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Furukawa Y. Clinical and Basic Research on Dopa-Responsive Dystonia: Neuropathological and Neurochemical Findings. JUNTENDO MEDICAL JOURNAL 2025; 71:2-10. [PMID: 40109402 PMCID: PMC11915469 DOI: 10.14789/ejmj.jmj24-0023-r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 08/22/2024] [Indexed: 03/22/2025]
Abstract
Dopa-responsive dystonia (DRD) is a clinical syndrome characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of levodopa. Typically, DRD presents with gait disturbance due to foot dystonia, later development of parkinsonism, and diurnal fluctuation of symptoms. Since the discovery of mutations responsible for DRD in GCH1, coding for GTP cyclohydrolase 1 (GTPCH) that catalyzes the rate-limiting step in tetrahydrobiopterin (BH4: the cofactor for tyrosine hydroxylase [TH]) biosynthesis, and in TH, coding for TH in catecholamine biosynthesis, our understanding of this syndrome has greatly increased. However, the underlying mechanisms of phenotypic heterogeneity are still unknown and physicians should learn from genetic, pathological, and biochemical findings of DRD. Neuropathological studies have shown a normal population of cells with decreased melanin and no Lewy bodies in the substantia nigra of classic GTPCH-deficient and TH-deficient DRD. Neurochemical investigations in GTPCH-deficient DRD have indicated that dopamine reduction in the striatum is caused not only by decreased TH activity resulting from low cofactor content but also by actual loss of TH protein without nerve terminal loss. This striatal TH protein loss may be due to a diminished regulatory effect of BH4 on stability of TH molecules. Neurochemical findings in an asymptomatic GCH1 mutation carrier versus symptomatic cases suggest that there may be additional genetic and/or environmental factors modulating the regulatory BH4 effect on TH stability and that the extent of striatal protein loss in TH (rather than that in GTPCH) may be critical in determining the symptomatic state of GTPCH-deficient DRD.
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Focke JK, Brokbals M, Becker J, Veltkamp R, van de Beek D, Brouwer MC, Westendorp WF, Kraemer M. Cerebral vasculitis related to neurosarcoidosis: a case series and systematic literature review. J Neurol 2025; 272:135. [PMID: 39812656 PMCID: PMC11735521 DOI: 10.1007/s00415-024-12868-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 12/12/2024] [Accepted: 12/15/2024] [Indexed: 01/16/2025]
Abstract
Cerebral vasculitis is a rare but severe manifestation of neurosarcoidosis (NS) that has received little attention. The aim of the present study was to characterize clinical and diagnostic features as well as potential treatment strategies of cerebral vasculitis related to NS. We assessed 29 patients with cerebral vasculitis related to NS (15 female, mean age at time of diagnosis 45 years, SD = 11.85) among these were four new cases from our hospital records and 25 previously published cases from a systematic literature review. The demographic, clinical, and diagnostic features of those 29 patients with cerebral vasculitis related to NS were compared with a group of 73 NS patients without vasculitic involvement (37 female, mean age at time of diagnosis 47 years, SD = 14.79). Neurologic deficits and MRI abnormalities were significantly more frequent in cerebral vasculitis related to NS than in NS without vasculitic involvement. Patients with cerebral vasculitis related to NS significantly more often presented with headache, motor symptoms, and cognitive and/or behavioral changes. Non-neurologic manifestations of sarcoidosis did not significantly differ in character or frequency between both groups. Glucocorticoids in combination with methotrexate, cyclophosphamide, or infliximab were the most frequently used treatment strategies in cerebral vasculitis related to NS. Within the complex diagnostic work-up that is required in cerebral vasculitis related to NS sufficient angiographic imaging as digital subtraction angiography or MRI vessel wall imaging and tissue biopsy are of particular significance as they can detect vascular changes caused by inflammatory processes.
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Affiliation(s)
- Jan K Focke
- Department of Neurology, Alfried Krupp Hospital, Essen, Germany
- Department of Psychiatry and Psychotherapy, LVR Hospital, Düsseldorf, Germany
| | - Mosche Brokbals
- Department of Neurology, Alfried Krupp Hospital, Essen, Germany
- Department of Psychiatry and Psychotherapy, Florence Nightingale Hospital, Düsseldorf, Germany
| | - Jana Becker
- Department of Neurology, Alfried Krupp Hospital, Essen, Germany
| | - Roland Veltkamp
- Department of Neurology, Alfried Krupp Hospital, Essen, Germany
- Department of Brain Sciences, Imperial College London, London, UK
| | - Diederik van de Beek
- Department of Neurology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
| | - Matthijs C Brouwer
- Department of Neurology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
| | - Willeke F Westendorp
- Department of Neurology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
| | - Markus Kraemer
- Department of Neurology, Alfried Krupp Hospital, Essen, Germany.
