Cerebrospinal Fluid Assays Research Articles

Case 317

A 44-year-old previously healthy man with a 9-month history of progressive cognitive decline, depression, urinary incontinence, and inability to perform tasks of daily living presented to the emergency department with worsening cognitive and neuropsychiatric symptoms. He had become more distressed, and his family noticed him departing the house without closing doors, leaving water faucets running, and sending his children to school on Sundays. History taken from the patient's wife revealed that his brother had passed away in his late 30s after a slowly progressing functional and cognitive decline over the course of 5 years. No further detailed family history could be obtained. The review of systems was negative; he had no prior medical, psychiatric, or surgical history; and he denied any history of recent travel, camping, hiking, or vaccination. The patient was not taking any dietary supplements, nor was he taking any over-the-counter or prescription medication. Examination revealed vital signs were within normal limits. Neurocognitive assessment revealed a conscious, coherent, and alert patient with impaired memory and concentration. He showed poor attention, depressed mood, and restricted affect. He was unable to spell the word world forward, nor was he able to understand a request to spell it backward. The rest of the physical and neurologic examination revealed no abnormalities. Extensive laboratory work-up was conducted and included the following: toxicology screening; screening for HIV-1, HIV-2, and syphilis treponemal antibodies; COVID-19 polymerase chain reaction; and measurement of B1 and B12 levels. The results of screening were negative. Cerebrospinal fluid (CSF) assays, including CSF oligoclonal bands and CSF flow cytometry, revealed values within normal limits. CT of the brain without intravenous contrast material was performed in the emergency department to rule out acute intracranial abnormality (Fig 1). Multiplanar multisequence MRI of the brain without and with intravenous contrast material was ordered for further assessment (Figs 2-4). CT images of chest, abdomen, and pelvis were unremarkable (images not shown).

Cerebrospinal Fluid Biomarkers for the Early Detection of Alzheimer’s Disease Neuropathology (S15.005)

Cerebrospinal Fluid Biomarkers for the Early Detection of Alzheimer’s Disease Neuropathology (S15.005)

Association Between Cerebrospinal Fluid Biomarkers of Amyloid and Tau and Neuropsychiatric Symptoms Among Participants from the National Alzheimer’s Coordinating Center Uniform Data Set (P10-6.004)

Association Between Cerebrospinal Fluid Biomarkers of Amyloid and Tau and Neuropsychiatric Symptoms Among Participants from the National Alzheimer’s Coordinating Center Uniform Data Set (P10-6.004)

Sex hormones differentially contribute to Parkinson disease in males: A multimodal biomarker study.

Parkinson disease (PD) presents relevant sex-related differences in epidemiology, pathophysiology, and clinical features, with males being more vulnerable to the disease. Sex hormones might have a role, as the experimental models suggest; however, human-based evidence is scarce. Here, we integrated multimodal biomarkers to investigate the relationships between circulating sex hormones and clinical-pathological features in male PD patients. A cohort of 63 male PD patients underwent comprehensive clinical evaluation of motor and nonmotor disturbances; measurement of estradiol, testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) blood levels; and cerebrospinal fluid (CSF) assay of total α-synuclein, amyloid-β-42, amyloid-β-40, total tau, and phosphorylated-181 tau levels. A subgroup of 47 PD patients underwent brain volumetry by 3-T magnetic resonance imaging for further correlations. A control group of 56 age-matched individuals was enrolled for comparative analyses. Male PD patients had higher estradiol and testosterone levels than controls. Estradiol had independent inverse associations with Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part 3 score and disease duration; it was also lower in nonfluctuating patients. Testosterone had inverse independent correlations with CSF α-synuclein and right globus pallidus volume. FSH and LH had age-dependent correlations with cognitive impairment and CSF amyloid-β-42/amyloid-β-40 ratio. The study suggested that sex hormones could differentially contribute to clinical-pathological features of PD in male patients. Whereas estradiol might have a protective role in motor impairment, testosterone might be involved in male vulnerability to PD neuropathology. Gonadotropins instead might mediate age-dependent phenomena of amyloidopathy and cognitive decline.

Temporal Arteritis Caused by Tertiary Syphilis.

