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INTRODUCTION We examined whether the aging suppressor KLOTHO gene's functionally advantageous KL‐VS variant (KL‐VS heterozygosity [KL‐VSHET]) confers resilience against deleterious effects of aging indexed by cerebrospinal fluid (CSF) biomarkers of neuroinflammation (interleukin‐6 [IL‐6], S100 calcium‐binding protein B [S100B], triggering receptor expressed on myeloid cells [sTREM2], chitinase‐3‐like protein 1 [YKL‐40], glial fibrillary acidic protein [GFAP]), neurodegeneration (total α‐synuclein [α‐Syn], neurofilament light chain protein), and synaptic dysfunction (neurogranin [Ng]). METHODS This Alzheimer disease risk‐enriched cohort consisted of 454 cognitively unimpaired adults (Mage = 61.5 ± 7.75). Covariate‐adjusted multivariate regression examined relationships between age (mean‐split[age ≥ 62]) and CSF biomarkers (Roche/NeuroToolKit), and whether they differed between KL‐VSHET (N = 122) and non‐carriers (KL‐VSNC; N = 332). RESULTS Older age was associated with a poorer biomarker profile across all analytes (Ps ≤ 0.03). In age‐stratified analyses, KL‐VSNC exhibited this same pattern (Ps ≤ 0.05) which was not significant for IL‐6, S100B, Ng, and α‐Syn (Ps ≥ 0.13) in KL‐VSHET. Although age‐related differences in GFAP, sTREM2, and YKL‐40 were evident for both groups (Ps ≤ 0.01), the effect magnitude was markedly stronger for KL‐VSNC. DISCUSSION Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults were attenuated in KL‐VSHET. Highlights Older age was associated with poorer profiles across all cerebrospinal fluid biomarkers of neuroinflammation, neurodegeneration, and synaptic dysfunction. KLOTHO KL‐VS non‐carriers exhibit this same pattern, which is does not significantly differ between younger and older KL‐VS heterozygotes for interleukin‐6, S100 calcium‐binding protein B, neurogranin, and total α‐synuclein. Although age‐related differences in glial fibrillary acidic protein, triggering receptor expressed on myeloid cells, and chitinase‐3‐like protein 1 are evident for both KL‐VS groups, the magnitude of the effect is markedly stronger for KL‐VS non‐carriers. Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults are attenuated in KL‐VS heterozygotes.

INTRODUCTION The role of neuroinflammation in preclinical Alzheimer's disease (AD) remains unclear. METHODS We assessed changes in microglial and astrocytic biomarkers in a well‐characterized cohort of 211 cognitively unimpaired individuals. Structural equation modeling was used to simultaneously assess all relationships among microglial and astrocytic responses and AD pathological events. RESULTS Plasma glial fibrillary acidic protein (GFAP) and cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were increased in preclinical AD. Plasma GFAP showed an inverse bidirectional relationship with CSF amyloid beta (Aβ)42/40. CSF sTREM2 directly influenced CSF phosphorylated tau‐181 (p‐tau181) and neurogranin, and correlated with CSF S100 calcium‐binding protein beta (S100β). CSF chitinase‐3‐like protein 1 (YKL‐40) mediated the association between CSF p‐tau181 and total tau (t‐tau), whereas CSF S100β and neurofilament light showed mutual influence. DISCUSSION Our findings suggest that microglial and astrocyte reactivity, measured through fluid biomarkers, occur early and impact the amyloid cascade on the preclinical Alzheimer´s continuum. Specifically, GFAP influences amyloid accumulation, sTREM2 promotes tau pathology, and YKL‐40 and S100β contribute to the progression of downstream neurodegenerative changes. Highlights Preclinical Alzheimer's disease (AD) showed increased levels of plasma glial fibrillary acidic protein (GFAP) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) compared to cerebrospinal fluid (CSF) in healthy subjects. Higher plasma GFAP levels was directly associated with lower CSF amyloid beta (Aβ)42/Aβ40. Higher CSF sTREM2 concentrations increased CSF phosphorylated tau‐181. Chitinase‐3‐like protein 1 (YKL‐40) mediated tau‐induced neurodegeneration. S100 calcium‐binding protein beta (S100β) was directly linked to higher neurofilament light (NfL) and showed a mutual relationship with sTREM2.

