Cerebrospinal Fluid Protein Levels Research Articles

Relationship between catheter related cerebrospinal fluid infections and systemic immune-inflammation index.

This study investigated the relationship between the systemic immune inflammation index (SII) and catheter-related infections and their effects on prognosis in pediatric patients. A total of 56 pediatric patients diagnosed with ventriculoperitoneal (V-P) shunt infection between January 2017 and October 2019 were included. V-P shunt infection diagnosis was made based on clinical findings. All cerebrospinal fluid (CSF) samples were subjected to direct microscopic examination and culture. Protein, glucose, and sodium levels in CSF, CSF leukocytes, and hematological and biochemical parameters were measured. Fifty-six patients with growth in CSF culture were included in this study. 55.4% of the cases were female and 44.6% male. V-P shunt was detected in 82.1% of the cases and external ventricular drainage (EVD) catheter-related infection in 17.9%. The CSF/blood glucose ratio was significantly lower (p=0.046), and SII was significantly increased (p=0.002) in non-coagulase-negative staphylococci. Early and appropriate antibiotic therapy reduces morbidity and mortality in catheter-related infections. However, it is important to start empirical antibiotherapy until culture results are expected. Therefore, further research on the estimation of possible factors is needed.

Quantitative evaluation of the thickened dura mater impacting clinical signs in immune-mediated hypertrophic pachymeningitis

ObjectiveThis study evaluated the volume of thickened dura mater lesions and their impact on clinical findings in immune-mediated hypertrophic pachymeningitis (HP). MethodsThe volume of contrast-enhanced dura mater on magnetic resonance imaging was evaluated using the imaging feature quantification system in 19 patients with immune-mediated HP, including 12 with antineutrophil cytoplasmic antibody-related, 4 with IgG4-related, and 3 with idiopathic HP, as well as 10 with multiple sclerosis (MS) as controls. The implications of HP volume on neurological manifestations and cerebrospinal fluid (CSF) laboratory markers were statistically analyzed in patients with immune-mediated HP. ResultsThe volumes of the contrast-enhanced dura mater in the convexity, cranial fossa, and tentorium cerebelli were significantly higher in patients with immune-mediated HP than in those with MS. Among patients with immune-mediated HP, those with cranial nerve (CN) VIII neuropathy had a significantly higher volume of the contrast-enhanced dura mater in the cranial fossa than those without CN VIII neuropathy. The volume of the contrast-enhanced dura mater in the tentorium cerebelli was positively correlated with CSF protein levels. ConclusionQuantification of the thickened dura mater is useful for elucidating the relationship with the clinical findings in immune-mediated HP. Thickened dura mater lesions in the cranial fossa may be implicated in the development of CN VIII neuropathy. The enlargement of HP lesions in the tentorium cerebelli can increase CSF protein levels.

Multiplex real-time PCR FilmArray performance in the diagnosis of meningoencephalitis: lights and shadows.

We aimed to evaluate the performance of the FilmArray (FA) meningitis/encephalitis (ME) panel. Secondarily, we analyzed the false positive (FP) and false negative (FN) results, as well as the predictive values of the technique, regarding the cerebrospinal fluid (CSF) characteristics. FA is a multiplex real-time PCR detecting 14 of the most common ME pathogens in CSF. All FA performed at our hospital (2018-2022) were retrospectively reviewed. FA was compared to conventional techniques and its performance was assessed based on the final diagnosis of the episode. FA was performed in 313 patients with suspicion of ME. Most patients had altered mental status (65.2%) and fever (61%). Regarding CSF characteristics, 49.8% and 53.7% presented high CSF proteins and pleocytosis, respectively. There were 84 (26.8%) positive FA results, mainly for HSV-1 (10.9%), VZV (5.1%), Enterovirus (2.6%), and S. pneumoniae (1.9%). In the 136 cases where both FA and routine methods were performed, there was a 25.7% lack of agreement. We identified 6.6% FN results, but 28.6% FP, mainly due to HSV-1. This resulted in a high negative predictive value (NPV) of 93.4%, but a positive predictive value (PPV) of 73%. Remarkably, PPV as low as 36.9%, and 70.2%, were found in cases without pleocytosis, or lack of high CSF protein levels, respectively. FA was associated with high NPV, but frequent FP results and low PPV, particularly for HSV-1, and especially in patients without high CSF protein levels or pleocytosis.

