Cerebrospinal Fluid Studies Research Articles

Cryptococcus Infection in an Immunocompetent Patient

A case of a 26-year-old female who was apparently healthy without any comorbidities presented with a history of headache, which was gradually progressive over 2 months with features suggestive of raised intracranial pressure. Cerebrospinal fluid (CSF) study was done, which revealed chronic meningitis. Indian ink staining of CSF showed Cryptococcus, and the species was identified as Cryptococcus gattii. She did not have any respiratory symptoms, but the chest radiography showed a consolidative patch caused by growing yeasts mimicking a mass. Cryptococcal infection is rarely seen in immunocompetent individuals. Among the two species of Cryptococcus, C. gattii is known to cause infections in immunocompetent. It is imperative to have a high index of suspicion and early diagnosis of such a condition to avoid unwanted complications in patients.

Cytotoxic Lesion of Corpus Callosum after COVID-19 Vaccination: Case Report

Purpose: Cytotoxic lesions of corpus callosum (CLOCCs) are associated with many disease entities. Serious neurological complications after coronavirus disease 2019 (COVID-19) vaccination are rare. Case report: A 20-year-old man presented with severe headache for 2 days. He had received the first dose of ChAdOx1nCoV-19 COVID-19 vaccine 5 days ago. Persistent dull headache occurred on the third day after vaccination and intensified gradually to awaken him from sleep at night. No neck stiffness was observed. Brain magnetic resonance angiography (MRA) 9 days after vaccination revealed an oval-shaped diffusion-weighted restriction lesion at the splenium of corpus callosum with a mildly high signal intensity on T2-weighted images (T2WI) and low signal intensity on apparent diffusion coefficient (ADC) imaging but without enhancement after contrast injection. A COVID-19 polymerase chain reaction test was negative. A blood test revealed slight leukocytopenia, thrombocytopenia, and hyponatremia. Further autoimmune and hematological studies were normal. A cerebrospinal fluid study revealed normal intracranial pressure. The patient’s headache improved gradually. Follow-up brain MRA 5 weeks after vaccination revealed complete disappearance of the diffusion-weighted restriction lesion of the splenium. Conclusion: CLOCCs are rare transient adverse effect of COVID-19 vaccination possibly related to a cytokine storm. The splenic lesion might disappear spontaneously with a good prognosis.

Is foramen magnum decompression for acquired Chiari I malformation like putting a finger in the dyke? - A simplistic overview of artificial intelligence in assessing critical upstream and downstream etiologies.

Missed diagnosis of evolving or coexisting idiopathic (IIH) and spontaneous intracranial hypotension (SIH) is often the reason for persistent or worsening symptoms after foramen magnum decompression for Chiari malformation (CM) I. We explore the role of artificial intelligence (AI)/convolutional neural networks (CNN) in Chiari I malformation in a combinatorial role for the first time in literature, exploring both upstream and downstream magnetic resonance findings as initial screening profilers in CM-1. We have also put together a review of all existing subtypes of CM and discuss the role of upright (gravity-aided) magnetic resonance imaging (MRI) in evaluating equivocal tonsillar descent on a lying-down MRI. We have formulated a workflow algorithm MaChiP 1.0 (Manjila Chiari Protocol 1.0) using upstream and downstream profilers, that cause de novo or worsening Chiari I malformation, which we plan to implement using AI. The PRISMA guidelines were used for "CM and machine learning and CNN" on PubMed database articles, and four articles specific to the topic were encountered. The radiologic criteria for IIH and SIH were applied from neurosurgical literature, and they were applied between primary and secondary (acquired) Chiari I malformations. An upstream etiology such as IIH or SIH and an isolated downstream etiology in the spine were characterized using the existing body of literature. We propose the utility of using four selected criteria for IIH and SIH each, over MRI T2 images of the brain and spine, predominantly sagittal sequences in upstream etiology in the brain and multiplanar MRI in spinal lesions. Using MaChiP 1.0 (patent/ copyright pending) concepts, we have proposed the upstream and downstream profilers implicated in progressive Chiari I malformation. The upstream profilers included findings of brain sagging, slope of the third ventricular floor, pontomesencephalic angle, mamillopontine distance, lateral ventricular angle, internal cerebral vein-vein of Galen angle, and displacement of iter, clivus length, tonsillar descent, etc., suggestive of SIH. The IIH features noted in upstream pathologies were posterior flattening of globe of the eye, partial empty sella, optic nerve sheath distortion, and optic nerve tortuosity in MRI. The downstream etiologies involved spinal cerebrospinal fluid (CSF) leak from dural tear, meningeal diverticula, CSF-venous fistulae, etc. AI would help offer predictive analysis along the spectrum of upstream and downstream etiologies, ensuring safety and efficacy in treating secondary (acquired) Chiari I malformation, especially with coexisting IIH and SIH. The MaChiP 1.0 algorithm can help document worsening of a previously diagnosed CM-1 and find the exact etiology of a secondary CM-I. However, the role of posterior fossa morphometry and cine-flow MRI data for intracranial CSF flow dynamics, along with advanced spinal CSF studies using dynamic myelo-CT scanning in the formation of secondary CM-I is still being evaluated.

