Elevated Cerebrospinal Fluid Research Articles

CSF GPNMB in Parkinson's disease: A potential association with age and microglial activation

Background Recent evidence suggests a link between glycoprotein non-metastatic melanoma protein B (GPNMB) and Parkinson's disease (PD) pathogenesis. Although elevated plasma GPNMB levels associated with disease severity have been reported in PD, cerebrospinal fluid (CSF) alterations remain elusive. Objective To explore CSF GPNMB alterations and its clinical significance in PD. Methods This study enrolled 118 sporadic PD patients and 40 controls. We examined the potential associations between CSF GPNMB levels and the clinical characteristics or biomarkers of neurodegenerative pathogenesis. Results PD patients had higher CSF GPNMB levels than controls ( p = 0.0159). In the PD group, CSF GPNMB levels correlated with age (age at examination: rs = 0.2511, p = 0.0061; age at onset: rs = 0.2800, p = 0.0021) and the severity of motor and cognitive dysfunction (MDS-UPDRS III score: rs = 0.1998, p = 0.0347; Mini-Mental State Examination score: rs = −0.1922, p = 0.0370). After correcting for multiple comparisons, the correlation with age at onset remained significant. CSF GPNMB levels were also positively correlated with CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) levels in both the PD ( rs = 0.3582, p < 0.0001) and control ( rs = 0.4743, p = 0.0023) groups. Furthermore, multiple regression analysis revealed CSF sTREM2 level as the strongest determinant of CSF GPNMB levels in the PD group (t-value = 3.49, p = 0.0007). Conclusions Elevated CSF GPNMB levels, linked with age and microglial activation, may be a valuable marker for understanding the interplay between aging, neuroinflammation, and PD pathology.

Elevated serum and cerebrospinal fluid levels of Interleukin-4 related to poor outcome of Aneurysmal subarachnoid hemorrhage

Aneurysmal subarachnoid hemorrhage (aSAH) is a hemorrhagic cerebrovascular disease that seriously jeopardizes human life and health. Some studies have shown that although Interleukin-4 (IL-4) acts as an anti-inflammatory factor, IL-4 levels are elevated when the disease occurs. This study focuses on exploring the relationship between IL and 4 concentrations in the serum and cerebrospinal fluid (CSF) and poor outcome in patients with aSAH. This study was a prospective observational study and 210 aSAH patients who met the inclusion criteria were divided into two groups according to the mRS score at 3 months after discharge, and 210 healthy people were selected as controls. The IL-4 concentrations were quantitatively determined with enzyme-linked adsorption assay (ELISA). We can draw a conclusion that Serum and CSF IL-4 concentrations are generally elevated in patients with poor outcome(P < 0.05), and the CSF IL-4 concentration decreased gradually over the progress of time (P < 0.05). The IL-4 concentration in the CSF was positively correlated with age, platelet-lymphocyte ratio (PLR), C-reactive protein (CRP), Hunt-Hess grade, mRS score, and World Federation of Neurological Surgeons score (WFNS) (P < 0.0001). Additionally, IL-4 concentrations in the CSF were correlated with complications such as intracranial infection (P = 0.01), cerebral edema (P < 0.01), hydrocephalus (P = 0.02), and complications by DCI (P = 0.02). Elevated serum and CSF concentrations of IL-4 may associated with the outcome of aSAH and may be a candidate early biomarkers for outcome of aSAH.

Elevated Cerebrospinal Fluid Ubiquitin Carboxyl-Terminal Hydrolase Isozyme L1 in Asymptomatic C9orf72 Hexanucleotide Repeat Expansion Carriers.