Identification of potential biomarkers related to mesenchymal stem cell response in patients with Alzheimer’s disease

BackgroundPreclinical studies showed that mesenchymal stem cells (MSCs) ameliorate tau phosphorylation, amyloid-beta accumulation, and inflammation in Alzheimer’s disease (AD) mouse models via secretion of neurotrophic factors and cytokines. We aimed to identify CSF biomarkers that can be used to predict or monitor the response to MSCs in patients with AD.MethodsAD patients were injected with human umbilical cord blood-MSCs (n = 22) or placebo (n = 12). The cerebrospinal fluid (CSF) samples were collected at baseline, one day after the first injection, and one day after the third injection. The patients injected with MSCs were classified into good responder (GR) or poor responder (PR) groups based on the rate of changes in the ratio of total-tau and phosphorylated-tau in the CSF. We selected three typical participants in each group, and their CSF protein levels were analyzed using liquid chromatography/tandem mass spectrometry (LC–MS/MS).ResultsIn the LC–MS/MS analysis, 1,667 proteins were identified. Eleven proteins showed significant differences between the typical GR and PR at baseline. Based on their significance level and known functions, two proteins, reticulocalbin-3 (RCN3) and follistatin-related protein 3 (FSTL3), were selected as potential biomarkers to predict MSC response. A total of 173 proteins showed significant change one day after the third injection compared to the baseline in typical GR. We excluded 45 proteins that showed significant change after the third injection compared to the baseline in the typical PR. Based on their significance level and known function, four proteins, scrapie-responsive protein 1 (SCRG1), neural proliferation differentiation and control protein (NPDC1), apolipoprotein E (ApoE), and cystatin C (CysC), were selected as potential biomarker to monitor MSC response. Additionally, functional analysis revealed that the increased CSF proteins after the third injection compared to the baseline in the typical GR were associated with synaptogenesis.ConclusionsThis study identified two proteins (RCN3 and FSTL3) that may be potential biomarkers for predicting MSC response and four proteins (SCRG1, NPDC1, ApoE, CysC) that may be potential biomarkers for monitoring MSC response in patients with AD. Further studies are needed to validate our results.Trial registration Clinical Trials.gov, NCT02054208. Registered on 4 February 2014. Samsung Medical Center IRB File No.2017-04-025. Registered on 20 June 2017.

The effect of double filtration plasmapheresis and corticosteroids on patients with anti-dipeptidyl-peptidase-like protein 6 encephalitis.

Anti-dipeptidyl-peptidase-like protein 6 (DPPX) encephalitis is a rare condition with varied symptoms including gastrointestinal issues, weight loss, cognitive and mental dysfunction, and hyperexcitability of the central nervous system. We studied five patients with anti-DPPX encephalitis who received immunotherapy, specifically DFPP, at our hospital. We analyzed their clinical symptoms, lab results, electrophysiological and imaging findings, and outcomes with immunotherapy. Patients presented with cognitive dysfunction, tremor, seizures, psychiatric disturbances, and cerebellar and brainstem dysfunction. Magnetic resonance imaging (MRI) showed brain abnormalities in one patient and elevated cerebrospinal fluid (CSF) protein levels in two patients. Antibodies against DPPX were detected in all patients and in CSF in two patients. One patient had antibodies against anti-CV2/contactin response mediator protein 5 (CRMP5). All patients responded well to DFPP and corticosteroids. DFPP may be an effective treatment for anti-DPPX encephalitis. Further research is needed to understand disease progression and evaluate immunotherapy efficacy.

Complement proteins are elevated in blood serum but not CSF in clinical high-risk and antipsychotic-naïve first-episode psychosis

