CSF Protein Research Articles

NCMP-09. SPONTANEOUS RESOLUTION OF PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) DEVELOPED AFTER RITUXIMAB TREATMENT FOR LOW-GRADE B-CELL LYMPHOMA

Abstract Progressive multifocal leukoencephalopathy (PML) is a rare viral infection caused by the reactivation of the JC virus, which causes significant morbidity and mortality. Rituximab, a CD20 inhibitor used for B-cell neoplasms as well as autoimmune diseases, is associated with the development of PML. Here, we report a case of a 74-year-old woman with a history of low-grade B-cell lymphoma with biopsy-proven PML with spontaneous immune reconstitution with clinical and radiographic improvement. For her low-grade B-cell lymphoma, she received six cycles of rituximab and bendamustine, followed by one cycle of maintenance rituximab, which was discontinued due to intolerance. Ten months later, she developed progressive left-sided paresthesias, paresis, and incoordination. Brain MRI revealed a large right subcortical frontal-parietal FLAIR hyperintense and peripherally enhancing lesion with leading-edge diffusion restriction. CSF studies revealed elevated protein (385 mg/dL) and negative JCV PCR. A brain biopsy was performed with tissue staining positive for SV40, consistent with PML. Her CD4 count was 88 cells/mm3. A repeat CSF sample one month later showed near normalization CSF protein (47 mg/dL) and negative CSF JCV PCR. MRI of the brain one month later demonstrated complete enhancement resolution and decreased FLAIR abnormality, which correlated with subjective and objective clinical improvement. Her serum CD4 also increased to 134 cells/mm3. This highlights a rare case of PML related to rituximab with spontaneous improvement, which may help guide clinicians in counseling patients who may also develop this complication. Furthermore, this supports the biological rationale for continued investigation of T-cell therapies to achieve immune reconstitution.

Accuracy of urinary dipstick for glucose and protein determination in canine cerebrospinal fluid.

To evaluate the precision of urinary dipstick (UD) to assess protein and glucose concentrations in canine CSF samples compared to the standard methods. Cerebrospinal fluid protein and glucose were measured in 22 samples from dogs with neurological diseases affecting the CNS using UD and biochemistry (pyrogallol red and glucose oxidase reaction, respectively). Results were converted into scores to allow comparison between methods. The proportion of divergence between methods and its CI were calculated. The sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), and accuracy (Ac) of UD were determined for 2 cutoff levels of CSF protein (15 and 30 mg/dL) and glucose (40 and 100 mg/dL). The proportion of divergence between methods was 64% (95% CI, 44% to 84%) for CSF protein (representing 14 of 22 erroneous samples), of which 92.9% (13 of 14) had a UD score lower than biochemistry. For CSF glucose, 73% (16 of 22 erroneous samples; 95% CI, 54% to 91%) had divergence between methods, of which 87.5% (14 of 16) had a UD score higher than biochemistry. Urinary dipstick had better results when the cutoff level was 15 mg/dL for protein (Se, 78.9%; Sp, 66.7%; PPV, 93.7%; NPV, 33.3%; Ac, 77.3%) and 40 mg/dL for glucose (Se, 89.5%; Sp, 33.3%; PPV, 89.5%; NPV, 33.3%; Ac, 81.8%) concentrations. Urinary dipstick was unreliable in estimating canine CSF protein and glucose concentrations. The UD underestimated protein and overestimated glucose levels in the canine CSF, which could have a significant diagnostic impact and should discourage its use as a bedside test.

Clinical predictors of poor outcome of bacterial meningitis in infants less than 90 days: a systematic review

