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1.
J Neurol ; 271(6): 3471-3485, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38430272

ABSTRACT

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neurodegenerative disease. This multicenter, randomized phase 3 study evaluated the efficacy and safety of 0.3 mg/kg intravenous mogamulizumab, a monoclonal antibody targeting-CC chemokine receptor 4, every 12 weeks in HAM/TSP patients. This study comprised a 24-week double-blind, placebo-controlled period, 24-week open-label period, and extension treatment period. The primary endpoint was the proportion of patients with a ≥ 1-grade improvement in the Osame motor disability score (OMDS). Secondary endpoints were changes in HTLV-1 proviral load, 10-m timed walk, cerebrospinal fluid (CSF) neopterin levels, and safety. The exploratory endpoint was CSF chemokine C-X-C motif ligand 10 (CXCL10) levels. Thirty-four and 33 patients were randomized to mogamulizumab and placebo arms, respectively. At the end of the double-blind period, no significant difference was found in the OMDS improvement rate or other secondary efficacy endpoints assessing motor activities. However, the mogamulizumab arm showed a significant decrease in HTLV-1 proviral load (- 59.39 ± 29.91% vs. placebo 2.32 ± 36.31%) and CSF neopterin (p < 0.001)/CXCL10 levels (p = 0.004). The baseline OMDS pattern and the 60-80% HTLV-1 proviral load reduction were sustained through the open-label and extension treatment periods. Although a higher incidence of rash (69.2%) was reported, the safety profile was similar compared with a previous phase 1/2a study. We found no significant difference in clinical benefit; however, mogamulizumab may provide long-term clinical benefit by preventing disease progression, as CSF neopterin/CXCL10 levels are associated with long-term prognosis in HAM/TSP.Clinical Trial Registration Number: NCT03191526 (registered date: 6-June-2017).


Subject(s)
Antibodies, Monoclonal, Humanized , Human T-lymphotropic virus 1 , Neopterin , Paraparesis, Tropical Spastic , Humans , Double-Blind Method , Antibodies, Monoclonal, Humanized/administration & dosage , Male , Middle Aged , Female , Paraparesis, Tropical Spastic/drug therapy , Paraparesis, Tropical Spastic/cerebrospinal fluid , Adult , Aged , Neopterin/cerebrospinal fluid , Human T-lymphotropic virus 1/drug effects , Chemokine CXCL10/cerebrospinal fluid , Viral Load/drug effects , Treatment Outcome
2.
J Neuroimmune Pharmacol ; 18(4): 551-562, 2023 12.
Article in English | MEDLINE | ID: mdl-37906406

ABSTRACT

The prevalence of neurocognitive impairment in people living with HIV is estimated between 30 and 50%. The pathogenesis of HIV-associated neurocognitive disorders is complex and multifactorial. Aim of the study was to measure the change in CSF biomarkers, Fibroscan and IMT measurements in PLWH with HAND randomized to a less neurotoxic regimen, or continuing their treatment. Adult patients with HAND were screened and enrolled if presenting no major resistance associated mutations, no HIV viral replication, not on efavirenz or darunavir, with R5-tropic HIV and without major confounding conditions. Lumbar puncture, IMT and Fibroscan measurements were performed. After 1:1 randomization to a less neurotoxic regimen consisting of darunavir/cobicistat plus emtricitabine plus maraviroc, or mantaining actual care, tests were repeated after 24 weeks: CSF biomarkes (HIV RNA, tau, p-tau, Beta-amyloid1-42, S100Beta and neopterin) were included. Non-parametric tests (Mann-Whitney and Wilcoxon's) were used. 28 participants completed the study. Male and European ancestry were prevalent; median age was 55 years (51-60). All patients were virally suppressed; median CD4 + count was 626 cell/uL (469-772). Baseline characteristics were similar between the study arms. A significant decrease in CSF p-tau and an increase in CSF neopterin and NFL were observed. We observed a significant reduction in liver stiffness at W24. Despite a small sample size we observed changes in neuromarkers and in hepatic stiffness in patients randomized to the experimental arm. We observed changes in CSF biomarkers (lower phosphorylated-tau and higher neopterin and NFL) that need to be replicated in large cohorts. Subclinical neurotoxicity may be observed in patients with HAND and warrants prospective studies.


Subject(s)
Carotid Intima-Media Thickness , HIV Infections , Adult , Humans , Male , Middle Aged , Biomarkers/cerebrospinal fluid , Darunavir , HIV Infections/complications , HIV Infections/drug therapy , Liver , Neopterin/cerebrospinal fluid , Neopterin/therapeutic use , Neurocognitive Disorders/diagnostic imaging , Neurocognitive Disorders/epidemiology , Neurocognitive Disorders/chemically induced , Prospective Studies , Viral Load , Female
3.
Hematol Oncol ; 41(4): 762-767, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37302122

ABSTRACT

Diagnosis of neuro-histiocytosis is challenging and relies on clinical presentation, imaging, and cerebrospinal fluid (CSF) analysis to exclude differential diagnoses. Brain biopsy remains the gold standard for accurate diagnosis, but it is rarely performed because of the risk of the procedure and the low rentability in neurodegenerative presentation. Therefore, there is an unmet need to identify a specific biomarker for diagnosing neurohistiocytosis in adults. Because microglia (brain macrophages) is involved in the pathogenesis of neurohistiocytosis and produces neopterin secondary to aggression, the purpose of our study was to evaluate the value of the CSF neopterin levels for the diagnosis of active neurohistiocytosis. Of the 21 adult patients with histiocytosis, four patients had clinical symptoms compatible with neurohistiocytosis. In the two patients with a confirmed diagnosis of neurohistiocytosis, CSF neopterin levels were elevated as well as IL-6 and IL-10 levels. In contrast, the two other patients in whom the diagnosis of neurohistiocytosis was infirmed and all other patients with histiocytosis without active neurological disease involvement had normal CSF neopterin levels. In summary, increased CSF neopterin concentration represented a valuable tool for diagnosing active neuro-histiocytosis in adults with histiocytic neoplasms in this preliminary study.


