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Sodium serves as one of the primary cations in the central nervous system, playing a crucial role in maintaining normal brain function. In this study, we investigated alterations in sodium concentrations in the brain and/or cerebrospinal fluid across multiple models, including an aging model, a stroke model, a nitroglycerin (NTG)-induced rat migraine model, a familial hemiplegic migraine type 2 (FHM2) mouse model, and a transgenic mouse model of Alzheimer's disease (AD). Our results reveal that older rats exhibited higher sodium concentrations in cerebrospinal fluid (CSF), plasma, and various brain regions compared to their younger counterparts. Additionally, findings from the stroke model demonstrated a significant increase in sodium in the ischemic/reperfused region, accompanied by a decrease in potassium and an elevated sodium/potassium ratio. However, we did not detect significant changes in sodium in the NTG-induced rat migraine model or the FHM2 mouse model. Furthermore, AD transgenic mice showed no significant differences in sodium levels compared to wild-type mice in CSF, plasma, or the hippocampus. These results underscore the nuanced regulation of sodium homeostasis in various neurological conditions and aging, providing valuable insights into potential mechanisms underlying these alterations. [ABSTRACT FROM AUTHOR]

Experimental studies identified a role of neuroinflammation in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the role of inflammatory molecules as diagnostic and prognostic biomarkers in patients with ALS is unclear. In this cross-sectional study, the cerebrospinal fluid (CSF) levels of a set of inflammatory cytokines and chemokines were analyzed in 56 newly diagnosed ALS patients and in 47 age- and sex-matched control patients without inflammatory or degenerative neurological disorders. The molecules analyzed included: interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-17, granulocyte colony stimulating factor (GCSF), macrophage inflammatory protein (MIP)-1a, MIP-1b, tumor necrosis factors (TNF), eotaxin. Principal component analysis (PCA) was used to explore possible associations between CSF molecules and ALS diagnosis. In addition, we analyzed the association between CSF cytokine profiles and clinical characteristics, including the disease progression rate score, and peripheral inflammation assessed using the Neutrophil-to-lymphocyte ratio (NLR). PCA identified six principal components (PCs) explaining 70.67% of the total variance in the CSF cytokine set. The principal component (PC1) explained 26.8% of variance and showed a positive load with CSF levels of IL-9, IL-4, GCSF, IL-7, IL-17, IL-13, IL-6, IL-1β, TNF, and IL-2. Logistic regression showed a significant association between PC1 and ALS diagnosis. In addition, in ALS patients, the same component was significantly associated with higher disease progression rate score and positively correlated with NLR. CSF inflammatory activation in present in ALS at the time of diagnosis and may characterize patients at higher risk for disease progression. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) core biomarkers of Alzheimer's disease (AD), including amyloid peptide beta-42 (Aβ42), Aβ42/40 ratio, and phosphorylated tau (pTau), are precious tools for supporting AD diagnosis. However, their use in clinical practice is limited due to the invasiveness of CSF collection. Thus, there is intensive research to find alternative, noninvasive, and widely accessible biological matrices to measure AD core biomarkers. In this study, we measured AD core biomarkers in saliva and plasma by a fully automated platform. We enrolled all consecutive patients with cognitive decline. For each patient, we measured Aβ42, Aβ40, and pTau levels in CSF, saliva, and plasma by Lumipulse G1200 (Fujirebio). We included forty-two patients, of whom 27 had AD. Levels of all biomarkers significantly differed in the three biofluids, with saliva having the lowest and CSF the highest levels of Aβ42, Aβ40, and pTau. A positive correlation of pTau, Aβ42/40 ratio, and pTau/Aβ42 ratio levels in CSF and plasma was detected, while no correlation between any biomarker in CSF and saliva was found. Our findings suggest that plasma but not saliva could represent a surrogate biofluid for measuring core AD biomarkers. Specifically, plasma Aβ42/40 ratio, pTau/Aβ42 ratio, and pTau could serve as surrogates of the corresponding CSF biomarkers. [ABSTRACT FROM AUTHOR]

This study examined the association between hearing loss in sporadic vestibular schwannoma patients and the proteome of perilymph (PL), cerebrospinal fluid (CSF), and vestibular schwannoma. Intraoperative sampling of PL and of CSF, and biopsy of vestibular schwannoma tissue, was performed in 32, 32, and 20 patients with vestibular schwannoma, respectively. Perilymph and CSF in three patients with meningioma and normal hearing were also sampled. The proteomes were identified by liquid chromatography coupled to high-resolution tandem mass spectrometry. Preoperative hearing function of the patients was evaluated with pure tone audiometry, with mean values at frequencies of 500, 1000, 2000, and 4000 Hz (PTA4) in the tumor-affected ear used to delineate three hearing groups. Analysis of the PL samples revealed significant upregulation of complement factor H-related protein 2 (CFHR2) in patients with severe to profound hearing loss after false discovery rate correction. Pathway analysis of biofunctions revealed higher activation scores in the severe/profound hearing loss group of leukocyte migration, viral infection, and migration of cells in PL. Upregulation of CFHR2 and activation of these pathways indicate chronic inflammation in the cochlea of vestibular schwannoma patients with severe to profound hearing loss compared with patients with normal hearing or mild hearing loss. [ABSTRACT FROM AUTHOR]

Affections of the central nervous system (CNS) rarely occur in Lyme neuroborreliosis (LNB). CNS manifestations can have residual neurological symptoms despite antibiotic treatment. We explored the spectrum of CNS affections in patients with LNB in a tertiary care center in a region endemic for Lyme borreliosis. We retrospectively included patients treated at a tertiary care center from January 2020–December 2021 fulfilling the case criteria for LNB as stated in the current German guideline on LNB. Clinical data, cerebrospinal fluid (CSF) findings and MRI imaging were collected. We included 35 patients with LNB, 24 with early manifestations and 11 with CNS-LNB. CNS-LNB patients had encephalomyelitis (n = 6) or cerebral vasculitis (n = 5). Patients with early LNB and CNS-LNB differed regarding albumin CSF/serum quotient and total protein in CSF. Duration from onset of symptoms until diagnosis was statistically significantly longer in patients with encephalomyelitis. MRI findings were heterogeneous and showed longitudinal extensive myelitis, perimedullar leptomeningeal enhancement, pontomesencephalic lesions or cerebral vasculitis. CNS-LNB can present with a variety of clinical syndromes and MRI changes. No clear pattern of MRI findings in CNS-LNB could be identified. The role of MRI consists in ruling out other causes of neurological symptoms. [ABSTRACT FROM AUTHOR]

We aimed to assess diagnostic accuracy of plasma p-tau181 and NfL separately and in combination in discriminating Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) patients carrying Alzheimer's Disease (AD) pathology from non-carriers; to propose a flowchart for the interpretation of the results of plasma p-tau181 and NfL. We included 43 SCD, 41 MCI and 21 AD-demented (AD-d) patients, who underwent plasma p-tau181 and NfL analysis. Twenty-eight SCD, 41 MCI and 21 AD-d patients underwent CSF biomarkers analysis (Aβ1-42, Aβ1-42/1–40, p-tau, t-tau) and were classified as carriers of AD pathology (AP+) it they were A+/T+ , or non-carriers (AP−) when they were A−, A+/T−/N−, or A+/T−/N+ according to the A/T(N) system. Plasma p-tau181 and NfL separately showed a good accuracy (AUC = 0.88), while the combined model (NfL + p-tau181) showed an excellent accuracy (AUC = 0.92) in discriminating AP+ from AP− patients. Plasma p-tau181 and NfL results were moderately concordant (Coehn's k = 0.50, p < 0.001). Based on a logistic regression model, we estimated the risk of AD pathology considering the two biomarkers: 10.91% if both p-tau181 and NfL were negative; 41.10 and 76.49% if only one biomarker was positive (respectively p-tau18 and NfL); 94.88% if both p-tau181 and NfL were positive. Considering the moderate concordance and the risk of presenting an underlying AD pathology according to the positivity of plasma p-tau181 and NfL, we proposed a flow chart to guide the combined use of plasma p-tau181 and NfL and the interpretation of biomarker results to detect AD pathology. [ABSTRACT FROM AUTHOR]