A 77-year-old man arrived at our hospital with bilateral shoulder pain persisting for several months and headache for 1 month. Giant cell arteritis with polymyalgia rheumatica was suspected. However, considering his medical history of testing positive for syphilis, we submitted a sample for a syphilis serology test, which yielded positive results. The Treponema pallidum hemagglutination assay of cerebrospinal fluid was positive, and a temporal artery biopsy revealed vasculitis, confirming the diagnosis of tertiary syphilis. He was successfully treated for two weeks with penicillin G infusions. Symptoms reminiscent of giant cell arteritis and polymyalgia rheumatica may reveal syphilis, which is called the "great imitator."

Central and peripheral α-synuclein in Parkinson disease detected by seed amplification assay.

Detection of α-synuclein aggregates by seed amplification is a promising Parkinson disease biomarker assay. Understanding intraindividual relationships of α-synuclein measures could inform optimal biomarker development. The objectives were to test accuracy of α-synuclein seed amplification assay in central (cerebrospinal fluid) and peripheral (submandibular gland) sources, compare to total α-synuclein measures, and investigate within-subject relationships. The Systemic Synuclein Sampling Study aimed to characterize α-synuclein in multiple tissues and biofluids within Parkinson disease subjects (n=59) and compared to healthy controls (n=21). Motor and non-motor measures and dopamine transporter scans were obtained. Four measures of α-synuclein were compared: seed amplification assay in cerebrospinal fluid and formalin-fixed paraffin-embedded submandibular gland, total α-synuclein quantified in biofluids using enzyme-linked immunoassay, and aggregated α-synuclein in submandibular gland detected by immunohistochemistry. Accuracy of seed amplification assay for Parkinson disease diagnosis was examined and within-subject α-synuclein measures were compared. Sensitivity and specificity of α-synuclein seed amplification assay for Parkinson disease diagnosis was 92.6% and 90.5% in cerebrospinal fluid, and 73.2% and 78.6% in submandibular gland, respectively. 25/38 (65.8%) Parkinson disease participants were positive for both cerebrospinal fluid and submandibular gland seed amplification assay. Comparing accuracy for Parkinson disease diagnosis of different α-synuclein measures, cerebrospinal fluid seed amplification assay was the highest (Youden Index=83.1%). 98.3% of all Parkinson disease cases had ≥1 measure of α-synuclein positive. α-synuclein seed amplification assay (cerebrospinal fluid>submandibular gland) had higher sensitivity and specificity compared to total α-synuclein measures, and within-subject relationships of central and peripheral α-synuclein measures emerged.

A Biomarker Study in Patients with GBA1-Parkinson's Disease and Healthy Controls.

Molecules related to glucocerebrosidase (GCase) are potential biomarkers for development of compounds targeting GBA1-associated Parkinson's disease (GBA-PD). Assessing variability of various glycosphingolipids (GSLs) in plasma, peripheral blood mononuclear cells (PBMCs), and cerebrospinal fluid (CSF) across GBA-PD, idiopathic PD (iPD), and healthy volunteers (HVs). Data from five studies were combined. Variability was assessed of glucosylceramide (various isoforms), lactosylceramide (various isoforms), glucosylsphingosine, galactosylsphingosine, GCase activity (using fluorescent 4-methylumbeliferryl-β-glucoside), and GCase protein (using enzyme-linked immunosorbent assay) in plasma, PBMCs, and CSF if available, in GBA-PD, iPD, and HVs. GSLs in leukocyte subtypes were compared in HVs. Principal component analysis was used to explore global patterns in GSLs, clinical characteristics (Movement Disorder Society - Unified Parkinson's Disease Rating Scale Part 3 [MDS-UPDRS-3], Mini-Mental State Examination [MMSE], GBA1 mutation type), and participant status (GBA-PD, iPD, HVs). Within-subject between-day variability ranged from 5.8% to 44.5% and was generally lower in plasma than in PBMCs. Extracellular glucosylceramide levels (plasma) were slightly higher in GBA-PD compared with both iPD and HVs, while intracellular levels were comparable. GSLs in the different matrices (plasma, PBMCs, CSF) did not correlate. Both lactosylceramide and glucosylsphingosine were more abundant in granulocytes compared with monocytes and lymphocytes. Absolute levels of GSL isoforms differed greatly. GBA1 mutation types could not be differentiated based on GSL data. Glucosylceramide can stably be measured over days in both plasma and PBMCs and may be used as a biomarker in clinical trials targeting GBA-PD. Glucosylsphingosine and lactosylceramide are stable in plasma but are strongly affected by leukocyte subtypes in PBMCs. GBA-PD could be differentiated from iPD and HVs, primarily based on glucosylceramide levels in plasma. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A comparative blind study between skin biopsy and seed amplification assay to disclose pathological α-synuclein in RBD