To identify biochemical changes in individuals at higher risk of developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) via C9orf72 hexanucleotide repeat expansion (HRE) heterozygosity. Cross-sectional observational study of 48 asymptomatic C9orf72 HRE carriers, 39 asymptomatic non-carrier controls, 19 people with sporadic ALS, 10 with C9orf72 ALS, 14 with sporadic FTD, and 10 with C9orf72 FTD. Relative abundance of 30 pre-defined cerebrospinal fluid biomarkers of ALS and FTD were compared in asymptomatic C9orf72 HRE carriers and age-matched non-carrier controls. Differential abundance of these proteins was quantified using data independent acquisition mass spectrometry or electro chemiluminescent assay for neurofilament light chain. Unbiased analysis of the entire cerebrospinal fluid proteome was then carried out. Ubiquitin carboxyl-hydrolase isozyme L1 levels were higher in asymptomatic C9orf72 HRE carriers compared with age-matched non-carriers (log2fold change 0.20, FDR-adjusted p-value = 0.034), whereas neurofilament light chain levels did not significantly differ. Ubiquitin carboxyl-hydrolase isozyme L1 levels remained elevated after matching of groups by neurofilament levels (p = 0.011), and after adjusting for age, sex, and neurofilament levels. A significant difference was also observed when restricting analysis to younger participants (<37) matched by neurofilament level (p = 0.007). Elevated cerebrospinal fluid ubiquitin carboxyl-hydrolase isozyme L1 levels in C9orf72 HRE carriers can occur in the absence of increased neurofilament levels, potentially reflecting either compensatory or pathogenic mechanisms preceding rapid neuronal loss. This brings forward the window on changes associated with the C9orf72 HRE carrier state, with potential to inform understanding of penetrance and approaches to prevention. ANN NEUROL 2024.

Chronic Immune Sensory Polyradiculopathy (CISP): A Systematic Review of the Literature.

Chronic immune sensory polyradiculopathy (CISP) is a rare inflammatory immune disorder affecting the nervous system, primarily targeting the proximal sensory nerve roots. The condition was first described by Sinreich in 2004. We conducted a systematic review of CISP cases published on PubMed to identify common clinical presentations, along with neurophysiological, radiological, cerebrospinal fluid (CSF), and other findings. Our review included a total of 22 patients from 8 articles. Many patients presented with gait difficulties and sensory ataxia and were found to have normal nerve conduction studies (NCS) and electromyography (EMG) but exhibited characteristic abnormalities in somatosensory evoked potentials (SSEP), elevated CSF protein levels, thickened nerve roots on contrast-enhanced lumbar spine MRIs, and histological changes on nerve root biopsies. Clinical improvement was observed following treatment with steroids and/or intravenous immunoglobulin (IVIG). The study concluded that while CISP is rare, it is an important clinical entity to consider, as accurate diagnosis and appropriate treatment can lead to significant improvements in neurological symptoms and disabilities.

IIH, SIH and headache: Diagnosis and treatment update

Idiopathic intracranial hypertension (IIH) and spontaneous intracranial hypotension (SIH) are two major secondary headache disorders resulting from abnormal intracranial pressure (ICP). This short communication outlines the pathophysiology, diagnostic criteria, and management strategies for IIH and SIH. IIH predominantly affects obese women of childbearing age and presents with daily headaches, visual disturbances, and papilledema. It is characterized by elevated cerebrospinal fluid (CSF) pressure, with diagnosis supported by imaging and lumbar puncture. Treatment includes weight reduction, medications, and surgical interventions in refractory cases. SIH, conversely, is caused by spontaneous spinal CSF leaks and presents with acute orthostatic headaches. Diagnosis is supported by neuroimaging and lumbar puncture, revealing low CSF pressure. Treatment includes supported care, (targeted) epidural blood patch, with surgical repair considered in refractory cases. Advances in imaging and treatment have significantly improved outcomes for both conditions.

Comparative study of pathogen detection methods for central nervous system infections: laboratory testing of tuberculous meningitis

BackgroundTuberculous meningitis (TBM) is a severe central nervous system (CNS) infection with a challenging diagnosis due to inadequate detection methods. This study evaluated current clinical detection methods and their applicability.MethodsA cohort of 514 CNS infection patients from 2018 to 2020 was studied. Data on general demographics, Cerebrospinal Fluid (CSF) analysis, epidemiology, and clinical outcomes were collected. TBM patients were identified, and the sensitivities of mmetagenomic next-generation sequencing (NGS), GeneXpert, and microbial culture were compared. Kappa statistic assessed the consistency between methods.ResultsAmong the patients involved, TBM (29%) and neurosyphilis (25%) were the two most prevalent CNS infections. CSF analysis indicated that 76% of patients had leukocytosis, suggesting a potential CNS inflammation. In TBM cases, 92.5% had elevated CSF protein and leukocyte counts. Moreover, the percentage of positive mNGS results was 55.6%. GeneXpert and MTB cultures alone had lower sensitivity, but combined use resulted in a 53.4% positive rate.ConclusionsThis study highlights the high sensitivity of mNGS, comparable to GeneXpert and MTB culture. The combined methods are cost-effective and straightforward, and can partially substitute for mNGS, offering valuable alternatives for TBM diagnosis and providing insights into multiple diagnostic strategies in clinical practice.

