Cerebrospinal Fluid Levels Research Articles

Simultaneous post-neurosurgical ventriculitis and bacteraemia by two different strains of KPC-producing K. pneumoniae successfully treated with meropenem/vaborbactam and high dose of fosfomycin

ObjectiveA case of post-neurosurgical ventriculitis caused by a KPC-producing Klebsiella pneumoniae (KPC-Kp) with a ceftazidime/avibactam-resistant, meropenem-susceptible phenotype is reported. Methods and resultsThe patient had a concomitant bloodstream infection with a wild-type KPC-Kp with a ceftazidime/avibactam-susceptible, meropenem-resistant phenotype. Prolonged treatment with intravenous fosfomycin and meropenem/vaborbactam achieved clinical success.Therapeutic drug monitoring performed during the first days of treatment showed for the first time that vaborbactam efficiently penetrates cerebrospinal fluid. In contrast, meropenem was undetectable in cerebrospinal fluid at each sampling, suggesting that additional doses of meropenem may be required to appropriately prescribe meropenem/vaborbactam for central nervous system infections. Plasma and cerebrospinal fluid levels of fosfomycin were adequate, confirming the potential of this agent possibly even in the fight against multidrug-resistant organisms. ConclusionsThis case highlights the need for therapeutic drug monitoring as a crucial tool for optimizing treatment in complicated cases where the pharmacokinetic behaviour of antibiotics is difficult to predict.

Neurofilament Light Chain Concentration in Cerebrospinal Fluid in Children with Acute Nontraumatic Neurological Disorders.

(1) Introduction: This pilot study aimed to analyze neurofilament light chain levels in cerebrospinal fluid (cNfL) in a cohort of children with different acute nontraumatic neurological conditions. (2) Methods: This prospective observational cohort study consisted of 35 children aged 3 months to 17 years and was performed from November 2017 to December 2019. Patients' clinical data were reviewed, and patients were assigned to the following groups: n = 10 (28.6%) meningitis, 5 (14.3%) Bell's palsy, 7 (20.0%) febrile non-CNS infection, 3 (8.6%) complex febrile seizure, 4 (11.4%) idiopathic intracranial hypertension, and 6 (17.1%) others. cNfL levels were measured using a sensitive single-molecule array assay. (3) Results: The cNfL levels [median (range)] in children with meningitis were 120.5 pg/mL (58.1-205.4), in Bell's palsy 88.6 pg/mL (48.8-144.5), in febrile non-CNS infection 103.9 pg/mL (60.1-210.8), in complex febrile seizure 56 pg/mL (53.2-58.3), and in idiopathic intracranial hypertension 97.1 pg/mL (60.1-124.6). Within the meningitis group, children with Lyme neuroborreliosis (LNB) had significantly higher cNfL concentrations (median 147.9 pg/mL; range 87.8-205.4 pg/mL) than children with enterovirus meningitis (72.5 pg/mL; 58.1-95.6 pg/mL; p = 0.048) and non-significantly higher cNfL levels when compared to Bell's palsy (88.6 pg/mL; 48.8-144.5 pg/mL; p = 0.082). There was no correlation between cNfL levels and age. (4) Conclusions: Although the number of patients in this pilot study cohort is limited, higher cNfL levels in children with LNB compared to those with viral meningitis (significant) and Bell's palsy (trend) may indicate the potential of cNfL as a biomarker in the differential diagnosis of pediatric meningitis and facial palsy.

Kynurenines Dynamics in the Periphery and Central Nervous System Steers Behavioral Deficits in Rats under Hypobaric Hypoxia.

People travel to high-altitude regions as tourists, workers, and military personnel on duty. Despite the consistent 21% oxygen content in the atmosphere, ascending to higher altitudes results in a decrease in the partial pressure of oxygen, inducing a state known as hypobaric hypoxia (HH). HH is an environmental stress that is responsible for neuroinflammation and behavioral deficits (anxiety, depression, mood disturbance, etc.), but little is known about its metabolic pathways. The kynurenine pathway (KP) is a promising candidate to uncover the mysteries of HH stress, as it is an important regulator of the immune system and is associated with behavioral deficits. To investigate the role of KP under HH, the levels of KP metabolites in the serum, cerebrospinal fluid (CSF), and brain tissue (prefrontal cortex-PFC, neocortex, and hippocampus) of male Sprague-Dawley rats exposed to HH at 7620 m for 1, 3, and 7 days were estimated utilizing high-performance liquid chromatography (HPLC). The behavioral analogs for anxiety-like and depression-like behavior were assessed using the open field test and forced swim test, respectively. Upon HH exposure, crosstalk between the periphery and central nervous system and KP metabolite region-dependent differential expression in the brain were observed. KP metabolites showed a positive correlation with behavioral parameters. The results of our study are indicative that KP can be proposed as the etiology of behavioral deficits, and KP metabolite levels in serum or CSF can be used as plausible markers for anxiety-like and depression-like behaviors under HH stress with a scope of targeted therapeutic interventions.