To compare the diagnostic accuracy of the immunofluorescence (IF) technique and aSyn-seed amplification assay (aSyn-SAA) of skin and cerebrospinal fluid (CSF) in disclosing pathological α-syn in idiopathic idiopathic REM sleep behavior disorder (iRBD) as early phase of a synucleinopathy. We prospectively recruited 41 patients with iRBD and 40 matched clinical controls including RBD associated with type 1 Narcolepsy (RBD-NT1, 21 patients), iatrogenic causes (2 pt) or OSAS (6 pt) and 11 patients with peripheral neuropathies. IF from samples taken by skin biopsy and aSyn-SAA from skin and CSF samples were analysed blinded to the clinical diagnosis. IF showed a good diagnostic accuracy (89%) that was lower in the case of skin and CSF-based aSyn-SAA (70% and 69%, respectively) because of a lower sensitivity and specificity. However, IF showed a significant agreement with CSF aSyn-SAA. In conclusion, our data may favor the use of skin biopsy and aSyn-SAA as diagnostic tools for a synucleinopathy in iRBD.

Quantitation of neurofilament light chain protein in serum and cerebrospinal fluid from patients with multiple sclerosis using the MSD R-PLEX NfL assay.

Neurofilament light (NfL) chain is a marker of neuroaxonal damage in various neurological diseases. Here we quantitated NfL levels in the cerebrospinal fluid (CSF) and serum from patients with multiple sclerosis (MS) and controls, using the R-PLEX NfL assay, which employs advanced Meso Scale Discovery® (MSD) electrochemiluminescence (ECL)-based detection technology. NfL was quantitated in samples from 116 individuals from two sites (Ottawa Hospital Research Institute and Mayo Clinic), consisting of patients with MS (n=71) and age- and sex-matched inflammatory neurological controls (n=13) and non-inflammatory controls (n=32). Correlation of NfL levels between CSF and serum was assessed in paired samples in a subset of MS patients and controls (n=61). Additionally, we assessed the correlation between NfL levels obtained with MSD's R-PLEX® and Quanterix's single molecule array (Simoa®) assays in CSF and serum (n=32). Using the R-PLEX, NfL was quantitated in 99% of the samples tested, and showed a broad range in the CSF (82-500,000ng/L) and serum (8.84-2,014ng/L). Nf-L levels in both biofluids correlated strongly (r=0.81, p<0.0001). Lastly, Nf-L measured by MSD's R-PLEX and Quanterix's Simoa assays were highly correlated for both biofluids (CSF: r=0.94, p<0.0001; serum: r=0.95, p<0.0001). We show that MSD's R-PLEX NfL assay can reliably quantitate levels of NfL in the CSF and serum from patients with MS and controls, where levels correlate strongly with Simoa.

Application of a six sigma model to evaluate the analytical performance of cerebrospinal fluid biochemical analytes and the design of quality control strategies for these assays: A single-centre study

BackgroundIn this study, we applied a six sigma model to examine cerebrospinal fluid (CSF) biochemical analytes for the first time. Our goal was to evaluate the analytical performance of various CSF biochemical analytes, design an optimized internal quality control (IQC) strategy, and formulate scientific and reasonable improvement plans. MethodsThe sigma values of CSF total protein (CSF-TP), albumin (CSF-ALB), chloride (CSF-Cl), and glucose (CSF-GLU) were calculated using the following formula: sigma = [TEa(%)−|bias(%)|]/CV(%). The analytical performance of each analyte was shown using a normalized sigma method decision chart. Individualized IQC schemes and improvement protocols for CSF biochemical analytes were formulated using the Westgard sigma rule flow chart with batch size and quality goal index (QGI). ResultsThe distribution of sigma values for CSF biochemical analytes ranged from 5.0 to 9.9, and the sigma values varied for different concentrations of the same analyte. The analytical performance of the CSF assays at the two QC levels is displayed visually in normalized sigma method decision charts. Individualized IQC strategies for CSF biochemical analytes were as follows: for CSF-ALB, CSF-TP and CSF-Cl, use 13s with N = 2 and R = 1000; for CSF-GLU, use 13s/22s/R4s with N = 2 and R = 450. In addition, priority improvement measures for analytes with sigma values less than 6 (CSF-GLU) were formulated based on the QGI, and their analytical performance was improved after the corresponding improvement measures were taken. ConclusionsThe six sigma model has significant advantages in practical applications involving CSF biochemical analytes and is highly useful for quality assurance and quality improvement.