Alterations in the complement system have been reported in some people with psychotic disorder, including in pre-psychotic individuals, suggesting that complement pathway dysregulation may be a feature of the early psychosis phenotype. Measurement of complement protein expression in psychosis has been largely restricted to the blood from patients with established illness who were taking antipsychotic medication. The present study examined a range of complement proteins in blood and cerebrospinal fluid (CSF) derived from individuals at clinical high-risk for psychosis (CHR), antipsychotic-naïve first-episode psychosis (FEP) and healthy controls.A panel of complement proteins (C1q, C3, C3b/iC3b, C4, factor B and factor H) were quantified in serum and matched CSF in 72 participants [n = 23 individuals at CHR, n = 24 antipsychotic-naïve FEP, n = 25 healthy controls] using a multiplex immunoassay. Analysis of covariance was used to assess between-group differences in complement protein levels in serum and CSF. Pearson’s correlation was used to assess the relationship between serum and CSF proteins, and between complement proteins and symptom severity.In serum, all proteins, except for C3, were significantly higher in FEP and CHR. While a trend was observed, protein levels in CSF did not statistically differ between groups and appeared to be impacted by BMI and sample storage time. Across the whole sample, serum and CSF protein levels were not correlated. In FEP, higher levels of serum classical and alternative grouped pathway components were correlated with symptom severity.Our exploratory study provides evidence for increased activity of the peripheral complement system in the psychosis spectrum, with such elevations varying with clinical severity. Further study of complement in CSF is warranted. Longitudinal investigations are required to elucidate whether complement proteins change peripherally and/or centrally with progression of psychotic illness.

Prospective outcome analysis of multiple sclerosis cases reveals candidate prognostic cerebrospinal fluid markers.

Predicting the long-term disability outcomes of multiple sclerosis (MS) cases is challenging. We prospectively analysed our previous MS cohort with initial cerebrospinal fluid (CSF) proteomics data to reveal disability markers after 8.2±2.2 years of follow-up. Patients with regular follow-up visits were assigned into two groups: those with an age-related MS severity (ARMSS) score ≥5 (unfavourable course group, N = 27) and ARMSS score <5 (favourable course group, N = 67). A machine learning-based algorithm was applied to reveal candidate poor prognosis-associated initial CSF proteins, which were measured in an independent MS cohort (verification group, N = 40) by ELISA. Additionally, the correlation of initial clinical and radiological parameters with long-term disability was analysed. CSF alpha-2-macroglobulin (P = 0.0015), apo-A1 (P = 0.0016), and haptoglobin (P = 0.0003) protein levels, as well as cerebral lesion load (>9 lesions) on magnetic resonance imaging, gait disturbance (P = 0.04), and bladder/bowel symptoms (P = 0.01) were significantly higher in the unfavourable course group than in the favourable course group. Optic nerve involvement evident on initial magnetic resonance imaging (P = 0.002) and optic neuritis (P = 0.01) were more frequent in the favourable course group. The herein identified initial CSF protein levels, in addition to the clinical and radiological parameters at disease onset, have predictive value for long-term disability in MS cases.

Identifying Protein Quantitative Trait Loci in the Cerebrospinal Fluid Proteome

AbstractBackgroundGenome‐wide association studies (GWAS) on dementia have successfully identified variants conferring risk to disease. Still, how such variants impact exact biological mechanisms underlying disease remains largely unclear. Protein quantitative trait loci (pQTLs) measured in cerebrospinal fluid (CSF) may provide insight into these neurobiological mechanisms, since CSF protein levels can reflect ongoing processes in the brain and have been related to genetic variants. We used a CSF pQTL approach in individuals along the Alzheimer’s disease (AD) spectrum to reveal intermediate molecular pathways by which genetic variance influences neurobiological processes. Improving the functional interpretation of genetic variants in a matrix relevant to neurological disease helps deciphering biological mechanisms underlying neurological traits.MethodWe selected 243 subjects (106 controls/67 mild cognitive impairment/70 AD‐dementia, age 66.8±8.1 years, 53.9%female) from the EMIF‐AD MBD study, who had genetic data and CSF data (n = 1,351 proteins, tandem mass tag (TMT) mass spectrometry) available. Association signals between genetic variants and CSF proteins were tested using linear regression, adjusted for principal components (PC1‐3), age and sex using the genome‐wide significance threshold (P&lt;5.0e−8). CSF pQTLs were identified as novel if the association has not been previously reported in Yang et al., (2021), Sasayama et al., (2017) or Kauwe et al., (2014).ResultsTwenty‐four out of 1,351 CSF proteins (1.78%) showed genome‐wide significant associations with in total 147 SNPs (Table 1; Figure 1). We identified 25 CSF pQTLs, representing three cis‐acting (IGH, LTF and ADAMTS8) and 22 trans‐acting pQTLs. Results included mostly novel CSF pQTL associations, exception for the cis association of LTF with LTF protein levels. Two novel cis‐acting pQTLs were previously reported in a study on human lymphocytes (IGH on IGHV2‐70D) (Theusch et al., 2020) and prefrontal cortex brain data (ADAMTS8 on ADAMTS8) (Ng et al., 2017).ConclusionsThese results contribute to the functional interpretation of genetic variance on neurobiological processes, by pinpointing inflammation and tissue remodeling as potential contributing mechanisms in AD.