Lumbar puncture increases Alzheimer’s disease biomarker levels in cerebrospinal fluid of rhesus monkeys

Cerebrospinal fluid (CSF) samples are commonly collected via lumbar puncture (LP) in both clinical and research settings for measurement of biomarkers of Alzheimer's disease (AD). To determine the effects of LP on CSF AD biomarkers, we collected CSF samples at seven different time points after an LP in rhesus monkeys. We find that amyloid-beta (Aβ) and Tau levels increased significantly on day 1, peaked on day 3, and returned to baseline on day 10 after LP. The NFL levels increased significantly on day 5, peaked on day 10, and returned to baseline after day 30. The increased AD biomarker levels were mainly due to CSF outflow and deep intrathecal invasion during LP. Therefore, if LPs are repeated within a short period of time, prior LP can affect Aβ and Tau levels within 10days and NFL levels within 30days, which may lead to clinical misdiagnosis or incorrect scientific conclusions.

The Associations of Phosphorylated Tau 181 and Tau 231 Levels in Plasma and Cerebrospinal Fluid with Cognitive Function in Alzheimer's Disease: A Systematic Review and Meta-Analysis.

Cerebrospinal fluid (CSF) or blood biomarkers like phosphorylated tau proteins (p-tau) are used to detect Alzheimer's disease (AD) early. Increasing studies on cognitive function and blood or CSF p-tau levels are controversial. Our study examined the potential of p-tau as a biomarker of cognitive status in normal control (NC), mild cognitive impairment (MCI), and AD patients. We searched PubMed, Cochrane, Embase, and Web of Science for relevant material through 12 January 2023. 5,017 participants from 20 studies-1,033 AD, 2,077 MCI, and 1,907 NC-were evaluated. Quantitative analysis provided continuous outcomes as SMDs with 95% CIs. Begg tested publication bias. MCI patients had lower CSF p-tau181 levels than AD patients (SMD =-0.60, 95% CI (-0.85, -0.36)) but higher than healthy controls (SMD = 0.67). AD/MCI patients had greater plasma p-tau181 levels than healthy people (SMD =-0.73, 95% CI (-1.04, -0.43)). MCI patients had significantly lower p-tau231 levels than AD patients in plasma and CSF (SMD =-0.90, 95% CI (-0.82, -0.45)). MCI patients showed greater CSF and plasma p-tau231 than healthy controls (SMD = 1.34, 95% CI (0.89, 1.79) and 0.43, (0.23, 0.64)). Plasma p-tau181/231 levels also distinguished the three categories. MCI patients had higher levels than healthy people, while AD patients had higher levels than MCI patients. CSF p-tau181 and p-tau231 biomarkers distinguished AD, MCI, and healthy populations. Plasma-based p-tau181 and p-tau231 biomarkers for AD and MCI need further study.

Blood levels of glial fibrillary acidic protein for predicting clinical progression to Alzheimer’s disease in adults without dementia: a systematic review and meta-analysis protocol