Subject(s)
Hematologic Neoplasms , Histiocytosis , Humans , Adult , Neopterin/cerebrospinal fluid , Biomarkers , Brain
4.
J Neuroimmune Pharmacol ; 18(1-2): 169-182, 2023 06.
Article in English | MEDLINE | ID: mdl-37166552

ABSTRACT

Plasma C-X-C-motif chemokine ligand-13 (CXCL13) has been linked to disease progression and mortality in people living with HIV (PLWH) and is a candidate target for immune-based strategies for HIV cure. Its role in central nervous system (CNS) of PLWH has not been detailed. We described CSF CXCL13 levels and its potential associations with neurological outcomes. Cross-sectional study enrolling PLWH without confounding for CXCL13 production. Subjects were divided according to CSF HIV-RNA in undetectable (< 20 cp/mL) and viremics. CSF CXCL13, and biomarkers of blood-brain barrier (BBB) impairment, intrathecal synthesis, and immune activation were measured by commercial immunoturbidimetric and ELISA assays. All subjects underwent neurocognitive assessment. Sensitivity analyses were conducted in subjects with intact BBB only. 175 participants were included. Detectable CSF CXCL13 was more common in the viremic (31.4%) compared to the undetectable group (13.5%; OR 2.9 [1.4-6.3], p = 0.006), but median levels did not change (15.8 [8.2-91.0] vs 10.0 [8.1-14.2] pg/mL). In viremics (n = 86), CXCL13 associated with higher CSF HIV-RNA, proteins, neopterin, intrathecal synthesis and BBB permeability. In undetectable participants (n = 89), CXCL13 associated with higher CD4+T-cells count, CD4/CD8 ratio, CSF proteins, neopterin, and intrathecal synthesis. The presence of CXCL13 in the CSF of undetectable participants was associated with increased odds of HIV-associated neurocognitive disorders (58.3% vs 28.6%, p = 0.041). Sensitivity analyses confirmed all these findings. CXCL13 is detectable in the CSF of PLWH that show increased intrathecal IgG synthesis and immune activation. In PLWH with CSF viral suppression, CXCL13 was also associated with neurocognitive impairment.


Subject(s)
Chemokine CXCL13 , HIV Infections , Humans , Biomarkers/cerebrospinal fluid , Chemokine CXCL13/cerebrospinal fluid , Cross-Sectional Studies , HIV Infections/cerebrospinal fluid , HIV Infections/complications , Immunoglobulin G , Neopterin/cerebrospinal fluid , RNA
5.
Clin Chem Lab Med ; 61(7): 1230-1234, 2023 06 27.
Article in English | MEDLINE | ID: mdl-36692943

ABSTRACT

OBJECTIVES: The aim of this study was to evaluate the impact of long-term sample storage on the concentrations of neopterin and neurofilament light (Nfl) in cerebrospinal fluid (CSF) samples. These are useful markers of neuroinflammation and neuronal damage and have been applied as biomarkers for several neurological diseases. However, different pre-analytical variables have potential to influence results. METHODS: Twenty-one CSF samples donated by patients with HTLV-1-associated myelopathy (HAM) and stored for up to 11 years at -80 °C were retested after three-years for neopterin (n=10) and Nfl (n=11) by ELISA. RESULTS: There was a strong correlation between the paired results (r>0.98, p<0.0001). Neopterin concentrations (nmol/L) ranged from 12.4 to 64 initially and from 11.5 to 64.4 when retested, with means (SD) of 30 (18.4) 1st test and 33 (19.1) 2nd test. Nfl concentrations (pg/mL) ranged from 79.9 to 3,733 initially and from 86.3 to 3,332, when retested with means (SD) of 1,138 (1,272) 1st test and 1,009 (1,114) at re-test. CONCLUSIONS: Storing CSF samples at -80 °C appears not to impact the quantification of neopterin and Nfl allowing confidence in the reporting of archived samples.