Three years after SARS-CoV-2 emerged as a global infectious threat, the virus has become endemic. The neurological complications such as depression, anxiety, and other CNS complications after COVID-19 disease are increasing. The brain, and CSF have been shown as viral reservoirs for SARS-CoV-2, yielding a potential hypothesis for CNS effects. Thus, we investigated the CNS pharmacology of orally dosed nirmatrelvir/ritonavir (NMR/RTV). Using both an in vitro and an in vivo rodent model, we investigated CNS penetration and potential pharmacodynamic activity of NMR. Through pharmacokinetic modeling, we estimated the median CSF penetration of NMR to be low at 18.11% of plasma with very low accumulation in rodent brain tissue. Based on the multiples of the 90% maximal effective concentration (EC90) for SARS-CoV-2, NMR concentrations in the CSF and brain do not achieve an exposure level similar to that of plasma. A median of only 16% of all the predicted CSF concentrations in rats were > 3xEC90 (unadjusted for protein binding). This may have implications for viral persistence and neurologic post-acute sequelae of COVID-19 if increased NMR penetration in the CNS leads to decreased CNS viral loads and decreased CNS inflammation. [ABSTRACT FROM AUTHOR]

Real-time quaking-induced conversion assay (RT-QuIC) exploits templating activity of pathogenic prion protein for ultrasensitive detection of prions. We have utilized second generation RT-QuIC assay to analyze matching post-mortem cerebrospinal fluid and skin samples of 38 prion disease patients and of 30 deceased neurological controls. The analysis of cerebrospinal fluid samples led to 100% sensitivity and 100% specificity, but some samples had to be diluted before the analysis to alleviate the effect of present RT-QuIC inhibitors. The analysis of the corresponding skin samples provided 89.5% sensitivity and 100% specificity. The median seeding dose present in the skin was one order of magnitude higher than in the cerebrospinal fluid, despite the overall fluorescent signal of the skin samples was comparatively lower. Our data support the use of post-mortem cerebrospinal fluid for confirmation of prion disease diagnosis and encourage further studies of the potential of skin biopsy samples for intra-vitam prion diseases´ diagnostics. [ABSTRACT FROM AUTHOR]

Prenatal cannabis use is associated with adverse offspring neurodevelopmental outcomes, however the underlying mechanisms are relatively unknown. We sought to determine the impact of chronic delta-9-tetrahydrocannabinol (THC) exposure on fetal neurodevelopment in a rhesus macaque model using advanced imaging combined with molecular and tissue studies. Animals were divided into two groups, control (n = 5) and THC-exposed (n = 5), which received a daily THC edible pre-conception and throughout pregnancy. Fetal T2-weighted MRI was performed at gestational days 85 (G85), G110, G135 and G155 to assess volumetric brain development. At G155, animals underwent cesarean delivery with collection of fetal cerebrospinal fluid (CSF) for microRNA (miRNA) studies and fetal tissue for histologic analysis. THC exposure was associated with significant age by sex interactions in brain growth, and differences in fetal brain histology suggestive of brain dysregulation. Two extracellular vesicle associated-miRNAs were identified in THC-exposed fetal CSF; pathway analysis suggests that these miRNAs are associated with dysregulated axonal guidance and netrin signaling. This data is indicative of subtle molecular changes consistent with the observed histological data, suggesting a potential role for fetal miRNA regulation by THC. Further studies are needed to determine whether these adverse findings correlate with long-term offspring neurodevelopmental health. [ABSTRACT FROM AUTHOR]

This manuscript presents the quantification and correlation of three aspects of Alzheimer's Disease evolution, including structural, biochemical, and cognitive assessments. We aimed to test a novel structural biomarker for neurodegeneration based on a cortical folding model for mammals. Our central hypothesis is that the cortical folding variable, representative of axonal tension in white matter, is an optimal discriminator of pathological aging and correlates with altered loadings in Cerebrospinal Fluid samples and a decline in cognition and memory. We extracted morphological features from T1w 3T MRI acquisitions using FreeSurfer from 77 Healthy Controls (age = 66 ± 8.4, 69% females), 31 Mild Cognitive Impairment (age = 72 ± 4.8, 61% females), and 13 Alzheimer's Disease patients (age = 77 ± 6.1, 62% females) of recruited volunteers in Brazil to test its discriminative power using optimal cut-point analysis. Cortical folding distinguishes the groups with reasonable accuracy (Healthy Control-Alzheimer's Disease, accuracy = 0.82; Healthy Control-Mild Cognitive Impairment, accuracy = 0.56). Moreover, Cerebrospinal Fluid biomarkers (total Tau, A β 1-40, A β 1-42, and Lipoxin) and cognitive scores (Cognitive Index, Rey's Auditory Verbal Learning Test, Trail Making Test, Digit Span Backward) were correlated with the global neurodegeneration in MRI aiming to describe health, disease, and the transition between the two states using morphology. [ABSTRACT FROM AUTHOR]

Idiopathic Normal Pressure Hydrocephalus (iNPH) is a neurological condition that often presents gait disturbance in the early stages of the disease and affects other motor activities. This study investigated changes in temporospatial gait variables after cerebrospinal fluid (CSF) removal using a spinal tap test in individuals with idiopathic normal pressure hydrocephalus (iNPH), and explored if the tap test responders and non-responders could be clinically identified from temporospatial gait variables. Sixty-two individuals with iNPH were recruited from an outpatient clinic, eleven were excluded, leaving a total of 51 who were included in the analysis. Temporospatial gait variables at self-selected speed were recorded at pre- and 24-h post-tap tests which were compared using Paired t-tests, Cohen's d effect size, and percentage change. A previously defined minimal clinical important change (MCIC) for gait speed was used to determine the changes and to classify tap test responders and non-responders. A mixed model ANOVA was used to determine the within-group, between-group, and interaction effects. Comparisons of the data between pre- and post-tap tests showed significant improvements with small to medium effect sizes for left step length, right step time, stride length and time, cadence, and gait speed. Gait speed showed the largest percentage change among temporospatial gait variables. Within-group and interaction effects were found in some variables but no between-group effect was found. Tap test responders showed significant improvements in right step length and time, stride length and time, cadence, and gait speed while non-responders did not. Some individuals with iNPH showed clinically important improvements in temporospatial gait variables after the tap test, particularly in step/stride length and time, cadence, who could be classified by gait speed. However, gait-related balance variables did not change. Therefore, additional treatments should focus on improving such variables. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a complex and heterogeneous neurodegenerative disorder with contributions from multiple pathophysiological pathways. One of the long-recognized and important features of AD is disrupted cerebral glucose metabolism, but the underlying molecular basis remains unclear. In this study, unbiased mass spectrometry was used to survey CSF from a large clinical cohort, comparing patients who are either cognitively unimpaired (CU; n = 68), suffering from mild-cognitive impairment or dementia from AD (MCI-AD, n = 95; DEM-AD, n = 72), or other causes (MCI-other, n = 77; DEM-other, n = 23), or Normal Pressure Hydrocephalus (NPH, n = 57). The results revealed changes related to altered glucose metabolism. In particular, two glycolytic enzymes, pyruvate kinase (PKM) and aldolase A (ALDOA), were found to be upregulated in CSF from patients with AD compared to those with other neurological conditions. Increases in full-length PKM and ALDOA levels in CSF were confirmed with immunoblotting. Levels of these enzymes furthermore correlated negatively with CSF glucose in matching CSF samples. PKM levels were also found to be increased in AD in publicly available brain-tissue data. These results indicate that ALDOA and PKM may act as technically-robust potential biomarkers of glucose metabolism dysregulation in AD. [ABSTRACT FROM AUTHOR]

Suspected central nervous system (CNS) infections may pose a diagnostic challenge, and often concern severely ill patients. We aim to identify predictors of unfavourable outcome to prioritize diagnostics and treatment improvements. Unfavourable outcome was assessed on the Glasgow Outcome Scale at hospital discharge, defined by a score of 1 to 4. Of the 1152 episodes with suspected CNS infection, from two Dutch prospective cohorts, the median age was 54 (IQR 37–67), and 563 episodes (49%) occurred in women. The final diagnoses were categorized as CNS infection (N = 358 episodes, 31%), CNS inflammatory disease (N = 113, 10%), non-infectious non-inflammatory neurological disorder (N = 388, 34%), non-neurological infection (N = 252, 22%), and other systemic disorder (N = 41, 4%). Unfavourable outcome occurred in 412 of 1152 (36%), and 99 died (9%). Predictors for unfavourable outcomes included advanced age, absence of headache, tachycardia, altered mental state, focal cerebral deficits, cranial nerve palsies, low thrombocytes, high CSF protein, and the final diagnosis of CNS inflammatory disease (odds ratio 4.5 [95% confidence interval 1.5–12.6]). Episodes suspected of having a CNS infection face high risk of experiencing unfavourable outcome, stressing the urgent need for rapid and accurate diagnostics. Amongst the suspected CNS infection group, those diagnosed with CNS inflammatory disease have the highest risk. [ABSTRACT FROM AUTHOR]