Comparing neuroimaging and cerebrospinal fluid markers of amyloid, tau, and neurodegenerative biomarkers: implications for understanding the biology of the disease

AbstractBackgroundAlzheimer disease (AD) is a complex disorder characterized by changes in amyloid, tau, as well as neurodegeneration. Neuroimaging and cerebrospinal fluid (CSF) assays provide complimentary measures of these pathologies although the Correspondence between such biomarkers is not well elucidated.MethodsData from 313 cognitively unimpaired and 59 impaired individuals aged 45 to 91 was drawn from the Charles F. and Joanne Knight Alzheimer Disease Research Center. Participants had neuroimaging, CSF, and clinical data acquired within one year. Neuroimaging variables included summary measures of amyloid (Centiloids from either PiB or Florebetapir), tau (Flortaucipir), and atrophy (MRI cortical signature). CSF variables were the Aβ42/40 ratio, ptau181, and neurofilament light chain (NfL). Biomarker cutoffs were determined using Gaussian‐Mixture modeling as well as a Youden Index to maximally separate cognitively unimpaired individuals from those with a clinical AD diagnosis. Rank order congruence between biomarkers was determined using Kendall correlations (t).ResultsGaussian Mixture Modeling (dashed lines) and Youden Index (solid lines) approaches produced disparate cutoffs, particularly for neurodegenerative markers (NfL/atrophy) indicating the challenges inherent to binarizing continuous variables (Figure 1). Kendall’s t provide an estimate of pairwise congruence between biomarkers in cognitively unimpaired (CN, CDR=0, upper left diagonal) and impaired individuals (CI, CDR &gt;0, lower right diagonal) (Figure 2). Measures of amyloid had generally high concordance (t ‐0.45 and ‐0.43 for CN and CI respectively ) than those of non‐specific neurodegeneration, which were quite low (t ‐0.16 and ‐0.23). Although ptau181 and tau were moderately related (t 0.21 and 0.23), ptau181 had higher Correspondence with both PET and CSF measures of amyloid. A sequential timing of biomarkers could be clearly seen when plotting z‐scored biomarkers as a function of amyloid PET (Figure 3).ConclusionsNeuroimaging and CSF markers provide complimentary information and help to deeply phenotype the AD biological cascade. While measures of amyloid are highly congruent, non‐specific markers of neurodegeneration have poor agreement., CSF measures of phosphorylated tau likely index a response to amyloidosis rather than being a marker of tau aggregation.

Comparing neuroimaging and cerebrospinal fluid markers of amyloid, tau, and neurodegenerative biomarkers: implications for understanding the biology of the disease

AbstractBackgroundAlzheimer disease (AD) is a complex disorder characterized by changes in amyloid, tau, as well as neurodegeneration. Neuroimaging and cerebrospinal fluid (CSF) assays provide complimentary measures of these pathologies although the Correspondence between such biomarkers is not well elucidated.MethodsData from 313 cognitively unimpaired and 59 impaired individuals aged 45 to 91 was drawn from the Charles F. and Joanne Knight Alzheimer Disease Research Center. Participants had neuroimaging, CSF, and clinical data acquired within one year. Neuroimaging variables included summary measures of amyloid (Centiloids from either PiB or Florebetapir), tau (Flortaucipir), and atrophy (MRI cortical signature). CSF variables were the Aβ42/40 ratio, ptau181, and neurofilament light chain (NfL). Biomarker cutoffs were determined using Gaussian‐Mixture modeling as well as a Youden Index to maximally separate cognitively unimpaired individuals from those with a clinical AD diagnosis. Rank order congruence between biomarkers was determined using Kendall correlations (t).ResultsGaussian Mixture Modeling (dashed lines) and Youden Index (solid lines) approaches produced disparate cutoffs, particularly for neurodegenerative markers (NfL/atrophy) indicating the challenges inherent to binarizing continuous variables (Figure 1). Kendall’s t provide an estimate of pairwise congruence between biomarkers in cognitively unimpaired (CN, CDR=0, upper left diagonal) and impaired individuals (CI, CDR &gt;0, lower right diagonal) (Figure 2). Measures of amyloid had generally high concordance (t ‐0.45 and ‐0.43 for CN and CI respectively ) than those of non‐specific neurodegeneration, which were quite low (t ‐0.16 and ‐0.23). Although ptau181 and tau were moderately related (t 0.21 and 0.23), ptau181 had higher Correspondence with both PET and CSF measures of amyloid. A sequential timing of biomarkers could be clearly seen when plotting z‐scored biomarkers as a function of amyloid PET (Figure 3).ConclusionsNeuroimaging and CSF markers provide complimentary information and help to deeply phenotype the AD biological cascade. While measures of amyloid are highly congruent, non‐specific markers of neurodegeneration have poor agreement., CSF measures of phosphorylated tau likely index a response to amyloidosis rather than being a marker of tau aggregation.