Background. Tuberculous meningitis (TBM) leads to death or disability in half the affected individuals. Tools to assess severity and predict outcome are lacking. Neurospecific biomarkers could serve as markers of the severity and evolution of brain injury, but have not been widely explored in TBM. We examined biomarkers of neurological injury (neuromarkers) and inflammation in pediatric TBM and their association with outcome. Methods. Blood and cerebrospinal fluid (CSF) of children with TBM and hydrocephalus taken on admission and over 3 weeks were analyzed for the neuromarkers S100B, neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP), in addition to multiple inflammatory markers. Results were compared with 2 control groups: patients with (1) a fatty filum (abnormal filum terminale of the spinal cord); and (2) pulmonary tuberculosis (PTB). Imaging was conducted on admission and at 3 weeks. Outcome was assessed at 6 months. Results. Data were collected from 44 patients with TBM (cases; median age, 3.3 [min–max 0.3–13.1] years), 11 fatty filum controls (median age, 2.8 [min–max 0.8–8] years) and 9 PTB controls (median age, 3.7 [min–max 1.3–11.8] years). Seven cases (16%) died and 16 (36%) had disabilities. Neuromarkers and inflammatory markers were elevated in CSF on admission and for up to 3 weeks, but not in serum. Initial and highest concentrations in week 1 of S100B and NSE were associated with poor outcome, as were highest concentration overall and an increasing profile over time in S100B, NSE, and GFAP. Combined neuromarker concentrations increased over time in patients who died, whereas inflammatory markers decreased. Cerebral infarcts were associated with highest overall neuromarker concentrations and an increasing profile over time. Tuberculomas were associated with elevated interleukin (IL) 12p40, interferon-inducible protein 10, and monocyte chemoattractant protein 1 concentrations, whereas infarcts were associated with elevated tumor necrosis factor α, macrophage inflammatory protein 1α, IL-6, and IL-8. Conclusions. CSF neuromarkers are promising biomarkers of injury severity and are predictive of mortality. An increasing trend suggested ongoing brain injury, even though markers of inflammation declined with treatment. These findings could offer novel insight into the pathophysiology of TBM.

Background and Objectives Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system in young adults. Over time, the disease progresses and, with accumulating disability, symptoms such as spasticity may occur. Although several treatment options are available, some patients may not respond to first-line therapeutics. However, some of these patients may benefit from intrathecally administered triamcinolone-acetonide (TCA), a derivative of glucocorticosteroids (GCS). GCS may have neurotoxic effects, and cell apoptosis may occur. The aim of this study was to investigate the effects of TCA on biomarkers in the cerebrospinal fluid (CSF) suggestive of neurodegeneration. Methods In order to assess neurotoxic effects of TCA, neurofilament heavy-chain (NfH) SMI35 , tau protein, and S-100B protein levels were determined before and during treatment with TCA in 54 patients with primary progressive MS, as well as relapsing MS (relapsing–remitting and secondary progressive MS). Results NfH SMI35 levels in the CSF of patients treated with TCA intrathecally did not increase significantly during the treatment cycle ( p  = 0.068). After application of TCA, tau protein levels were increased significantly at day 4 ( p  = 0.03) and at day 8 ( p  ≤ 0.001). S-100B protein levels decreased significantly ( p  ≤ 0.05) during treatment with TCA. Conclusion NfH SMI35 levels did not change significantly; however, tau protein levels did increase significantly within the reference range. Taking these findings together, the long-term effects of TCA on NfH SMI35 and tau protein levels need to be investigated further to understand whether levels of both biomarkers will change over repeated TCA applications. Interestingly, S-100B protein levels decreased significantly during the first applications, which may have represented reduced astrocytic activity during TCA treatment.