Retinoid X Receptor Signaling Mediates Cancer Cell Lipid Metabolism in the Leptomeninges.

Cancer cells metastatic to the leptomeninges encounter a metabolically-challenging extreme microenvironment. To understand adaptations to this space, we subjected leptomeningeal-metastatic (LeptoM) mouse breast and lung cancers isolated from either the leptomeninges or orthotopic primary sites to ATAC-and RNA-sequencing. When inhabiting the leptomeninges, the LeptoM cells demonstrated transcription downstream of retinoid-X-receptors (RXRs). We found evidence of local retinoic acid (RA) generation in both human leptomeningeal metastasis and mouse models in the form of elevated spinal fluid retinol and expression of RA-generating dehydrogenases within the leptomeningeal microenvironment. Stimulating LeptoM cells with RA induced expression of transcripts encoding de novo fatty acid synthesis pathway enzymes in vitro . In vivo , while deletion of Stra6 did not alter cancer cell leptomeningeal growth, knockout of Rxra/b/g interrupted cancer cell lipid biosynthesis and arrested cancer growth. These observations illustrate a mechanism whereby metastatic cancer cells awake locally-generated developmental cues for metabolically reprograming, suggesting novel therapeutic approaches.

Cerebrospinal fluid L-lactate as a diagnostic marker for infectious-inflammatory disorders in the central nervous system of cattle.

Bacterial infection of the central nervous system (CNS) poses a clinical challenge and is a leading cause of neurological disorders in cattle. Human studies have demonstrated an increase in cerebrospinal fluid (CSF) L-lactate levels in bacterial meningitis. The aims of this study were to establish a Reference Interval (RI) for L-lactate in bovine CSF and assess its potential as a biomarker for detecting infectious-inflammatory disorders. CSF L-lactate was measured in the field using a commercially available lactate monitor. The RI for CSF L-lactate was calculated on healthy animals; univariate and receiver operating characteristic (ROC) analyses were performed to disclose an association between CSF L-lactate levels and interpretation of CSF in sick animals. Twenty-seven healthy cattle and 86 sick cattle with either CNS infectious-inflammatory disorders (47/86) or CNS disorders of other etiology (39/86) were included in this prospective study. The RI for CSF L-lactate was 1.1-2.4 mmol/L. The concentration was higher in the cattle with neutrophilic pleocytosis and the area under the ROC curve was 0.92 compared to other animals. Based on a cut-off of 3.15 mmol/L, CSF L-lactate had diagnostic sensitivity and specificity for neutrophilic pleocytosis of 93 and 80%, respectively. This is the first study to determine a RI for CSF L-lactate in cattle. Elevated CSF L-lactate levels indicated neutrophilic pleocytosis, which is often manifested in acute bacterial infection. The present findings may aid in diagnosis and correct use of antimicrobial drugs.

Elevated plasma and CSF neurofilament light chain concentrations are stabilized in response to mutant huntingtin lowering in the brains of Huntington’s disease mice

BackgroundTherapeutic approaches aimed at lowering toxic mutant huntingtin (mHTT) levels in the brain can reverse disease phenotypes in animal models of Huntington's disease (HD) and are currently being evaluated in clinical trials. Sensitive and dynamic response biomarkers are needed to assess the efficacy of such candidate therapies. Neurofilament light chain (NfL) is a biomarker of neurodegeneration that increases in cerebrospinal fluid (CSF) and blood with progression of HD. However, it remains unknown whether NfL in biofluids could serve as a response biomarker for assessing the efficacy of disease-modifying therapies for HD.MethodsLongitudinal plasma and cross-sectional CSF samples were collected from the YAC128 transgenic mouse model of HD and wild-type (WT) littermate control mice throughout the natural history of disease. Additionally, biofluids were collected from YAC128 mice following intracerebroventricular administration of an antisense oligonucleotide (ASO) targeting the mutant HTT transgene (HTT ASO), at ages both before and after the onset of disease phenotypes. NfL concentrations in plasma and CSF were quantified using ultrasensitive single-molecule array technology.ResultsPlasma and CSF NfL concentrations were significantly elevated in YAC128 compared to WT littermate control mice from 9 months of age. Treatment of YAC128 mice with either 15 or 50 µg HTT ASO resulted in a dose-dependent, allele-selective reduction of mHTT throughout the brain at a 3-month interval, which was sustained with high-dose HTT ASO treatment for up to 6 months. Lowering of brain mHTT prior to the onset of regional brain atrophy and HD-like motor deficits in this model had minimal effect on plasma NfL at either dose, but led to a dose-dependent reduction of CSF NfL. In contrast, initiating mHTT lowering in the brain after the onset of neuropathological and behavioural phenotypes in YAC128 mice resulted in a dose-dependent stabilization of NfL increases in both plasma and CSF.ConclusionsOur data provide evidence that the response of NfL in biofluids is influenced by the magnitude of mHTT lowering in the brain and the timing of intervention, suggesting that NfL may serve as a promising exploratory response biomarker for HD.