Be Alert to ALERD: Acute Leukoencephalopathy with Restricted Diffusion—Atypical Presentation of a Rare Case

AbstractAcute leukoencephalopathy with restricted diffusion (ALERD) is a novel entity observed in children with acute encephalopathy. It is characterized by diffusion restriction on magnetic resonance imaging (MRI), which can be the distinctive and sometimes the only imaging finding. Other routine MRI sequences may appear normal. ALERD can have infectious or noninfectious causes. In this case, we present a patient with infectious ALERD associated with influenza B virus. A 10-year-old boy presented to the emergency room with a brief history of fever and cough, followed by altered sensorium. He was irritable and ataxic. Neck stiffness was elicited upon examination. An MRI of the brain showed extensive symmetric diffusion restriction in the periventricular and deep white matter, corpus callosum, posterior limb of the internal capsule, and cerebral peduncles of both cerebral hemispheres. Cerebrospinal fluid study, blood and urine toxicology panels were noncontributory. The respiratory panel test was positive for influenza B. A diagnosis of infectious ALERD was made. Following treatment with steroids, intravenous immunoglobulin, antiglutamate agents, and supportive measures, he showed clinical and radiological improvement. The reporting of ALERD has risen in recent years due to its increased detection using MRI. Diffusion-weighted image plays the key role in the final diagnosis. Supportive care and prompt treatment of seizures are very important for better outcome. Follow-up imaging is also required to assess reappearance of white matter edema and development of cerebral atrophy or gliosis.

Ocular Manifestations of Multiple Sclerosis: A Population-Based Study.

To evaluate the population-based frequency and severity of multiple sclerosis (MS)-related ocular diseases. Retrospective, population-based study examining patients with MS between January 1, 1998 and December 31, 2011. Patients were identified using the Rochester Epidemiology Project, which is a record-linkage system of medical records for all patient-physician encounters among Olmsted County, Minnesota residents. Diagnosis of MS was confirmed based on neuroimaging, cerebrospinal fluid studies, and serum studies for each patient according to the 2017 McDonald criteria. Patient data were obtained using the medical records and followed through April 1, 2018. Of the 116 patients with MS, 66% were female and the median age of onset was 36 years (interquartile range 27.5-43.5 years). About half (61/116, 53%) had MS-related neuro-ophthalmic manifestations during their disease course, and about one-fourth (33/116, 28%) had visual symptoms as their presenting symptom of MS, most commonly as optic neuritis (26/116, 22%). Optic neuritis was the leading MS-related ocular condition (37%), followed by internuclear ophthalmoplegia (16%) and nystagmus (13%). Optic neuritis was mostly unilateral (40/43, 93%), with 16% (6/43) having a visual acuity of 20/200 or worse at nadir but ultimately 95% (35/37) improving to a visual acuity of 20/40 or better. This study provides the population-based frequency of MS-related ocular disease, which demonstrates a high frequency of ocular manifestations in MS both at disease onset and during the disease course, emphasizing the utility of neuro-ophthalmologists, or collaboration between neurologists and ophthalmologists, in the care of patients with MS.