In Alligator mississippiensis the spinal dura is surrounded by a venous sinus; pressure waves can propagate in the spinal venous blood, and these spinal venous pressures can be transmitted to the spinal cerebrospinal fluid (CSF). This study was designed to explore pressure transfer between the spinal venous blood and the spinal CSF. At rest the cardiac-related CSF pulsations are attenuated and delayed, while the ventilatory-related pulsations are amplified as they move from the spinal venous blood to the spinal CSF. Orthostatic gradients resulted in significant alterations of both cardiac- and ventilatory-related CSF pulsations. Manual lateral oscillations of the alligator's tail created pressure waves in the spinal CSF that propagated, with slight attenuation but no delay, to the cranial CSF. Oscillatory pressure pulsations in the spinal CSF and venous blood had little influence on the underlying ventilatory pulsations, though the same oscillatory pulsations reduced the ventilatory- and increased the cardiac-related pulsations in the cranial CSF. In Alligator the spinal venous anatomy creates a more complex pressure relationship between the venous and CSF systems than has been described in humans. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) leak can be diagnosed in clinical laboratories by detecting a diagnostic marker β2-transferrin (β2-Tf) in secretion samples. β2-Tf and the typical transferrin (Tf) proteoform in serum, β1-transferrin (β1-Tf), are Tf glycoforms. An innovative affinity capture technique for sample preparation, called microprobe-capture in-emitter elution (MPIE), was incorporated with high-resolution mass spectrometry (HR-MS) to study the Tf glycoforms and the primary structures of β1-Tf and β2-Tf. To implement MPIE, an analyte is first captured on the surface of a microprobe, and subsequently eluted from the microprobe inside an electrospray emitter. The capture process is monitored in real-time via next-generation biolayer interferometry (BLI). When electrospray is established from the emitter to a mass spectrometer, the analyte is immediately ionized via electrospray ionization (ESI) for HR-MS analysis. Serum, CSF, and secretion samples were analyzed using MPIE-ESI-MS. Based on the MPIE-ESI-MS results, the primary structures of β1-Tf and β2-Tf were elucidated. As Tf glycoforms, β1-Tf and β2-Tf share the amino acid sequence but contain varying N-glycans: (1) β1-Tf, the major serum-type Tf, has two G2S2 N-glycans on Asn413 and Asn611; and (2) β2-Tf, the major brain-type Tf, has an M5 N-glycan on Asn413 and a G0FB N-glycan on Asn611. The resolving power of the innovative MPIE-ESI-MS method was demonstrated in the study of β2-Tf as well as β1-Tf. Knowing the N-glycan structures on β2-Tf allows for the design of more novel test methods for β2-Tf in the future. [ABSTRACT FROM AUTHOR]

Recent studies have suggested the glymphatic system as a key mechanism of waste removal in the brain. Dynamic contrast-enhanced MRI (DCE-MRI) using intracisternally administered contrast agents is a promising tool for assessing glymphatic function in the whole brain. In this study, we evaluated the transport kinetics and distribution of three MRI contrast agents with vastly different molecular sizes in mice. Our results demonstrate that oxygen-17 enriched water (H217O), which has direct access to parenchymal tissues via aquaporin-4 water channels, exhibited significantly faster and more extensive transport compared to the two gadolinium-based contrast agents (Gd-DTPA and GadoSpin). Time-lagged correlation and clustering analyses also revealed different transport pathways for Gd-DTPA and H217O. Furthermore, there were significant differences in transport kinetics of the three contrast agents to the lateral ventricles, reflecting the differences in forces that drive solute transport in the brain. These findings suggest the size-dependent transport pathways and kinetics of intracisternally administered contrast agents and the potential of DCE-MRI for assessing multiple aspects of solute transport in the glymphatic system. [ABSTRACT FROM AUTHOR]

Integration of the omics data, including metabolomics and proteomics, provides a unique opportunity to search for new associations within metabolic disorders, including Alzheimer's disease. Using metabolomics, we have previously profiled oxylipins, endocannabinoids, bile acids, and steroids in 293 CSF and 202 matched plasma samples from AD cases and healthy controls and identified both central and peripheral markers of AD pathology within inflammation-regulating cytochrome p450/soluble epoxide hydrolase pathway. Additionally, using proteomics, we have identified five cerebrospinal fluid protein panels, involved in the regulation of energy metabolism, vasculature, myelin/oligodendrocyte, glia/inflammation, and synapses/neurons, affected in AD, and reflective of AD-related changes in the brain. In the current manuscript, using metabolomics-proteomics data integration, we describe new associations between peripheral and central lipid mediators, with the above-described CSF protein panels. Particularly strong associations were observed between cytochrome p450/soluble epoxide hydrolase metabolites, bile acids, and proteins involved in glycolysis, blood coagulation, and vascular inflammation and the regulators of extracellular matrix. Those metabolic associations were not observed at the gene-co-expression level in the central nervous system. In summary, this manuscript provides new information regarding Alzheimer's disease, linking both central and peripheral metabolism, and illustrates the necessity for the "omics" data integration to uncover associations beyond gene co-expression. [ABSTRACT FROM AUTHOR]

The Myodural Bridge (MDB) is a physiological structure that is highly conserved in mammals and many of other tetrapods. It connects the suboccipital muscles to the cervical spinal dura mater (SDM) and transmits the tensile forces generated by the suboccipital muscles to the SDM. Consequently, the MDB has broader physiological potentials than just fixing the SDM. It has been proposed that MDB significantly contributes to the dynamics of cerebrospinal fluid (CSF) movements. Animal models of suboccipital muscle atrophy and hyperplasia were established utilizing local injection of BTX-A and ACE-031. In contrast, animal models with surgical severance of suboccipital muscles, and without any surgical operation were set as two types of negative control groups. CSF secretion and reabsorption rates were then measured for subsequent analysis. Our findings demonstrated a significant increase in CSF secretion rate in rats with the hyperplasia model, while there was a significant decrease in rats with the atrophy and severance groups. We observed an increase in CSF reabsorption rate in both the atrophy and hyperplasia groups, but no significant change was observed in the severance group. Additionally, our immunohistochemistry results revealed no significant change in the protein level of six selected choroid plexus-CSF-related proteins among all these groups. Therefore, it was indicated that alteration of MDB-transmitted tensile force resulted in changes of CSF secretion and reabsorption rates, suggesting the potential role that MDB may play during CSF circulation. This provides a unique research insight into CSF dynamics. [ABSTRACT FROM AUTHOR]

We aimed to investigate whether mitochondrial dysfunction in extracellular cerebrospinal fluid (CSF), which is associated with autophagy and mitophagy, might be involved in neurological outcomes in adult patients with hemorrhagic moyamoya disease (MMD) whose pathogenesis related to poor outcomes is not well-known. CSF samples were collected from 43 adult MMD patients and analyzed according to outcomes at 3 months. Fluorescence-activated cell sorter analysis (FACS) and the JC-1 red/green ratio were used to assess mitochondrial cells and intact mitochondrial membrane potential (MMP). We performed quantitative real-time polymerase chain reaction and Western blotting analyses of autophagy and mitophagy-related markers, including HIF1α, ATG5, pBECN1, BECN1, BAX, BNIP3L, DAPK1, and PINK1. Finally, FACS analysis with specific fluorescence-conjugated antibodies was performed to evaluate the potential cellular origin of CSF mitochondrial cells. Twenty-seven females (62.8%) with a mean age of 47.4 ± 9.7 years were included in the study. Among 43 patients with hemorrhagic MMD, 23 (53.5%) had poor outcomes. The difference in MMP was evident between the two groups (2.4 ± 0.2 in patients with poor outcome vs. 3.5 ± 0.4 in patients with good outcome; p = 0.02). A significantly higher expression (2–ΔCt) of HIF1α, ATG5, DAPK1 followed by BAX and BNIP3L mRNA and protein was also observed in poor-outcome patients compared to those with good outcomes. Higher percentage of vWF-positive mitochondria, suggesting endothelial cell origins, was observed in patients with good outcome compared with those with poor outcome (25.0 ± 1.4% in patients with good outcome vs. 17.5 ± 1.5% in those with poor outcome; p < 0.01). We observed the association between increased mitochondrial dysfunction concomitant with autophagy and mitophagy in CSF cells and neurological outcomes in adult patients with hemorrhagic MMD. Further prospective multicenter studies are needed to determine whether it has a diagnostic value for risk prediction. [ABSTRACT FROM AUTHOR]