The Initial Clinical and Electrophysiological Characteristics of Different Subtypes of Guillain-Barré Syndrome Diagnosed Based on Serial Electrophysiological Examinations.

We aimed to identify different Guillain-Barré syndrome (GBS) subtypes, demyelination, axonal degeneration, and reversible conduction failure (RCF) as early as possible by analyzing the initial clinical and electrophysiological examinations. This study retrospectively collected GBS patients between October 2018 and December 2022 at Beijing Tiantan Hospital. The diagnostic criteria for the initial electrophysiological study were based on Rajabally's criteria, and the criteria for the serial electrophysiological study were based on Uncini's criteria. All subjects underwent clinical and electrophysiological evaluations at least twice within 8 weeks. A total of 47 eligible patients with GBS were included, comprising 19 acute inflammatory demyelinating polyradiculoneuropathy (AIDP), 18 axonal degenerations, and 10 RCFs. In the RCF group, 40%, 30%, and 30% patients were diagnosed as AIDP, axonal, and equivocal at the initial study, respectively. The AIDP group had significantly higher cerebrospinal fluid (CSF) protein than the RCF (123.8 [106.4, 215.1] mg/dL vs. 67.1 [36.8, 85.6] mg/dL, p=0.002) and axonal degeneration (123.8 [106.4, 215.1] mg/dL vs. 60.8 [34.8, 113.0] mg/dL, p<0.001) groups. The RCF group had significantly lower Hughes functional grades at admission (3 [2, 4] vs. 4 [4, 4], p=0.012) and discharge (1.0 [1.0, 2.0] vs. 3.0 [2.0, 3.0], p<0.001) than the axonal degeneration group and showed significantly shorter distal motor latency (DML), Fmin, Fmean, Fmax, and lower F% than the AIDP group (p<0.05). The early identification of RCF from AIDP had relatively obvious features, including slightly elevated CSF protein levels and normal or slightly prolonged DML and F-wave latencies, contrasting with the apparent elevation and prolongation seen in AIDP. Differentiating RCF from axonal degeneration remains challenging. One potential distinguishing factor is that the motor function in RCF tends to be better than in the latter.

Characterization of Laboratory-Confirmed Creutzfeldt-Jakob Disease From 3 Ontario Tertiary Care Centers Between 2012 and 2022: A Retrospective Cohort Study.

Globally, Creutzfeldt-Jakob disease (CJD) affects one in one million people annually, but there is a paucity of recent Canadian data. This study summarizes epidemiology trends and diagnostic timelines of laboratory-confirmed CJD cases in three tertiary Ontario hospitals. Using laboratory information systems, we identified 30 patients with a laboratory-confirmed CJD diagnosis between 2012 and 2022 at three major tertiary hospitals in Ontario. Retrospective chart reviews were then completed. Patients had a mean of 2.2 hospital visits (SD, 1.2) prior to being admitted for testing. The most common symptom presentations included loss of coordination (63.3%), behavioral changes (60%), progressive mobility loss (53.4%), memory loss (50.0%), and involuntary movements (50.0%). Magnetic resonance imaging findings showed potential CJD in 76.7% of cases, and 56.7% exhibited periodic sharp wave complexes characteristic of CJD on electroencephalogram. The mean duration from symptom onset to microbiologic testing was 91 days (SD, 90.7). End-point quaking-induced conversion (EP-QuIC) testing of cerebrospinal fluid was positive in 90.0% of patients, while 83.3% tested positive for 14-3-3 on enzyme-linked immunosorbent assay. Elevated cerebrospinal fluid 14-3-3 levels significantly correlated with shorter duration from symptom onset to death (R 2 = 0.71, F = 19.55, P = .0022). Post-diagnosis, 46.7% of patients were discharged home, 16.6% were transferred to external palliative care or hospice facilities, and 36.7% died during admission. The mean time from symptom onset to death was 121 days (SD, 120.7), and from diagnosis to death 35 days (SD, 83.9). This study highlights the importance of early CJD consideration and laboratory testing when appropriate neurologic symptoms are present.