Outbreak analysis of meningococcal meningitis: A case series from a tertiary care hospital in Eastern India

In a span of 4 months, there were 7 cases of meningococcal meningitis who presented with diagnostic dilemma and also a few atypical manifestations. A retrospective data analysis was carried out in children diagnosed with meningococcal meningitis who were admitted from October 2022 to January 2023. There were 7 confirmed cases of Neisseria meningitidis infections during the study period. The median age of presentation was 6 years (range: 4.5 months–9 years) with four males and three females. All the children presented with fever, but none had signs of meningeal irritation as such. Routine blood and cerebrospinal fluid (CSF) analysis were also near normal. Reverse transcriptase polymerase chain reaction (RT-PCR) for N. meningitidis was positive in the CSF samples of all the seven cases. All of the patients recovered completely, except that there were residues of neurodeficit in one patient. In endemic areas, pediatricians should have a low threshold of suspicion for N. meningitidis in children presenting with signs and symptoms involving the central nervous system and consider an RT-PCR of the CSF sample even if routine blood and CSF studies are near normal.

Human herpesvirus-6 infection in a critically ill and immunocompetent patient: a case report

BackgroundHuman herpesvirus-6 is a rare infection in an immunocompetent adult. In existing literature, there is a dearth of knowledge that mainly exists as case reports and case series.Case PresentationIn this case report, we described a 29-year-old female of Myanmarese descent patient from Myanmar who presented with altered mental status and non-specific respiratory and gastrointestinal symptoms. She was initially treated for pneumonia and discharged well. However, she re-presented to the hospital and was subsequently treated for severe central nervous system infection. Cerebrospinal fluid studies detected human herpesvirus-6 polymerase chain reaction with associated high serum human herpesvirus-6 concentration. This infection also triggered hemophagocytic lymphohistiocytosis. Treatment was initiated against both human herpesvirus-6 infection and hemophagocytic lymphohistiocytosis, and she responded to antiviral treatment and steroids, respectively.ConclusionThis case study highlights the need for prompt diagnosis and treatment of this severe disease and the dangerous complications. Additionally, the authors share insights on the diagnostic challenges faced in the treatment of this patient.

Pro-inflammatory cerebrospinal fluid profile of neonates with intraventricular hemorrhage: clinical relevance and contrast with CNS infection.

Interpretation of cerebrospinal fluid (CSF) studies can be challenging in preterm infants. We hypothesized that intraventricular hemorrhage (IVH), post-hemorrhagic hydrocephalus (PHH), and infection (meningitis) promote pro-inflammatory CSF conditions reflected in CSF parameters. Biochemical and cytological profiles of lumbar CSF and peripheral blood samples were analyzed for 81 control, 29 IVH grade 1/2 (IVH1/2), 13 IVH grade 3/4 (IVH3/4), 15 PHH, 20 culture-confirmed bacterial meningitis (BM), and 27 viral meningitis (VM) infants at 36.5 ± 4weeks estimated gestational age. PHH infants had higher (p < 0.02) CSF total cell and red blood cell (RBC) counts compared to control, IVH1/2, BM, and VM infants. No differences in white blood cell (WBC) count were found between IVH3/4, PHH, BM, and VM infants. CSF neutrophil counts increased (p ≤ 0.03) for all groups compared to controls except IVH1/2. CSF protein levels were higher (p ≤ 0.02) and CSF glucose levels were lower (p ≤ 0.003) for PHH infants compared to all other groups. In peripheral blood, PHH infants had higher (p ≤ 0.001) WBC counts and lower (p ≤ 0.03) hemoglobin and hematocrit than all groups except for IVH3/4. Similarities in CSF parameters may reflect common pathological processes in the inflammatory response and show the complexity associated with interpreting CSF profiles, especially in PHH and meningitis/ventriculitis.

Evaluation of enterovirus concentration, species identification, and cerebrospinal fluid parameters in patients of different ages with aseptic meningitis in São Paulo, Brazil.