Age-related cognitive decline is associated with dysfunctional lymphatic drainage of cerebrospinal fluid (CSF) through meningeal lymphatic vessels. In this study, intrathecal [64Cu]Cu-albumin positron emission tomography (PET) was applied in mice to evaluate lymphatic drainage of CSF and its variation with age. [64Cu]Cu-albumin PET was performed at multiple time points after intrathecal injection of [64Cu]Cu-albumin at an infusion rate of 700 nl/min in adult and aged mice (15–25 months old). CSF clearance and paravertebral lymph nodes were quantified after injection and during the stationary phase. Stationary phase of the next day followed the initial perturbed state by injection of 6 ul (1/7 of total CSF volume) and CSF clearance half-time from the subarachnoid space was 93.4 ± 19.7 and 123.3 ± 15.6 min in adult and aged mice (p = 0.01), respectively. While the % injected dose of CSF space were higher, the activity of the paravertebral lymph nodes were lower in the aged mice on the next day. [64Cu]Cu-albumin PET enabled us to quantify CSF-lymphatic drainage across all levels of brain spinal cords and to visualize and quantify lymph node activity due to CSF drainage. [64Cu]Cu-albumin PET revealed the age-related decrease of the lymphatic drainage of CSF due to this decreased drainage from the subarachnoid space, especially during the stationary phase, in aged mice. [ABSTRACT FROM AUTHOR]

The proteomic profile of extracellular vesicles (EVs) from cerebrospinal fluid (CSF) can reveal novel biomarkers for diseases of the brain. Here, we validate an ultrafiltration combined with size-exclusion chromatography (UF-SEC) method for isolation of EVs from canine CSF and probe the effect of starting volume on the EV proteomics profile. First, we performed a literature review of CSF EV articles to define the current state of art, discovering a need for basic characterisation of CSF EVs. Secondly, we isolated EVs from CSF by UF-SEC and characterised the SEC fractions by protein amount, particle count, transmission electron microscopy, and immunoblotting. Data are presented as mean ± standard deviation. Using proteomics, SEC fractions 3–5 were compared and enrichment of EV markers in fraction 3 was detected, whereas fractions 4–5 contained more apolipoproteins. Lastly, we compared starting volumes of pooled CSF (6 ml, 3 ml, 1 ml, and 0.5 ml) to evaluate the effect on the proteomic profile. Even with a 0.5 ml starting volume, 743 ± 77 or 345 ± 88 proteins were identified depending on whether 'matches between runs' was active in MaxQuant. The results confirm that UF-SEC effectively isolates CSF EVs and that EV proteomic analysis can be performed from 0.5 ml of canine CSF. [ABSTRACT FROM AUTHOR]

There is a growing literature investigating the effects of selenium on the central nervous system and cognitive function. However, little is known about the role of selenoprotein P, the main selenium transporter, which can also have adverse biological effects. We conducted a prospective cohort study of individuals aged 42–81 years who received a clinical diagnosis of mild cognitive impairment. Using sandwich ELISA methods, we measured full-length selenoprotein P concentrations in serum and cerebrospinal fluid to assess the relation with dementia incidence during a median follow-up of 47.3 months. We used Cox proportional hazards regression and restricted cubic splines to model such relation. Of the 54 participants, 35 developed dementia during follow-up (including 26 cases of Alzheimer's dementia). Selenoprotein P concentrations in serum and cerebrospinal fluid were highly correlated, and in spline regression analyses they each showed a positive non-linear association with dementia risk, particularly after excluding dementia cases diagnosed within 24 months of follow-up. We also observed differences in association according to the dementia subtypes considered. Risk ratios of dementia peaked at 2–6 at the highest levels of selenoprotein P, when compared to its median level, also depending on matrix, analytical methodology and dementia subtype. Findings of this study, the first to assess selenoprotein P levels in the central nervous system in vivo and the first to use a prospective study design to evaluate associations with dementia, suggest that higher circulating concentrations of selenoprotein P, both in serum and cerebrospinal fluid, predict progression of MCI to dementia. However, further confirmation of these findings is required, given the limited statistical precision of the associations and the potential for residual confounding. [ABSTRACT FROM AUTHOR]

The pathophysiology of degenerative cervical myelopathy (DCM) is characterized by chronic compression-induced damage to the spinal cord leading to secondary harm such as disruption of the blood spinal cord barrier (BSCB). It is therefore the purpose of this study to analyze BSCB disruption in pre- and postoperative DCM patients and to correlate those with the clinical status and postoperative outcome. This prospectively controlled cohort included 50 DCM patients (21 female; 29 male; mean age: 62.9 ± 11.2 years). As neurological healthy controls, 52 (17 female; 35 male; mean age 61.8 ± 17.3 years) patients with thoracic abdominal aortic aneurysm (TAAA) and indication for open surgery were included. All patients underwent a neurological examination and DCM-associated scores (Neck Disability Index, modified Japanese Orthopaedic Association Score) were assessed. To evaluate the BSCB status, blood and cerebrospinal fluid (CSF) samples (lumbar puncture or CSF drainage) were taken preoperatively and in 15 DCM patients postoperatively (4 female; 11 male; mean age: 64.7 ± 11.1 years). Regarding BSCB disruption, CSF and blood serum were examined for albumin, immunoglobulin (Ig) G, IgA and IgM. Quotients for CSF/serum were standardized and calculated according to Reiber diagnostic criteria. Significantly increased preoperative CSF/serum quotients were found in DCM patients as compared to control patients: AlbuminQ (p <.001), IgAQ (p <.001) and IgGQ (p <.001). IgMQ showed no significant difference (T = − 1.15, p =.255). After surgical decompression, neurological symptoms improved in DCM patients, as shown by a significantly higher postoperative mJOA compared to the preoperative score (p =.001). This neurological improvement was accompanied by a significant change in postoperative CSF/serum quotients for Albumin (p =.005) and IgG (p =.004) with a trend of a weak correlation between CSF markers and neurological recovery. This study further substantiates the previous findings, that a BSCB disruption in DCM patients is evident. Interestingly, surgical decompression appears to be accompanied by neurological improvement and a reduction of CSF/serum quotients, implying a BSCB recovery. We found a weak association between BSCB recovery and neurological improvement. A BSCB disruption might be a key pathomechanism in DCM patients, which could be relevant to treatment and clinical recovery. [ABSTRACT FROM AUTHOR]

Neurosarcoidosis presents a diagnostic challenge in clinical settings, as it has no pathognomonic symptoms or signs and a wide range of differential diagnoses. The aim of this report is to present the pathological features of our group of patients, obtained through a systematic diagnostic approach. This retrospective cohort study enrolled all adult patients primarily diagnosed with neurosarcoidosis at the neurology department of a tertiary center in Sweden over a period of 30 years, from 1990 to 2021. We identified 90 patients, 54 with possible neurosarcoidosis and 36 with probable neurosarcoidosis. CNS biopsy revealed an alternative diagnosis for 24 patients, who were then excluded. The collected data from medical records included demographic and clinical characteristics, systemic and/or neurological isolated involvement, various laboratory tests, including cerebrospinal fluid (CSF), serum analysis, imaging studies (MRI, FDG-PET/CT, and HRCT), nerve conduction studies, electromyography, and pathology reports of central nervous system (CNS), and extra-neural tissue biopsies. Sixty-six patients were included in our cohort. The median age at onset of symptoms was 49 years, with a similar sex distribution. Cranial neuropathies (38%), motor deficit (32%), headache (16%), and pituitary dysfunction (12%) were the most common presenting features. CSF studies were abnormal in 77% of the patients, who showed lymphocytosis (57%), elevated protein (44%), oligoclonal bands (40%), elevated ACE (28%), and raised T lymphocyte CD4+/CD8+ ratios (13%). Strikingly, MRI showed that 17% of the patients presented with isolated pituitary gland lesions. FDG-PET/CT was performed in 22 patients (33%) and confirmed systemic sarcoidosis in 11. Despite our extensive workup, the final classification for our patients only allowed for a definite diagnosis in 14 patients; the remainder were classified as probable (32) or possible (20) neurosarcoidosis. Since 2007, the employment of a structured laboratory and imaging approach and the increasing number of CNS biopsies have facilitated and improved the process of correct attribution in patients with presumptive neurosarcoidosis, especially in patients with isolated neurological lesions. We highlight a higher frequency of pituitary lesions due to neurosarcoidosis than has been classically described. A detailed laboratory diagnostic workup is included. [ABSTRACT FROM AUTHOR]