Subject(s)
Intermediate Filaments , Neurons , Humans , Neopterin/cerebrospinal fluid , Enzyme-Linked Immunosorbent Assay , Biomarkers/cerebrospinal fluid , Neurofilament Proteins/analysis
6.
Viruses ; 14(10)2022 09 29.
Article in English | MEDLINE | ID: mdl-36298702

ABSTRACT

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease that leads to motor impairment due to a chronic inflammatory process in the central nervous system (CNS). However, the HAM/TSP pathogenesis is not completely clear, and biomarkers to define the disease prognosis are still necessary. Thus, we aimed to identify biomarkers for HAM/TSP and potential mechanisms involved in disease development. To that end, the concentrations of VILIP-1, BDNF, VEGF, ß-NGF, TGF-ß1, fractalkine/CX3CL1, IL-6, IL-18, and TNF-α, and the soluble forms of TREM-1, TREM-2, and RAGE, were assessed using a multiplex bead-based immunoassay in paired cerebrospinal fluid (CSF) and serum samples from HAM/TSP patients (n = 20), asymptomatic HTLV-1 carriers (AC) (n = 13), and HTLV-1-seronegative individuals (n = 9), with the results analyzed according to the speed of HAM/TSP progression. HAM/TSP patients had elevated fractalkine in the serum but not in the CSF, particularly those with low neuroinflammatory activity (CSF/serum ratio of neopterin <1 and of CXCL10 < 2). HAM/TSP patients with normal CSF levels of neurofilament light chain (NfL) showed elevated ß-NGF in serum, and serum BDNF levels were increased in HTLV-1-infected individuals, particularly in HTLV-1 AC. Both HTLV-1 AC and HAM/TSP patients had lower TGF-ß1 levels in CSF compared to uninfected individuals, and HAM/TSP patients with active CNS inflammation showed higher CSF levels of IL-18, which correlated with markers of inflammation, neuronal death, and blood−brain-barrier permeability. Although none of the factors evaluated were associated with the speed of HAM/TSP progression, reduced TGF-ß1 levels in CSF suggest that suppressive responses to control subclinical and/or active neurodegeneration are impaired, while increased CSF IL-18 indicates the involvement of inflammasome-mediated mechanisms in HAM/TSP development.


Subject(s)
HTLV-I Infections , Human T-lymphotropic virus 1 , Neurodegenerative Diseases , Paraparesis, Tropical Spastic , Humans , Chemokine CX3CL1 , Interleukin-18 , Transforming Growth Factor beta1 , Nerve Growth Factor , Neopterin/cerebrospinal fluid , Tumor Necrosis Factor-alpha , Inflammasomes , Brain-Derived Neurotrophic Factor , Interleukin-6 , Triggering Receptor Expressed on Myeloid Cells-1 , Vascular Endothelial Growth Factor A , Biomarkers , Inflammation , HTLV-I Infections/pathology
7.
JAMA Netw Open ; 5(5): e2213253, 2022 05 02.
Article in English | MEDLINE | ID: mdl-35604688

ABSTRACT

Importance: Neurologic symptoms are common in COVID-19, but the central nervous system (CNS) pathogenesis is unclear, and viral RNA is rarely detected in cerebrospinal fluid (CSF). Objective: To measure viral antigen and inflammatory biomarkers in CSF in relation to neurologic symptoms and disease severity. Design, Setting, and Participants: This cross-sectional study was performed from March 1, 2020, to June 30, 2021, in patients 18 years or older who were admitted to Sahlgrenska University Hospital, Gothenburg, Sweden, with COVID-19. All patients had CSF samples taken because of neurologic symptoms or within a study protocol. Healthy volunteer and prepandemic control groups were included. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: Outcomes included CSF SARS-CoV-2 nucleocapsid antigen (N-Ag) using an ultrasensitive antigen capture immunoassay platform and CSF biomarkers of immune activation (neopterin, ß2-microglobulin, and cytokines) and neuronal injury (neurofilament light protein [NfL]). Results: Forty-four patients (median [IQR] age, 57 [48-69] years; 30 [68%] male; 26 with moderate COVID-19 and 18 with severe COVID-19 based on the World Health Organization Clinical Progression Scale), 10 healthy controls (median [IQR] age, 58 [54-60] years; 5 [50%] male), and 41 patient controls (COVID negative without evidence of CNS infection) (median [IQR] age, 59 [49-70] years; 19 [46%] male) were included in the study. Twenty-one patients were neuroasymptomatic and 23 were neurosymptomatic (21 with encephalopathy). In 31 of 35 patients for whom data were available (89%), CSF N-Ag was detected; viral RNA test results were negative in all. Nucleocapsid antigen was significantly correlated with CSF neopterin (r = 0.38; P = .03) and interferon γ (r = 0.42; P = .01). No differences in CSF N-Ag concentrations were found between patient groups. Patients had markedly increased CSF neopterin, ß2-microglobulin, interleukin (IL) 2, IL-6, IL-10, and tumor necrosis factor α compared with controls. Neurosymptomatic patients had significantly higher median (IQR) CSF interferon γ (86 [47-172] vs 21 [17-81] fg/mL; P = .03) and had a significantly higher inflammatory biomarker profile using principal component analysis compared with neuroasymptomatic patients (0.54; 95% CI, 0.03-1.05; P = .04). Age-adjusted median (IQR) CSF NfL concentrations were higher in patients compared with controls (960 [673-1307] vs 618 [489-786] ng/L; P = .002). No differences were seen in any CSF biomarkers in moderate compared with severe disease. Conclusions and Relevance: In this study of Swedish adults with COVID-19 infection and neurologic symptoms, compared with control participants, viral antigen was detectable in CSF and correlated with CNS immune activation. Patients with COVID-19 had signs of neuroaxonal injury, and neurosymptomatic patients had a more marked inflammatory profile that could not be attributed to differences in COVID-19 severity. These results highlight the clinical relevance of neurologic symptoms and suggest that viral components can contribute to CNS immune responses without direct viral invasion.