BackgroundThere is urgent clinical need to identify reliable prognostic biomarkers that predict the progression of dementia symptoms in individuals with early-phase Alzheimer’s disease (AD) especially given the research on and predicted applications of amyloid-beta (Aβ)-directed immunotherapies to remove Aβ from the brain. Cross-sectional studies have reported higher levels of cerebrospinal fluid and blood glial fibrillary acidic protein (GFAP) in individuals with AD-associated dementia than in cognitively unimpaired individuals. Further, recent longitudinal studies have assessed the prognostic potential of baseline blood GFAP levels as a predictor of future cognitive decline in cognitively unimpaired individuals and in those with mild cognitive impairment (MCI) due to AD. In this systematic review and meta-analysis, we propose analyzing longitudinal studies on blood GFAP levels to predict future cognitive decline.MethodsThis study will include prospective and retrospective cohort studies that assessed blood GFAP levels as a prognostic factor and any prediction models that incorporated blood GFAP levels in cognitively unimpaired individuals or those with MCI. The primary outcome will be conversion to MCI or AD in cognitively unimpaired individuals or conversion to AD in individuals with MCI. Articles from PubMed and Embase will be extracted up to December 31, 2023, without language restrictions. An independent dual screening of abstracts and potentially eligible full-text reports will be conducted. Data will be dual-extracted using the CHeck list for critical appraisal, data extraction for systematic Reviews of prediction Modeling Studies (CHARMS)-prognostic factor, and CHARMS checklists, and we will dual-rate the risk of bias and applicability using the Quality In Prognosis Studies and Prediction Study Risk-of-Bias Assessment tools. We will qualitatively synthesize the study data, participants, index biomarkers, predictive model characteristics, and clinical outcomes. If appropriate, random-effects meta-analyses will be performed to obtain summary estimates. Finally, we will assess the body of evidence using the Grading of Recommendation, Assessment, Development, and Evaluation Approach.DiscussionThis systematic review and meta-analysis will comprehensively evaluate and synthesize existing evidence on blood GFAP levels for prognosticating presymptomatic individuals and those with MCI to help advance risk-stratified treatment strategies for early-phase AD.Trial registrationPROSPERO CRD42023481200.

Progranulin and neuropathological features of Alzheimer’s disease: longitudinal study

BackgroundProgranulin is an anti-inflammatory protein that plays an essential role in the synapse function and the maintenance of neurons in the central nervous system (CNS). It has been shown that the CSF level of progranulin increases in Alzheimer’s disease (AD) patients and is associated with the deposition of amyloid-beta (Aβ) and tau in the brain tissue. In this study, we aimed to assess the longitudinal changes in cerebrospinal fluid (CSF) progranulin levels during different pathophysiological stages of AD and investigate associated AD pathologic features.MethodsWe obtained the CSF and neuroimaging data of 1001 subjects from the ADNI database. The participants were classified into four groups based on the A/T/N framework: A + /TN + , A + /TN−, A−/TN + , and A−/TN−.ResultsBased on our analysis there was a significant difference in CSF progranulin (P = 0.001) between ATN groups. Further ANOVA analysis revealed that there was no significant difference in the rate of change of CSF-progranulin ATN groups. We found that the rate of change of CSF progranulin was associated with baseline Aβ-PET only in the A−/TN + group. A significant association was found between the rate of change of CSF progranulin and the Aβ-PET rate of change only in A−/TN + ConclusionOur findings revealed that an increase in CSF progranulin over time is associated with faster formation of Aβ plaques in patients with only tau pathology based on the A/T/N classification (suspected non-Alzheimer’s pathology). Together, our findings showed that the role of progranulin-related microglial activity on AD pathology can be stage-dependent, complicated, and more prominent in non-AD pathologic changes. Thus, there is a need for further studies to consider progranulin-based therapies for AD treatment.

Associations between multidomain modifiable dementia risk factors with AD biomarkers and cognition in middle-aged and older adults

This study aimed to determine associations between modifiable dementia risk factors (MDRF), across domains mood symptomatology, lifestyle behaviors, cardiovascular conditions, cognitive/social engagement, sleep disorders/symptomatology, with cognition, beta-amyloid (Aβ) and tau, and brain volume. Middle-aged/older adults (n=82) enrolled in a sub-study of the Healthy Brain Project completed self-report questionnaires and a neuropsychological battery. Cerebrospinal fluid levels of Aβ 1–42, total tau (t-tau), and phosphorylated tau (p-tau181) (Roche Elecsys), and MRI markers of hippocampal volume and total brain volume were obtained. Participants were classified as no/single domain risk (≤1 domains) or multidomain risk (≥2 domains). Compared to the no/single domain risk group, the multidomain risk group performed worse on the Preclinical Alzheimer’s Cognitive Composite (d=0.63, p=.005), and Executive Function (d=0.50, p=.016), and had increased p-tau181 (d=0.47, p=.042) and t-tau (d=0.54, p=.021). In middle-aged/older adults, multidomain MDRFs were related to increases in tau and worse cognition, but not Aβ or brain volume. Findings suggest that increases in AD biomarkers are apparent in midlife, particularly for individuals with greater burden, or variety of MDRFs.