- Department of Neurology, Heinrich Heine University Hospital, Düsseldorf, Germany.
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Lackey E, Shen J, Sharma A, Eckstein C. Beyond biopsy for neurosarcoidosis: A review of blood and CSF biomarkers. J Neuroimmunol 2024; 393:578394. [PMID: 38875863 DOI: 10.1016/j.jneuroim.2024.578394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/09/2024] [Accepted: 06/09/2024] [Indexed: 06/16/2024]
Abstract
Neurosarcoidosis, a rare granulomatous disease, causes inflammation and damage to the central nervous system (CNS). A major diagnostic challenge in neurosarcoidosis is the absence of well-defined biomarkers. The need for biopsy to make the diagnosis can lead to delays and misdiagnosis if histopathology is inaccessible or indeterminate, highlighting the need for more accessible diagnostic indicators. The current gold standard for a "definite" neurosarcoidosis diagnosis requires biopsy of CNS tissue revealing non-caseating granulomas. However, such biopsies are inherently invasive and carry associated procedural risks. Notably, angiotensin-converting enzyme (ACE), commonly associated with systemic sarcoidosis, is recognized as a poor biomarker for neurosarcoidosis due to its lack of accuracy in the context of CNS involvement. Furthermore, imaging in neurosarcoidosis, while widely utilized and important for narrowing the diagnosis, lacks specificity. Decades of research have yielded molecular and immunologic biomarkers-soluble interleukin-2 receptor (IL-2R), serum amyloid A1, the CD4/CD8 ratio, neopterin, interferon-gamma (IFN-γ), and chemokine ligand 2 (CCL2)-that hold potential for improving diagnostic accuracy. However, these biomarkers are not yet established in clinical care as they may be difficult to obtain and are derived from small studies. They also suffer from a lack of specificity against other inflammatory and infectious central nervous system diseases. New biomarkers are needed for use alongside those previously discovered to improve diagnosis of this rare disease. This review synthesizes existing literature on neurosarcoidosis biomarkers, aiming to establish a foundation for further research in this evolving field. It also consolidates information on biomarkers of systemic sarcoidosis such as IL-8 and soluble CD40L that have not yet been studied in neurosarcoidosis but hold potential as markers of CNS disease.
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Affiliation(s)
- Elijah Lackey
- Duke University, Department of Neurology, Division of MS and Neuroimmunology, DUMC 3849, Durham, NC 27710, United States of America.
| | - Jeffrey Shen
- Duke University, Department of Neurology, Division of MS and Neuroimmunology, DUMC 3849, Durham, NC 27710, United States of America
| | - Aditya Sharma
- Duke University, Department of Neurology, Division of MS and Neuroimmunology, DUMC 3849, Durham, NC 27710, United States of America
| | - Christopher Eckstein
- Duke University, Department of Neurology, Division of MS and Neuroimmunology, DUMC 3849, Durham, NC 27710, United States of America
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Miyaue N, Yamanishi Y, Ito Y, Ando R, Nagai M. CSF Neopterin Levels Are Elevated in Various Neurological Diseases and Aging. J Clin Med 2024; 13:4542. [PMID: 39124808 PMCID: PMC11312611 DOI: 10.3390/jcm13154542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024] Open
Abstract
Background/Objectives: Cerebrospinal fluid (CSF) neopterin reflects inflammation of the central nervous system (CNS) and is a potentially useful biomarker for neuroinflammatory assessment and differential diagnosis. However, its optimal cut-off level in adult patients with neurological disease has not been established and it has not been adequately studied in controls. We aimed to determine its usefulness as a biomarker of neuroinflammation and the effect of age on its level. Methods: In this retrospective study, CSF neopterin was evaluated in 652 patients in 38 disease groups. Its levels were analyzed with high-performance liquid chromatography with fluorometric detection. Results: A receiver operating characteristic analysis revealed that the optimal cut-off value of 33.57 pmol/mL for CSF neopterin distinguished the control and meningitis/encephalitis groups with a sensitivity of 100.0% and specificity of 94.4%. In the control group, which consisted of 170 participants (99 men and 71 women; mean ± standard deviation age, 52.56 ± 17.99 years), age was significantly positively correlated with CSF protein (r = 0.474, p < 0.001) and CSF neopterin (r = 0.476, p < 0.001) levels but not with CSF cell count (r = 0.144, p = 0.061). Both male and female controls exhibited significant increases in CSF neopterin levels with age. Similarly, the CSF neopterin level was significantly positively correlated with age in patients with amyotrophic lateral sclerosis, independently of disease duration and respiratory function. Conclusions: CSF neopterin levels were elevated in patients with various CNS diseases, reflecting CNS inflammation; they were also elevated with age. Prospective studies are required to establish CSF neopterin as a sensitive biomarker of neuroinflammation.