Subject(s)
COVID-19 , Adult , Antigens, Viral , Biomarkers/cerebrospinal fluid , Cross-Sectional Studies , Female , Humans , Interferon-gamma , Male , Middle Aged , Neopterin/cerebrospinal fluid , Neurofilament Proteins , RNA, Viral , SARS-CoV-2
8.
J Neurovirol ; 28(2): 226-235, 2022 04.
Article in English | MEDLINE | ID: mdl-35044644

ABSTRACT

HIV-associated neurocognitive disorders (HAND) are highly prevalent in people living with HIV (PLWH) despite successful treatment with combination antiretroviral therapy (cART). HAND pathogenesis is complex and definitive surrogate biomarkers are not clearly defined. Brain function has been assessed through the evaluation of cortical source rhythms with delta waves associated with neurological impairment. The aim of this study was to assess the correlation between EEG cortical sources, cerebrospinal fluid (CSF) biomarkers, and neurocognitive tests in PLWH with HAND. PLWH with HAND without significant comorbidities were enrolled. Baseline rsEEG-LORETA waves, CSF biomarkers (t-tau, p-tau, ß-amiloid42, neopterin, S100ß), and neurocognitive tests were correlated and compared through non-parametric tests (Spearman's rho and Mann-Whitney); data are presented as medians (interquartile ranges). Fifty-four patients were enrolled. Median time of suppressed HIV-RNA and CD4+ T-lymphocyte were 10 years (5.5-15) and 691/uL (477-929). Thirty-nine participants (72%) underwent CSF collection: abnormal biomarkers were found in a small percentage. Only neopterin showed a statistically significant correlation with delta activity [parietal (rho 0.579; p < 0.001), occipital (rho 0.493; p = 0.007), and global sources (rho 0.464 p = 0.011)]. Seven patients (12.9%) showed an abnormal neopterin level (> 1.5 ng/mL) with significantly higher delta source activity compared to the ones with in-range concentrations. We observed a statistically significant correlation between working memory test Trail Making B with both CSF neopterin levels and delta waves (p values < 0.05). In a small sample of PLWH with HAND, we observed that higher CSF neopterin levels were associated with higher EEG delta waves and worse working memory tests.


Subject(s)
HIV Infections , Biomarkers/cerebrospinal fluid , Electroencephalography , HIV Infections/cerebrospinal fluid , HIV Infections/complications , HIV Infections/drug therapy , Humans , Mental Status and Dementia Tests , Neopterin/cerebrospinal fluid , Neurocognitive Disorders/complications , Neurocognitive Disorders/diagnosis
9.
Clin Infect Dis ; 75(3): 493-502, 2022 08 31.
Article in English | MEDLINE | ID: mdl-34747481

ABSTRACT

BACKGROUND: The aim of this large multicenter study was to determine variations in cerebrospinal fluid (CSF) HIV-RNA in different phases of untreated human immunodeficiency virus type 1 (HIV-1) infection and its associations with plasma HIV-RNA and other biomarkers. METHODS: Treatment naive adults with available CSF HIV-RNA quantification were included and divided into groups representing significant disease phases. Plasma HIV-RNA, CSF white blood cell count (WBC), neopterin, and albumin ratio were included when available. RESULTS: In total, 1018 patients were included. CSF HIV-RNA was in median (interquartile range [IQR]) 1.03 log10 (0.37-1.86) copies/mL lower than in plasma, and correlated with plasma HIV-RNA (r = 0.44, P < .01), neopterin concentration in CSF (r = 0.49, P < .01) and in serum (r = 0.29, P < .01), CSF WBC (r = 0.34, P < .01) and albumin ratio (r = 0.25, P < .01). CSF HIV-RNA paralleled plasma HIV-RNA in all groups except neuroasymptomatic patients with advanced immunodeficiency (CD4 < 200) and patients with HIV-associated dementia (HAD) or opportunistic central nervous system (CNS) infections. Patients with HAD had the highest CSF HIV-RNA (in median [IQR] 4.73 (3.84-5.35) log10 copies/mL). CSF > plasma discordance was found in 126 of 972 individuals (13%) and varied between groups, from 1% in primary HIV, 11% in neuroasymptomatic groups, up to 30% of patients with HAD. CONCLUSIONS: Our study confirms previous smaller observations of variations in CSF HIV-RNA in different stages of HIV disease. Overall, CSF HIV-RNA was approximately 1 log10 copies/mL lower in CSF than in plasma, but CSF discordance was found in a substantial minority of subjects, most commonly in patients with HAD, indicating increasing CNS compartmentalization paralleling disease progression.