Backgroundbacterial meningitis (BM) is more common in infants than at any other time in life and remains a devastating disease with considerable risk of death and morbidity. This article aims to gather the currently available evidence to perform a systematic review of clinical factors that may predict or be associated with BM death and/or sequelae in infants < 90 days of age.MethodsThe Medline/PubMed, Cochrane Library and Embase databases were systematically searched for prognostic studies that described risk factors for mortality and sequelae in infants aged <90d with BM. The databases were searched from the beginning of the database to December 31st, 2022.The quality of cohort studies was assessed by the Newcastle-Ottawa Scale (NOS). The quality of cross-section studies was assessed by the Agency for Healthcare Research and Quality (AHRQ). A systematic review was undertaken to ascertain the prognostic factors proven to be noteworthy.ResultsOf the 1,431 studies retrieved, 20 were eligible for the final analysis including 11 cohort and 9 cross-sectional studies were identified. Four risk factors predicting poor outcome were mentioned mostly in those studies, including prematurity or low birth weight (LBW), seizures, coma, and elevated CSF protein. But only preterm, coma and elevated CSF protein were identified by multivariate analyses in more than one study.ConclusionsThis study demonstrates several potential predictive factors to the poor outcomes of BM in infant. But with large heterogeneity, these predictors should be evaluated by further well-designed prospective studies.Systematic Review Registrationhttps://www.crd.york.ac.uk/, identifier CRD42017074949.

Neuroinflammation, cerebrovascular dysfunction and diurnal cortisol biomarkers in a memory clinic cohort: Findings from the Co-STAR study

Cortisol dysregulation, neuroinflammation, and cerebrovascular dysfunction are biological processes that have been separately shown to be affected in Alzheimer’s disease (AD). Here, we aimed to identify biomarker signatures reflecting these pathways in 108 memory clinic patients with subjective cognitive decline (SCD, N = 40), mild cognitive impairment (MCI, N = 39), and AD (N = 29). Participants were from the well-characterized Cortisol and Stress in Alzheimer’s Disease (Co-STAR) cohort, recruited at Karolinska University Hospital. Salivary diurnal cortisol measures and 41 CSF proteins were analyzed. Principal component analysis was applied to identify combined biosignatures related to AD pathology, synaptic loss, and neuropsychological assessments, in linear regressions adjusted for confounders, such as age, sex, education and diagnosis. We found increased CSF levels of C-reactive protein (CRP), interferon γ-inducible protein (IP-10), thymus and activation-regulated chemokine (TARC), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in MCI patients. Further, markers of cortisol dysregulation (flattened salivary cortisol awakening response and flattened cortisol slope) correlated with increased levels of placental growth factor (PlGF), IP-10, and chitinase 3-like 1 (YKL-40) in the total cohort. A biosignature composed of cortisol awakening response, cortisol slope, and CSF IL-6 was downregulated in AD patients. Moreover, biomarker signatures reflecting overlapping pathophysiological processes of neuroinflammation and vascular injury were associated with AD pathology, synaptic loss, and worsened processing speed. Our findings suggest an early dysregulation of immune and cerebrovascular processes during the MCI stage and provide insights into the interrelationship of chronic stress and neuroinflammation in AD.

Diagnostic Dilemma between Scrub Typhus Meningoencephalitis and Dengue Encephalopathy Resolved! - A Novel Prediction Score.

Scrub typhus and dengue, common etiologies of acute encephalitis syndrome, present with similar clinico-laboratory profiles but differ in management protocol. We aimed to devise a score differentiating between scrub typhus meningoencephalitis (STM) and dengue encephalopathy (DE). A prospective cohort of 204 children, (aged 6 months to 14 years) presenting with acute encephalitis syndrome in a public teaching hospital in northern India was subjected to standardized workup including serum IgM against Orientia tsutsugamushi and Dengue virus. Clinico-laboratory features were compared between STM and DE using univariate and multivariate analysis. Area under the receiver operating characteristic (ROC) curve (AUROC) for the score derived from independent predictors and its sensitivity, specificity, predictive values was calculated at cutoffs. STM and DE IgM ELISA were positive in 38 (18.6%) and 41 (20.1%) children, respectively. Longer duration of fever, prodromal stage, respiratory complaints and pneumonia were significantly frequent in STM; however, swelling, petechiae and myalgia were significantly prevalent in DE. STM had higher blood total leukocyte count (TLC), higher CSF protein and lower CSF sugar compared to DE. At admission, TLC >10,000/mm3, pneumonia, absence of myalgia and petechiae were independent predictors for differentiating STM from DE. AUROC of novel score (range: -5 to 5) was 0.879 (95% CI: 0.805-0.952). Score at cutoff ≥5 had 100% specificity and 100% PPV for differentiating STM from DE. Prediction score may benefit physicians to differentiate between these two infections and treat them accordingly.