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Affiliation(s)
- Noriyuki Miyaue
- Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Tohon 791-0295, Japan; (Y.Y.); (Y.I.); (R.A.); (M.N.)
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Carreras N, Arnaez J, Valls A, Agut T, Sierra C, Garcia-Alix A. CSF neopterin and beta-2-microglobulin as inflammation biomarkers in newborns with hypoxic-ischemic encephalopathy. Pediatr Res 2023; 93:1328-1335. [PMID: 35388137 DOI: 10.1038/s41390-022-02011-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 02/01/2022] [Accepted: 02/15/2022] [Indexed: 11/09/2022]
Abstract
BACKGROUND Inflammation plays a crucial role in the pathogenesis of hypoxic-ischemic encephalopathy (HIE). The aim of this study was to measure inflammation in HIE through an analysis of CSF neopterin and β2-microglobulin and to study the association with brain injury as shown by MRI findings and neurodevelopmental outcomes. METHODS CSF biomarkers were measured in study patients at 12 and 72 h. Brain injury was evaluated by MRI, and neurodevelopmental outcomes were assessed at 2-3 years of life. An adverse outcome was defined as the presence of motor or cognitive impairment. RESULTS Sixty-nine HIE infants were included. Median values of neopterin and β2-microglobulin paralleled the severity of HIE. Adverse outcomes were associated with early neopterin and β2-microglobulin values, late neopterin values, and the neopterin percentage change between the two samples. A cutoff value of 75% neopterin change predicted adverse outcomes with a specificity of 0.9 and a sensitivity of 0.75. CONCLUSIONS CSF neopterin and β2-microglobulin are elevated in HIE, indicating the activation of inflammation processes. Infants with adverse neurodevelopmental outcomes show higher levels of CSF neopterin and β2-microglobulin. The evolution of neopterin levels provides a better predictive capacity than a single determination. IMPACT Brain inflammation in newborns with HIE could be measurable through the analysis of CSF neopterin and β2-microglobulin, both of which are associated with neurodevelopmental outcomes. Our study introduces two inflammatory biomarkers for infants with HIE that seem to show a more stable profile and are easier to interpret than cytokines. CSF neopterin and β2-m may become clinical tools to monitor inflammation in HIE and might eventually be helpful in measuring the response to emerging therapies.
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Affiliation(s)
- Nuria Carreras
- Río Hortega Program, Carlos III Health Institute, Madrid, Spain
- Department of Neonatology, Hospital Sant Joan de Déu, Barcelona, Spain
- Institut de Recerca Sant Joan de Déu, Barcelona, Spain
| | - Juan Arnaez
- Department of Neonatology, Complejo Asistencial Universitario de Burgos, Burgos, Spain
- NeNe Foundation, Madrid, Spain
| | - Ana Valls
- Institut de Recerca Sant Joan de Déu, Barcelona, Spain
- Clinical Biochemistry Department, Hospital Sant Joan de Déu, Barcelona, Spain
| | - Thais Agut
- Department of Neonatology, Hospital Sant Joan de Déu, Barcelona, Spain
- Institut de Recerca Sant Joan de Déu, Barcelona, Spain
- NeNe Foundation, Madrid, Spain
| | - Cristina Sierra
- Institut de Recerca Sant Joan de Déu, Barcelona, Spain
- Clinical Biochemistry Department, Hospital Sant Joan de Déu, Barcelona, Spain
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Chaumont H, Kaczorowski F, San-Galli A, Michel PP, Tressières B, Roze E, Quadrio I, Lannuzel A. Cerebrospinal fluid biomarkers in SARS-CoV-2 patients with acute neurological syndromes. Rev Neurol (Paris) 2023; 179:208-217. [PMID: 36610823 PMCID: PMC9708608 DOI: 10.1016/j.neurol.2022.11.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/28/2022] [Accepted: 11/03/2022] [Indexed: 12/05/2022]
Abstract