Cognitive impairments in autoimmune encephalitis: the role of autoimmune antibodies and oligoclonal bands.

The presence of oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) is a pivotal diagnostic marker for multiple sclerosis (MS). These bands play a crucial role in the diagnosis and understanding of a wide array of immune diseases. In this study, we explore the relationship between the cognitive profile of autoimmune encephalitis (AIE) and the presence of OCBs in CSF, with a particular emphasis on NMDA receptor antibodies. We studied a cohort of 21 patients across five tertiary centers, segregated into two distinct categories. One group comprised individuals who tested positive only for autoimmune encephalitis antibodies indicative of encephalitis, while the other group included patients whose CSF was positive for both autoimmune encephalitis antibodies and OCBs. Our investigation focused primarily on cognitive functions and behavioral alterations, supplemented by auxiliary diagnostic assessments such as CSF cell count, magnetic resonance imaging (MRI), and electroencephalogram (EEG) results, evaluated for the two patient groups. To validate our findings, we employed statistical analyses such as Fisher's exact test with Benjamini-Hochberg correction. Our study included 21 patients, comprising 14 who were presented with only autoimmune encephalitis antibodies, and 7 who were dual-positive. Among these patients, we focused on those with NMDA receptor antibodies. Of these, five were dual positive, and nine were positive only for NMDA receptor antibodies. The dual-positive NMDA group, with an average age of 27 ± 16.47 years, exhibited significantly higher CSF cell counts (p=0.0487) and more pronounced language and attention deficits (p= 0.0264). MRI and EEG results did not differ significantly between the groups. Our results point to OCBs as an additional marker of disease severity in AIE, especially in NMDA receptor-antibody positive patients, possibly indicating a broader inflammatory process, as reflected in elevated CSF lymphocytes. Regular testing for OCBs in cases of suspected AIE may aid in disease prognosis and identification of patients more prone to language and attention disorders, improving diagnosis and targeting treatment for these cognitive aspects.

Possible association of elevated CSF IL-6 levels with anxiety and frustration in psychiatric disorders.

Neuroinflammation is an important causal factor for a variety of psychiatric disorders. We previously reported increased cerebrospinal fluid interleukin-6 levels in patients with schizophrenia and major depressive disorder. The present study aimed to examine the possible association of interleukin-6 levels with anxiety and frustration, negative valence symptoms shared in various psychiatric disorders. We included 129 patients with psychiatric disorders and 70 controls. CSF and plasma interleukin-6 levels were measured by immunoassay kits, and psychological symptoms were assessed with the State-Trait Anxiety Inventory, and the Basic Psychological Need Satisfaction and Frustration Scale. To examine regional cerebral blood flow, patients underwent arterial spin labeling analysis using magnetic resonance imaging. Cerebrospinal fluid interleukin-6 levels were significantly correlated with State-Trait Anxiety Inventory-trait anxiety (r = 0.25, P = 0.046) and Basic Psychological Need Satisfaction and Frustration Scale-autonomy frustration scores (r = 0.29, P = 0.018). Patients with abnormally high cerebrospinal fluid interleukin-6 levels (defined >97.5 percentile of the controls) had higher scores for trait anxiety (P = 0.035) and autonomy frustration (P = 0.026), and significantly increased regional cerebral blood flow in the left superior temporal gyrus, bilateral nucleus accumbens, and cerebellum than the remaining patients. Patients with elevated cerebrospinal fluid interleukin-6 constitute a subpopulation of psychiatric disorders associated with anxiety and autonomy frustration, which may be related to altered functions in specific brain areas.

Cerebrospinal Fluid Lactate Levels as a Prognostic Indicator in Patients With Cryptococcal Meningitis Who Are HIV Negative: A Retrospective Cohort Study.