Blood based biomarkers for movement disorders.

Movement disorders have been carefully clinically defined, based on clinico-pathological series; however there is often diagnostic and prognostic uncertainty, especially in early stage disease. Blood-based biomarkers for Alzheimer's disease (AD), particularly p-tau181 and p-tau217, may be useful in the movement disorder clinic, especially in identifying corticobasal syndrome due to AD pathology and in identifying Parkinson's disease (PD) patients at high risk for the future development of dementia. Serum or plasma neurofilament light (NfL) may be useful in separating Parkinson's plus syndromes (progressive supranuclear palsy-PSP, multiple system atrophy - MSA, and corticobasal syndrome-CBS) from PD. NfL is also a prognostic biomarker, in that the level of baseline or cross-sectional plasma/serum NfL is associated with a worse prognosis in PD and PSP. The development of protein aggregation assays in cerebrospinal fluid and multiplex assays which can measure 100 s-1000s of proteins in blood will provide new tools and insights for movement disorders for clinicians and researchers. The challenge is in efficiently integrating these tools into clinical practice and multi-modal approaches, where biomarkers are combined with clinical, genetic, and imaging data may guide the future use of these technologies.

S7.1d Reliability of bedside point-of-care tests for Candida neoformans , M. tuberculosis and S. pneumoniae in adults living with HIV presenting with suspected central nervous system infection (CNS) in low- and middle-income settings: Preliminary results from the DREAMM study

S7.1 Update in management of fungal infection in adult hematology, September 23, 2022, 10:30 AM - 12:00 PMBackgroundBedside point-of-care (POC) testing, with parallel laboratory testing, represents a unique opportunity to improve and speed up the diagnostic workup of people living with HIV with suspected CNS infection in resource-limited settings.ObjectivesTo assess the agreement between POC tests for Cryptococcus neoformans, Mycobacterium tuberculosis, and Streptococcus pneumoniae performed at the bedside and in the routine laboratory, in African low- and middle-income countries (LMICs).MethodsFrom January 2018 to March 2021, the following POC tests were performed in parallel at the bedside and in the routine laboratory: Cryptococcal antigen lateral flow assay (CrAg LFA, Immy) in blood and cerebrospinal fluid (CSF), tuberculosis lipoarabinomannan (TB-LAM, Alere) in urine, and, where indicated, pneumococcal antigen (Streptococcus pneumoniae (SP), Biosynex) in CSF.Participants: HIV-infected adults (>18 years old) suspected of CNS infection.Setting: The prospective multicenter DREAMM project (Driving Reduced AIDS Meningo-Encephalitis Mortality) in five hospital sites in Cameroon, Malawi, and Tanzania.Primary outcome: Cohen's kappa statistic of agreement between the results of POC tests obtained at the bedside and the routine laboratory.ResultsThe study included 356 consecutive participants (mean age 39.5 +/- 10 years; 68.7% ART-experienced; 46.3% male; median CD4 count 75/mm3; abnormal mental status 75%). In total, 148/355 (41.7%) participants had positive bedside CrAg in blood, 140/315 (44.4%) positive bedside CrAg in CSF, 64/339 (18.9%) positive bedside TB-LAM in urine, and 10/175 (5.7%) positive bedside SP in CSF. Kappa statistics evaluating agreement between bedside and laboratory test results were: 0.98 [95% confidence interval (CI) 0.96-1.00; n = 347] for blood CrAg, 0.99 (95%CI, 0.98-1.00; n = 307) for CSF CrAg, 0.92 (95% CI, 0.87-0.98; n = 330) for urinary TB-LAM, and 0.68 (95%CI, 0.40-0.96; n = 34) for CSF SP.ConclusionsBedside POC tests for Cryptococcus spp. are highly reliable and can be safely performed in parallel to laboratory testing to expedite targeted treatment in people living with HIV with suspected CNS infection in African LMICs. Other bedside POC tests need further evaluation before large-scale implementation.