BACKGROUND AND PURPOSE Mechanisms underlying acute brain injury in SARS-CoV-2 patients remain poorly understood. A better characterization of such mechanisms remains essential to preventing long-term neurological sequelae. Our present aim was to study a panel of biomarkers of neuroinflammation and neurodegeneration in the cerebrospinal fluid (CSF) of NeuroCOVID patients. METHODS We retrospectively collected clinical and CSF biomarkers data from 24 NeuroCOVID adults seen at the University Hospital of Guadeloupe between March and June 2021. RESULTS Among 24 NeuroCOVID patients, 71% had encephalopathy and 29% meningoencephalitis. A number of these patients also experienced de novo movement disorder (33%) or stroke (21%). The CSF analysis revealed intrathecal immunoglobulin synthesis in 54% of NeuroCOVID patients (two with a type 2 pattern and 11 with a type 3) and elevated neopterin levels in 75% of them (median 9.1nM, IQR 5.6-22.1). CSF neurofilament light chain (NfL) was also increased compared to a control group of non-COVID-19 patients with psychiatric illnesses (2905ng/L, IQR 1428-7124 versus 1222ng/L, IQR 1049-1566). Total-tau was elevated in the CSF of 24% of patients, whereas protein 14-3-3, generally undetectable, reached intermediate levels in two patients. Finally, CSF Aß1-42 was reduced in 52.4% of patients (median 536ng/L, IQR 432-904) with no change in the Aß1-42/Aß1-40 ratio (0.082, IQR 0.060-0.096). CONCLUSIONS We showed an elevation of CSF biomarkers of neuroinflammation in NeuroCOVID patients and a rise of CSF NfL, evocative of neuronal damage. However, longitudinal studies are needed to determine whether NeuroCOVID could evolve into a chronic neurodegenerative condition.
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Affiliation(s)
- H Chaumont
- Service de neurologie, centre hospitalier universitaire de la Guadeloupe, Pointe-à-Pitre/Abymes, French West Indies, France; Faculté de médecine de l'université des Antilles, French West Indies, Pointe-à-Pitre, France; U 1127, CNRS, unité mixte de recherche (UMR) 7225, faculté de médecine de Sorbonne université, Institut national de la santé et de la recherche médicale, Institut du Cerveau, ICM, Paris, France.
| | - F Kaczorowski
- Laboratory of neurobiology and neurogenetics, department of biochemistry and molecular biology, Lyon university hospital, Bron, France; CNRS UMR 5292, Inserm U1028, BIORAN team, Lyon neuroscience research center, Lyon 1 university, Bron, France
| | - A San-Galli
- Service de neurologie, centre hospitalier universitaire de la Guadeloupe, Pointe-à-Pitre/Abymes, French West Indies, France
| | - P P Michel
- U 1127, CNRS, unité mixte de recherche (UMR) 7225, faculté de médecine de Sorbonne université, Institut national de la santé et de la recherche médicale, Institut du Cerveau, ICM, Paris, France
| | - B Tressières
- Inserm CIC 1424, centre d'investigation Clinique Antilles Guyane, CHU de la Guadeloupe, Pointe-à-Pitre, France
| | - E Roze
- U 1127, CNRS, unité mixte de recherche (UMR) 7225, faculté de médecine de Sorbonne université, Institut national de la santé et de la recherche médicale, Institut du Cerveau, ICM, Paris, France; Département de neurologie, hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France
| | - I Quadrio
- Laboratory of neurobiology and neurogenetics, department of biochemistry and molecular biology, Lyon university hospital, Bron, France; CNRS UMR 5292, Inserm U1028, BIORAN team, Lyon neuroscience research center, Lyon 1 university, Bron, France
| | - A Lannuzel
- Service de neurologie, centre hospitalier universitaire de la Guadeloupe, Pointe-à-Pitre/Abymes, French West Indies, France; Faculté de médecine de l'université des Antilles, French West Indies, Pointe-à-Pitre, France; U 1127, CNRS, unité mixte de recherche (UMR) 7225, faculté de médecine de Sorbonne université, Institut national de la santé et de la recherche médicale, Institut du Cerveau, ICM, Paris, France; Inserm CIC 1424, centre d'investigation Clinique Antilles Guyane, CHU de la Guadeloupe, Pointe-à-Pitre, France
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Zhao JL, Wang ZY, Li SJ, Ma HK, Liu X, Zhan XW, Niu WW, Shen P. The efficacy of haemoperfusion combined with continuous venovenous haemodiafiltration in the treatment of severe viral encephalitis in children. Ital J Pediatr 2023; 49:21. [PMID: 36793135 PMCID: PMC9930290 DOI: 10.1186/s13052-023-01411-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 01/04/2023] [Indexed: 02/17/2023] Open
Abstract