Cryptococcal meningitis (CM) is a severe central nervous system infection. In patients with HIV infections and coexisting CM, elevated baseline cerebrospinal fluid (CSF) lactate levels can predict increased mortality. However, the CSF lactate level's significance in patients with CM who are HIV negative remains unclear, necessitating further investigation to elucidate the potential distinctions and enhance patient management. This study investigated the significance of CSF lactate levels in patients with CM who were HIV negative. This retrospective study utilized data from the clinical databases of patients who underwent lumbar punctures at a medical center in Kaohsiung City, southern Taiwan. Demographic data, CSF lactate levels, routine CSF analyses, and hematologic and neurologic findings were evaluated. The optimal CSF lactate threshold value was determined by the Youden index. This retrospective study included 70 patients with CM, among whom 44 (63%) and 26 (37%) tested negative and positive for HIV, respectively. The group without HIV exhibited higher CSF lactate levels, with an optimal CSF lactate cutoff point of 7.935 mmol/L for predicting 90-day mortality, resulting in significant predictive accuracies (area under the curve, 0.755; sensitivity, 57.1%; specificity, 100%); this value was an independent mortality predictor in patients who were HIV negative. In patients with CM who were HIV negative, CSF lactate levels ≥7.935 mmol/L correlated with higher mortality rates but without statistical significance. All patients with CM who were HIV negative and had CSF lactate levels ≥7.935 mmol/L died within 3 months of admission. Patients with CM who were HIV negative had elevated CSF lactate levels that correlated with adverse outcomes, enabling early identification of high-risk individuals.

Elevated cerebrospinal fluid neuronal injury biomarkers within 24 hours of onset in infection-triggered acute encephalopathy compared to complex febrile seizures

ObjectiveThis study aimed to measure and compare cerebrospinal fluid neuronal injury biomarkers in the acute phase of complex febrile seizure (CFS) and infection-triggered acute encephalopathy (AE). Furthermore, we determined the pathogenesis of AE with biphasic seizures and late reduced diffusion (AESD). MethodsPediatric patients with febrile status epilepticus who visited Hyogo Prefectural Kobe Children's Hospital from November 1, 2016, to December 31, 2022, and whose cerebrospinal fluid samples were collected within 24 h of neurological symptom onset were included. Patients were classified as having CFS or infection-triggered AE according to their definitions. Patients with AE were further categorized into AESD or unclassified AE. Cerebrospinal fluid biomarkers (neuron-specific enolase, growth differentiation factor 15 [GDF-15], S100 calcium-binding protein B [S100B], glial fibrillary acidic protein, and tau protein were measured and compared among the groups. ResultsTotal of 63 patients (45 with CFS and 18 with AE) were included. Among the AE patients, nine were classified as having AESD and nine as having unclassified AE. S100B levels were significantly higher in patients with AESD than in patients with CFS (485 pg/ml vs. 175.3 pg/ml) and were even higher in patients with AESD and neurological sequelae (702.4 pg/ml). GDF-15 levels were significantly elevated in patients with AE compared to patients with CFS (85.8 pg/ml vs. 23.6 pg/ml). ConclusionsThe elevation of S100B suggests that activated astrocytes may be closely associated with the early pathology of AESD. Elevated GDF-15 levels in infection-triggered AE suggest the activation of defense mechanisms caused by stronger neurological injury.

CSF neurogranin levels as a biomarker in Alzheimer’s disease and frontotemporal lobar degeneration: a cross-sectional analysis

BackgroundThere is initial evidence suggesting that biomarker neurogranin (Ng) may distinguish Alzheimer’s disease (AD) from other neurodegenerative diseases. Therefore, we assessed (a) the discriminant ability of cerebrospinal fluid (CSF) Ng levels to distinguish between AD and frontotemporal lobar degeneration (FTLD) pathology and between different stages within the same disease, (b) the relationship between Ng levels and cognitive performance in both AD and FTLD pathology, and (c) whether CSF Ng levels vary by apolipoprotein E (APOE) polymorphism in the AD continuum.MethodsParticipants with subjective cognitive decline (SCD) (n = 33), amnestic mild cognitive impairment (aMCI) due to AD (n = 109), AD dementia (n = 67), MCI due to FTLD (n = 25), and FTLD dementia (n = 29) were recruited from the Czech Brain Aging Study. One-way analysis of covariance (ANCOVA) assessed Ng levels in diagnostic subgroups. Linear regressions evaluated the relationship between CSF Ng levels, memory scores, and APOE polymorphism.ResultsNg levels were higher in aMCI-AD patients compared to MCI-FTLD (F[1, 134] = 15.16, p < .001), and in AD-dementia compared to FTLD-dementia (F[1, 96] = 4.60, p = .029). Additionally, Ng levels were higher in FTLD-dementia patients compared to MCI-FTLD (F[1, 54]= 4.35, p = .034), lower in SCD participants compared to aMCI-AD (F[1, 142] = 10.72, p = .001) and AD-dementia (F[1, 100] = 20.90, p < .001), and did not differ between SCD participants and MCI-FTLD (F[1, 58]= 1.02, p = .491) or FTLD-dementia (F[1, 62]= 2.27, p = .051). The main effect of diagnosis across the diagnostic subgroups on Aβ1−42/Ng ratio was significant too (F[4, 263]=, p < .001). We found a non-significant association between Ng levels and memory scores overall (β=-0.25, p = .154) or in AD diagnostic subgroups, and non-significant differences in this association between overall AD APOE ε4 carriers and non-carriers (β=-0.32, p = .358).ConclusionsIn this first study to-date to assess MCI and dementia due to AD or FTLD within one study, elevated CSF Ng appears to be an early biomarker of AD-related impairment, but its role as a biomarker appears to diminish after dementia diagnosis, whereby dementia-related underlying processes in AD and FTLD may begin to merge. The Aβ1−42/Ng ratio discriminated AD from FTLD patients better than Ng alone. CSF Ng levels were not related to memory in AD or FTLD, suggesting that Ng may be a marker of the biological signs of disease state rather than cognitive deficits.