Large‐scale pQTL analysis of over 3,000 CSF samples

AbstractBackgroundExpression quantitative trait locus (eQTL) studies have been influential in identifying gene targets for many complex diseases. However, levels of mRNA often correlate poorly with levels of the protein that they encode, due to rates of degradation, translation, or alternative splicing, among other reasons. By correlating protein levels to genetic variation, pQTLs can elucidate a more accurate genetic architecture that underlies disease. While few large‐scale studies have considered cerebrospinal fluid (CSF) protein levels, CSF biomarker levels are one of the primary diagnostic tools in Alzheimer’s disease (AD), highlighting CSF’s relevance to brain aging and AD pathology. Here, we present CSF pQTL analysis of over 3,000 individuals.MethodWe generated CSF levels of 7,584 analytes for 3,065 samples using the aptamer‐based SOMAscan 7k platform. CSF levels of 4,884 analytes for additional 1,158 samples were also included. After stringent quality control, 3,107 unrelated European samples were selected for analysis. We performed pQTL analysis using a linear model with protein levels as the outcome variable, using a three‐stage study design: discovery, replication, and meta‐analysis. We performed colocalization of our pQTLs with eQTLs and GWAS loci, and compared our results to pQTLs from plasma studies to identify CSF‐specific pQTLs. We used Mendelian Randomization (MR) to identify proteins potentially causative for AD and other traits.ResultThis study represents the first use of the SOMAscan 7k platform in CSF, as well as the largest pQTL analysis of CSF to date. Of 3818 analytes currently tested in our discovery set, 1480 have at least one SNP associated with analyte level at p &lt; 5×10−8. Analyses are ongoing.ConclusionWe previously performed pQTL analysis of CSF using the SOMAscan 1.3k platform, where 425 pQTLs were identified and 3 proteins (PTP1B, Siglec‐3, and SLAF5) were found through MR to be involved in AD risk, as well as 48 additional protein associations for other neurodegenerative diseases. This study expands on those findings by including 6,000 more proteins and much larger samples, allowing for greater power. This study will be vital for identifying novel proteins involved in AD and elucidate novel drug targets for AD and other neurodegenerative disorders.

Correction: Hoshi et al. High Correlation among Brain-Derived Major Protein Levels in Cerebrospinal Fluid: Implication for Amyloid-Beta and Tau Protein Changes in Alzheimer’s Disease. Metabolites 2022, 12, 355

In the original publication [...]

Características clínicas y diagnósticas de tuberculosis meníngea en adultos, Bogotá (Colombia)

Resumen&#x0D; Introducción: La infección por Mycobacterium tuberculosis es una enfermedad con presencia mundial, cuya principal manifestación clínica es pulmonar; la tuberculosis meníngea es la segunda presentación extrapulmonar más frecuente después de la pleural y ocasiona alta morbimortalidad, pero un diagnóstico y tratamiento tempranos disminuyen estos desenlaces.&#x0D; Objetivo: Establecer las características clínicas de pacientes con tuberculosis meníngea en nuestras instituciones y la evaluación de los resultados obtenidos con los métodos diagnósticos disponibles.&#x0D; Materiales y métodos: Se realizó un estudio observacional descriptivo de corte transversal, mediante revisión de historias clínicas de pacientes con tuberculosis meníngea en el periodo 2003-2012, en dos instituciones de tercer y cuarto nivel de atención en Bogotá.&#x0D; Resultados: Se evaluaron 36 pacientes con tuberculosis meníngea, con edad media de 52,4 años, 63,8% sexo masculino y 16,6% coinfección con virus de inmunodeficiencia humana. La presentación clínica subaguda y crónica fue de 49,9%; 86,1% tuvieron cefalea; otros síntomas fueron: fiebre, rigidez nucal. En líquido cefalorraquídeo, todos tuvieron hiperproteinorraquia y 88,8% hipoglucorraquia. En estudios microbiológicos 71,8% tuvieron adenosin deaminasa positiva, 30,4% reacción en cadena de polimerasa positiva y 41,1% cultivo positivo. La hiponatremia fue de 36,1%. En neuroimágenes 18,7% presentaron hidrocefalia y 17,6% paquimeningitis.&#x0D; Conclusión: La tuberculosis meníngea representa hoy un reto diagnóstico, ya que no existe un método disponible con las características ideales de una prueba diagnóstica, debiendo considerarse las manifestaciones clínicas de meningitis subaguda o crónica y los hallazgos en líquido cefalorraquídeo primordiales para el diagnóstico e inicio temprano del tratamiento.