Subject(s)
AIDS Dementia Complex , Central Nervous System Diseases , HIV Infections , HIV-1 , Adult , Albumins , Cerebrospinal Fluid , Cross-Sectional Studies , HIV Infections/complications , HIV-1/genetics , Humans , Neopterin/cerebrospinal fluid , RNA, Viral , Viral Load
10.
Dev Med Child Neurol ; 64(2): 266-271, 2022 02.
Article in English | MEDLINE | ID: mdl-34415581

ABSTRACT

Janus kinase (JAK) 1 inhibition represents a precision medicine approach in the treatment of Aicardi-Goutières syndrome (AGS), through targeting of type I interferon-mediated cell signalling. Blood interferon mRNAseq has been proposed as a biomarker of disease with utility in therapeutic monitoring. Objective cerebrospinal fluid (CSF) biomarkers tracking treatment efficacy are currently lacking. Here, we report a retrospective case series of 13 patients (median age 6y, range 2y 6mo-17y; five females, eight males) with AGS demonstrating significantly elevated CSF neopterin levels at first sampling (median 200nmol/L, range 45-2024nmol/L), compared to 13 age-matched controls with non-inflammatory neurological conditions (median 23nmol/L, range 5-34nmol/L, p<0.001). Five patients with AGS treated with JAK inhibitors demonstrated a median 81.5% reduction of CSF neopterin (range -36% to -88% change from baseline), compared to eight untreated patients with AGS demonstrating a median 7% reduction in CSF neopterin (range -63% to +117% change) (p=0.047). Our data indicate a biological effect of JAK inhibitors, and the potential role of CSF neopterin as a biomarker of treatment response.


Subject(s)
Autoimmune Diseases of the Nervous System/cerebrospinal fluid , Autoimmune Diseases of the Nervous System/drug therapy , Janus Kinase Inhibitors/pharmacology , Neopterin/cerebrospinal fluid , Nervous System Malformations/cerebrospinal fluid , Nervous System Malformations/drug therapy , Adolescent , Biomarkers/cerebrospinal fluid , Child , Child, Preschool , Female , Humans , Janus Kinase 1/antagonists & inhibitors , Male , Retrospective Studies
11.
Front Immunol ; 12: 737941, 2021.
Article in English | MEDLINE | ID: mdl-34764955

ABSTRACT

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease due to axonal damage of the corticospinal secondary to an inflammatory response against infected T-cells. In the present work, we aimed to evaluate biomarkers of neurodegeneration and neuroinflammation in the definition of HAM/TSP prognosis. Neurofilament light (NfL) and phosphorylated heavy (pNfH) chains, total Tau protein, cellular prion protein (PrPc), inflammatory chemokines, and neopterin were quantified in paired cerebrospinal fluid (CSF) and serum samples from HAM/TSP patients (n=21), HTLV-1 asymptomatic carriers (AC) (n=13), and HTLV-1 seronegative individuals with non-inflammatory non-degenerative neurological disease (normal-pressure hydrocephalus) (n=9) as a control group. HTLV-1 proviral load in peripheral blood mononuclear cells and the expression of chemokine receptors CCR4, CCR5, and CXCR3 in infected CD4+ T-cells (HTLV-1 Tax+ cells) were also assessed. CSF levels of Tau, NfL, and pNfH were similar between groups, but PrPc and neopterin were elevated in HAM/TSP patients. Most individuals in the control group and all HTLV-1 AC had CSF/serum neopterin ratio < 1.0, and two-thirds of HAM/TSP patients had ratio values > 1.0, which positively correlated with the speed of disease progression and pNfH levels, indicating active neuroinflammation. HAM/TSP patients showed high serum levels of CXCR3-binding chemokines (CXCL9, CXCL10, and CXCL11) and elevated CSF levels of CCL2, CCL3, CCL4, CCL17, CXCL5, CXCL10, and CXCL11. Indeed, CXCL10 concentration in CSF of HAM/TSP patients was 5.8-fold and 8.7-fold higher in than in HTLV-1 AC and controls, respectively, and correlated with CSF cell counts. HAM/TSP patients with typical/rapid disease progression had CSF/serum CXCL10 ratio > 1.0 and a higher frequency of CXCR3+Tax+CD4+ T-cells in blood, which indicated a positive gradient for the migration of infected cells and infiltration into the central nervous system. In conclusion, the slow progression of HAM/TSP abrogates the usefulness of biomarkers of neuronal injury for the disease prognosis. Thus, markers of inflammation provide stronger evidence for HAM/TSP progression, particularly the CSF/serum neopterin ratio, which may contribute to overcome differences between laboratory assays.


Subject(s)
Cytokines , Human T-lymphotropic virus 1/pathogenicity , Inflammation Mediators , Nerve Degeneration , Nerve Tissue Proteins , Neurodegenerative Diseases/diagnosis , Paraparesis, Tropical Spastic/diagnosis , Adult , Aged , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Case-Control Studies , Cross-Sectional Studies , Cytokines/blood , Cytokines/cerebrospinal fluid , Disease Progression , Female , Host-Pathogen Interactions , Humans , Inflammation Mediators/blood , Inflammation Mediators/cerebrospinal fluid , Male , Middle Aged , Neopterin/blood , Neopterin/cerebrospinal fluid , Nerve Tissue Proteins/blood , Nerve Tissue Proteins/cerebrospinal fluid , Neurodegenerative Diseases/blood , Neurodegenerative Diseases/cerebrospinal fluid , Neurodegenerative Diseases/virology , Paraparesis, Tropical Spastic/blood , Paraparesis, Tropical Spastic/cerebrospinal fluid , Paraparesis, Tropical Spastic/virology , Predictive Value of Tests , Prognosis
12.
Article in English | MEDLINE | ID: mdl-34611039