Human enteroviruses (EV) are the most common cause of aseptic meningitis worldwide. Data on EV viral load in cerebrospinal fluid (CSF) and related epidemiological studies are scarce in Brazil. This study investigated the influence of EV viral load on CSF parameters, as well as identifying the involved species. CSF samples were collected in 2018-2019 from 140 individuals at The Hospital das Clínicas, São Paulo. The EV viral load was determined usingreal-time quantitative polymerase chain reaction,while EV species were identified by5'UTR region sequencing.Median viral load was 5.72 log10 copies/mL and did not differ by subjects'age and EV species. Pleocytosis was observed in 94.3% of cases, with the highest white blood cell (WBC) counts in younger individuals. Viral load and WBC count were correlated in children (p = 0.0172). Elevated lactate levels were observed in 60% of cases and correlated with the viral load in preteen-teenagers (p = 0.0120) and adults (p = 0.0184). Most individuals had normal total protein levels (70.7%), with higher in preteen-teenagers and adults (p < 0.0001). By sequencing, 8.2% were identified as EV species A and 91.8% as species B. Age-specific variations in CSF characteristics suggest distinct inflammatory responses in each group.

Biomarkers in Alzheimer's Disease: Are Olfactory Neuronal Precursors Useful for Antemortem Biomarker Research?

Alzheimer's disease (AD), as the main cause of dementia, affects millions of people around the world, whose diagnosis is based mainly on clinical criteria. Unfortunately, the diagnosis is obtained very late, when the neurodegenerative damage is significant for most patients. Therefore, the exhaustive study of biomarkers is indispensable for diagnostic, prognostic, and even follow-up support. AD is a multifactorial disease, and knowing its underlying pathological mechanisms is crucial to propose new and valuable biomarkers. In this review, we summarize some of the main biomarkers described in AD, which have been evaluated mainly by imaging studies in cerebrospinal fluid and blood samples. Furthermore, we describe and propose neuronal precursors derived from the olfactory neuroepithelium as a potential resource to evaluate some of the widely known biomarkers of AD and to gear toward searching for new biomarkers. These neuronal lineage cells, which can be obtained directly from patients through a non-invasive and outpatient procedure, display several characteristics that validate them as a surrogate model to study the central nervous system, allowing the analysis of AD pathophysiological processes. Moreover, the ease of obtaining and harvesting endows them as an accessible and powerful resource to evaluate biomarkers in clinical practice.

Primary amebic meningoencephalitis: a review of Naegleria fowleri and analysis of successfully treated cases.

Primary amebic meningoencephalitis (PAM) is a necrotizing and hemorrhagic inflammation of the brain and meninges caused by Naegleria fowleri, a free-living thermophilic ameba of freshwater systems. PAM remains a neglected disease that disproportionately affects children in tropical and subtropical climates, with an estimated mortality rate of 95-98%. Due to anthropogenic climate change, the average temperature in the USA has increased by 0.72 to 1.06 °C in the last century, promoting the poleward spread of N. fowleri. PAM is often misdiagnosed as bacterial meningitis or viral encephalitis, which shortens the window for potentially life-saving treatment. Diagnosis relies on the patient's history of freshwater exposure and the physician's high index of suspicion, supported by cerebrospinal fluid studies. While no experimental trials have been conducted to assess the relative efficacy of treatment regimens, anti-amebic therapy with adjunctive neuroprotection is standard treatment in the USA. We performed a literature review and identified five patients from North America between 1962 and 2022 who survived PAM with various degrees of sequelae.

Deep and unbiased proteomics, pathway enrichment analysis, and protein-protein interaction of biomarker signatures in migraine.