Associations of Multimorbidity with Cerebrospinal Fluid Biomarkers for Neurodegenerative Disorders in Early Parkinson's Disease: A Crosssectional and Longitudinal Study.

The study aims to determine whether multimorbidity status is associated with cerebrospinal fluid (CSF) biomarkers for neurodegenerative disorders. A total of 827 patients were enrolled from the Parkinson's Progression Markers Initiative (PPMI) database, including 638 patients with early-stage Parkinson's disease (PD) and 189 healthy controls (HCs). Multimorbidity status was evaluated based on the count of long-term conditions (LTCs) and the multimorbidity pattern. Using linear regression models, cross-sectional and longitudinal analyses were conducted to assess the associations of multimorbidity status with CSF biomarkers for neurodegenerative disorders, including α-synuclein (αSyn), amyloid-β42 (Aβ42), total tau (t-tau), phosphorylated tau (p-tau), glial fibrillary acidic protein (GFAP), and neurofilament light chain protein (NfL). At baseline, the CSF t-tau (p = 0.010), p-tau (p = 0.034), and NfL (p = 0.049) levels showed significant differences across the three categories of LTC counts. In the longitudinal analysis, the presence of LTCs was associated with lower Aβ42 (β < -0.001, p = 0.020), and higher t-tau (β = 0.007, p = 0.026), GFAP (β = 0.013, p = 0.022) and NfL (β = 0.020, p = 0.012); Participants with tumor/musculoskeletal/mental disorders showed higher CSF levels of t-tau (β = 0.016, p = 0.011) and p-tau (β = 0.032, p = 0.044) than those without multimorbidity. Multimorbidity, especially severe multimorbidity and the pattern of mental/musculoskeletal/ tumor disorders, was associated with CSF biomarkers for neurodegenerative disorders in early-stage PD patients, suggesting that multimorbidity might play a crucial role in aggravating neuronal damage in neurodegenerative diseases.

Glypican-4 serum levels are associated with cognitive dysfunction and vascular risk factors in Parkinson’s disease

Glypicans are biomarkers for various pathologies, including cardiovascular disease, cancer and diabetes. Increasing evidence suggests that glypicans also play a role in the context of neurodegenerative disorders. Initially described as supporting functionality of synapses via glutamate receptors during CNS development, Glypican 4 (GPC-4) also plays a role in the context of dementia via tau hyperphosphorylation in Alzheimer’s disease, which is also a co-pathology in Parkinson’s disease dementia. However, clinical evidence of circulating GPC-4 in Parkinson’s disease (PD) is missing so far. We therefore investigated GPC-4 in biofluids of PD patients. We analyzed GPC-4 levels in cerebrospinal fluid (CSF, n = 140), serum (n = 80), and tear fluid samples (n = 70) of PD patients and control subjects in a similar age range by ELISA (serum, CSF) and western blot (tear fluid). Expression of circulating GPC-4 was confirmed in all three biofluids, with highest levels in serum. Interestingly, GPC-4 levels were age-dependent, and multiple regression analysis revealed a significant association between GPC-4 serum levels and MoCA score, suggesting an involvement of GPC-4 in PD-associated cognitive decline. Furthermore, stratification of PD patients for vascular risk factors revealed a significant increase of GPC-4 serum levels in PD patients with vascular risk factors. Our results suggest GPC-4 as a clinical biomarker for vascular risk stratification in order to identify PD patients with increased risk of developing dementia.

Repetitive head injuries in German American football players do not change blood-based biomarker candidates for CTE during a single season