Providing an accurate prognosis for individual dementia patients remains a challenge since they greatly differ in rates of cognitive decline. In this study, we used machine learning techniques with the aim to identify cerebrospinal fluid (CSF) biomarkers that predict the rate of cognitive decline within dementia patients. First, longitudinal mini-mental state examination scores (MMSE) of 210 dementia patients were used to create fast and slow progression groups. Second, we trained random forest classifiers on CSF proteomic profiles and obtained a well-performing prediction model for the progression group (ROC–AUC = 0.82). As a third step, Shapley values and Gini feature importance measures were used to interpret the model performance and identify top biomarker candidates for predicting the rate of cognitive decline. Finally, we explored the potential for each of the 20 top candidates in internal sensitivity analyses. TNFRSF4 and TGF β -1 emerged as the top markers, being lower in fast-progressing patients compared to slow-progressing patients. Proteins of which a low concentration was associated with fast progression were enriched for cell signalling and immune response pathways. None of our top markers stood out as strong individual predictors of subsequent cognitive decline. This could be explained by small effect sizes per protein and biological heterogeneity among dementia patients. Taken together, this study presents a novel progression biomarker identification framework and protein leads for personalised prediction of cognitive decline in dementia. [ABSTRACT FROM AUTHOR]

Scheuermann's disease, also referred to as Scheuermann's kyphosis, is the second most frequent spine deformity occurring in humans after adolescent idiopathic scoliosis (AIS), both with an unclear etiology. Recent genetic studies in zebrafish unraveled new mechanisms linked to AIS, highlighting the role of the Reissner fiber, an acellular polymer bathing in the cerebrospinal fluid (CSF) in close proximity with ciliated cells and mechanosensory neurons lining the central canal of the spinal cord (CSF-cNs). However, while the Reissner fiber and ciliary beating have been linked to AIS-like phenotypes in zebrafish, the relevance of the sensory functions of CSF-cNs for human spine disorders remains unknown. Here, we show that the thoracic hyper-kyphosis of the spine previously reported in adult pkd2l1 mutant zebrafish, in which the mechanosensory function of CSF-cNs is likely defective, is restricted to the sagittal plane and is not associated with vertebral malformations. By applying orthopedic criteria to analyze the amplitude of the curvature at the apex of the kyphosis, the curve pattern, the sagittal balance and sex bias, we demonstrate that pkd2l1 knock-outs develop a phenotype reminiscent of Scheuermann's disease. Altogether our work consolidates the benefit of combining genetics and analysis of spine deformities in zebrafish to model idiopathic spine disorders in humans. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is caused by a cytosine adenine guanine-repeat expansion in the huntingtin gene. This results in the production of toxic mutant huntingtin protein (mHTT), which has an elongated polyglutamine (polyQ) stretch near the protein's N-terminal end. The pharmacological lowering of mHTT expression in the brain targets the underlying driver of HD and is one of the principal therapeutic strategies being pursued to slow or stop disease progression. This report describes the characterisation and validation of an assay designed to quantify mHTT in the cerebrospinal fluid of individuals with HD, for use in registrational clinical trials. The assay was optimised, and its performance was characterised with recombinant huntingtin protein (HTT) varying in overall and polyQ-repeat length. The assay was successfully validated by two independent laboratories in regulated bioanalytical environments and showed a steep signal increase as the polyQ stretch of recombinant HTTs pivoted from wild-type to mutant protein forms. Linear mixed effects modelling confirmed highly parallel concentration–response curves for HTTs, with only a minor impact of individual slopes of the concentration–response for different HTTs (typically < 5% of the overall slope). This implies an equivalent quantitative signal behaviour for HTTs with differing polyQ-repeat lengths. The reported method may be a reliable biomarker tool with relevance across the spectrum of HD mutations, which can facilitate the clinical development of HTT-lowering therapies in HD. [ABSTRACT FROM AUTHOR]

Research on the markers of immunoregulatory response in multiple sclerosis (MS) is still of great importance. The aim of our study was the evaluation of leptin, fibronectin, and UCHL1 concentrations as potential biomarkers of a relapsing–remitting type of MS (RRMS). Surface Plasmon Resonance Imaging (SPRI) biosensors were used for the evaluation of proteins concentrations in 100 RRMS patients and 46 healthy volunteers. Plasma leptin, fibronectin, and UCHL1 concentrations were significantly higher in RRMS patients compared to the control group (p < 0.001, respectively). UCHL1 concentration evaluation revealed the highest diagnostic sensitivity (100%) and negative predictive value (100%) in differentiating MS patients from healthy individuals. There was no significant difference in the UCHL1 concentrations depending on the patient's sex, the presence of relapse within the last 24 months, and the EDSS value (p > 0.05, respectively). In RRMS patients UCHL1 concentration positively correlated with fibronectin levels (r = 0.3928; p < 0.001). In the current cohort of patients plasma UCHL1 concentration was independent of the time of MS relapse and the severity of neurological symptoms. Thus current study may indicate that plasma UCHL1, besides leptin and fibronectin, also could be a promising high-sensitive potential biomarker of relapsing–remitting type of MS. However, these results should be validated with a larger group of patients, taking into account neuroimaging and cerebrospinal fluid analysis data, and by comparing them to patients with other neurological diseases as a control group. [ABSTRACT FROM AUTHOR]

To strengthen the understanding of the clinical features for CASPR2 neurological autoimmunity in children. A multicenter retrospective and prospective analysis of CASPR2 autoimmunity was conducted. Twenty-six patients were enrolled, including 25 with serum positivity and 3 with cerebrospinal fluid (CSF) positivity; 5 patients were co-positive with anti-NMDAR or anti-GABABR antibodies. Eleven patients (who manifested with refractory epilepsy, psychobehavioral abnormalities or germinoma) presented with low antibody titers, relatively normal MRI/EEG/CSF examinations, and poor response to immunotherapy and were thus considered false positive (42.3%). Fifteen patients were diagnosed with autoimmune encephalitis/ encephalopathy/ cerebellitis (including 1 whose condition was secondary to Japanese encephalitis). The most common symptoms included disorders of consciousness (10/15), fever (8/15), psychological symptoms/abnormal behaviors (8/15), sleep disorders (8/15), seizures (7/15), movement disorders (5/15), autonomic symptoms (5/15). Brain MRI revealed abnormalities in 10 patients (66.7%). Electroencephalography (EEG) recordings revealed a slow wave background in 13 patients (86.7%). Five patients showed elevated WBCs in CSF, and 4 patients showed elevated protein levels in the CSF. Thirteen patients received immunotherapy (rituximab was adopted in 2 cases) and recovered well. Two patients received symptomatic treatment, and the recovery was slow and accompanied by emotional abnormalities and developmental delay. Autoimmune encephalitis is the most common clinical phenotype; it can be secondary to Japanese encephalitis. Rituximab can be used in patients who respond poorly to conventional immunotherapy. The high false-positive rate of anti-CASPR2 in refractory epilepsy and the psychobehavioral abnormalities needs to be explored further. [ABSTRACT FROM AUTHOR]