Currently, there are no biomarkers for migraine. We aimed to identify proteomic biomarker signatures for diagnosing, subclassifying, and predicting treatment response in migraine. This is a cross-sectional and longitudinal study of untargeted serum and cerebrospinal fluid (CSF) proteomics in episodic migraine (EM; n = 26), chronic migraine (CM; n = 26), and healthy controls (HC; n = 26). We developed classification models for biomarker identification and natural clusters through unsupervised classification using agglomerative hierarchical clustering (AHC). Pathway analysis of differentially expressed proteins was performed. Of 405 CSF proteins, the top five proteins that discriminated between migraine patients and HC were angiotensinogen, cell adhesion molecule 3, immunoglobulin heavy variable (IGHV) V-III region JON, insulin-like growth factor binding protein 6 (IGFBP-6), and IGFBP-7. The top-performing classifier demonstrated 100% sensitivity and 75% specificity in differentiating the two groups. Of 229 serum proteins, the top five proteins in classifying patients with migraine were immunoglobulin heavy variable 3-74 (IGHV 3-74), proteoglycan 4, immunoglobulin kappa variable 3D-15, zinc finger protein (ZFP)-814, and mediator of RNA polymerase II transcription subunit 12. The best-performing classifier exhibited 94% sensitivity and 92% specificity. AHC separated EM, CM, and HC into distinct clusters with 90% success. Migraine patients exhibited increased ZFP-814 and calcium voltage-gated channel subunit alpha 1F (CACNA1F) levels, while IGHV 3-74 levels decreased in both cross-sectional and longitudinal serum analyses. ZFP-814 remained upregulated during the CM-to-EM reversion but was suppressed when CM persisted. CACNA1F was pronounced in CM persistence. Pathway analysis revealed immune, coagulation, glucose metabolism, erythrocyte oxygen and carbon dioxide exchange, and insulin-like growth factor regulation pathways. Our data-driven study provides evidence for identifying novel proteomic biomarker signatures to diagnose, subclassify, and predict treatment responses for migraine. The dysregulated biomolecules affect multiple pathways, leading to cortical spreading depression, trigeminal nociceptor sensitization, oxidative stress, blood-brain barrier disruption, immune response, and coagulation cascades. NCT03231241, ClincialTrials.gov.

A Case of Creutzfeldt–Jakob disease with psychiatric presentation

ABSTRACT Creutzfeldt–Jakob disease (CJD) belongs to the group of fatal neurodegenerative disorders known as prion diseases. We are going to describe the case of a 54-year-old married man who initially presented with rapidly progressive cognitive decline along with behavioral symptoms and was subsequently diagnosed with probable CJD. He presented with 1½ months history of disinhibited behavior, decreased social interaction, persecutory ideas, food refusal, and decreased sleep along with cognitive decline. On examination, the patient had myoclonus and ataxia. Routine blood investigations, serological tests, and autoimmune and paraneoplastic profiles were normal. Injection haloperidol 2.5 mg intramuscular for behavioral symptoms was given with no improvement. The cerebrospinal fluid study revealed positive results for 14-3-3 protein. The patient was diagnosed with probable CJD and subsequently passed away within 1 month of presentation. Thus, CJD should be kept in the differential diagnosis of patients with cognitive decline and persistent behavioral symptoms despite standard psychiatric treatment.

Atypical Manifestation of Zoster Meningitis Presented with Headache and Multiple Cerebral Vasoconstrictions

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by headaches and multiple transient cerebral vasoconstrictions. Central nervous system (CNS) infections related to the varicella zoster virus (VZV) can complicate various neurological disorders, including cerebral vasculopathy. We present the case of a patient who complained of a severe headache without any other symptoms or focal neurological signs. Brain magnetic resonance angiography showed multiple focal stenoses, especially in the right middle cerebral artery (MCA), and transcranial Doppler sonography revealed increased velocities in the MCA and right anterior cerebral artery. Initially, the headache was attributed to RCVS, and nimodipine infusion was initiated; however, the headache worsened. A cerebrospinal fluid study showed pleocytosis, increased protein levels, and positive polymerase chain reaction markers for VZV. No skin lesions or fever were observed during treatment. Our case emphasizes considering VZV meningitis as a cause of cerebral vasoconstriction, even in the absence of typical signs of CNS infection.

Observation of Clinical Profile of Different Types of Meningitis in a Tertiary Care Hospital

Background: Meningitis, an inflammation of the membranes surrounding the brain and spinal cord, presents significant diagnostic challenges due to its varied etiologies and overlapping clinical symptoms. This study aims to observe and document the clinical and laboratory characteristics of viral, bacterial, and tubercular meningitis in a tertiary care hospital setting. Methods: This descriptive observational study was conducted at the Department of Neuromedicine, Cumilla Medical College Hospital, Bangladesh, from January 2020 to December 2020. We enrolled 159 patients diagnosed with meningitis based on clinical, biochemical, and investigative criteria. Detailed demographic data, clinical examination findings, and relevant investigations, including cerebrospinal fluid (CSF) studies, were recorded. Data analysis was performed using SPSS software version 20 and MS-Excel 2016. Results: Among the 159 participants, 36.7% were diagnosed with bacterial meningitis, 32.5% with viral meningitis, and 24.9% with tubercular meningitis. Fever was a universal symptom, while headache was reported by 87.3% of viral, 87.1% of bacterial, and 95.2% of tubercular meningitis patients. Vomiting was more prevalent in tubercular (57.1%) and bacterial (50%) meningitis. Laboratory findings showed the highest mean white blood cell count in bacterial meningitis (11803.18±2905.55 cells/cmm). C-reactive protein levels were also highest in bacterial meningitis (21.23±16.20 mg/dl). Elevated adenosine deaminase levels were a distinguishing feature of tubercular meningitis (14.18±10.60 Unit/L). Conclusion: This study highlights the distinct clinical and laboratory profiles associated with different types of meningitis. The findings emphasize the importance of comprehensive evaluations for accurate diagnosis and effective management of meningitis. Further research should aim to refine diagnostic criteria and explore advanced diagnostic tools to improve patient outcomes. , , , , , ,