CEACAM6 serves as a biomarker for leptomeningeal metastasis in lung adenocarcinoma.

Diagnosis of leptomeningeal metastasis (LM) is challenging. In our previous study, CEACAM6 mRNA was found to be highly expressed in the circulating tumor cells of cerebrospinal fluid (CSF) from patients with lung adenocarcinoma with LM (LUAD-LM). The aim of this study was to identify whether CEACAM6 could be used as a biomarker for LUAD-LM. The level of CEACAM6 was determined by enzyme-linked immunosorbent assay (ELISA) in CSF from 40 LUAD-LM and 44 normal controls, and additional serum samples from 138 LUAD patients, including 12 LUAD-LM patients, and 30 healthy controls. Carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA 21-1) and neuron-specific enolase (NSE) levels in the CSF and sera were detected by chemiluminescent immunoassay. Receiver operating characteristic curve was plotted to evaluate the diagnostic performance for LUAD-LM. CSF CEACAM6 level was higher in LUAD-LM than that in normal controls. In serum, LUAD patients had a higher level of CAECAM6 than healthy controls, and LM patients had the highest level among them. Serum CEACAM6 had a higher AUC than CEA in differentiating LM from non-LM in LUAD patients (0.95 vs. 0.64, p < 0.001). CEACAM6 may serve as a potential biomarker in diagnosing LUAD-LM.

Outcome of Lenalidomide Treatment for Cognitive Impairment Caused by Immune Reconstitution Inflammatory Syndrome in Patients with HIV-Related Cryptococcal Meningitis.

PurposeCognitive impairment associated with human immunodeficiency virus (HIV)-related cryptococcal meningitis (HCM) in the context of immune reconstitution inflammatory syndrome is difficult to address. This study was a follow-up of lenalidomide treatment outcomes in patients with HCM and cognitive impairment after complete cryptococcal clearance.Patients and MethodsSeven HCM patients with neuroinflammation and cognitive impairment after complete cryptococcal clearance were enrolled in this prospective study. Neurocognitive assessment, clinical examination and cerebrospinal fluid (CSF) assays were performed before and after lenalidomide treatment.ResultsAfter lenalidomide treatment, the Montreal Cognitive Assessment [week (W) 0 (median [interquartile range]: 23.0 (13.0–24.0) vs W24: 26.0 (24.0–28.00), P=0.018] and International HIV Dementia Scale scores [W0: 9.0 (2.5–10.5) vs W24: 11.0 (10.00–12.0), P=0.028] improved significantly, mainly in the domain of memory function. There was no significant difference in the Center for Epidemiological Research Depression scores for anxiety and depression before and after treatment. Further stratified analyses revealed that the patients with cognitive improvement group had higher levels of CSF white blood cells [94.0 (44.0–180.0) vs 0 (0–1.5), P=0.032], CSF protein [4.9 (3.0–6.6) vs 0.6 (0.5–0.7), P=0.034], CSF albumin [318.5 (190.9–346.5) vs 33.5 (30.4–46.2), P=0.034], and CSF IgG [160.5 (73.8–256. 0) vs 4.7 (4.3–7.4), P=0.034] but a lower CSF glucose level [2.4 (2.0–2.7) vs 2.8 (2.8–3.9), P=0.032] than the patients with cognitive non-improvement group before treatment. CSF inflammatory cytokines of the growth-related oncogene, interleukin [IL]-10, granulocyte-colony stimulating factor, IL-6, IL-8, complement factor H, tumor necrosis factor-α, and α-2 macroglobulin were obviously decreased in patients with cognitive improvement group after lenalidomide treatment.ConclusionLenalidomide potentially reduces cognitive impairment caused by immune reconstitution inflammatory syndrome in patients with HCM after cryptococcal clearance by inhibiting intracranial inflammation.