Background The prognostic value of serum biomarkers after out-of-hospital cardiac arrest (OHCA) depends on timing, but the physiological basis remains unclear. We investigated whether blood–brain barrier (BBB) integrity and biomarker-specific properties explain the time-dependent differences in prognostic performance. Methods This retrospective study included comatose adult OHCA survivors who underwent paired serum and cerebrospinal fluid (CSF) measurements of neuron-specific enolase (NSE; 47 kDa) and S100 calcium-binding protein B (S100B; 21 kDa) at 0 (H0), 24 (H24), 48 (H48), and 72 (H72) h after return of spontaneous circulation. BBB disruption was assessed using the CSF/serum albumin quotient (Q A ). Prognostic performance was assessed using AUC analysis for 6-month poor neurological outcome (Cerebral Performance Category 3–5). Results Among 111 patients (59% poor outcome), 646 serum and 620 CSF samples were analyzed. BBB disruption was more severe in the poor outcome group at all timepoints (all P  < 0.001), peaking at H24 (Q A 0.0282 [IQR 0.0150–0.120]) and remaining elevated at H72 (0.0228 [IQR 0.0147–0.0598]). In the poor outcome group, serum S100B levels peaked at H0 (0.80 ng/mL [IQR 0.39–2.81]) and declined despite a persistent elevation in CSF levels at or above the upper detection limit (≥ 30 ng/mL). Conversely, NSE levels progressively increased in both compartments, with serum and CSF levels increasing in parallel over time. Serum NSE concentrations showed a time-dependent improvement in prognostic accuracy, peaking at H72 (AUC 0.88), whereas S100B concentrations maintained stable performance across all timepoints (AUCs 0.79–0.85, all P  > 0.4). Notably, the prognostic performance of S100B remained relatively consistent regardless of BBB disruption severity, whereas NSE showed progressively improved predictive accuracy with increased BBB disruption. Across all timepoints, CSF biomarkers—particularly S100B and NSE—showed consistently higher AUCs than serum, suggesting superior prognostic utility. Conclusions Serum NSE levels closely reflect the degree of BBB disruption and CSF levels, while S100B exhibits a transient early-phase profile, with decreased serum detectability over time, even in the presence of sustained CSF elevation or severe BBB disruption. These findings highlight the importance of interpreting biomarker kinetics across compartments and timepoints rather than relying on molecular weight or BBB status alone.

Alzheimer’s disease and related dementias (ADRD) present a significant global disease burden that is only expected to grow in the future. As such, there is a need to develop and investigate biomarkers that identify individuals at risk of developing ADRD with the goal of providing early interventions and treatments. Non-human primate (NHP) models of neurodegeneration present opportunities to examine such biomarkers in a preclinical model with the ability to control several confounding factors present in research with humans. Baboons naturally develop several ADRD-related neuropathologies that humans also exhibit, including age-related tau and amyloid deposition. However, to our knowledge, there are no data characterizing fluid biomarkers relevant to neurodegeneration or ADRD in baboons. We collected plasma (N = 139) and cerebrospinal fluid (CSF, N = 44) from captive baboons ranging in age from 3–19 years old. We characterized biomarkers as a function of age, sex, and rearing status in baboons using a bead-based bioplex human assay (Thermo Fisher Scientific’s Neuroscience 18-Plex Human ProcartaPlex™ Panel). Fluid biomarkers were more detectable in CSF compared to plasma. Additionally, while sex and rearing did not significantly predict biomarkers in baboons, age significantly predicted levels of eight of the 12 biomarkers detected in the assay. Linear regressions showed that CSF levels of total tau, pTau181, NGF-beta, GFAP, NF-H, and S100B were higher in older baboons, as were plasma levels of NGF-beta. Lastly, older baboons showed a higher incidence of co-occurrence of multiple biomarkers as measured in CSF, but not in plasma. These data show that baboons exhibit age-dependent changes in biomarkers used in humans for clinical screening, diagnosis, and prognosis of ADRD, thereby further demonstrating the value of baboons as a model of aging and, possibly, ADRD.

Traumatic brain injuries (TBIs) are clinically grouped by severity: mild, moderate and severe. Mild TBI (the least severe form) is synonymous with concussion and is typically caused by blunt non-penetrating head trauma. The trauma causes stretching and tearing of axons, which leads to diffuse axonal injury — the best-studied pathogenetic mechanism of this disorder. However, mild TBI is defined on clinical grounds and no well-validated imaging or fluid biomarkers to determine the presence of neuronal damage in patients with mild TBI is available. Most patients with mild TBI will recover quickly, but others report persistent symptoms, called post-concussive syndrome, the underlying pathophysiology of which is largely unknown. Repeated concussive and subconcussive head injuries have been linked to the neurodegenerative condition chronic traumatic encephalopathy (CTE), which has been reported post-mortem in contact sports athletes and soldiers exposed to blasts. Insights from severe injuries and CTE plausibly shed light on the underlying cellular and molecular processes involved in mild TBI. MRI techniques and blood tests for axonal proteins to identify and grade axonal injury, in addition to PET for tau pathology, show promise as tools to explore CTE pathophysiology in longitudinal clinical studies, and might be developed into diagnostic tools for CTE. Given that CTE is attributed to repeated head trauma, prevention might be possible through rule changes by sports organizations and legislators. Traumatic brain injuries (TBIs) result from an external force and can result in a range of clinical manifestations and neuropathological changes, many of which are only beginning to be understood. Here, the authors argue that the cellular and molecular processes involved in TBIs of different severities are probably similar, just to different degrees.