Autoimmune Retinopathy in a Patient with Stiff-Person Syndrome: A Case Report.

To describe a patient who developed retinal degeneration associated with autoimmune retinopathy (AIR) and who was also found to have anti-glutamic acid decarboxylase (GAD65) autoantibodies and the diagnosis of stiff-person syndrome (SPS). Ophthalmologic workup consisted of clinical examination, multi-modality retinal imaging, and electrophysiologic testing. Further neurologic assessment including relevant serum and cerebrospinal fluid studies was also conducted. We highlight the case of a 45-year-old patient who developed subacute, sequential vision loss, along with bilateral lower extremity weakness. On initial presentation, optical coherence tomography (OCT) of the left eye was notable for diffuse attenuation of the outer retinal bands. Fundus autofluorescence demonstrated a ring of hyper-autofluorescence encircling the fovea of the left eye. At fifteen-month follow-up, the right eye also became similarly affected. He was found to have elevated serum and cerebrospinal anti-GAD65 autoantibodies and was diagnosed with both SPS and AIR. There is a potential association of anti-GAD65 autoantibodies with the development of AIR.

Genomic atlas of human cerebrospinal fluid and brain metabolomics provides in‐depth understanding of cellular mechanism for neurodegeneration

AbstractBackgroundBrain metabolism is critical for the pathological mechanism of neurodegeneration. However, most metabolite quantitative trait loci (MQTL) studies have used tissues other than brain or cerebrospinal fluid (CSF) and are not ideal for neurodegeneration. We therefore pursued a large‐scale brain and CSF study to identify metabolites contributing to 27 brain‐related diseases.MethodWe obtained 440 metabolites in 2311 CSF samples and 962 metabolites in 1016 brain samples (WashU, ROSMAP, MAYO). We identified MQTL and performed metabolome‐wide association study (MWAS) to identify metabolites affecting diseases. Mendelian randomization (MR) and colocalization was performed for causality and shared genetic regulations.ResultWe identified 192 associations for 144 CSFmetabolites at 102 loci. Of those, 122 associations and 24 loci were novel, indicating tissue specificity. The brain study found 35 associations at 27 loci. Through MWAS, we identified 57 metabolites associated with 17 traits, in which 21 colocalized. Of the eight metabolites associated with AD, succinylcarnitine and adenine were causal. Succinylcarnitine was associated with AD risk gene LACTB, which product regulates lipid metabolism in mitochondrial, where succinylcarnitine generates energy. Both succinylcarnitine and LACTB have been implicated in obesity, a risk factor for AD. For Parkinson disease (PD), low galactosylglycerol level was causal, with signal colocalized at GALC with PD. The knockout of GALC gene prevented alpha‐synuclein accumulation in PD mice model, indicating that galactosylceramidase contributed to the development of PD. For cognitive performance, high levels of three metabolites (6‐oxopiperidine‐2‐carboxylate, 3‐hydroxyisobutyrate and argininosuccinate) were causal for low cognition, with additional support from colocalization and literature evidences. Pyridoxine‐dependent epilepsy patients, often with impaired cognition, had increased level of 6‐oxopiperidine‐2‐carboxylate. AD patients who underwent medium chain triglycerides treatment and improved cognition had changed level of beta‐hydroxybutyrate, related to 3‐hydroxyisobutyrate. Moreover, argininosuccinate lyase deficiency patients often develop severe cognitive impairment and seizures.ConclusionOur large‐scale CSF and brain MQTL study identified tissue‐specific MQTLs and multiple metabolites contributing to neurodegenerative disorders. Our results expand the knowledge on neurodegeneration, providing insights to neurodegeneration etiology, including AD, PD, and cognitive function.