BACKGROUND This study investigated the efficacy of the integrated blood purification mode of early haemoperfusion (HP) combined with continuous venovenous haemodiafiltration (CVVHDF) in children with severe viral encephalitis, and evaluated the correlation of cerebrospinal fluid (CSF) neopterin (NPT) levels with prognosis. METHODS The records of children with viral encephalitis who received blood purification treatment in the authors' hospital from September 2019 to February 2022 were retrospectively analysed. According to the blood purification treatment mode, they were divided into the experimental group (HP + CVVHDF, 18 cases), control group A (CVVHDF only, 14 cases), and control group B (16 children with mild viral encephalitis who did not receive blood purification treatment). The correlation between the clinical features, severity of the disease and the extent of lesions on brain magnetic resonance imaging (MRI) and the CSF NPT levels was analysed. RESULTS The experimental group and control group A were comparable with respect to age, gender and hospital course (P > 0.05). There was no significant difference in speech and swallowing functions between the two groups after treatment (P > 0.05) and no significant difference in 7 and 14-day mortality (P > 0.05). The CSF NPT levels in the experimental group before treatment were significantly higher compared with control group B (P < 0.05). The extent of brain MRI lesions correlated positively with CSF NPT levels (P < 0.05). In the experimental group (14 cases), the serum NPT levels decreased after treatment, whereas the CSF NPT levels increased after treatment, and the differences were statistically significant (P < 0.05). Dysphagia and motor dysfunction correlated positively with CSF NPT levels (P < 0.05). CONCLUSION Early HP combined with CVVHDF in the treatment of severe viral encephalitis in children may be a better approach than CVVHDF only for improving prognosis. Higher CSF NPT levels indicated the likelihood of a more severe brain injury and a greater possibility of residual neurological dysfunction.
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Affiliation(s)
- Jun-Lin Zhao
- grid.493088.e0000 0004 1757 7279Department of Pediatrics, The First Affiliated Hospital of Xinxiang Medical University, No. 88 of Jiankang Road, Weihui, 453100 Henan Province China
| | - Zhi-Yuan Wang
- grid.493088.e0000 0004 1757 7279Department of Pediatrics, The First Affiliated Hospital of Xinxiang Medical University, No. 88 of Jiankang Road, Weihui, 453100 Henan Province China
| | - Shu-Jun Li
- Department of Pediatrics, The First Affiliated Hospital of Xinxiang Medical University, No. 88 of Jiankang Road, Weihui, 453100, Henan Province, China.
| | - He-Kai Ma
- grid.493088.e0000 0004 1757 7279Department of Pediatrics, The First Affiliated Hospital of Xinxiang Medical University, No. 88 of Jiankang Road, Weihui, 453100 Henan Province China
| | - Xue Liu
- grid.493088.e0000 0004 1757 7279Department of Pediatrics, The First Affiliated Hospital of Xinxiang Medical University, No. 88 of Jiankang Road, Weihui, 453100 Henan Province China
| | - Xiao-Wen Zhan
- grid.493088.e0000 0004 1757 7279Department of Pediatrics, The First Affiliated Hospital of Xinxiang Medical University, No. 88 of Jiankang Road, Weihui, 453100 Henan Province China
| | - Wei-Wei Niu
- grid.493088.e0000 0004 1757 7279Department of Pediatrics, The First Affiliated Hospital of Xinxiang Medical University, No. 88 of Jiankang Road, Weihui, 453100 Henan Province China
| | - Peng Shen
- grid.493088.e0000 0004 1757 7279Department of Pediatrics, The First Affiliated Hospital of Xinxiang Medical University, No. 88 of Jiankang Road, Weihui, 453100 Henan Province China
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Emerson JS, Gruenewald SM, Gomes L, Lin MW, Swaminathan S. The conundrum of neuropsychiatric systemic lupus erythematosus: Current and novel approaches to diagnosis. Front Neurol 2023; 14:1111769. [PMID: 37025200 PMCID: PMC10070984 DOI: 10.3389/fneur.2023.1111769] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 03/07/2023] [Indexed: 04/08/2023] Open
Abstract