Role of cerebrospinal fluid adenosine deaminase measurement in the diagnosis of tuberculous meningitis: an updated systematic review and meta-analysis.

Tuberculous meningitis (TBM) can be difficult to diagnose. Elevated cerebrospinal fluid (CSF) adenosine deaminase (ADA) is often seen in TBM, but its reliability has been questioned. A previous meta-analysis in 2017 had demonstrated the diagnostic utility of CSF ADA in TBM versus non-TBM. We sought to update this meta-analysis with more recent studies, to determine whether CSF ADA could be used to aid in the early recognition of TBM. Electronic searches were performed in PubMed and Scopus on studies published from 2016 to 2022. Ten additional studies were identified and added to 20 studies (from 2000 to 2016) from a previous meta-analysis. Meta-analysis was conducted using the random effects method, estimating the pooled diagnostic odds ratio (DOR) for elevated CSF ADA in the diagnosis of TBM. Of the 30 studies included, 16/30 (53.3%) used the Giusti method for measuring ADA. Fourteen (46.7%) studies used an ADA cut-off of 10 IU/L, and 11 (36.7%) studies used an even lower cut-off. The pooled DOR for elevated CSF ADA in the diagnosis of TBM was 45.40 (95% confidence interval [CI] 31.96-64.47, I2 = 44%). When only studies using the Giusti method were considered, DOR was 44.21 (95% CI 28.37-68.91, I2 = 40%). Among the studies that used a cut-off of 10 IU/L, DOR was 58.09 (95% CI 33.76-99.94, I2 = 41%). Studies remain heterogeneous but demonstrate that CSF ADA can differentiate TBM from non-TBM. In line with most studies, CSF ADA >10 IU/L supports the diagnosis of TBM in a patient with compatible symptoms and high-risk epidemiology.

Clinical characteristics and outcomes of patients with antibody-related autoimmune encephalitis presenting with disorders of consciousness: A prospective cohort study.

To explore the clinical characteristics, short- and long-term functional outcomes, and risk factors for antibody-related autoimmune encephalitis (AE) in patients with disorders of consciousness (DoC). Clinical data were collected from AE patients admitted to Xuanwu Hospital of Capital Medical University from January 2012 to December 2021, and patients were followed up for up to 24 months after immunotherapy. A total of 312 patients with AE were included: 197 (63.1%) with anti-NMDAR encephalitis, 71 (22.8%) with anti-LGI1 encephalitis, 20 (6.4%) with anti-GABAbR encephalitis, 10 (3.2%) with anti-CASPR2 encephalitis, 10 (3.2%) with anti-GAD65 encephalitis, and 4 (1.3%) with anti-AMPAR2 encephalitis. Among these patients, 32.4% (101/312) presented with DoC, and the median (interquartile range, IQR) time to DoC was 16 (7.5, 32) days. DoC patients had higher rates of various clinical features of AE (p < .05). DoC was associated with elevated lumbar puncture cerebrospinal fluid (CSF) pressure, CSF leukocyte count, and specific antibody titer (p < .05). A high percentage of patients in the DoC group had a poor prognosis at discharge and at 6 months after immunotherapy (p < .001), but no significant difference in prognosis was noted between the DoC group and the non-DoC group at 12 and 24 months after immunotherapy. Dyskinesia (OR = 3.266, 95% CI: 1.550-6.925, p = .002), autonomic dysfunction (OR = 5.871, 95% CI: 2.574-14.096, and p < .001), increased CSF pressure (OR = 1.007, 95% CI: 1.001-1.014, p = .046), and modified Rankin scale (mRS) score ≥3 at the initiation of immunotherapy (OR = 7.457, 95% CI: 3.225-18.839, p < .001) were independent risk factors for DoC in AE patients. DoC is a relatively common clinical symptom in patients with AE, especially critically ill patients. Despite requiring longer hospitalization, DoC mostly improves with treatment of the primary disease and has a good long-term prognosis after aggressive life support and combination immunotherapy.