Early autoimmunity and outcome in virus encephalitis: a retrospective study based on tissue-based assay

To explore the autoimmune response and outcome in the central nervous system (CNS) at the onset of viral infection and correlation between autoantibodies and viruses.MethodsA retrospective observational study was conducted...

RT-QuIC Testing for Prions: Applying a Sensitive but Imperfect Test in Clinical Practice (P5-12.010)

<h3>Objective:</h3> Identify the clinical, laboratory, and pathologic features associated with false negative real-time quaking-induced conversion (RT-QuIC) testing for prions. <h3>Background:</h3> Heterogeneity in clinical presentation, abundant mimics, and potential for iatrogenic transmission emphasize the need for accurate diagnostic tests for Creutzfeldt-Jakob disease (CJD). While RT-QuIC is an excellent test, false negative results are recognized in clinical practice. <h3>Design/Methods:</h3> One-hundred twelve patients with probable or definite prion disease were assessed at two tertiary care centers from 2013–2021. RT-QuIC testing for prions was performed in cerebrospinal fluid (CSF) in all patients via the National Prion Disease Pathology Surveillance Center (Cleveland, OH). Demographic data, clinical features, and results of common tests and laboratory studies were abstracted from electronic medical records, and differences between RT-QuIC positive and negative patients considered using univariate statistics. <h3>Results:</h3> Initial RT-QuIC testing was negative in 12/112 patients (sensitivity 89%). Median age at presentation was younger in RT-QuIC negative patients (56.9 vs 66 years, p&lt;0.01), who were also less likely to present with ataxia (3/12 vs 61/100, p=0.03). CSF cell count, protein, and glucose levels were similar between cohorts, while rates of 14-3-3 positivity (2/12 vs 77/100, p&lt;0.01) and median CSF total tau levels were lower in RT-QuIC negative patients (2318 vs 4001 pg/mL, p&lt;0.01). RT-QuIC negative patients also had a longer median days from symptom onset to first presentation (125 vs 47, p=0.04), and longer symptomatic disease duration (530 vs 148, p&lt;0.01). Two RT-QuIC-negative patients underwent repeat testing, of which both were positive. <h3>Conclusions:</h3> RT-QuIC is a sensitive yet imperfect measure necessitating incorporation of other test results when prion disease is suspected. Patients with negative RT-QuIC had lower CSF biomarkers of neuronal damage (total-tau and 14-3-3) and longer symptomatic duration of prion disease raising the possibility that false negative RT-QuIC testing may associate with a more indolent disease course. <b>Disclosure:</b> Dr. Jones has nothing to disclose. Dr. Lazar has nothing to disclose. Dr. Porter has nothing to disclose. Dr. Prusinski has nothing to disclose. Dr. Brier has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. The institution of Dr. Brier has received research support from NIH. Dr. Bucelli has received personal compensation for serving as an employee of Biogen. Dr. Bucelli has received personal compensation for serving as an employee of Biogen. Dr. Bucelli has received personal compensation for serving as an employee of Neuroquestions. Dr. Bucelli has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen . Dr. Bucelli has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Bucelli has stock in Neuroquestions.com. An immediate family member of Dr. Bucelli has stock in Neuroquestions.com. The institution of Dr. Bucelli has received research support from Biogen. The institution of Dr. Bucelli has received research support from Ionis. Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Parabon Nanolabs. The institution of Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Eli Lilly. Dr. Day has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for DynaMed (EBSCO Health). Dr. Day has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Barrow Law. Dr. Day has stock in ANI Pharmaceuticals. The institution of Dr. Day has received research support from National Institutes of Health / NIA. The institution of Dr. Day has received research support from Chan Zuckerberg Initiative. The institution of Dr. Day has received research support from Alzheimer’s Association. The institution of Dr. Day has received research support from National Institutes of Health / NINDS. The institution of Dr. Day has received research support from Horizon Therapeutics. Dr. Day has received personal compensation in the range of $500-$4,999 for serving as a Presenter at Annual Meeting (CME) with American Academy of Neurology. Dr. Day has received personal compensation in the range of $500-$4,999 for serving as a Content Development (CME) with PeerView, Inc. Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving as a Content Development (CME) with Continuing Education, Inc. Dr. Day has a non-compensated relationship as a Clinical Director with AntiNMDA Receptor Encephalitis Foundation that is relevant to AAN interests or activities.