Progression predictors of clinically isolated syndrome to multiple sclerosis: A prospective study in China

ObjectivesClinically isolated syndrome (CIS) is a preclinical phase of multiple sclerosis (MS). The progression rate of CIS to clinical definite MS (CDMS) varies significantly across different populations, and identifying predictors of progression is crucial for early diagnosis and treatment. We aimed to investigate predictors of progression from CIS to CDMS in a Chinese cohort. MethodsA single-center cohort study was conducted with newly diagnosed patients with CIS in China between 2018 and 2021. All patients underwent a comprehensive clinical evaluation, including neurological examination, magnetic resonance imaging, and laboratory tests. Follow-up assessments were conducted at regular intervals to monitor disease progression. Progression to CDMS was defined according to the 2017 McDonald criteria. Age, sex, Expanded Disability Status Scale (EDSS) score, number of patients with magnetic resonance imaging gadolinium-enhancing (Gd+) lesions, T2 lesions and Gd+ lesions count, CSF cell count, CSF total protein, CSF and serum neurofilament light chain (NfL), progranulin (PGRN) and Th17-related cytokines (IL-6, IL-17, IL-21, IL-22, IL-23 and TGF-β) were measured for association with risk of progression to CDMS. ResultsA total of 96 CIS patients were recruited in the study. During the at least 24 months follow-up period, 57 (59.38 %) CIS patients progressed to CDMS, while 39 (40.62 %) patients without progression remained stable as CIS. Multivariate analysis revealed that younger age at onset (OR= 43.43, 95 % CI= 1.76–1071.68, p<0.021), higher CSF elevated protein (OR=58.64, 95 % CI=2.72–1264.51, p=0.009), higher CSF NfL levels (OR= 97.00, 95 % CI= 4.68–2012.99, p=0.003) and higher CSF IL-23 levels (OR= 412.02, 95 % CI=6.56–25869.60, p=0.004) were associated with high risk of progression to CDMS. ConclusionYounger age at onset, elevated CSF NfL, IL-23 and protein levels might be progression predictors of CIS to CDMS in Chinese population.

Lactate dehydrogenase-1 may play a key role in the brain energy disturbance caused by cryptococcal meningitis

BackgroundCryptococcal meningitis (CM) may affect the conversion of lactate to pyruvate in the brain, resulting in abnormal levels of adenosine triphosphate (ATP) throughout the brain. Lactate conversion to pyruvate is mainly caused by lactic dehydrogenase 1 (LDH1), which is composed of four LDHB subunits. However, the underlying mechanism of LDH1 in CM remains unclear. MethodsCerebrospinal fluid (CSF) from 17 patients was collected, including eight patients with non-infectious diseases of the central nervous system and nine patients with CM. Based on clinical data and laboratory reports, data regarding intracranial pressure, CSF white cell counts, lactate dehydrogenase (LDH), adenosine deaminase, glucose, protein, and chloridion were collected. Meanwhile, LDH1, LDH5, lactate, pyruvate, and ATP levels were detected in CSF. Whereafter, the levels of lactate, pyruvate, ATP, and the amplitude and frequency of action potentials in the neurons with low expression of LDHB were explored. ResultsIntracranial pressure and white cell count in CSF were significantly increased in patients with CM. In patients with CM, the LDH1, pyruvate, and ATP levels in the CSF were significantly decreased, and the levels of lactate were found to be increased. Furthermore, pyruvate and ATP levels were decreased, while lactate was increased in the neurons with low expression of LDHB. The amplitude and frequency of APs in the neurons with low expression of LDHB were significantly decreased. ConclusionReduced levels of LDH1 in the brain of patients with CM may lead to increased lactate levels, decreased pyruvate and ATP levels, and negatively affect neuronal activity.

Distinct Clinical Courses and Shortened Lifespans in Childhood-Onset DNA Polymerase Gamma Deficiency.

