytes, with local loss of astrocytes, while the other showed severe astrocyte depletion with loss of neurofilaments around the vessels. Eighteen patients received immunotherapy, and improved except one with ALS-like symptoms. We identified anti-vimentin in this patient. There are unidentified astrocyte antibodies. The manifestations of double-negativity are heterogeneous; nevertheless, the pathology and biomarkers remain consistent with astrocytopathy. Immunotherapy is effective.

Neurofilament Light Chain Serum Levels Mirror Age and Disability in Secondary Progressive Multiple Sclerosis: A Cross-Sectional Study.

To assess neurofilament light chain serum (sNfL) levels in patients with secondary progressive multiple sclerosis (SP-MS). Using a single molecule array, we analyzed sNfL levels in a cross-sectional cohort study of 153 patients with SP-MS hospitalized for rehabilitation in a clinic specialized in the care for patients with multiple sclerosis (MS). In addition, we investigated the correlation of disease activity with sNfL levels in 36 patients with relapsing-remitting MS (RR-MS). Mean sNfL levels in patients with SP-MS were consistently elevated when compared with age-matched controls and patients with RR-MS. In SP-MS, age dependency of sNfL levels was pronounced, whereas patients with RR-MS younger than 41 years without recent disease activity were not distinguishable from age-matched healthy controls. In a multivariate analysis, clinical disability was a risk factor for elevated sNfL levels in SP-MS, whereas no correlation with comorbidities, such as cardiovascular disease, diabetes mellitus, smoking status, or vitamin D serum levels, could be detected. These findings highlight that measurement of sNfL levels represents a useful tool to assess the extent of neuroaxonal damage as a surrogate for clinical progression in patients with SP-MS, when age and disease activity as major confounders are taken into account.

Specific plasma biomarker signatures associated with patients undergoing surgery for back pain

BACKGROUND CONTEXTIntervertebral disc degeneration (IDD) affects numerous people worldwide. The role of inflammation is increasingly recognized but remains incompletely resolved. Peripheral molecules could access neovascularized degenerated discs and contribute to the ongoing pathology. PURPOSETo assess a large array of plasma molecules in patients with IDD to identify biomarkers associated with specific spinal pathologies and prognostic biomarkers for the surgery outcome. DESIGNProspective observational study combining clinical data and plasma measures. PATIENT SAMPLEPlasma samples were collected just before surgery. Extensive clinical data (age, sex, smoking status, Modic score, glomerular filtration rate, etc.) were extracted from clinical files from 83 patients with IDD undergoing spine surgery. OUTCOME MEASURESRecovery 2 months postsurgery as assessed by the treating neurosurgeon. METHODSOver 40 biological molecules were measured in patients’ plasma using multiplex assays. Statistical analyses were performed to identify associations between biological and clinical characteristics (age, sex, Body Mass Index (BMI), smoking status, herniated disc, radiculopathy, myelopathy, stenosis, MODIC score, etc.) and plasma levels of biological molecules. RESULTSPlasma levels of Neurofilament Light chain (NfL) were significantly elevated in patients with myelopathy and spinal stenosis compared to herniated disc. Plasma levels of C- reactive protein (CRP), Neurofilament Light chain (NfL), and Serum Amyloid A (SAA) were negatively associated, while CCL22 levels were positively associated with an efficient recovery 2 months postsurgery. CONCLUSIONSOur results show that CRP and CCL22 plasma levels combined with the age of the IDD patient can predict the 2-month postsurgery recovery (Area Under the Curve [AUC]=0.883). Moreover, NfL could become a valuable monitoring tool for patients with spinal cord injuries.

Cerebrospinal fluid and blood neurofilament light chain levels in amyotrophic lateral sclerosis and frontotemporal degeneration: A meta-analysis.

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. 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. 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. 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.

Global huntingtin knockout in adult mice leads to fatal neurodegeneration that spares the pancreas.