A comparison of infectious and autoimmune meningoencephalitis: Clinical presentation, biochemical markers and MRI findings

Objective: This study investigates distinguishing patterns in lesion distribution, relevant clinical presentation and biochemical markers in MRI to differentiate infective encephalitis (IE) and autoimmune encephalitis (AE). Methods: Retrospective study of adult patients with a confirmed diagnosis of IE and AE admitted to the Neurology unit from January 2012 to December 2020 with MRI Brain. Selected cases with confirmed IE (according to the 2013 Infective Encephalitis Consortium diagnostic criteria) or antibody-positive AE (detection of Neuronal auto-antibody from blood or CSF), coupled by clinical presentation. MRI brain lesion distribution, lobar involvement, enhancement, haemorrhage, vasculopathy and atrophy were analysed. Results: Forty-seven patients (21 IE and 26 AE, respectively) were selected. IE group are older (48.0 ± 16.81) compared to AE (28.4 ± 14.10). Fever and vomiting were significant in IE (p&lt;0.001), whereas psychosis, seizure, movement disorder, and tumour (ovarian teratoma) were significant in the AE cohort. Cerebrospinal fluid (CSF) analysis showed elevated leucocytes with polymorphism and high protein levels in IE (2.081 g/L ± 2.93 vs AE (0.352g/L ± 0.18). MR imaging detected abnormal findings in 61.9% of cases with infectious encephalitis (IE), while 76.9% of cases with autoimmune encephalitis (AE) exhibited normal MRI results. Asymmetrical lesions and inferior frontal lobe distribution (57.1%) were significantly prevalent in IE (p&lt;0.05). Enhancement patterns and haemorrhage were rarely observed in AE patients. Conclusion: IE presented at an older age, with the majority having MRI findings such as asymmetrical lesions, leptomeningeal enhancement, and involvement of medial temporal, hippocampus and inferior frontal cortex. IE clinically presents with fever, vomiting, and elevated CSF leucocytes and protein levels. AE presents at a younger age with seizure, psychosis, movement disorder, tumour (ovarian teratoma). Fewer AE have MRI findings, and if present, tend to be symmetrical in distribution. Lobar involvement in the inferior frontal was the MRI feature that significantly favoured the diagnosis of IE compared to AE. IE and AE have distinct clinical, biochemical, and MRI abnormalities that can be discriminated between the 2 entities.

Elevated cerebrospinal fluid glial fibrillary acidic protein levels in Smith-Lemli-Opitz syndrome

Smith-Lemli-Opitz syndrome (SLOS) is a rare, multiple malformation/intellectual disability disorder caused by pathogenic variants of DHCR7. DHCR7 catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol in the final step of cholesterol biosynthesis. This results in accumulation of 7DHC and a cholesterol deficiency. Although the biochemical defect is well delineated and multiple mechanisms underlying developmental defects have been explored, the post developmental neuropathological consequences of altered central nervous system sterol composition have not been studied. Preclinical studies suggest that astroglial activation may occur in SLOS. To determine if astroglial activation is present in individuals with SLOS, we quantified cerebrospinal fluid (CSF) glial fibrillary acidic protein using a Quanterix Simoa® GFAP Discovery Kit for SR-X™. Relative to an age-appropriate comparison group, we found that CSF GFAP levels were elevated 3.9-fold in SLOS (3980 ± 3732 versus 1010 ± 577 pg/ml, p = 0.0184). Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, has previously been shown to increase expression of hypomorphic DHCR7 alleles and in a placebo-controlled trial improved serum sterol levels and decreased irritability. Using archived CSF samples from that prior study, we observed a significant decrease (p = 0.0119) in CSF GFAP levels in response to treatment with simvastatin. Although further work needs to be done to understand the potential contribution of neuroinflammation to SLOS neuropathology and cognitive dysfunction, these data confirm astroglial activation in SLOS and suggest that CSF GFAP may be a useful biomarker to monitor therapeutic responses.