BackgroundRepetitive traumatic brain injuries in American football players (AFPs) can lead to the neurodegenerative disease chronic traumatic encephalopathy (CTE). Clinical symptoms of CTE range from mood and behavioral changes to cognitive impairment, depression, and suicidality. So far, CTE cannot be diagnosed in vivo and thus specific diagnostic parameters for CTE need to be found, to observe and treat exposed athletes as early as possible. Promising blood-based biomarkers for CTE include total tau (tTau), hyperphosphorylated tau (pTau), neurofilament light protein (NF-L), glial fibrillary acidic protein (GFAP), amyloid-β40 (Aβ40), amyloid-β42 (Aβ42) and calcium-binding protein B (S100-B). Previous studies have found elevated levels of these biomarkers in subjects exposed to TBIs, whereas cerebrospinal fluid (CSF) levels of Aβ40 and Aβ42 were decreased in CTE subjects. Here, we investigated whether young AFPs already exhibit changes of these biomarker candidates during the course of a single active season.MethodsBlood samples were drawn from n = 18 American Football Players before and after a full season and n = 18 male age-matched control subjects. The plasma titers of tTau, pTau, NF-L, GFAP, Aβ40, Aβ42 and S100-B were determined. Additionally, Apathy, Depression, and Health status as well as the concussion history and medical care were assessed and analyzed for correlations.ResultsHere we show, that the selected biomarker candidates for CTE do not change significantly during the seven-month period of a single active season of American Football in blood samples of AFPs compared to healthy controls. But interestingly, they exhibit generally elevated pTau titers. Furthermore, we found correlations of depression, quality-of-life, career length, training participation and training continuation with headache after concussion with various titers.ConclusionOur data indicates, that changes of CTE marker candidates either occur slowly over several active seasons of American Football or are exclusively found in CSF. Nevertheless, our results underline the importance of a long-term assessment of these biomarker candidates, which might be possible through repeated blood biomarker monitoring in exposed athletes in the future.

Association of reduced cerebrospinal fluid NPTX2 levels with postoperative delirium in patients undergoing knee/hip replacement: a prospective cohort study

BackgroundPostoperative delirium (POD) is a common complication with poor prognosis in the elderly, but its mechanism has not been fully elucidated. There is evidence that the changes in synaptic activity in the brain are closely related to the occurrence of POD. And neuronal pentraxin 2 (NPTX2) can regulate synaptic activity in vivo.AimsThis study aims to explore whether decreased NPTX2 levels affects POD and whether the cerebrospinal fluid (CSF) biomarkers of POD mediate this association.MethodsIn this prospective cohort study, we interviewed patients with knee/hip replacement 1 day before surgery to collect patient information and assess their cognitive function. CSF was extracted for measuring the CSF levels of NPTX2 and other POD biomarkers on the day of surgery. And postoperative follow-up visits were performed 1–7 days after surgery.ResultsFinally, 560 patients were included in the study. The patients were divided into POD group and NPOD (non-POD) group. The POD group had a median age of 80 years, a female proportion of 45%, a median BMI of 24.1 kg/m2, and a median years of education of 9 years. The Mann–Whitney U test showed that CSF NPTX2 levels were significantly lower in POD group, compared with the NPOD group (P < 0.05). Univariate binary logistic regression analysis showed that reduced CSF levels of NPTX2 protected against POD (crude OR = 0.994, 95% CI 0.993–0.995, P < 0.001). The receiver-operating characteristic (ROC) curve indicated that CSF NPTX2 level had high predictive value for POD. Mediation analyses showed that CSF T-tau (mediating proportion = 21%) and P-tau (mediating proportion = 29%) had significant mediating effects on the association between CSF NPTX2 and POD.ConclusionCSF NPTX2 levels were associated with the occurrence of POD. Low CSF NPTX2 levels may be an independent protective factor for POD. CSF T-tau and P-tau could mediate the association between CSF NPTX2 and POD occurrence.Clinical trial registrationThe trial registration number (TRN): ChiCTR2200064740, Date of Registration: 2022-10-15.

Profiling amyloid-β peptides as biomarkers for cerebral amyloid angiopathy.

Brain amyloid-β (Aβ) deposits are key pathological hallmarks of both cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). Microvascular deposits in CAA mainly consist of the Aβ40 peptide, whereas Aβ42 is the predominant variant in parenchymal plaques in AD. The relevance in pathogenesis and diagnostic accuracy of various other Aβ isoforms in CAA remain understudied. We aimed to investigate the biomarker potential of various Aβ isoforms in cerebrospinal fluid (CSF) to differentiate CAA from AD pathology. We included 25 patients with probable CAA, 50 subjects with a CSF profile indicative of AD pathology (AD-like), and 23 age- and sex-matched controls. CSF levels of Aβ1-34, Aβ1-37, Aβ1-38, Aβ1-39, Aβ1-40, and Aβ1-42 were quantified by liquid chromatography mass spectrometry. Lower CSF levels of all six Aβ peptides were observed in CAA patients compared with controls (p = 0.0005-0.03). Except for Aβ1-42 (p = 1.0), all peptides were decreased in CAA compared with AD-like subjects (p = 0.007-0.03). Besides Aβ1-42, none of the Aβ peptides were decreased in AD-like subjects compared with controls. All Aβ peptides combined differentiated CAA from AD-like subjects better (area under the curve [AUC] 0.84) than individual peptide levels (AUC 0.51-0.75). Without Aβ1-42 in the model (since decreased Aβ1-42 served as AD-like selection criterion), the AUC was 0.78 for distinguishing CAA from AD-like subjects. CAA patients and AD-like subjects showed distinct disease-specific CSF Aβ profiles. Peptides shorter than Aβ1-42 were decreased in CAA patients, but not AD-like subjects, which could suggest different pathological mechanisms between vascular and parenchymal Aβ accumulation. This study supports the potential use of this panel of CSF Aβ peptides to indicate presence of CAA pathology with high accuracy.