Central Nervous System Involvement in Dengue Virus Type 1 Infection: A Pediatric Case Series

AbstractCentral nervous system involvement accounted for 0.5 to 21.2% of dengue virus infections. Dengue virus type 2 and type 3 were commonly found in patients with central nervous system manifestations, while dengue virus type 1 (DENV-1) was rarely reported. We reported three dengue fever cases with neurological complications associated with DENV-1 infection. A previously healthy boy presented with fever, agitation, and an altered mental status in the first case. The other two cases presented with fever and seizures. All of them had no plasma leakage from dengue infection. DENV-1 was detected by reverse transcriptase-polymerase chain reaction assay in cerebrospinal fluid, serum, or both. All three cases were resolved entirely without neurological sequelae. This study can alert hospitals to prepare for the next epidemic in which there could be increasing cases of unusual or severe manifestations of dengue.

FDA Clears First In Vitro Assay to Improve Alzheimer’s Diagnosis

Back to table of contents Previous article Next article Clinical & ResearchFull AccessFDA Clears First In Vitro Assay to Improve Alzheimer’s DiagnosisNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:22 Jul 2022https://doi.org/10.1176/appi.pn.2022.08.7.15AbstractThe assay, which measures the ratio of two forms of amyloid protein, was cleared through the FDA’s De Novo premarket review, a regulatory pathway for low- to moderate-risk devices of a new type.The Food and Drug Administration (FDA) has cleared for marketing the first diagnostic laboratory test to aid in the diagnosis of Alzheimer’s disease. The Lumipulse G β-Amyloid Ratio (1-42/1-40) test, manufactured by Fujirebio Inc., is intended for use in adults aged 55 years and older who present with cognitive impairment.The test measures two variants of the amyloid beta protein in cerebrospinal fluid (CSF). A positive result suggests that a patient likely has amyloid plaques in the brain—a hallmark feature of Alzheimer’s disease.Amyloid plaques can be identified definitively only with positron emission tomography (PET) brain scans—a process that is time consuming, expensive, and exposes people to radiation. A lumbar puncture to acquire CSF, though potentially uncomfortable, is cheaper than a PET scan and can usually be performed on an outpatient basis.“A lot of people are looking ahead to blood-based Alzheimer’s biomarkers, but the CSF will always be a better source than plasma, because it has a direct connection with the brain,” said Anne Fagan, Ph.D., a professor of neurology at Washington University School of Medicine and the Fluid Biomarker Core Leader of Washington University’s Knight Alzheimer Disease Research Center. Fagan, who has received research support from Fujirebio and other diagnostic companies, says she has used Lumipulse assays in her Alzheimer’s research studies and found them to be easy to work with and reliable.“With this test now available, I think that more patients will get an early confirmation of an Alzheimer’s diagnosis,” said Henrik Zetterberg, M.D., Ph.D., a professor of neurochemistry at the University of Gothenburg in Sweden. Zetterberg, who also studies Alzheimer’s biomarkers, noted that an early diagnosis can give patients more time to try treatments that may slow cognitive decline and prepare for the future.There are, however, limits to what the Lumipulse test can tell patients and their physicians, Fagan said.“This is not giving you a diagnosis of Alzheimer’s; it’s giving a diagnosis of amyloidosis.” She noted that amyloid buildup is associated with other neurodegenerative disorders, such as Lewy body dementia. In addition, many people can develop amyloid plaques and not yet have the associated neurodegeneration that would lead to dementia, she said.The FDA noted that the results of the Lumipulse test should be interpreted in conjunction with other clinical information before any diagnoses are made.The FDA cleared the Lumipulse test following a study of CSF samples from 292 older adults participating in the Alzheimer’s Disease Neuroimaging Initiative. In this clinical study, 97% of adults with a positive Lumipulse test had amyloid plaques in their brains as confirmed by PET scan, while only 16% of adults with a negative Lumipulse test had confirmed amyloid plaques. The low rate of false positive results in the study suggests that those scanned with the test are unlikely to be incorrectly diagnosed with amyloid plaques, which could result in unnecessary treatments and psychological distress. False negative test results could lead to potential delays in diagnosis.Zetterberg said that as other CSF assays come to market, the testing process will become even more comprehensive, which may enhance accuracy and/or uncover the specific underlying disorder. “That’s another advantage of CSF testing; it is very versatile. One can screen for numerous different biomarkers in the same sample,” he said. “With a PET scan, you can see amyloid and only amyloid.”Both Zetterberg and Fagan believe PET scans still have use in clinical settings. “Scans have drawbacks, but they do give a spatial representation of the amyloid buildup, which may impact clinical decision-making,” Fagan said. ■ResourcesThe FDA Statement on the Clearance of the Lumipulse G β-Amyloid Ratio (1-42/1-40) test ISSUES NewArchived