MiR-31-5p as a Potential Circulating Biomarker and Tracer of Clinical Improvement for Chronic Inflammatory Demyelinating Polyneuropathy.

MicroRNAs are endogenous, small noncoding RNA molecules that play a pivotal role in the regulation of gene expression. MicroRNAs are involved in many biological processes such as proliferation, cell differentiation, neovascularization, and apoptosis. Studies on microRNA expression may contribute to a better understanding of the pathomechanism of chronic inflammatory demyelinating polyneuropathy (CIDP) and consequently enable the development of new therapeutic measures using antisense miRNAs (antagomirs). In this study, we evaluated the level of miR-31-5p in the serum of patients with CIDP and its correlation with the miR-31-5p level and clinical presentation and electrophysiological and biochemical parameters. The study group consisted of 48 patients, mean age 61.60 ± 11.76, who fulfilled the diagnostic criteria of a typical variant of CIDP. The expression of miR-31-5p in patient serum probes was investigated by droplet digital PCR. The results were correlated with neurophysiological findings and the patient's clinical and biochemical parameters. The mean copy number of miRNA-31 in 100 μl serum was 1288.64 ± 2001.02 in the CIDP group of patients, while in the control group, it was 3743.09 ± 4026.90. There was a significant positive correlation (0.426) between IgIV treatment duration and miR-31-5p expression. Patients without IgIV treatment showed significantly lower levels of miR-31 compared to the treated group (259.44 ± 304.02 vs. 1559.48 ± 2168.45; p = 0.002). The group of patients with body weight > 80 kg showed statistically significantly lower levels of miRNA-31-5p than the patients with lower body weight (934.37 ± 1739.66 vs. 1784.62 ± 2271.62, respectively; p = 0.014). Similarly, the patients with elevated cerebrospinal fluid (CSF) protein levels had significantly higher miRNA-31-5p expression than those with normal protein levels (1393.93 ± 1932.27 vs. 987.38 ± 2364.10, respectively; p = 0.044). The results may support the hypothesis that miR-31-5p is strongly involved in the autoimmune process in CIDP. The positive correlation between higher miR-31-5p levels and duration of IVIg treatment may be an additional factor explaining the efficacy of prolonged IVIg therapy in CIDP.

Real-time quaking-induced conversion assays for prions: Applying a sensitive but imperfect test in clinical practice.

Real-time quaking-induced conversion (RT-QuIC) assays offer a sensitive and specific means for detection of prions, although false negative results are recognized in clinical practice. We profile the clinical, laboratory, and pathologic features associated with false negative RT-QuIC assays and extend these to frame the diagnostic approach to patients with suspected prion disease. A total of 113 patients with probable or definite prion disease were assessed at Mayo Clinic (Rochester, MN; Jacksonville, FL; Scottsdale, AZ) or Washington University School of Medicine (Saint Louis, MO) from 2013 to 2021. RT-QuIC testing for prions was performed in cerebrospinal fluid (CSF) at the National Prion Disease Pathology Surveillance Center (Cleveland, OH). Initial RT-QuIC testing was negative in 13 of 113 patients (sensitivity=88.5%). RT-QuIC negative patients were younger (median=52.0 years vs. 66.1 years, p< 0.001). Other demographic and presenting features, and CSF cell count, protein, and glucose levels were similar in RT-QuIC negative and positive patients. Frequency of 14-3-3 positivity (4/13 vs. 77/94, p< 0.001) and median CSF total tau levels were lower in RT-QuIC negative patients (2517 vs. 4001 pg/mL, p= 0.020), and time from symptom onset to first presentation (153 vs. 47 days, p= 0.001) and symptomatic duration (710 vs. 148 days, p= 0.001) were longer. RT-QuIC is a sensitive yet imperfect measure necessitating incorporation of other test results when evaluating patients with suspected prion disease. Patients with negative RT-QuIC had lower markers of neuronal damage (CSF total tau and protein 14-3-3) and longer symptomatic duration of disease, suggesting that false negative RT-QuIC testing associates with a more indolent course.