DNA polymerase subunit gamma (POLG) deficiency is likely the most frequent cause of nuclear-encoded mitochondrial disorders. POLG-related disorders reportedly constitute a spectrum of overlapping phenotypes from infancy to late adulthood. We retrospectively reviewed natural histories for 40 children carrying biallelic pathogenic POLG variants. The patients were identified by the French coordinating center for mitochondrial disorders (CARAMMEL), making this a large monocentric series on childhood-onset POLG deficiency. Three patterns of clinical course and survival were observed, distinguished by main category of symptoms: neurologic, hepatic, and gastrointestinal. A total of 24 patients needed urgent neurointensive care for tonic-clonic seizures, myoclonic epilepsy, and status epilepticus, occasionally precipitated by valproate administration. Other neurologic symptoms included dystonia, cerebellar ataxia, and peripheral neuropathy. We report 6 POLG-deficient patients with polyradiculoneuropathy mimicking subacute Guillain-Barré syndrome and provide postgadolinium MRI evidence of diffuse cranial nerve root and cauda equina enhancement, suggesting these disorders have an inflammatory component. Children presenting with enteral nervous system involvement had vomiting, gastroparesis, and chronic intestinal pseudo-obstruction. They had later ages of onset and lived much longer. Primarily, hepatic presentations had the earliest onset and shortest survivals. Secondary hepatic failure was frequently precipitated by valproate administration given before diagnosis to patients with focal impaired awareness seizures or absence of seizures. These POLG deficiencies were often fatal, with age at death ranging from 3 months to 10 years, with a significant difference in survival between the 3 clinical forms; 6 of the 40 children did survive. No genotype-phenotype correlations were found for the 3 clinical course types. The study demonstrates the prevalence of neurologic presentation and the extent of central, peripheral, and autonomous nervous system involvement in 60% of patients. Most of the patients with early onset and rapidly fatal hepatic failure did not live long enough to develop neurologic symptoms. The study revealed a new clinical form of POLG deficiency presenting with neurodigestive symptoms with longer lifespan. We also propose that POLG deficiency should be considered in children presenting with unexplained polyradiculoneuropathy, demyelinating neuropathy, and elevated CSF protein. Finally, valproate administration remains a notable cause of avoidable death in POLG-deficient patients.

A man who changed six spectacles: а case of Heidenhain variant of the Creutzfeldt–Jakob disease

Creutzfeldt–Jakob Disease (CJD) is a rare and rapidly progressive condition. A 54-year-old professor initially presented with insidious, progressive visual symptoms. Imaging suggested post-infectious encephalitis, but symptoms progressed to ataxia, coordination difficulties, and cognitive decline. Repeat MRI revealed findings consistent with CJD, supported by clinical and electrophysiological evidence. Though 14-3-3 protein in CSF was inconclusive, Heidenhain variant CJD was strongly suspected. Isolated visual symptoms progressing rapidly alongside ataxia and dementia prompt suspicion of this variant. Clinical examination, neuroimaging, and EEG play crucial roles in the diagnosis.

Cerebellitis following COVID-19 infection: A case-based systematic review and pooled analysis

BackgroundThe COVID-19 pandemic has been linked to neurological complications, including Cerebellitis. This study aims to investigate the clinical features, and consequences of Cerebellitis following COVID-19 infection, informing medical management strategies. MethodsA systematic search was conducted through PubMed, Web of Science, Embase, ProQuest, and Cochrane databases from January 2018 to September 12, 2023, on cases post-COVID-19. Demographics, clinical characteristics, and diagnostic techniques were analyzed using descriptive statistics. Chi-Square tests assessed associations between diagnoses and treatments, with visualizations including heatmaps and scatter plots. ResultsAfter the final Screening, the analysis of 18 cases revealed Cerebellitis post-COVID-19 spanned 9 countries, predominantly from the USA (27.8 %), with a mean patient age of 40.1 years (±24.6). Males comprised 94.4 % of cases. Common underlying conditions included hypertension (22.2 %) and diabetes (11.1 %). Neurological symptoms presented on average 15.15 ± 12.7 days post-COVID-19 infection. A moderate negative correlation (r = −0.358) was observed between age and symptom onset. Blood and CSF biomarkers showed weak correlations with symptom onset intervals. Treatment efficacy varied, with most cases achieving symptom-free outcomes. The Chi-Square test for diagnosis-treatment associations yielded a p-value of 0.089, and for follow-up outcomes, a p-value of 0.283, indicating no significant statistical associations. ConclusionThis systematic review highlights increased reports of Cerebellitis in males in their fourth decade of life, with the highest comorbidities being vascular diseases. Marker assessments show a decrease in CSF protein in half of patients, along with complete recovery following combination treatment with antivirals and steroids in acute Cerebellitis.