Proteo‐genomics of soluble TREM2 in cerebrospinal fluid provides novel insights for TREM2 biology and identifies novel modulators for Alzheimer’s disease

AbstractBackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer’s disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). Here, we pursued the largest CSF study to identify additional novel genetic modifiers of sTREM2.MethodWe performed the genome‐wide association study (GWAS) of CSF sTREM2 in 3350 individuals of European ancestry from eight cohorts. To identify functional genes, we performed multi‐ethnic fine mapping with 250 non‐European individuals. Functional validation using peripheral blood mononuclear cell‐derived macrophages was performed. Colocalization and Mendelian randomization (MR) was performed for the causality of sTREM2 in AD.ResultThe known MS4A locus and three novel loci were identified at genome‐wide significance. In the MS4A locus, we identified two independent missense variants (p.M178V in MS4A4A and p.A112T in MS4A6A) that drove the association through multi‐ethnic fine mapping. They showed an epistatic effect for sTREM2 and AD risk. The novel TREM2 locus on chromosome 6 contained two rare missense variants (rs142232675 p.D87N, P = 2.71×10‐10; rs75932628 p.R47H, P = 7.16×10‐19) associated with sTREM2 and AD risk. Another novel locus in the intergenic region between TGFBR2 and RBMS3 (rs73823326, P = 3.86×10‐9) included a regulatory variant with a microglia‐specific chromatin loop for promoters of TGFBR2. Using cell‐ based assays we demonstrate that TGFBR2, but not RBMS3, modify sTREM2 levels. The last novel locus NECTIN2 on chromosome 19 (rs11666329, P = 2.52×10‐8) was independent of APOE genotype and colocalized with cis‐eQTL of NECTIN2 in the brain cortex and cis‐pQTL of NECTIN2 in CSF (PP.H4 = 0.83). This variant was also associated with AD risk (P = 1.52×10‐66) and age at onset (P = 3.26×10‐5). Our MR results confirmed the significant protective effect of sTREM2 on reducing AD risk.ConclusionTo our knowledge, this is the largest study to date aiming at identifying genetic modifiers of CSF sTREM2. We provided novel insights for MS4A and TREM2, the two well‐ known gens for AD risk. We also identified TGFBR2 and NECTIN2 as additional modulators involved in TREM2 biology. Our findings provide new insight to unravel sTREM2 modulators and their role in AD.

Optic nerve sheath diameter and severity of central nervous infection

Background Central nervous system (CNS) infection affects the brain, and can cause cerebral edema, increased intracranial pressure (ICP), cerebral herniation, and death. Measurement of the optic nerve sheath diameter (ONSD) by ultrasound is a new, non–invasive examination to predict ICP, with high sensitivity and specificity.Objective To analyze for a possible association between ONSD measured by ultrasonographic examination and severity of CNS infection.&#x0D; Methods This cross–sectional study was performed in the Pediatric Department of Hasan Sadikin Hospital, Bandung, West Java. Subjects were chosen by consecutive sampling. We measured ONSD, examined clinical manifestations, as well as performed a cerebrospinal fluid (CSF) study and imaging of CNS infection. Data analysis was done by paired T–test and one–way ANOVA, followed by Tukey test on significant variables.&#x0D; Results Subjects consisted of 32 children with CNS infection. The most common clinical symptoms were fever, decreased consciousness, and nuchal rigidity. Bivariate analysis revealed strong positive associations between ONSD and Glasgow Coma Scale (GCS), increased protein levels in CSF, and type of CNS infection.&#x0D; Conclusion Larger ONSD is significantly associated with lower GCS, increases CSF protein, and particular CNS infections. The ONSD is also associated with meningitis tuberculosis grade III, with a higher mean ONSD of both eyes compares to other CNS infections. Hence, the higher the ONSD, the more severe the degree of CNS infection.