α-Synuclein Seed Amplification in CSF and Brain from Patients with Different Brain Distributions of Pathological α-Synuclein in the Context of Co-Pathology and Non-LBD Diagnoses.

The purpose of this study was to determine the sensitivity and specificity of α-synuclein seed amplification assay (αSyn-SAA) in antemortem and postmortem cerebrospinal fluid (CSF) of autopsy-confirmed patients with different distributions of pathological αSyn, co-pathologies, and clinical diagnoses. The αSyn-SAA was used to test antemortem CSF samples from 119 subjects with a variety of clinical syndromes and standardized neuropathological examinations from Oregon Health and Science University (OHSU) and University of California San Diego (UCSD; 56 additional postmortem CSF samples available). The αSyn-SAA was also applied to frontal cortex and amygdala homogenates. Sensitivity and specificity were compared across distributions of αSyn pathology. Clinical data and co-pathologies were compared across αSyn-SAA positive and negative groups. Fifty-three individuals without and 66 with αSyn-pathology (neocortical [n=38], limbic [n=7], and amygdala-predominant [n=21]) were included. There was a sensitivity of 97.8% and specificity of 98.1% of the αSyn-SAA to identify patients with limbic/neocortical pathology from antemortem CSF. Sensitivity to detect amygdala-predominant pathology was only 14.3%. Postmortem CSF and brain tissue αSyn-SAA analyses also showed higher assay positivity in samples from limbic/neocortical cases. CSF αSyn-SAA reliably identifies αSyn seeds in patients with diffuse αSyn pathology in the context of co-pathology and non-Lewy body disease (LBD) diagnoses. The analysis of brain homogenates suggests that pathological αSyn in the amygdala might differ from pathological αSyn in the frontal cortex. The αSyn-SAA might facilitate the differential diagnosis of dementias with mixed pathologies. ANN NEUROL 2022;92:650-662.

Simultaneous Determination of Ceftazidime and Avibactam in Human Plasma and Cerebrospinal Fluid by High-Performance Liquid Chromatography – Tandem Mass Spectrometry (HPLC-MS/MS)

A method is reported for the simultaneous determination of ceftazidime and avibactam in human plasma and cerebrospinal fluid utilizing high-performance liquid chromatography – tandem mass spectrometry (HPLC-MS/MS). The validated method was used to monitor the drugs in the treatment of central nervous system infections. The analytes were extracted from plasma and cerebrospinal fluid by simple protein precipitation using acetonitrile. A reversed-phase HSS T3 column (5.0 μm, 4.6 × 100 mm, Waters) was employed for the separation with a total analysis time of 5 minutes. Ceftazidime and avibactam eluted in 2.15 min and 2.87 min, respectively. The acquisition was separated into two periods to allow analysis in different ionization modes. A multi-reaction monitoring analysis was performed with the transition m/z 547.2–468.1 for ceftazidime, and m/z 552.3–468.1 for ceftazidime-d5 (positive mode), m/z 263.9–96.1 for avibactam, and m/z 136.8–92.8 for salicylic acid (negative mode). The plasma calibration curves of the analytes displayed good linearity across the range from 1 to 100 μg/mL for ceftazidime and 0.1–20 μg/mL for avibactam. Calibration curves for cerebrospinal fluid assay were established from 0.4 to 16 μg/mL (ceftazidime) and 0.2–8 μg/mL (avibactam). The accuracy was between 89.5% and 108.5%. The within- and between-batch precisions with the relative standard deviation were lower than 15%. The developed method had no observed matrix effects. The analytes were stable during the analytical and sample processing. The developed and validated method was successfully applied in routine clinical practice and helps to assess the adequacy of therapy and ensure sufficient ceftazidime and avibactam levels in central nervous system infections.