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG tract in the huntingtin (HTT) gene, leading to toxic gains of function. HTT-lowering treatments are in clinical trials, but the risks imposed are unclear. Recent studies have reported on the consequences of widespread HTT loss in mice, where one group described early HTT loss leading to fatal pancreatitis, but later loss as benign. Another group reported no pancreatitis but found widespread neurological phenotypes including subcortical calcification. To better understand the liabilities of widespread HTT loss, we knocked out Htt with two separate tamoxifen-inducible Cre lines. We find that loss of HTT at 2 mo of age leads to progressive tremors and severe subcortical calcification at examination at 14 mo of age but does not result in acute pancreatitis or histological changes in the pancreas. We, in addition, report that HTT loss is followed by sustained induction of circulating neurofilament light chain. These results confirm that global loss of HTT in mice is associated with pronounced risks, including progressive subcortical calcification and neurodegeneration.

Acute neuroaxonal remodelling after electroconvulsive treatment in patients with major depressive disorder: A pilot study

Electroconvulsive therapy (ECT) is an effective treatment for major depressive disorder (MDD). Neurofilament light chain (NfL) is a novel blood marker of neuroaxonal integrity, which is altered in some psychiatric disorders including MDD. Prior studies reported no long-term impact of ECT on NfL levels, but the acute effects are unclear yet. Therefore, we investigated serum NfL levels from 19 single ECT sessions in 13 patients with MDD. We found an acute increase in NfL levels post-ECT (Cohen's d=0.45), suggesting transient cytoskeletal remodelling in axons. Further research is needed to ascertain if these transient changes correspond to treatment response or side effects such as cognitive impairment.

Establishment of Neurofilament Light Chain in Plasma-Derived Neuronal Extracellular Vesicles as a Biomarker for Disease Progression in Multiple Sclerosis Patients

Establishment of Neurofilament Light Chain in Plasma-Derived Neuronal Extracellular Vesicles as a Biomarker for Disease Progression in Multiple Sclerosis Patients

Neurobiological Effects of Lipoid Proteinosis: A Study on Phosphorylated Tau, S100B, NSE, NEFL, and GFAP

Background: Lipoid Proteinosis (LP), also termed Urbach-Wiethe disease, is an enigmatic genodermato-sis marked by the systemic deposition of hyaline material. With its etiology rooted in ECM1 mutations, LP’s neuropathological spectrum has been hypothesized to involve an array of neurodegenerative biomarkers, underscoring a potential for substantial neurobiological implications. This study endeav-ored to elucidate the serum concentrations of neurodegenerative biomarkers—phosphorylated Tau (pMAPT), S100B, Neuron-Specific Enolase (NSE), Neurofilament Light Chain (NEFL), and Glial Fibrillary Acidic Protein (GFAP)—in LP patients, seeking to establish their diagnostic utility for the condition. Materials and Methods: Fifteen LP patients and 15 matched healthy controls were enrolled. Serum levels of the biomarkers were quantified using ELISA, and their predictive power was assessed through binary logistic regression and Receiver Operating Characteristic (ROC) analysis. Results: Elevated serum levels of NSE, NEFL, and GFAP were observed in LP subjects relative to healthy counterparts, reaching statistical significance (p&amp;lt;0.05). In contrast, pMAPT and S100B levels did not differ appreciably. GFAP is considered a predictive marker for LP with an area under the curve (AUC) value of 0.813 and a 95% confidence interval (CI) of 0.658-0.968 (p=0.003). Conclusions: The study underscores a distinctive neurodegenerative profile in LP, with NSE, NEFL, and GFAP concentrations significantly amplified. These biomarkers, particularly GFAP, may represent novel indicators for LP, offering prospective biomarker-based diagnostic strategies. The insights garnered herein pave the way for advanced understanding and clinical management of LP, delineating a novel avenue for future high-impact research.

Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study.