Lumbar cerebrospinal fluid (CSF) parameters are widely studied and have wide clinical applications, but ventricular CSF has rarely been studied since it is relatively difficult to obtain. To determine whether there are differences between ventricular and lumbar CSF parameters and whether the differences have clinical significance, we retrospectively reviewed 77 patients with Cryptococcal meningitis who received a ventriculoperitoneal shunt. We analyzed the following parameters: white blood cell count, total protein concentration, CSF/blood glucose ratio, chloride ion concentration, and Cryptococcal count. All parameters between lumbar and ventricular CSF were remarkably different (all p < 0.001). White blood cell count, total protein level and Cryptococcal count were lower in ventricular CSF than in lumbar CSF, while CSF/blood glucose ratio and chloride ion concentration were higher. Compared to patients without ventriculomegaly, patients with ventriculomegaly had a significantly higher total protein concentration in ventricular CSF (p = 0.047). Compared to patients without surgical complications, patients with complications had a significantly lower CSF/blood glucose ratio in ventricular CSF (p = 0.032). The lumbar CSF parameters had no significant differences between these groups. The changes in lumbar CSF indices over time after shunt placement were also analyzed. After shunt placement, total protein concentration was transiently increased, white blood cell count, CSF/blood glucose ratio and chloride ion concentration were continued at the preoperative level until two months after shunting surgery. These findings suggest that the composition of ventricular CSF differs from that of lumbar CSF, and different CSF parameters have disparate rostro-caudal gradients in patients with Cryptococcal meningitis. Furthermore, ventricular and lumbar CSF parameters may have different clinical implications. Transient deterioration of lumbar CSF parameters after ventriculoperitoneal shunt placement may not be due to disease progression, but to change in CSF flow rate by CSF shunts. [ABSTRACT FROM AUTHOR]

The accurate assessment of cerebrospinal fluid opening pressure during spinal puncture provides important medical information in diagnosis, prognosis and therapy of several neurological conditions. However, purpose-specific spinal needle choice is debated. While atraumatic needles are associated with lower incidence of post-puncture headache and re-hospitalisation, some clinicians believe that they lack in accuracy of CSF opening pressure assessment. Our primary objective was to investigate different needle types on correctly assessing CSF opening pressure. We compared typical clinically utilised traumatic (0.9 mm outer diameter) and atraumatic (0.7 mm; 0.45 mm) spinal needles with regards to the assessment of the opening pressure in an experimental spinal puncture model testing experimental and cerebrospinal fluids in predefined pressures. Our goal was to measure the time until indicated pressure levels were correctly shown. Atraumatic needles of at least 0.7 mm diameter had a similar accuracy as traumatic needles without significant differences in time-to-equilibrium. These results were independent of protein and glucose concentration and the presence of haemoglobin. This study demonstrates that atraumatic needles can be used to accurately measure CSF opening pressure. This knowledge might guide clinicians in their choice of needle and help to reduce post-puncture headaches and re-hospitalisation. [ABSTRACT FROM AUTHOR]

We report here the identification and validation of prefoldin 5-alpha (PFDN5-α) for the first time as prognostic biomarker for prediction of central nervous system (CNS) leukemia of B cell acute lymphoblastic leukemia (B-ALL) origin. Since cerebrospinal fluid (CSF) cytology being the gold standard of diagnosis for CNS leukemia with poor sensitivity, mandatory prophylactic intrathecal chemotherapy is administered irrespective of patients develop CNS leukemia. Thus, using interactome studies, we identified PFDN5-α as a prognostic biomarker for predicting CNS leukemia by interacting lymphoblastic proteins and CSF from B-ALL patients using far-western clinical proteomics approach. Validation by both western and ELISA methods confirmed our results. For further clinical translation, we performed Receiver Operating Characteristic (ROC) curve analysis generated from CNS +ve (n = 25) and −ve (n = 40) CSF samples from B-ALL patients and identified PFDN5-α-CSF reactivity cut-off value as 0.456. Values below 0.456 indicate the patient is at risk of developing CNS leukemia and suggestive of having intrathecal chemotherapy. Further flow cytometry validation for CNS leukemia positivity revealed that with increasing blast cells, a decrease in PFDN5-α-CSF reactivity confirming ELISA based PFDN5α-CSF reactivity assay. Predicting CNS leukemia development risk by ELISA based PFDN5-α-CSF reactivity assay could have potential in the clinical management of CNS leukemia. [ABSTRACT FROM AUTHOR]

One-third of pneumococcal meningitis (PM) survivors suffer from neurological sequelae including learning disabilities and hearing loss due to excessive neuroinflammation. There is a lack of efficacious compounds for adjuvant therapy to control this long-term consequence of PM. One hallmark is the recruitment of leukocytes to the brain to combat the bacterial spread. However, this process induces excessive inflammation, causing neuronal injury. Maraviroc (MVC)—a CCR5 antagonist—was demonstrated to inhibit leukocyte recruitment and attenuate neuroinflammation in several inflammatory diseases. Here, we show that in vitro, MVC decreased nitric oxide production in astroglial cells upon pneumococcal stimulation. In vivo, infant Wistar rats were infected with 1 × 104 CFU/ml S. pneumoniae and randomized for treatment with ceftriaxone plus MVC (100 mg/kg) or ceftriaxone monotherapy. During the acute phase, neuroinflammation in the CSF was measured and histopathological analyses were performed to determine neuronal injury. Long-term neurofunctional outcome (learning/memory and hearing capacity) after PM was assessed. MVC treatment reduced hippocampal cell apoptosis but did not affect CSF neuroinflammation and the neurofunctional outcome after PM. We conclude that MVC treatment only exerted limited effect on the pathophysiology of PM and is, therefore, not sufficiently beneficial in this experimental paradigm of PM. [ABSTRACT FROM AUTHOR]

To examine the influence of movement on cerebrospinal fluid (CSF) dynamics, intracranial subdural pressure recordings were taken from sub-adult alligators (Alligator mississippiensis) locomoting on a treadmill. Pressure recordings documenting the cardiac, ventilatory, and barostatic influences on the CSF were in good agreement with previous studies. During locomotion the CSF exhibits sinusoidal patterns of pressure change that spanned a mean amplitude of 56 mm Hg, some 16 × the amplitude of the cardiac-linked pulsations. These sinusoidal CSF pulsations were closely linked to the locomotor kinematics, particularly the lateral oscillations of the alligator's head. Data recorded from the freely moving alligators suggest that fluid inertia, body cavity pressures, and likely other factors all influence the CSF pressure. The clear relationship between movement and CSF pressure described in this study suggests that the paucity of studies examining human CSF dynamics during movement should be addressed. [ABSTRACT FROM AUTHOR]

In this prospective single-arm study of 50 pediatric patients with acute lymphoblastic leukemia (ALL), we evaluated the clinical performance of a novel bioimpedance spinal needle system in 152 intrathecal treatment lumbar punctures (LP) of these patients. The system detects in real-time when the needle tip reaches the cerebrospinal fluid (CSF) in the spinal canal. The success was defined as getting a CSF sample and/or administering the intrathecal treatment with one needle insertion. Incidence of traumatic LP (TLP) was defined as ≥ 10 erythrocytes/µL of CSF. Post-procedural complications were monitored with a one-week diary and one-month register follow-up. The success of the first attempt was 79.5%, with the CSF detection sensitivity of 86.1%. The incidence of TLP was 17.3%. A successful first attempt was associated with a significantly lower incidence of TLP (10% vs 40%, p = 0.0015). During the week after the procedure, the incidence of post-dural puncture headache was 6%. During the follow-up, no major complications were observed. In conclusion, the novel bioimpedance spinal needle system achieved a high success rate and low incidence of TLP and other complications in pediatric patients with ALL in a real-world clinical setting, indicating clinical utility for this system in pediatric hemato-oncology. [ABSTRACT FROM AUTHOR]

The detection of intrathecal IgA synthesis (IAS) in multiple sclerosis (MS) could be underestimated. To assess it, we develop a highly sensitive assay based on isoelectric focusing (IEF). 151 MS patients and 53 controls with different neurological diseases were recruited. IgA concentration was analyzed using a newly developed in house ELISA. IgA oligoclonal bands to detect IAS were determined by IEF. Most individuals showed an IgA concentration within normal range in serum samples (90.69%) but 31.37% of individuals had a IgA concentration below the normal range in the cerebrospinal fluid (CSF). No significant differences were observed between MS and control groups, neither in CSF nor in serum. The new IEF was more sensitive than those previously described (0.01 mg/dl of IgA), and clearly identified patients with and without IAS, that was not related with IgA concentration. Using IEF, MS patients showed higher percentage of IAS-IEF (43.00%) than the control group (16.98) (p = 0.001). The incidence was especially higher in patients with clinically isolated syndrome (66.00%). The new IFE demonstrated a higher percentage of IAS in MS patients than assumed in the past. The presence of IAS-IEF in MS is higher than in other neurological diseases. [ABSTRACT FROM AUTHOR]