ABSTRACT

BACKGROUND AND OBJECTIVES: To evaluate the usefulness of CSF and plasma neurofilament light (Nf-L) as a biomarker for human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM). METHODS: Nf-L, CXCL10, and neopterin were measured by ELISA in 83 CSF samples obtained from 49 individuals living with HTLV-1/2. Plasma Nf-L was also measured by single molecule array. Results were correlated with duration of disease, age, mobility, CSF cell counts, CSF protein, and HTLV-1 proviral load. RESULTS: Nf-L was detected in all CSF samples (median [range] = 575 [791.8-2,349] pg/mL) and positively correlated with markers of inflammation (CXCL10 (r = 0.733), neopterin (r = 0.499), cell count (r = 0.403), and protein levels (r = 0.693) in CSF; p < 0.0015). There was an inverse correlation between Nf-L and duration of disease (r = -0.584, p < 0.0001). Wheelchair-dependent patients had high concentrations of markers of inflammation and neuronal damage. Concentrations of CXCL10, neopterin, and Nf-L remained elevated in follow-up samples (mean follow-up 5.2 years). Nf-L in plasma correlated with concentration of Nf-L, neopterin, CXCL10, and protein in CSF. CONCLUSIONS: Nf-L in plasma and CSF has potential to be used as a biomarker of disease activity in HAM. Neuronal damage seems to be more intense early in disease but persists long term. Wheelchair-dependent patients have ongoing neuroinflammation.


Subject(s)
HTLV-I Infections/diagnosis , Neurofilament Proteins/blood , Neurofilament Proteins/cerebrospinal fluid , Neuroinflammatory Diseases/blood , Neuroinflammatory Diseases/cerebrospinal fluid , Spinal Cord Diseases/diagnosis , Adult , Aged , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Chemokine CXCL10/blood , Chemokine CXCL10/cerebrospinal fluid , Female , Follow-Up Studies , HTLV-I Infections/blood , HTLV-I Infections/cerebrospinal fluid , Humans , Male , Middle Aged , Neopterin/blood , Neopterin/cerebrospinal fluid , Neuroinflammatory Diseases/pathology , Neuroinflammatory Diseases/physiopathology , Spinal Cord Diseases/blood , Spinal Cord Diseases/cerebrospinal fluid
13.
Dev Med Child Neurol ; 63(12): 1483-1486, 2021 12.
Article in English | MEDLINE | ID: mdl-34155623

ABSTRACT

Aicardi-Goutières syndrome (AGS) is a rare genetic neuroinflammatory disorder caused by abnormal upregulation of type 1 interferon signalling. Opsoclonus-myoclonus syndrome is a rare autoimmune phenotype demonstrating a disturbance in the humoral immune response mostly seen in the context of paraneoplastic or postinfectious states, although its pathophysiology is incompletely understood. We report the first three children described with AGS demonstrating transient opsoclonus and myoclonus after irritability and/or developmental regression, suggesting a pathological association. We describe the presentation, clinical features, progress, cerebrospinal fluid (CSF) inflammatory markers, electroencephalogram (EEG), and magnetic resonance imaging (MRI) findings in these children. Two patients had developmental regression but demonstrated a positive response to JAK1/2 inhibition clinically and on serial examination of CSF inflammatory markers. These findings suggest that AGS should be considered in children presenting with opsoclonus-myoclonus, and that the association between AGS and opsoclonus-myoclonus further supports the role of immune dysregulation as causal in the rare neurological phenomenon opsoclonus and myoclonus. What this paper adds There is a phenotypic association between opsoclonus-myoclonus syndrome and Aicardi-Goutières syndrome. There is clinical evidence of immune dysregulation in the pathogenesis of opsoclonus and myoclonus.


Subject(s)
Autoimmune Diseases of the Nervous System/complications , Nervous System Malformations/complications , Opsoclonus-Myoclonus Syndrome/complications , Autoimmune Diseases of the Nervous System/cerebrospinal fluid , Autoimmune Diseases of the Nervous System/diagnostic imaging , Biomarkers/cerebrospinal fluid , Brain/diagnostic imaging , Female , Humans , Infant , Magnetic Resonance Imaging , Male , Neopterin/cerebrospinal fluid , Nervous System Malformations/cerebrospinal fluid , Nervous System Malformations/diagnostic imaging , Opsoclonus-Myoclonus Syndrome/cerebrospinal fluid , Opsoclonus-Myoclonus Syndrome/diagnostic imaging , White Matter/diagnostic imaging
14.
Brain Dev ; 43(9): 967-971, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34092404

ABSTRACT

BACKGROUND: Autoimmune mediated encephalitis (AME), which includes autoantibody-associated encephalitis and acute disseminated encephalomyelitis, is a common cause of encephalitis as well as infectious encephalitis in children. AME may be triggered by autoimmune responses to paraneoplastic syndromes and infections. Infectious encephalitis associated with an immunocompromised status caused by anti-cancer chemotherapy is well recognized; however, there have been few reports on the relationship between AME and chemotherapy. CASE REPORT: A ten-year-old previously healthy, developmentally normal girl was diagnosed with a pure germinoma in the suprasellar region. Following 30 days of induction chemotherapy, she developed a depressed level of consciousness with accompanying right hemiplegia, aphasia, and unexplained fever. Cerebrospinal fluid (CSF) analysis revealed positive oligoclonal bands and elevated neopterin levels. Neither atypical cells suggesting tumor exacerbation nor pathogens known to cause encephalitis were identified in the CSF. She was administrated immunosuppressive therapy and her symptoms rapidly improved. No known autoantibodies associated with autoantibody-associated encephalitis were identified in blood or CSF. However, the presence of oligoclonal bands and elevated neopterin levels in the CSF, and the favorable response to immunosuppressive therapy were consistent with an AME diagnosis. Thirteen days after the third course of chemotherapy, the patient developed a depressed level of consciousness again. Due to the recurrence of encephalitis, re-administration of immunosuppressive therapy was performed, which led to improvement in her symptoms. Recurrence of encephalitis has not occurred for 1 year after completion of chemotherapy. CONCLUSION: The chemotherapy-induced abnormal immune response might have triggered the AME.