Evaluating the associations between intelligence quotient and multi-tissue proteome from the brain, CSF and plasma.

Intelligence quotient is a vital index to evaluate the ability of an individual to think rationally, learn from experience and deal with the environment effectively. However, limited efforts have been paid to explore the potential associations of intelligence quotient traits with the tissue proteins from the brain, CSF and plasma. The information of protein quantitative trait loci was collected from a recently released genome-wide association study conducted on quantification data of proteins from the tissues including the brain, CSF and plasma. Using the individual-level genotypic data from the UK Biobank cohort, we calculated the polygenic risk scores for each protein based on the protein quantitative trait locus data sets above. Then, Pearson correlation analysis was applied to evaluate the relationships between intelligence quotient traits (including 120 330 subjects for 'fluid intelligence score' and 38 949 subjects for 'maximum digits remembered correctly') and polygenic risk scores of each protein in the brain (17 protein polygenic risk scores), CSF (116 protein polygenic risk scores) and plasma (59 protein polygenic risk scores). The Bonferroni corrected P-value threshold was P < 1.30 × 10-4 (0.05/384). Finally, Mendelian randomization analysis was conducted to test the causal relationships between 'fluid intelligence score' and pre-specific proteins from correlation analysis results. Pearson correlation analysis identified significant association signals between the protein of macrophage-stimulating protein and fluid intelligence in brain and CSF tissues (P brain = 1.21 × 10-8, P CSF = 1.10 × 10-7), as well as between B-cell lymphoma 6 protein and fluid intelligence in CSF (P CSF = 1.23 × 10-4). Other proteins showed close-to-significant associations with the trait of 'fluid intelligence score', such as plasma protease C1 inhibitor (P CSF = 4.19 × 10-4, P plasma = 6.97 × 10-4), and with the trait of 'maximum digits remembered correctly', such as tenascin (P plasma = 3.42 × 10-4). Additionally, Mendelian randomization analysis results suggested that macrophage-stimulating protein (Mendelian randomization-Egger: β = 0.54, P = 1.64 × 10-61 in the brain; β = 0.09, P = 1.60 × 10-12 in CSF) had causal effects on fluid intelligence score. We observed functional relevance of specific tissue proteins to intelligence quotient and identified several candidate proteins, such as macrophage-stimulating protein. This study provided a novel insight to the relationship between tissue proteins and intelligence quotient traits.

Ventriculoperitoneal shunt complication in pediatric hydrocephalus: risk factor analysis from a single institution

Introduction: Ventriculoperitoneal (VP) shunt surgery is a commonly performed neurosurgical procedure. Complications due to shunt failure are associated with high morbidity and mortality. There is an absence of research in Indonesia that focuses on demographic factors related to complications from ventriculoperitoneal shunts. We report an analysis of risk factors for shunt failure in pediatric patients from a single institution Method: A retrospective analytical study with prospective data was designed. Pediatric patients with hydrocephalus were performed ventriculoperitoneal shunt in 5 years (January 2018 - December 2023). All of risk factors such as age, comorbidity, etiologies, types of shunts, CSF analysis were followed up. Result: 448 pediatric patients underwent VP shunts, and 175 of them had complications. The age group &lt;12 months, with 98 patients, noticed the highest number of complications of VP shunt. The logistic regression test showed that age, surgery duration, protein, CSF cells, and birth weight all had p-values &lt;0.05. The number of CSF cells has the largest OR value (OR = 136,800) (95% CI 27.185 – 688.391). The Kaplan Meier survival test showed that the age group (p 0.008, OR 0.580 and 95% CI 0.387 – 0.868). Conclusion: Patients under the age of six months had the highest incidence of VP shunt complications. Cell number, CSF protein, surgery duration, age, and birth weight all influence the risk of VP shunt complications in pediatric patients.

Impact of Cerebrospinal Fluid Leukocyte Infiltration and Neuroimmmune Mediators on Survival with HIV-Associated Cryptococcal Meningitis.