Infection in the central nervous system is a severe condition associated with high morbidity and mortality. Despite ample testing, the majority of encephalitis and meningitis cases remain undiagnosed. Metagenomic sequencing of cerebrospinal fluid has emerged as an unbiased approach to identify rare microbes and novel pathogens. However, several major hurdles remain, including establishment of individual limits of detection, removal of false positives and implementation of universal controls. Twenty-one cerebrospinal fluid samples, in which a known pathogen had been positively identified by available clinical techniques, were subjected to metagenomic DNA sequencing. Fourteen samples contained minute levels of Epstein-Barr virus. The detection threshold for each sample was calculated by using the total leukocyte content in the sample and environmental contaminants found in the bioinformatic classifiers. Virus sequences were detected in all ten samples, in which more than one read was expected according to the calculations. Conversely, no viral reads were detected in seven out of eight samples, in which less than one read was expected according to the calculations. False positive pathogens of computational or environmental origin were readily identified, by using a commonly available cell control. For bacteria, additional filters including a comparison between classifiers removed the remaining false positives and alleviated pathogen identification. Here we show a generalizable method for identification of pathogen species using DNA metagenomic sequencing. The choice of bioinformatic method mainly affected the efficiency of pathogen identification, but not the sensitivity of detection. Identification of pathogens requires multiple filtering steps including read distribution, sequence diversity and complementary verification of pathogen reads. [ABSTRACT FROM AUTHOR]

Anorexia Nervosa has been associated with white matter abnormalities implicating subcortical abnormal myelination. Extending these findings to intracortical myelin has been challenging but ultra-high field neuroimaging offers new methodological opportunities. To test the integrity of intracortical myelin in AN we used 7 T neuroimaging to acquire T1-weighted images optimized for intracortical myelin from seven females with AN (age range: 18–33) and 11 healthy females (age range: 23–32). Intracortical T1 values (inverse index of myelin concentration) were extracted from 148 cortical regions at ten depth-levels across the cortical ribbon. Across all cortical regions, these levels were averaged to generate estimates of total intracortical myelin concentration and were clustered using principal component analyses into two clusters; the outer cluster comprised T1 values across depth-levels ranging from the CSF boundary to the middle of the cortical regions and the inner cluster comprised T1 values across depth-levels ranging from the middle of the cortical regions to the gray/white matter boundary. Individuals with AN exhibited higher T1 values (i.e., decreased intracortical myelin concentration) in all three metrics. It remains to be established if these abnormalities result from undernutrition or specific lipid nutritional imbalances, or are trait markers; and whether they may contribute to neurobiological deficits seen in AN. [ABSTRACT FROM AUTHOR]

Neuroinflammation after surgery and its contribution to peri-operative neurocognitive disorders (PND) is not well understood. Studying the association between central and peripheral cytokines and neuroinflammation is a prelude to the development of treatments for PND. Here, we investigate the hypotheses that there is a greater cytokine response in cerebrospinal fluid (CSF) than plasma after orthopaedic surgery, and that plasma cytokine levels are directly related to CSF cytokine levels, indicating that plasma cytokine levels may have potential as biomarkers of neuroinflammation. Patients admitted with a fractured neck of femur were invited to participate in this study. Participants had a spinal catheter inserted just prior to induction of anaesthesia. Samples of blood and CSF were taken before, immediately after, and on the first day following emergency surgery. The catheter was then removed. Samples were analysed for the presence of ten cytokines by immunoassay. A spinal catheter was successfully inserted in 11 participants during the 18-month study period. Five plasma cytokines (IL-4, IL-6, IL-10, IL-12p70 and IL-13) rose significantly following surgery, whereas all ten CSF cytokines rose significantly (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IFN-γ and TNF-α) (adjusted-p < 0.05). Central (CSF) cytokine levels were consistently higher than their peripheral (plasma) counterparts after surgery, with some patients having a particularly marked neuroinflammatory response. The greatest increases occurred in IL-8 in CSF and IL-6 in plasma. There were significant, strong positive correlations between several of the measured cytokines in the CSF after surgery, but far fewer in plasma. There was no significant correlation between cytokine levels in the plasma and CSF at each of the three time points. To our knowledge, this is the first study to analyse paired samples of plasma and CSF for cytokine levels before and after emergency orthopaedic surgery. This study demonstrates that following surgery for a fractured neck of femur, there is a far greater rise in cytokines in the CSF compared to plasma. The lack of correlation between peripheral and central cytokines suggests measurement of peripheral cytokines are not necessarily related to which patients may have a large neuroinflammatory response. [ABSTRACT FROM AUTHOR]

Intranasal insulin (INI) has shown promise as a treatment for Alzheimer's disease (AD) in pilot clinical trials. In a recent phase 2 trial, participants with mild cognitive impairment (MCI) or AD who were treated with INI with one of two delivery devices showed improved cerebral spinal fluid (CSF) biomarker profiles and slower symptom progression compared with placebo. In the cohort which showed benefit, we measured changes in CSF markers of inflammation, immune function and vascular integrity and assessed their relationship with changes in cognition, brain volume, and CSF amyloid and tau concentrations. The insulin-treated group had increased CSF interferon-γ (p = 0.032) and eotaxin (p = 0.049), and reduced interleukin-6 (p = 0.048) over the 12 month trial compared to placebo. Trends were observed for increased CSF macrophage-derived chemokine for the placebo group (p = 0.083), and increased interleukin-2 in the insulin-treated group (p = 0.093). Insulin-treated and placebo groups showed strikingly different patterns of associations between changes in CSF immune/inflammatory/vascular markers and changes in cognition, brain volume, and amyloid and tau concentrations. In summary, INI treatment altered the typical progression of markers of inflammation and immune function seen in AD, suggesting that INI may promote a compensatory immune response associated with therapeutic benefit. [ABSTRACT FROM AUTHOR]

Delayed diagnosis and misdiagnosis are frequent in people with amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease (MND). Neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) are elevated in ALS patients. We retrospectively quantified cerebrospinal fluid (CSF) NFL, CSF pNFH and plasma NFL in stored samples that were collected at the diagnostic work-up of ALS patients (n = 234), ALS mimics (n = 44) and controls (n = 9). We assessed the diagnostic performance, prognostication value and relationship to the site of onset and genotype. CSF NFL, CSF pNFH and plasma NFL levels were significantly increased in ALS patients compared to patients with neuropathies & myelopathies, patients with myopathies and controls. Furthermore, CSF pNFH and plasma NFL levels were significantly higher in ALS patients than in patients with other MNDs. Bulbar onset ALS patients had significantly higher plasma NFL levels than spinal onset ALS patients. ALS patients with C9orf72HRE mutations had significantly higher plasma NFL levels than patients with SOD1 mutations. Survival was negatively correlated with all three biomarkers. Receiver operating characteristics showed the highest area under the curve for CSF pNFH for differentiating ALS from ALS mimics and for plasma NFL for estimating ALS short and long survival. All three biomarkers have diagnostic value in differentiating ALS from clinically relevant ALS mimics. Plasma NFL levels can be used to differentiate between clinical and genetic ALS subgroups. [ABSTRACT FROM AUTHOR]

To explore markers for synaptic function and Alzheimer disease (AD) pathology in late life depression (LLD), predementia AD and normal controls (NC). A cross-sectional study to compare cerebrospinal fluid (CSF) levels of neurogranin (Ng), Beta-site amyloid-precursor-protein cleaving enzyme1 (BACE1), Ng/BACE1 ratio and Amyloid-β 42/40 ratio, phosphorylated-tau and total-tau in LLD with (LLD AD) or without (LLD NoAD) AD pathology, predementia AD and normal controls (NC). We included 145 participants (NC = 41; predementia AD = 66 and LLD = 38). LLD comprised LLD AD (n = 16), LLD NoAD (n = 19), LLD with non-AD typical changes (n = 3, excluded). LLD AD (pADJ < 0.05) and predementia AD (pADJ < 0.0001) showed significantly higher Ng than NC. BACE1 and Ng/BACE1 ratio were altered similarly. Compared to LLD NoAD, LLD AD showed significantly higher Ng (pADJ < 0.001), BACE1 (pADJ < 0.05) and Ng/BACE1 ratio (pADJ < 0.01). All groups had significantly lower Aβ 42/40 ratio than NC (predementia AD and LLD AD, p < 0.0001; LLD NoAD, p < 0.05). Both LLD groups performed similarly on tests of memory and executive function, but significantly poorer than NC. Synaptic function in LLD depended on AD pathology. LLD showed an association to Amyloid dysmetabolism. The LLD groups performed poorer cognitively than NC. LLD AD may be conceptualized as "predementia AD with depression". [ABSTRACT FROM AUTHOR]