We investigated blood DNA methylation patterns associated with 15 well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration. 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. 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. 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. 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 ofsingle-nucleotide polymorphisms (SNPs) in YKL-40 on CSF protein levels.

Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis

BackgroundPositive effects of RNS60 on respiratory and bulbar function were observed in a phase 2 randomized, placebo-controlled trial in people with amyotrophic lateral sclerosis (ALS). Objective: to investigate the long-term survival of trial participants and its association with respiratory status and biomarkers of neurodegeneration and inflammation. Study design and settingsA randomized, double blind, phase 2 clinical trial was conducted. Trial participants were enrolled at 22 Italian Expert ALS Centres from May 2017 to January 2020. Vital status of all participants was ascertained thirty-three months after the trial’s last patient last visit (LPLV). Participants were patients with Amyotrophic Lateral Sclerosis, classified as slow or fast progressors based on forced vital capacity (FVC) slope during trial treatment. Demographic, clinical, and biomarker levels and their association with survival were also evaluated. ResultsMean duration of follow-up was 2.8 years. Long-term median survival was six months longer in the RNS60 group (p = 0.0519). Baseline FVC, and rates of FVC decline during the first 4 weeks of trial participation, were balanced between the active and placebo treatment arms. After 6 months of randomized, placebo-controlled treatment, FVC decline was significantly slower in the RNS60 group compared to the placebo group. Rates of FVC progression during the treatment were strongly associated with long-term survival (median survival: 3.7 years in slow FVC progressors; 1.6 years in fast FVC progressors). The effect of RNS60 in prolonging long-term survival was higher in participants with low neurofilament light chain (NfL) (median survival: >4 years in low NfL − RNS60 group; 3.3 years in low NfL − placebo group; 1.9 years in high NfL − RNS60 group; 1.8 years in high NfL − placebo group) and Monocyte Chemoattractant Protein-1 (MCP-1) (median survival: 3.7 years in low MCP-1 − RNS60 group; 2.3 years in low MCP-1 − placebo group; 2.8 years in high MCP-1 − RNS60 group; 2.6 years in high MCP-1 − placebo group) levels at baseline. Conclusions and relevanceIn this post-hoc analysis, long term survival was longer in participants randomized to RNS60 compared with those randomized to placebo and was correlated with slower FVC progression rates, suggesting that longer survival may be mediated by the drug’s effect on respiratory function. In these post-hoc analyses, the beneficial effect of RNS60 on survival was most pronounced in participants with low NfL and MCP-1 levels at study entry, suggesting that this could be a subgroup to target in future studies investigating the effects of RNS60 on survival. Trial registrationStudy preregistered on 13/Jan/2017 in EUDRA-CT (2016-002382-62). The study was also registered at ClinicalTrials.gov number NCT03456882.

Associations of Microbleeds and Their Topography With Imaging and CSF Biomarkers of Alzheimer Pathology in Individuals With Down Syndrome.

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. 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. 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 β = -0.18 [-0.31, -0.06], p < 0.005) and CSF p-tau-181 concentrations (β = 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. 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.

Relationship between serum neurofilament light chain protein and depression: A nationwide survey and Mendelian randomization study

BackgroundInvestigating the link between serum neurofilament protein (sNfL) levels and depression remains an area of limited understanding. This study explores the correlation in US adults and employs Mendelian randomization (MR) to ascertain causality. MethodsOur cross-sectional study analyzed data from participants aged 20 and above in the National Health and Nutrition Examination Survey (2013–2014). We employed a weighted multiple logistic regression model to examine the relationship between ln (sNfL) and depression. Restricted cubic splines (RCS) were used to visualize non-linear relationships. Stratified analyses examined associations between ln(sNfL) and depression in different subgroups. Subsequently, we conducted a two-sample bidirectional Mendelian randomization (MR) to assess the causal relationship between sNfL and depression. The inverse variance-weighted (IVW) method was utilized as the primary analysis. ResultsAmong 1765 participants (mean age 45.19 years; 49.37 % male), 166 had depression with a Patient Health Questionnaire (PHQ-9) score ≥ 10. After adjusting for covariates, a positive correlation remained between sNfL and depression (OR 1.511, 95 % CI: 1.050–2.175). RCS curves indicated a non-linear association, with a turning point at 2.76 pg/ml. Stratified analyses revealed positive correlations in specific subgroups, with interactions involving age, race, family income, recreational activity, and ln(sNfL). MR using IVW found no significant causal relationship between sNfL and depression genetically (OR = 0.956, 95 % CI: 0.878–1.042), with reverse analysis yielding similar results (OR = 0.897, 95 % CI: 0.756–1.065). ConclusionsThis cross-sectional study highlights a significant correlation between ln(sNfL) and depression. However, MR results indicate no causal relationship between sNfL and depression.