383 Artificial Neural Network Modeling of Outcomes in Subarachnoid Hemorrhage

INTRODUCTION: Aneurysmal subarachnoid hemorrhage is a devastating neurological condition which requires complex neurocritical care and neurosurgical decision-making yet results in remarkably variable outcomes. Robust methods of identifying patients who may need operative and critical care interventions, such as those who develop hydrocephalus requiring long-term shunting or cerebral vasospasm, or predicting patients who may go on to have long-term disability or worsened neurological outcomes are lacking. METHODS: Data used to train our models included demographic data (gender, age and race), history of medical conditions (hypertension, diabetes, coronary artery disease, hyperlipidemia, tobacco use), Hunt and Hess scale, ventriculostomy data (external ventricular drain (EVD) output, EVD level, EVD age), and cerebrospinal fluid (CSF) lab values (CSF protein and glucose levels). The models were trained on a subpopulation of 85% of subjects and then individually validated in a training-naive subset of 15% of subjects with high accuracy. RESULTS: Using this data, we have generated artificial neural network classifiers with hyperparameter tuning which predict the need for long-term cerebrospinal fluid (CSF) diversion via placement of a shunt (receiver operating characteristic area under the curve) (ROC AUC) = 0.8312), vasospasm (ROC AUC = 0.8058), and the categorical outcome of patient disposition (model accuracy = 0.7786). CONCLUSIONS: We hope the use of artificial intelligence and machine learning techniques will continue to demonstrate power in predicting complex medical outcomes and ultimately help neurosurgeons and neuro-critical care personnel prognosticate and provide appropriate and timely treatment.

The Diagnostic Value of Cerebrospinal Fluid Lactate for Detection of Sepsis in Community-Acquired Bacterial Meningitis.

Community-acquired bacterial meningitis conveys significant morbidity and mortality due to intracranial and systemic complications, and sepsis is a major contributor to the latter. While cerebrospinal fluid (CSF) analysis is essential in the diagnosis of bacterial meningitis, its predictive utility for detection of sepsis is unknown. We investigated the diagnostic performance of CSF parameters for sepsis defined by the Sepsis-3 criteria in a retrospective cohort of patients with community-acquired bacterial meningitis. Among 103 patients, 69.5% developed sepsis. CSF lactate was associated with sepsis with an odds ratio of 1.11 (p = 0.022), while CSF cell counts, glucose and protein levels were not (all p > 0.4). Employing the optimal cutoff of 8.2 mmol/L, elevated CSF lactate resulted in a sensitivity of 81.5% and specificity of 61.5% for sepsis. In exploratory analyses, CSF lactate was also associated with in-hospital mortality with an odds ratio of 1.21 (p = 0.011). Elevated CSF lactate might contribute to early diagnosis of sepsis as well as prognostication in patients with community-acquired bacterial meningitis.

Cerebrospinal Fluid Protein Concentrations in Hydrocephalus

CSF protein levels are altered in neurological disorders, such as hydrocephalus of different etiologies. In this retrospective observational study, we analyzed cerebrospinal fluid (CSF) samples in hydrocephalic diseases such as aqueductal stenosis (AQS, n = 27), normal pressure hydrocephalus (NPH, n = 24), hydrocephalus communicans (commHC, n = 25) and idiopathic intracranial hypertension (IIH)/pseudotumor cerebri (PC, n = 7) in comparison with neurological patients without hydrocephalic configuration (control, n = 95). CSF was obtained through CSF diversion procedures and lumbar punction and analyzed for protein concentrations according to the institution's laboratory standards. We found significantly decreased CSF protein levels in patients suffering from AQS (0.13 mg/dL [0.1-0.16 mg/dL] p = 2.28 × 10-8) and from PC (0.18 mg/dL [0.12-0.24 mg/dL] p = 0.01) compared with controls (0.34 mg/dL [0.33-0.35 mg/dL]). Protein levels were not altered in patients suffering from commHC and NPH compared with neurologically healthy individuals. We propose that a decrease in CSF protein levels is part of an active counterregulatory mechanism to lower CSF volume and, subsequently, intracranial pressure in specific diseases. Research regarding said mechanism and more specific proteomic research on a cellular level must still be performed to prove this hypothesis. Differences in protein levels between different diseases point to different etiologies and mechanisms in different hydrocephalic pathologies.