Primary CNS Lymphoma in Latin America: A Grupo De Estudio Latinoamericano De Linfoproliferativos (GELL) Survey in 80 Cancer Centers in Latin America

Introduction: Primary Central Nervous System Lymphoma (PCNSL) is a rare and aggressive subtype of lymphoma, representing 4-6% of extranodal lymphomas. Management of PCNSL involves a multidisciplinary approach which includes neurosurgery, ophthalmology, radiotherapy, autologous stem cell transplantation (ASCT) and the use of novel agents such as BTK-inhibitors, immunomodulatory agents and chimeric antigen receptor T-cell (CAR-T cell) therapy. These strategies can be costly and not readily available in developing countries. GELL, a multinational group for studying lymphoproliferative disorders, conducted a multicenter international survey to investigate the diagnosis, clinical staging and treatment patterns in Latin America (LATAM). Methods: We conducted an on-line survey consisting of 22 questions regarding diagnostic and treatment patterns of PCNSL in LATAM. All invited centers agreed to participate and contributed for the development of the survey. No identifiable patient information was abstracted at any time during the survey. Questions were structured based on 3 pillars: (1) diagnostic approach, including available biopsy procedures, immunohistochemistry markers, ophthalmology evaluation, flow cytometry and molecular testing; (2) first line therapy, including preferred regimens used for both transplant eligible and ineligible patients, and availability of novel agents, and (3) consolidation therapies including ASCT and whole brain radiation therapy (WBRT) Results: A total of 90 surveys were completed from 80 cancer centers in LATAM. Geographical distribution of the participating cancer centers are as followed: Argentina (n=11), Bolivia (n=2), Brazil (n=9), Chile (n=5), Colombia (n=17), Cuba (n=1), Ecuador (n=5), Mexico (n=10), Panama (n=1), Paraguay (n=4), Peru (n=5), Dominican Republic (n=1), Uruguay (n=5) and Venezuela (n=4). Most centers treat up to 5 new cases of PCNSL/year (84%), with only 3 centers treating more than 15 cases/year. Stereotaxic biopsy was the preferred diagnostic procedure in 78%, and complete resection was done in a minority of centers (3%). Cerebrospinal fluid studies were done in 82% and flow cytometry was available in 87% of the centers. Only 65% of centers had access to PET-CT at diagnosis. Interestingly, 80% of the physicians performed bone marrow biopsy at diagnosis, and ophthalmology evaluation was not available in 20% of the centers. Regarding IHC markers, EBV-LEMP was available in 55% and PDL-1 in only 38% of the centers. FISH for Myc/Bcl2 was performed in 32% and molecular testing in only 23% of the centers. The median time for treatment initiation was 0-10 days in 36%, 10-20 days in 37% and &amp;gt;30 days in 26% of the centers. Regarding first line therapy, MATRIX regimen was the preferred regimen for fit transplant eligible patients in 53% of the participants. However, thiotepa was not readily available as per 45% of the survey participants. Methotrexate (MTX) with Cytarabine was the preferred regimen for 36% of participants. Interestingly, serum monitoring of MTX was not available in 27% of the centers. ASCT was the preferred consolidation regimen for transplant eligible patients (78%), and the most used conditioning regimen was BEAM (49%), suggesting an impact of not availability of thiotepa in these centers. For transplant ineligible patients, MTR (27%), MATRIX (22%) and R-MVP (19%) were the preferred regimens, and 32% of survey participants considered WBRT as the preferred consolidation for these patients. Regarding relapsed/refractory (R/R) PCNSL, MTX-based salvage therapy was the preferred regimen in 38%, followed by cytarabine based in 23% and BTK-inhibitor based in 20% of the participants. CAR-T cell therapy was available in only 3 centers. Conclusion: Management of PCNSL is highly variable in LATAM. Access to targeted agents and novel therapies such as CAR-T cell therapy is limited. Moreover, most centers lack basic diagnostic approaches such as serum MTX level monitoring and ophthalmology evaluation. Lack of access to thiotepa was a common issue encountered by most cancer centers in LATAM. The use of thiotepa-containing regimens has demonstrated improved survivals both as consolidation and in the R/R setting. Thus, the absence of such agent in LATAM carries a profound impact on PCNSL outcomes in this area of the world. A retrospective evaluation on PNCSL outcomes is planned by the GELL group to better investigate our results.