Alzheimer's disease CSF biomarkers correlate with early pathology and alterations in neuronal and glial gene expression.

Normal pressure hydrocephalus (NPH) patients undergoing cortical shunting frequently show early Alzheimer's disease (AD) pathology on cortical biopsy, which is predictive of progression to clinical AD. The objective of this study was to use samples from this cohort to identify cerebrospinal fluid (CSF) biomarkers for AD-related central nervous system (CNS) pathophysiologic changes using tissue and fluids with early pathology, free of post mortem artifact. We analyzed Simoa, proteomic, and metabolomic CSF data from 81 patients with previously documented pathologic and transcriptomic changes. AD pathology on biopsy correlates with CSF β-amyloid-42/40, neurofilament light chain (NfL), and phospho-tau-181(p-tau181)/β-amyloid-42, while several gene expression modules correlate with NfL. Proteomic analysis highlights seven core proteins that correlate with pathology and gene expression changes on biopsy, and metabolomic analysis of CSF identifies disease-relevant groups that correlate with biopsy data. As additional biomarkers are added to AD diagnostic panels, our work provides insight into the CNS pathophysiology these markers are tracking. AD CSF biomarkers correlate with CNS pathology and transcriptomic changes. Seven proteins correlate with CNS pathology and gene expression changes. Inflammatory and neuronal gene expression changes correlate with YKL-40 and NPTXR, respectively. CSF metabolomic analysis identifies pathways that correlate with biopsy data. Fatty acid metabolic pathways correlate with β-amyloid pathology.

Multi-Modal Assessment of Cerebral Hemodynamics in Resuscitated Out-of-Hospital Cardiac Arrest Patients: A Case-Series.

We assessed the feasibility of concurrent monitoring of cerebral hemodynamics in adult, comatose out-of-hospital cardiac arrest (OHCA) patients admitted to the National University Heart Centre Singapore from October 2021 to August 2023. Patients underwent continuous near-infrared spectroscopy (NIRS) monitoring in the first 72 h after return of spontaneous circulation (ROSC) and 30-min transcranial Doppler ultrasound (TCD) monitoring at least once. With constant mechanical ventilatory settings and continuous electrocardiographic, pulse oximeter and end-tidal carbon dioxide monitoring, blood pressure was manipulated via vasopressors and cerebral autoregulation assessed by measuring changes in regional cerebral oxygenation (NIRS) and cerebral blood flow velocities (TCD) in response to changes in mean arterial pressure. The primary outcome was neurological recovery at hospital discharge. Amongst the first 16 patients (median age 61, 94% males), we observed four unique patterns: preserved cerebral autoregulation, loss of cerebral autoregulation, cardio-cerebral asynchrony and cerebral circulatory arrest. Patients with preserved cerebral autoregulation had lower levels of neuro-injury biomarkers (neurofilaments light and heavy) and the majority (86%) were discharged with good neurological recovery. Multi-modal assessment of cerebral hemodynamics after OHCA is feasible and derived patterns correlated with neurological outcomes. The between- and within-patient heterogeneity in cerebral hemodynamics calls for more research on individualized treatment strategies.