Cryptococcal meningitis remains a prominent cause of death in persons with advanced HIV disease. CSF leukocyte infiltration predicts survival at 18 weeks; however, how CSF immune response relates to CSF leukocyte infiltration is unknown. We enrolled 401 adults with HIV-associated cryptococcal meningitis in Uganda who received amphotericin and fluconazole induction therapy. We assessed the association of CSF leukocytes, chemokine, and cytokine responses with 18-week survival. Participants with CSF leukocytes ≥50/μL, had higher probability 68% (52/77) of 18-week survival compared with 52% (151/292) 18-week survival in those with ≤50 cells/μL (Hazard Ratio=1.63, 95% confidence intervals 1.14-2.23; p=0.008). Survival was also associated with higher expression of T helper (Th)-1, Th17 cytokines, and immune regulatory elements. CSF levels of Programmed Death-1 Ligand, CXCL10, and Interleukin (IL)-2 independently predicted survival. In multivariate analysis, CSF leukocytes were inversely associated with CSF fungal burden and positively associated with CSF protein, interferon-gamma (IFN-γ), IL-17A, tumor necrosis factor (TNF)-α, and peripheral blood CD4+ and CD8+ T cells expression. 18-week survival after diagnosis of cryptococcal meningitis was associated with higher CSF leukocytes at baseline with greater T helper 1 (IFN-γ, IL-2 and TNF-α cytokines), T helper 17 (IL-17A cytokine) and CXCR3+ T cell (CXCL10 chemokine) responses. These results highlight the interdependent contribution of soluble and cellular immune responses in predicting survival with HIV-associated cryptococcal meningitis.

Anti-neurofascin-155 antibody mediated a distinct phenotype of chronic inflammatory demyelinating polyradiculoneuropathy.

To investigate Ranvier's autoantibodies prevalence and isotypes in various peripheral neuropathy variants, compare clinical features between seronegative and seropositive patients, and elucidate immune mechanisms underlying antibody generation. Antibodies against anti-neurofascin-155 (NF155), NF186, contactin-1 (CNTN1), CNTN2, contactin-associated protein 1 (CASPR1), and CASPR2 were identified through cell-based assays. Plasma cytokines were analyzed in anti-NF155 antibody-positive chronic inflammatory demyelinating polyneuropathy (NF155+ CIDP) and Ranvier's antibodies-negative CIDP (Ab- CIDP) patients using a multiplexed fluorescent immunoassay, validated in vitro in a cell culture model. In 368 plasma samples, 50 Ranvier's autoantibodies were found in 45 individuals, primarily in CIDP cases (25 out of 69 patients) and in 10 out of 122 Guillain-Barré syndrome patients. Anti-NF155 and CNTN1-IgG were exclusive to CIDP. Fourteen samples were NF155-IgG, primarily IgG4 subclass, linked to CIDP features including early onset, tremor, sensory disturbance, elevated CSF protein, prolonged motor latency, conduction block, and poor treatment response. NF155-IgG had low sensitivity (20.28%) but high specificity (100%) for CIDP, rising to 88.88% with tremor and prolonged motor latency. Cytokine profiling in NF155+ CIDP revealed distinct immune responses involving helper T cells, toll-like receptor pathways. Some NF155+ CIDP patients had circulating NF155-specific B cells producing NF155-IgG without antigen presence, suggesting therapeutic potential. The study emphasizes the high specificity and sensitivity of NF155-IgG for diagnosing CIDP characterized by distinctive features. Further investigation into circulating NF155-specific B cell phenotypes may pave the way for B cell directed therapy.

Clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma.

The clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma (ND-DLBCL) remains largely unexplored. One hundredND-DLBCL patients were consecutively enrolled as training cohort and another 26 ND-DLBCL patients were prospectively enrolled in validation cohort. CSF-ctDNA positivity (CSF(+)) was identified in 25 patients (25.0%) in the training cohort and 7 patients (26.9%) in the validation cohort, extremely higher than CNS involvement rate detected by conventional methods. Patients with mutations of CARD11, JAK2, ID3, and PLCG2 were more predominant with CSF(+) while FAT4 mutations were negatively correlated with CSF(+). The downregulation of PI3K-AKT signaling, focal adhesion, actin cytoskeleton, and tight junction pathways were enriched in CSF(+) ND-DLBCL. Furthermore, pretreatment CSF(+) was significantly associated with poor outcomes. Three risk factors, including high CSF protein level, high plasma ctDNA burden, and involvement of high-risk sites were used to predict the risk of CSF(+) in ND-DLBCL. The sensitivity and specificity of pretreatment CSF-ctDNA to predict CNS relapse were 100% and 77.3%. Taken together, we firstly present the prevalence and the genomic and transcriptomic landscape for CSF-ctDNA(+) DLBCL and highlight the importance of CSF-ctDNA as a noninvasive biomarker in detecting and monitoring of CSF infiltration and predicting CNS relapse in DLBCL.