Chronic diseases affecting the central nervous system (CNS) like Alzheimer's or Parkinson's disease typically develop with advanced chronological age. Yet, aging at the metabolic level has been explored only sporadically in humans using biofluids in close proximity to the CNS such as the cerebrospinal fluid (CSF). We have used an untargeted liquid chromatography high-resolution mass spectrometry (LC-HRMS) based metabolomics approach to measure the levels of metabolites in the CSF of non-neurological control subjects in the age of 20 up to 74. Using a random forest-based feature selection strategy, we extracted 69 features that were strongly related to age (page < 0.001, rage = 0.762, R2Boruta age = 0.764). Combining an in-house library of known substances with in silico chemical classification and functional semantic annotation we successfully assigned putative annotations to 59 out of the 69 CSF metabolites. We found alterations in metabolites related to the Cytochrome P450 system, perturbations in the tryptophan and kynurenine pathways, metabolites associated with cellular energy (NAD+, ADP), mitochondrial and ribosomal metabolisms, neurological dysfunction, and an increase of adverse microbial metabolites. Taken together our results point at a key role for metabolites found in CSF related to the Cytochrome P450 system as most often associated with metabolic aging. [ABSTRACT FROM AUTHOR]

The frequency of bacterial factors causing central nervous system infections has decreased as a result of the development of our national immunization program. In this study, it is aimed to obtain the data of our local surveillance by defining the viral etiology in cases diagnosed with meningoencephalitis for 1 year. Previously healhty 186 children, who applied with findings suggesting viral meningoencephalitis to 8 different tertiary health centers between August 2018 and August 2019, in Istanbul, were included. The cerebrospinal fluid (CSF) sample was evaluated by polymerase chain reaction. The M:F ratio was 1.24 in the patient group, whose age ranged from 1 to 216 months (mean 40.2 ± 48.7). Viral factor was detected in 26.8%. Enterovirus was the most common agent (24%) and followed by Adenovirus (22%) and HHV type 6 (22%). In the rest of the samples revealed HHV type 7 (10%), EBV (6%), CMV (6%), HSV type 1 (6%), Parvovirus (4%) and VZV (2%). The most common symptoms were fever (79%) and convulsions (45.7%). Antibiotherapy and antiviral therapy was started 48.6% and 4% respectively. Mortality and sequela rate resulted 0.53% and 3.7%, respectively. This highlights the importance of monitoring trends in encephalitis in Turkey with aview to improving pathogen diagnosis for encephalitis and rapidly identifying novel emerging encephalitis-causing pathogens that demand public health action especially in national immunisation programme. [ABSTRACT FROM AUTHOR]

Unlike variant Creutzfeldt–Jakob disease prions, sporadic Creutzfeldt–Jakob disease prions have been shown to be difficult to amplify in vitro by protein misfolding cyclic amplification (PMCA). We assessed PMCA of pathological prion protein (PrPTSE) from 14 human sCJD brain samples in 3 substrates: 2 from transgenic mice expressing human prion protein (PrP) with either methionine (M) or valine (V) at position 129, and 1 from bank voles. Brain extracts representing the 5 major clinicopathological sCJD subtypes (MM1/MV1, MM2, MV2, VV1, and VV2) all triggered seeded PrPTSE amplification during serial PMCA with strong seed- and substrate-dependence. Remarkably, bank vole PrP substrate allowed the propagation of all sCJD subtypes with preservation of the initial molecular PrPTSE type. In contrast, PMCA in human PrP substrates was accompanied by a PrPTSE molecular shift during heterologous (M/V129) PMCA reactions, with increased permissiveness of V129 PrP substrate to in vitro sCJD prion amplification compared to M129 PrP substrate. Combining PMCA amplification sensitivities with PrPTSE electrophoretic profiles obtained in the different substrates confirmed the classification of 4 distinct major sCJD prion strains (M1, M2, V1, and V2). Finally, the level of sensitivity required to detect VV2 sCJD prions in cerebrospinal fluid was achieved. [ABSTRACT FROM AUTHOR]

Brain tumors are the most common solid tumors in childhood. There is the need for biomarkers of residual disease, therapy response and recurrence. Cerebrospinal fluid (CSF) is a source of brain tumor biomarkers. We analyzed the proteome of waste CSF from extraventricular drainage (EVD) from 29 children bearing different brain tumors and 17 controls needing EVD insertion for unrelated causes. 1598 and 1526 proteins were identified by liquid chromatography-coupled tandem mass spectrometry proteomics in CSF control and brain tumor patients, respectively, 263 and 191 proteins being exclusive of either condition. Bioinformatic analysis revealed promising protein biomarkers for the discrimination between control and tumor (TATA-binding protein-associated factor 15 and S100 protein B). Moreover, Thymosin beta-4 (TMSB4X) and CD109, and 14.3.3 and HSP90 alpha could discriminate among other brain tumors and low-grade gliomas plus glyoneuronal tumors/pilocytic astrocytoma, or embryonal tumors/medulloblastoma. Biomarkers were validated by ELISA assay. Our method was able to distinguish among brain tumor vs non-tumor/hemorrhagic conditions (controls) and to differentiate two large classes of brain tumors. Further prospective studies may assess whether the biomarkers proposed by our discovery approach can be identified in other bodily fluids, therefore less invasively, and are useful to guide therapy and predict recurrences. [ABSTRACT FROM AUTHOR]

Biomarkers sensitive to prodromal or early pathophysiological changes in Alzheimer's disease (AD) symptoms could improve disease detection and enable timely interventions. Changes in brain hemodynamics may be associated with the main clinical AD symptoms. To test this possibility, we measured the variability of blood oxygen level-dependent (BOLD) signal in individuals from three independent datasets (totaling 80 AD patients and 90 controls). We detected a replicable increase in brain BOLD signal variability in the AD populations, which constituted a robust biomarker for clearly differentiating AD cases from controls. Fast BOLD scans showed that the elevated BOLD signal variability in AD arises mainly from cardiovascular brain pulsations. Manifesting in abnormal cerebral perfusion and cerebrospinal fluid convection, present observation presents a mechanism explaining earlier observations of impaired glymphatic clearance associated with AD in humans. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Quantifying the relationship between spreading depolarization and perivascular cerebrospinal fluid flow" published in Scientific Reports. The correction addresses an error in Reference 8 of the original article, providing the correct reference information. The correction was made by Saikat Mukherjee, Mahsa Mirzaee, and Jeffrey Tithof. [Extracted from the article]

Correction to: I Scientific Reports i https://doi.org/10.1038/s41598-021-99794-9, published online 13 October 2021 The original version of this Article omitted an affiliation for Nikias Siafarikas. The original article can be found online at https://doi.org/10.1038/s41598-021-99794-9. [Extracted from the article]

Amyloid-β (Aβ) is one of the few neuropathological biomarkers associated with transporters of the blood-brain barrier (BBB). Despite the well-characterized clinical indication of decreasing Aβ levels in the cerebrospinal fluid (CSF) during the development of Alzheimer's disease (AD), the link between the alternation of Aβ level in the blood and the progress of the disorder is still controversial. Here, we report a direct correlation of Aβ(1-42) levels between CSF and plasma in AD mouse model. We injected monomeric Aβ(1-42) directly into the intracerebroventricular (ICV) region of normal adult mouse brains to induce AD-like phenotypes. Using sandwich enzyme-linked immunosorbent assays, we observed proportional elevation of Aβ(1-42) levels in both CSF and plasma in a dose-dependent manner. Our findings that plasma Aβ(1-42) reflects the condition of CSF Aβ(1-42) warrant further investigation as a biomarker for the blood diagnosis of AD. [ABSTRACT FROM AUTHOR]