ObjectiveTo review clinical and investigation findings in patients referred to a specialist prion clinic who were suspected to have sporadic Creutzfeldt-Jakob disease (sCJD) and yet were found to have an alternative final diagnosis.MethodsReview the clinical findings and investigations in 214 patients enrolled into the UK National Prion Monitoring Cohort Study between October 2008 and November 2015 who had postmortem confirmed sCJD and compare these features with 50 patients referred over the same period who had an alternative final diagnosis (CJD mimics).ResultsPatients with an alternative diagnosis and those with sCJD were of similar age, sex and frequency of dementia but CJD mimics had a longer clinical history. Myoclonus, rigidity and hallucinations were more frequent in patients with sCJD but these features were not helpful in classifying individual patients. Alzheimer’s disease, dementia with Lewy bodies and genetic neurodegenerative disorders were alternative diagnoses in more than half of the CJD mimic cases, and 10% had an immune-mediated encephalopathy; lymphoma, hepatic encephalopathy and progressive multifocal leukoencephalopathy were seen more than once. Diffusion-weighted MRI was the most useful readily available test to classify cases correctly (92% CJD, 2% CJD mimics). The CSF cell count, 14-3-3 protein detection and S100B were of limited value. A positive CSF RT-QuIC test, introduced during the course of the study, was found in 89% of tested CJD cases and 0% CJD mimics.ConclusionThe combination of diffusion-weighted MRI analysis and CSF RT-QuIC allowed a perfect classification of sCJD versus its mimics in this study.

Abstract Neurological diseases are a major health concern, and brain injury is a typical pathological process in various neurological disorders. Different biomarkers in the blood or the cerebrospinal fluid are associated with specific physiological and pathological processes. They are vital in identifying, diagnosing, and treating brain injuries. In this review, we described biomarkers for neuronal cell body injury (neuron-specific enolase, ubiquitin C-terminal hydrolase-L1, αII-spectrin), axonal injury (neurofilament proteins, tau), astrocyte injury (S100β, glial fibrillary acidic protein), demyelination (myelin basic protein), autoantibodies, and other emerging biomarkers (extracellular vesicles, microRNAs). We aimed to summarize the applications of these biomarkers and their related interests and limits in the diagnosis and prognosis for neurological diseases, including traumatic brain injury, status epilepticus, stroke, Alzheimer’s disease, and infection. In addition, a reasonable outlook for brain injury biomarkers as ideal detection tools for neurological diseases is presented.

As an astrocytic protein specific to the central nervous system, S100b is a potentially useful marker in outcome prediction after traumatic brain injury (TBI). Some studies have questioned the validity of S100b, citing the extracerebral origins of the protein as reducing the specificity of the marker. This study evaluated S100b as a prognostic biomarker in adult subjects with severe TBI (sTBI) by comparing outcomes with S100b temporal profiles generated from both cerebrospinal fluid (CSF) (n=138 subjects) and serum (n=80 subjects) samples across a 6-day time course. Long-bone fracture, Injury Severity Score (ISS), and isolated head injury status were variables used to assess extracerebral sources of S100b in serum. After TBI, CSF and serum S100b levels were increased over healthy controls across the first 6 days post-TBI (p≤0.005 and p≤0.031). Though CSF and serum levels were highly correlated during early time points post-TBI, this association diminished over time. Bivariate analysis showed that subjects who had temporal CSF profiles with higher S100b concentrations had higher acute mortality (p<0.001) and worse Glasgow Outcome Scale (GOS; p=0.002) and Disability Rating Scale (DRS) scores (p=0.039) 6 months post-injury. Possibly as a result of extracerebral sources of S100b in serum, as represented by high ISS scores (p=0.032), temporal serum profiles were associated with acute mortality (p=0.015). High CSF S100b levels were observed in women (p=0.022) and older subjects (p=0.004). Multivariate logistic regression confirmed CSF S100b profiles in predicting GOS and DRS and showed mean and peak serum S100b as acute mortality predictors after sTBI.