The Relationship between p-tau217, p-tau231, and p-tau205 in the Human Brain Is Affected by the Cellular Environment and Alzheimer's Disease Pathology.

The levels of p-tau217 and p-tau231 in cerebrospinal fluid (CSF) are associated with early amyloid beta (Aß) changes in the brain, while the CSF levels of p-tau205 are foremost related to tau pathology in the later stages of the disease. To investigate if the three p-tau variants are found to the same degree in different tau structures and if their co-localization is affected by the diagnosis and presence of Aß plaques, we immunostained sections of the entorhinal cortex (EC) and inferior temporal gyrus (ITG) from non-demented controls (NC), patients with Alzheimer's disease (AD), and primary age-related tauopathy (PART) against p-tau217, p-tau231, and p-tau205 together with Methoxi-X04. An analysis using confocal microscopy showed that the co-localization variable, the Pearson correlation coefficient (PCC), was significantly higher between p-tau231 and p-tau205 in neurofibrillary tangles compared to neuropil threads and dystrophic neurites in plaques. The PCC value between all three p-tau variants in the neuropil threads was significantly lower in the ECs of patients with AD compared to the NC and in the ITGs of patients with AD, with a high Aß load compared to PART. The lowered value was associated with proportionally higher amounts of non-colocalized p-tau231 and p-tau217 compared to p-tau205, and the PCC values were negatively correlated with Aß and the tangle loads in patients with AD, but positively correlated with tangles in PART. These results suggest that the proportion of and co-localization between p-tau217, p-tau231, and p-tau205 are dependent on cellular localization and are altered in response to AD pathology in a spatial-temporal manner.

CSF levels of Chitinase3like1 correlate with early response to cladribine in multiple sclerosis.

Cladribine has been introduced as a high-efficacy drug for treating relapsing-remitting multiple sclerosis (RRMS). Initial cohort studies showed early disease activity in the first year after drug initiation. Biomarkers that can predict early disease activity are needed. To estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine. Forty-two RRMS patients (30F/12M) treated with cladribine were included in a longitudinal prospective study. All patients underwent a CSF examination at treatment initiation, clinical follow-up including Expanded Disability Status Scale (EDSS) assessment, and a 3T MRI scan after 6,12 and 24 months, including the evaluation of white matter (WM) and cortical lesions (CLs). CSF levels of 67 inflammatory markers were assessed with immune-assay multiplex techniques. The 'no evidence of disease activity' (NEDA-3) status was assessed after two years and defined by no relapses, no disability worsening measured by EDSS and no MRI activity, including CLs. Three patients were lost at follow-up. At the end of follow-up, 19 (48%) patients remained free from disease activity. IFNgamma, Chitinase3like1, IL32, Osteopontin, IL12(p40), IL34, IL28A, sTNFR2, IL20 and CCL2 showed the best association with disease activity. When added in a multivariate regression model including age, sex, and baseline EDSS, Chitinase 3 like1 (p = 0.049) significantly increased in those patients with disease activity. Finally, ROC analysis with Chitinase3like1 added to a model with EDSS, sex, age previous relapses, WM lesion number, CLs, number of Gad enhancing lesions and spinal cord lesions provided an AUC of 0.76 (95%CI 0.60-0.91). CSF Chitinase 3 like1 might provide prognostic information for predicting disease activity in the first years after initiation of cladribine. The drug's effect on chronic macrophage and microglia activation deserves further evaluation.

Different reactive profiles of calmodulin in the CSF samples of Chinese patients of four types of genetic prion diseases.