Assessment of glial fibrillary acidic protein and anti-glial fibrillary acidic protein autoantibody concentrations and necrotising meningoencephalitis risk genotype in dogs with pug dog myelopathy.

Pugs commonly present with thoracolumbar myelopathy, also known as pug dog myelopathy (PDM), which is clinically characterised by progressive signs involving the pelvic limbs, no apparent signs of pain and, often, incontinence. In addition to meningeal fibrosis and focal spinal cord destruction, histopathology has confirmed lymphohistiocytic infiltrates in the central nervous system (CNS) in a considerable number of pugs with PDM. Lymphohistiocytic CNS inflammation also characterises necrotising meningoencephalitis (NME) in pugs. This study aimed to investigate the potential contribution of an immunological aetiology to the development of PDM. The concentrations of glial fibrillary acidic protein (GFAP) in serum and CSF and of anti-GFAP autoantibodies in CSF were measured with an ELISA. In addition, a commercial test was used for genetic characterisation of the dog leukocyte antigen class II haplotype, which is associated with NME susceptibility. This study included 87 dogs: 52 PDM pugs, 14 control pugs, four NME pugs and 17 dogs of breeds other than pugs that were investigated for neurological disease (neuro controls). Anti-GFAP autoantibodies were present in 15 of 19 (79%) of the PDM pugs tested versus six of 16 (38%) of the neuro controls tested (p = 0.018). All 18 PDM pugs evaluated had detectable CSF GFAP. Serum GFAP was detected in two of three (67%) of the NME pugs and in two of 11 (18%) of the control pugs but not in any of the 40 tested PDM pugs. Male pugs heterozygous for the NME risk haplotype had an earlier onset of clinical signs (70 months) compared to male pugs without the risk haplotype (78 months) (p = 0.036). The study was limited bythe lack of healthy dogs of breeds other than pugs and the small numbers of control pugs and pugs with NME. The high proportion of PDM pugs with anti-GFAP autoantibodies and high CSF GFAP concentrations provide support for a potential immunological contribution to the development of PDM.

Biochemical, Biomarker, and Behavioral Characterization of the GrnR493X Mouse Model of Frontotemporal Dementia.

Heterozygous loss-of-function mutations in the progranulin gene (GRN) are a major cause of frontotemporal dementia due to progranulin haploinsufficiency; complete deficiency of progranulin causes neuronal ceroid lipofuscinosis. Several progranulin-deficient mouse models have been generated, including both knockout mice and knockin mice harboring a common patient mutation (R493X). However, the GrnR493X mouse model has not been characterized completely. Additionally, while homozygous GrnR493X and Grn knockout mice have been extensively studied, data from heterozygous mice is still limited. Here, we performed more in-depth characterization of heterozygous and homozygous GrnR493X knockin mice, which includes biochemical assessments, behavioral studies, and analysis of fluid biomarkers. In the brains of homozygous GrnR493X mice, we found increased phosphorylated TDP-43 along with increased expression of lysosomal genes, markers of microgliosis and astrogliosis, pro-inflammatory cytokines, and complement factors. Heterozygous GrnR493X mice did not have increased TDP-43 phosphorylation but did exhibit limited increases in lysosomal and inflammatory gene expression. Behavioral studies found social and emotional deficits in GrnR493X mice that mirror those observed in Grn knockout mouse models, as well as impairment in memory and executive function. Overall, the GrnR493X knockin mouse model closely phenocopies Grn knockout models. Lastly, in contrast to homozygous knockin mice, heterozygous GrnR493X mice do not have elevated levels of fluid biomarkers previously identified in humans, including neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in both plasma and CSF. These results may help to inform pre-clinical studies that use this Grn knockin mouse model and other Grn knockout models.

Neurological Involvement in a Portuguese Cohort of IgG4-Related Disease.