Subject(s)
Autoimmune Diseases/chemically induced , Encephalitis/chemically induced , Encephalitis/diagnosis , Germinoma/drug therapy , Sella Turcica , Child , Drug Therapy , Female , Humans , Neopterin/cerebrospinal fluid , Oligoclonal Bands/cerebrospinal fluid
15.
J Infect Dis ; 224(8): 1432-1441, 2021 10 28.
Article in English | MEDLINE | ID: mdl-33617646

ABSTRACT

BACKGROUND: Cerebral malaria (CM) pathogenesis remains incompletely understood. Having shown low systemic levels of tetrahydrobiopterin (BH4), an enzymatic cofactor for neurotransmitter synthesis, we hypothesized that BH4 and BH4-dependent neurotransmitters would likewise be low in cerebrospinal fluid (CSF) in CM. METHODS: We prospectively enrolled Tanzanian children with CM and children with nonmalaria central nervous system conditions (NMCs). We measured CSF levels of BH4, neopterin, and BH4-dependent neurotransmitter metabolites, 3-O-methyldopa, homovanillic acid, and 5-hydroxyindoleacetate, and we derived age-adjusted z-scores using published reference ranges. RESULTS: Cerebrospinal fluid BH4 was elevated in CM (n = 49) compared with NMC (n = 51) (z-score 0.75 vs -0.08; P < .001). Neopterin was increased in CM (z-score 4.05 vs 0.09; P < .001), and a cutoff at the upper limit of normal (60 nmol/L) was 100% sensitive for CM. Neurotransmitter metabolite levels were overall preserved. A higher CSF BH4/BH2 ratio was associated with increased odds of survival (odds ratio, 2.94; 95% confidence interval, 1.03-8.33; P = .043). CONCLUSION: Despite low systemic BH4, CSF BH4 was elevated and associated with increased odds of survival in CM. Coma in malaria is not explained by deficiency of BH4-dependent neurotransmitters. Elevated CSF neopterin was 100% sensitive for CM diagnosis and warrants further assessment of its clinical utility for ruling out CM in malaria-endemic areas.


Subject(s)
Biopterins/cerebrospinal fluid , Malaria, Cerebral/mortality , Neopterin/cerebrospinal fluid , Neurotransmitter Agents/cerebrospinal fluid , Pterins/cerebrospinal fluid , Biopterins/analogs & derivatives , Central Nervous System Diseases/cerebrospinal fluid , Child , Child, Preschool , Female , Homovanillic Acid/cerebrospinal fluid , Humans , Hydroxyindoleacetic Acid/cerebrospinal fluid , Infant , Malaria, Cerebral/cerebrospinal fluid , Male , Prospective Studies , Reference Values , Tanzania/epidemiology , Tyrosine/analogs & derivatives
16.
Sci Rep ; 10(1): 18291, 2020 10 26.
Article in English | MEDLINE | ID: mdl-33106568

ABSTRACT

The elevation of neopterin in cerebrospinal fluid (CSF) has been reported in several neuroinflammatory disorders. However, it is not expected that neopterin alone can discriminate among different neuroinflammatory etiologies. We conducted an observational retrospective and case-control study to analyze the CSF biomarkers neopterin, total proteins, and leukocytes in a large cohort of pediatric patients with neuroinflammatory disorders. CSF samples from 277 subjects were included and classified into four groups: Viral meningoencephalitis, bacterial meningitis, acquired immune-mediated disorders, and patients with no-immune diseases (control group). CSF neopterin was analyzed with high-performance liquid chromatography. Microbiological diagnosis included bacterial CSF cultures and several specific real-time polymerase chain reactions. Molecular testing for multiple respiratory pathogens was also included. Antibodies against neuronal and glial proteins were tested. Canonical discriminant analysis of the three biomarkers was conducted to establish the best discriminant functions for the classification of the different clinical groups. Model validation was done by biomarker analyses in a new cohort of 95 pediatric patients. CSF neopterin displayed the highest values in the viral and bacterial infection groups. By applying canonical discriminant analysis, it was possible to classify the patients into the different groups. Validation analyses displayed good results for neuropediatric patients with no-immune diseases and for viral meningitis patients, followed by the other groups. This study provides initial evidence of a more efficient approach to promote the timely classification of patients with viral and bacterial infections and acquired autoimmune disorders. Through canonical equations, we have validated a new tool that aids in the early and differential diagnosis of these neuroinflammatory conditions.