Calmodulin (CaM) levels exhibit significant elevation in the brain tissue of rodent and cell line models infected with prion, as well as in the cerebrospinal fluid (CSF) samples from patients diagnosed with sporadic Creutzfeldt-Jakob disease (sCJD). However, the status of CSF CaM in patients with genetic prion diseases (gPrDs) remains unclear. This study aims to assess the characteristics of CSF CaM in Chinese patients presenting four subtypes of gPrDs. A total of 103 CSF samples from patients diagnosed with T188K-gCJD, E200K-gCJD, D178N-FFI, P102L-GSS were included in this study, along with 40 CSF samples from patients with non-prion diseases (non-PrDs). The presence of CSF CaM and 14-3-3 proteins was assessed using Western blots analysis, while levels of CSF 14-3-3 and total tau were measured using enzyme-linked immunosorbent assays (ELISAs). Statistical methods including multivariate logistic regression were employed to evaluate the association between CSF CaM positivity and relevant clinical, laboratory, and genetic factors. The positive rates of CSF CaM were significantly higher in cases of T188K-gCJD (77.1%), E200K-gCJD (86.0%), and P102-GSS (90.9%) compared to non-PrD cases (22.5%). In contrast, CSF CaM positivity was slightly elevated in D178N-FFI (34.3%). CSF CaM positivity was remarkably high in patients who tested positive for CSF 14-3-3 by Western blot and exhibited high levels of total tau (≥1400 pg/ml) as measures by ELISA. Multivariate logistic regression analysis confirmed a significant association between CSF CaM positivity and specific mutations in PRNP, as well as with CSF 14-3-3 positivity. Furthermore, the diagnostic performance of CaM surpassed that of 14-3-3 and tau when analyzing CSF samples from T188K-gCJD and E200K-gCJD patients. Western blot analysis reveals significant variations in the positivity of CSF CaM among the four genotypes of gPrD cases, demonstrating a positive correlation with 14-3-3 positivity and elevated tau levels in CSF.

Unraveling the neuroimmune interface in chronic pain-the association between cytokines in the cerebrospinal fluid and pain in patients with lumbar disk herniation or degenerative disk disease.

Recent evidence highlights the importance of the neuroimmune interface, including periphery-to-central nervous system (CNS) neuroimmune crosstalk, in chronic pain. Although neuroinflammatory processes have been implicated in central sensitization for a long time, their potential neuroprotective and analgesic effects remain relatively elusive. We have explored the relationships between cytokine expression and symptom severity, and candidates for periphery-to-CNS crosstalk. Patients with degenerative disk disease (DDD) (nociceptive pain) or patients with lumbar disk herniation (LDH) with radiculopathy (predominantly neuropathic pain) completed questionnaires regarding pain and functional disability, underwent quantitative sensory testing, and provided blood and cerebrospinal fluid (CSF) samples. Proximity extension assay (PEA) was used to measure the levels of 92 inflammatory proteins in the CSF and serum from a total of 160 patients and controls, and CSF/serum albumin quotients was calculated for patients with DDD and patients with LDH. We found signs of neuroimmune activation, in the absence of systemic inflammation. Regarding periphery-to-CNS neuroimmune crosstalk, there were significant associations between several cytokines and albumin quotient, despite the latter being primarily at subclinical levels. The cytokines CCL11, CD5, IL8, and MMP-10 were elevated in the CSF, had positive correlations between CSF and serum levels, and associated in a nonlinear manner with back, but not leg, pain intensity in the LDH, but not the DDD, group. In conclusion, we found evidence for neuroimmune activation in the CNS of both patient groups in the absence of systemic inflammation and signs of a communication between CSF and serum. Complex and disease-specific associations were found between cytokines in CSF and back pain intensity.

Elevated levels of β2-microglobulin in cerebrospinal fluid in adult patients with viral encephalitis/meningitis