Efficacy and safety of lenalidomide in HIV-associated cryptococcal meningitis patients with persistent intracranial inflammation: an open-label, single-arm, prospective interventional study

BackgroundPatients with human immunodeficiency virus-associated cryptococcal meningitis (HIV-CM) have persistent intracranial inflammation despite negative cerebrospinal fluid (CSF) fungal cultures after optimal treatment for CM, which could be devastating for the central nervous system. However, a definitive treatment strategy for persistent intracranial inflammation despite optimal antifungal therapies is undefined.MethodsWe identified 14 HIV-CM patients with persistent intracranial inflammation and conducted a 24-week, prospective, interventional study. All participants received lenalidomide (25 mg, p.o.) on days 1 to 21 of a 28-day cycle. Follow-up lasted for 24 weeks with visits at baseline and weeks 4, 8, 12, and 24. The primary endpoint was the change in clinical manifestations, routine CSF parameters, and MRI findings after lenalidomide treatment. An exploratory analysis was made on changes in cytokine levels in CSF. Safety and efficacy analyses were undertaken in patients who received at least one dose of lenalidomide.ResultsOf 14 participants, 11 patients completed the 24 weeks of follow-up. Rapid clinical remission following lenalidomide therapy was observed. Clinical manifestations (fever, headache, altered mentation) were reversed fully by week-4 and remained stable during follow-up. A significant reduction in white blood cell (WBC) count in CSF was noted occurred at week-4 (P = 0.009). The median protein concentration in CSF decreased from 1.4 (0.7–3.2) g/L at baseline to 0.9 (0.6–1.4) at week-4 (P = 0.004). The median albumin concentration in CSF decreased from 79.2 (48.4–149.8) mg/L at baseline to 55.3 (38.3–89.0) mg/L at week-4 (P = 0.011). The WBC count, protein level, and albumin level in CSF remained stable and approached a normal range through week-24. There was no significant change in immunoglobulin-G, intracranial pressure (ICP), or chloride-ion concentration at each visit. Brain MRI demonstrated multiple lesions to be absorbed post-therapy. Levels of tumor necrosis factor-α granulocyte colony stimulating factor, interleukin (IL)-6, and IL-17A decreased significantly during 24-week follow-up. Two (14.3%) patients had mild skin rash, which resolved spontaneously. Lenalidomide-related serious adverse events were not observed.ConclusionLenalidomide could improve persistent intracranial inflammation in HIV-CM patients significantly and was well tolerated without serious adverse events observed. And the additional randomized controlled study is required to further validate the finding.

Population-Based Evaluation of Total Protein in Cerebrospinal Fluid

ObjectivesTo present a normal range of cerebrospinal fluid (CSF) protein levels in a community-based population and to evaluate factors that contribute to CSF protein level variability. Patients and MethodsSamples of CSF protein were obtained from participants aged 32 to 95 years who underwent lumbar puncture (LP) between November 1, 2007, and October 1, 2017, as part of the Mayo Clinic Study of Aging, a longitudinal, population-based study of residents of Olmsted County, Minnesota. ResultsA total of 633 participants (58.1% male; 99.1% White; mean ± SD age, 70.9±11.6 years) underwent LP with recorded CSF protein level. Mean ± SD CSF protein level was 52.2±18.4 mg/dL (to convert to mg/L, multiply by 10), with a 95% reference interval of 24.0 to 93.4 mg/dL (range, 14.0-148.0 mg/dL). Spinal stenosis and arterial hypertension were associated with higher CSF protein levels on univariable analysis (P<.001). Increasing age, male sex, and diabetes were all independently associated with higher CSF protein levels on multivariable analysis (P<.001). In the 66 participants with repeated LPs within 2.5 years, the coefficient of repeatability was 26.1 mg/dL. Eleven participants (16.7%) had a CSF protein level difference of 20 mg/dL or more between serial LPs, and 4 (6.1%) had a difference of 25 mg/dL or more. There was a trend toward greater CSF protein level variability in patients with spinal stenosis (P=.054). ConclusionThis large population-based study showed that CSF protein level can vary significantly among individuals. Elevated CSF protein level was independently associated with older age, male sex, and diabetes and is higher than listed in many laboratories. These findings emphasize the necessity of evidence-based reevaluation and standardization of CSF protein metrics.