Subject(s)
Acquired Immunodeficiency Syndrome/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Meningitis, Bacterial/cerebrospinal fluid , Meningoencephalitis/virology , Neopterin/cerebrospinal fluid , Virus Diseases/cerebrospinal fluid , Adolescent , Case-Control Studies , Child , Child, Preschool , Chromatography, High Pressure Liquid , Female , Humans , Infant , Infant, Newborn , Male , Meningoencephalitis/cerebrospinal fluid , Retrospective Studies , Young Adult
17.
J Neuroimmunol ; 348: 577396, 2020 11 15.
Article in English | MEDLINE | ID: mdl-32971299

ABSTRACT

Rheumatoid meningitis (RM) is a rare but treatable central nervous system (CNS) manifestation of rheumatoid arthritis (RA) with various clinical presentations and atypical cerebrospinal fluid (CSF) findings. There are no established biomarkers for RM, making diagnosis a challenge. Herein, we present three cases of RM: two patients with RA diagnosis and one without. CSF analysis showed pleocytosis in only one case. In contrast, CSF neopterin levels were elevated in all three cases and decreased after steroid therapy. This study suggests that CSF neopterin levels may be a useful biomarker for diagnosing and therapeutically monitoring CNS inflammation in patients with RM.


Subject(s)
Arthritis, Rheumatoid/cerebrospinal fluid , Arthritis, Rheumatoid/complications , Biomarkers/cerebrospinal fluid , Meningitis/cerebrospinal fluid , Meningitis/etiology , Neopterin/cerebrospinal fluid , Aged , Aged, 80 and over , Female , Humans , Male
18.
CNS Spectr ; 25(3): 402-408, 2020 06.
Article in English | MEDLINE | ID: mdl-31130152

ABSTRACT

BACKGROUND: Central nervous system (CNS) may be infected by several agents, resulting in different presentations and outcomes. Analysis of cerebrospinal fluid (CSF) markers could be helpful to differentiate specific conditions and setting an appropriate therapy. METHODS: Patients presenting with signs and symptoms were enrolled if, before receiving a diagnostic lumbar puncture, signed a written informed consent. We analyzed CSF indexes of blood-brain barrier permeability (CSF to serum albumin ratio or CSAR), inflammation (CSF to serum IgG ratio, neopterin), amyloid deposition (1-42 ß-amyloid), neuronal damage (Total tau (T-tau), Phosphorylated tau (P-tau), and 14.3.3 protein) and astrocyte damage (S-100ß). RESULTS: Two hundred and eighty-one patients were included: they were mainly affected by herpesvirus encephalitis, enterovirus meningoencephalitis, bacterial meningitis (Neisseria meningitidis and Streptococcus pneumoniae), and infection by other etiological agents or unknown pathogen. Their CSF features were compared with HIV-negative patients and native HIV-positive individuals without CNS involvement. 14.3.3 protein was found in bacterial and HSV infections while T-tau and neopterin were abnormally high in the herpesvirus group. P-tau, instead, was elevated in enterovirus meningitis. S-100ß was found to be high in patients with HSV-1 and HSV-2 infections but not in those with Varicella Zoster Virus (VZV). Thirty-day mortality was unexpectedly low (2.7%): patients who died had higher levels of T-tau and, significantly, lower levels of Aß1-42. CONCLUSION: This work demonstrates that CSF biomarkers of neuronal damage or inflammation may vary during CNS infections according to different causative agents. The prognostic value of these biomarkers needs to be assessed in prospective studies.


Subject(s)
Central Nervous System Infections/cerebrospinal fluid , 14-3-3 Proteins/cerebrospinal fluid , Adult , Amyloid beta-Peptides/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Central Nervous System Infections/mortality , Female , Humans , Male , Middle Aged , Neopterin/cerebrospinal fluid , S100 Calcium Binding Protein beta Subunit/cerebrospinal fluid , Survival Analysis , tau Proteins/cerebrospinal fluid
20.
Biomed Res Int ; 2019: 6070176, 2019.
Article in English | MEDLINE | ID: mdl-31886231

ABSTRACT

Human African Trypanosomiasis may become manageable in the next decade with fexinidazole. However, currently stage diagnosis remains difficult to implement in the field and requires a lumbar puncture. Our study of an Angolan cohort of T. b. gambiense-infected patients used other staging criteria than those recommended by the WHO. We compared WHO criteria (cell count and parasite identification in the CSF) with two biomarkers (neopterin and CXCL-13) which have proven potential to diagnose disease stage or relapse. Biological, clinical, and neurological data were analysed from a cohort of 83 patients. A neopterin concentration below 15.5 nmol/L in the CSF denoted patients with stage 1 disease, and a concentration above 60.31 nmol/L characterized patients with advanced stage 2 (trypanosomes in CSF and/or cytorachia higher than 20 cells) disease. CXCL-13 levels below 91.208 pg/mL denoted patients with stage 1 disease, and levels of CXCL-13 above 395.45 pg/mL denoted patients with advanced stage 2 disease. Values between these cut-offs may represent patients with intermediate stage disease. Our work supports the existence of an intermediate stage in HAT, and CXCL-13 and neopterin levels may help to characterize it.


Subject(s)
Chemokine CXCL13/cerebrospinal fluid , Neopterin/cerebrospinal fluid , Trypanosomiasis, African , Adolescent , Adult , Aged , Aged, 80 and over , Angola , Biomarkers/cerebrospinal fluid , Female , Follow-Up Studies , Humans , Male , Middle Aged , ROC Curve , Trypanosomiasis, African/cerebrospinal fluid , Trypanosomiasis, African/classification , Trypanosomiasis, African/diagnosis , Young Adult
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