BackgroundIncreased cerebrospinal fluid (CSF) β2-microglobulin (β2-MG) values are attributed to immune activation, lymphoid cell turnover and release of tissue destruction in the central nervous system (CNS). We investigated plasma and CSF β2-MG levels in adult patients with viral encephalitis/meningitis and their correlations with clinical parameters. MethodCSF samples from 26 patients with viral encephalitis/meningitis were collected. Moreover, 24 CSF samples from patients with non-inflammatory neurological disorders (NIND) as controls were collected. Plasma samples from 22 enrolled patients and 20 healthy individuals were collected. The β2-MG levels were measured by immunoturbidimetry on an automatic biochemical analyzer. Clinical data were extracted from an electronic patient documentation system. ResultCSF levels of β2-MG, adenosine deaminase (ADA), white blood cell (WBC), lactate dehydrogenase (LDH), protein and lactate were significantly increased in patients with viral encephalitis/meningitis respectively (p < 0.001, p < 0.001, p < 0.001, p = 0.001, p < 0.001, p = 0.013). In contrast, no statistically significant difference was found in plasma levels of β2-MG. Furthermore, CSF levels of β2-MG were weakly correlated with WBC (r = 0.426, p = 0.030), lymphocyte percentage (r = 0.599, p = 0.018), ADA (r = 0.545, p = 0.004) and LDH (r = 0.414, p = 0.036), but not with lactate (r = 0.381, p = 0.055), protein (r = 0.179, p = 0.381) and plasma levels of β2-MG (r = -0.156, p = 0.537) in viral encephalitis/meningitis patients. ConclusionCSF β2-MG may be a potential inflammatory marker for viral encephalitis/meningitis in adult patients diagnosed with viral encephalitis/meningitis.

Clinical and genetic analysis of children with glucose transporter type 1 deficiency syndrome.

Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a rare metabolic encephalopathy with a wide variety of clinical phenotypes. In the present study, 15 patients diagnosed with GLUT1-DS were selected, all of whom had obvious clinical manifestations and complete genetic testing. Their clinical data and genetic reports were collated. All patients were provided with a ketogenic diet (KD) and an improvement in their symptoms was observed during a follow-up period of up to 1 year. The results revealed that the 15 cases had clinical symptoms, such as convulsions or dyskinesia. Although none had a cerebrospinal fluid/glucose ratio <0.4, the genetic report revealed that all had the solute carrier family 2 member 1 gene variant, and their clinical symptoms basically improved following the use of the KD. GLUT1-DS is a genetic metabolic disease that causes a series of neurological symptoms due to glucose metabolism disorders in the brain. Low glucose levels in cerebrospinal fluid and genetic testing are key diagnostic criteria, and the KD is a highly effective treatment option. By summarizing and analyzing patients with GLUT1-DS, summarizing clinical characteristics and expanding their gene profile, the findings of the present study may be of clinical significance for the early recognition and diagnosis of the disease, so as to conduct early treatment and shorten the duration of brain energy deficiency. This is of utmost importance for improving the prognosis and quality of life of affected children.

Abstract WP152: Association Between Cerebrospinal Fluid Interleukin-6 Levels and Cerebral Autoregulation After Aneurysmal Subarachnoid Hemorrhage

Introduction: Elevated levels of Interleukin-6 (IL-6) levels in cerebrospinal fluid (CSF) have been correlated with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, the role of neuroinflammation in SAH pathophysiology remains incompletely understood. In a pig stroke model, IL-6 antagonist prevented hypotension-induced pial artery impairment, suggesting a role in post-stroke vascular derangement. This research assesses serial CSF IL-6 levels' relationship with cerebral autoregulation in aSAH patients. Methods: We prospectively enrolled aSAH patients at Yale-New Haven Hospital. Autoregulatory function was measured by interrogating changes in near-infrared spectroscopy-derived tissue oxygenation response to changes in mean arterial pressure (MAP). The resulting autoregulatory index was used to trend the MAP range at which autoregulation was most preserved. Percent time that MAP exceeded the upper limit of autoregulation or decreased below the lower limit of autoregulation was calculated for each patient. IL-6 levels were assessed through serial CSF samples and correlated with hemodynamic parameters. Results: We calculated limits of autoregulation for twenty-two patients (mean age 60 ± 9 years, mean Hunt Hess score 3.4 ± 1.2, mean modified Fisher score 3.7 ± 0.58, average monitoring time 10.1 ± 7.3 hours). Optimal MAP and limits were calculated an average of 74% ± 20% of monitoring time. Our study provides preliminary support for a potential association between IL-6 levels and percent time that MAP was within limits of autoregulation (b = -0.31, p=0.009, Fig. 1A). Additionally, there was a significant correlation between IL-6 levels and the extent to which MAP deviated from computed optimal MAP (r= 0.636, p=0.009, Fig. 1B). Conclusions: IL-6 may contribute to impaired autoregulation post aSAH. Further studies are needed to validate findings and refine MAP management for improved outcomes in aSAH patients.