Neurological involvement in immunoglobulin G4-related disease (IgG4-RD) is increasingly recognized. Its diagnosis can be challenging due to clinical mimics and difficulty in obtaining nervous system biopsies. The aim of this study was to describe a cohort of neurological IgG4-RD patients. Patients were recruited from a neuroimmunology tertiary center. Clinical, laboratory, neuroimaging and histological data were reviewed. Fifteen patients (60% women), with a median age of 53 years (48.5 - 65.0) were included: 13 (86.7%) classified as possible IgG4-RD, one (6.7%) as probable and one (6.7%) as definitive. The most common neurological phenotypes were meningoencephalitis (26.7%), orbital pseudotumor (13.3%), cranial neuropathies (13.3%), peripheral neuropathy (13.3%), and longitudinally extensive transverse myelitis (LTEM) (13.3%). Median serum IgG4 concentration was 191.5 (145.0 - 212.0) mg/dL. Seven in 14 patients had CSF pleocytosis (50.0%) and oligoclonal bands restricted to the intrathecal compartment, while most cases presented elevated CSF proteins (64.3%). Magnetic resonance imaging abnormalities included white matter lesions in four (26.7%), hypertrophic pachymeningitis in two (13.3%), and LETM in two (13.3%). Two patients had biopsy-proven IgG4-RD in extra-neurological sites. This study highlights the phenotypical variability of the neurological IgG4-RD. Biopsy inaccessibility reinforces the importance of new criteria for the diagnosis of this subset of patients.

CSF neurofilament light chain profiling and quantitation in neurological diseases.

Neurofilament light chain is an established marker of neuroaxonal injury that is elevated in CSF and blood across various neurological diseases. It is increasingly used in clinical practice to aid diagnosis and monitor progression and as an outcome measure to assess safety and efficacy of disease-modifying therapies across the clinical translational neuroscience field. Quantitative methods for neurofilament light chain in human biofluids have relied on immunoassays, which have limited capacity to describe the structure of the protein in CSF and how this might vary in different neurodegenerative diseases. In this study, we characterized and quantified neurofilament light chain species in CSF across neurodegenerative and neuroinflammatory diseases and healthy controls using targeted mass spectrometry. We show that the quantitative immunoprecipitation-tandem mass spectrometry method developed in this study strongly correlates to single-molecule array measurements in CSF across the broad spectrum of neurodegenerative diseases and was replicable across mass spectrometry methods and centres. In summary, we have created an accurate and cost-effective assay for measuring a key biomarker in translational neuroscience research and clinical practice, which can be easily multiplexed and translated into clinical laboratories for the screening and monitoring of neurodegenerative disease or acute brain injury.

A Clinicopathological study of Guillain-Barrḗ Syndrome in a Tertiary Level Hospital

Background: Guillain-Barre syndrome (GBS) stands out as the most prevalent autoimmune neurological disorder. This investigation involves a comparative analysis of clinical observations, neurophysiological assessments, and cerebrospinal fluid examination, outcomes among patients with GBS. Method: A retrospective review of medical records constituted the methodology for this study, spanning from July 1, 2023, to December 31, 2023. Sociodemographic traits, antecedent illnesses, clinical progression, laboratory results, therapeutic interventions, and ultimate outcomes were assessed and compared among the study participants. Results: The study encompassed 8 patients, with an average age of 42.75 years. Respiratory complications were evident in 87.5% of the patients. In CSF analysis, 62.50% exhibited a normal cell count, while 37.50% displayed an elevated count. Elevated CSF protein levels were observed in 50% of patients, with a corresponding 50% revealing normal CSF protein levels. Increased CSF protein was associated with delayed lumbar puncture, demyelinating nerve conduction study subtype, and sensory motor variant. Regarding treatment modalities, 37.5% received intravenous immunoglobulin, and 25% underwent plasma exchange therapy. The acute phase of the disease resulted in a 25% mortality rate among patients. Conclusion: Guillain-Barre syndrome manifests diverse clinical presentations and laboratory findings. Notably, a high cerebrospinal fluid cell count challenges the widely accepted Brighton criteria for GBS diagnosis. Further investigations are warranted to elucidate the correlation between elevated CSF cell count and other factors influencing pathogenesis and outcomes in GBS patients. Bangladesh Crit Care J March 2024; 12 (1): 25-28