Recognising neuropsychiatric involvement by systemic lupus erythematosus (SLE) is of growing importance, however many barriers to this exist at multiple levels of our currently available diagnostic algorithms that may ultimately delay its diagnosis and subsequent treatment. The heterogeneous and non-specific clinical syndromes, serological and cerebrospinal fluid (CSF) markers and neuroimaging findings that often do not mirror disease activity, highlight important research gaps in the diagnosis of neuropsychiatric SLE (NPSLE). Formal neuropsychological assessments or the more accessible screening metrics may also help improve objective recognition of cognitive or mood disorders. Novel serum and CSF markers, including autoantibodies, cytokines and chemokines have also shown increasing utility as part of diagnosis and monitoring, as well as in distinguishing NPSLE from SLE patients without SLE-related neuropsychiatric manifestations. Novel neuroimaging studies also expand upon our existing strategy by quantifying parameters that indicate microarchitectural integrity or provide an assessment of neuronal function. Some of these novel markers have shown associations with specific neuropsychiatric syndromes, suggesting that future research move away from considering NPSLE as a single entity but rather into its individually recognized neuropsychiatric manifestations. Nevertheless, it is likely that a composite panel of these investigations will be needed to better address the gaps impeding recognition of neuropsychiatric involvement by SLE.
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Affiliation(s)
- Jonathan S. Emerson
- Department of Clinical Immunology and Immunopathology, Westmead Hospital, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Centre for Immunology and Allergy Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- *Correspondence: Jonathan S. Emerson,
| | - Simon M. Gruenewald
- Department of Nuclear Medicine, PET and Ultrasound, Westmead Hospital, Sydney, NSW, Australia
| | - Lavier Gomes
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Department of Radiology, Westmead Hospital, Sydney, NSW, Australia
| | - Ming-Wei Lin
- Department of Clinical Immunology and Immunopathology, Westmead Hospital, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Sanjay Swaminathan
- Department of Clinical Immunology and Immunopathology, Westmead Hospital, Sydney, NSW, Australia
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Department of Clinical Immunology, Blacktown Hospital, Sydney, NSW, Australia
- School of Medicine, Western Sydney University, Sydney, NSW, Australia
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Vlad B, Neidhart S, Hilty M, Ziegler M, Jelcic I. Differentiating neurosarcoidosis from multiple sclerosis using combined analysis of basic CSF parameters and MRZ reaction. Front Neurol 2023; 14:1135392. [PMID: 37034091 PMCID: PMC10080049 DOI: 10.3389/fneur.2023.1135392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 03/06/2023] [Indexed: 04/11/2023] Open
Abstract
Background Neurosarcodosis is one of the most frequent differential diagnoses of multiple sclerosis (MS) and requires central nervous system (CNS) biopsy to establish definite diagnosis according to the latest consensus diagnostic criteria. We here analyzed diagnostic values of basic cerebrospinal fluid (CSF) parameters to distinguish neurosarcoidosis from MS without CNS biopsy. Methods We retrospectively assessed clinical, radiological and laboratory data of 27 patients with neurosarcoidosis treated at our center and compared following CSF parameters with those of 138 patients with relapsing-remitting MS: CSF white cell count (WCC), CSF/serum albumin quotient (Qalb), intrathecal production of immunoglobulins including oligoclonal bands (OCB), MRZ reaction, defined as a polyspecific intrathecal production of IgG reactive against ≥2 of 3 the viruses measles (M), rubella (R), and zoster (Z) virus, and CSF lactate levels. Additional inflammatory biomarkers in serum and/or CSF such as neopterin, soluble interleukin-2 receptor (sIL-2R) and C-reactive protein (CRP) were assessed. Results There was no significant difference in the frequency of CSF pleocytosis, but a CSF WCC > 30/μl was more frequent in patients with neurosarcoidosis. Compared to MS, patients with neurosarcoidosis showed more frequently an increased Qalb and CSF lactate levels as well as increased serum and CSF levels of sIL-2R, but a lower frequency of intrathecal IgG synthesis and positive MRZ reaction. Positive likelihood ratio (PLR) of single CSF parameters indicating neurosarcoidosis was highest, if (a) CSF WCC was >30/μl (PLR 7.2), (b) Qalb was >10 × 10-3 (PLR 66.4), (c) CSF-specific OCB were absent (PLR 11.5), (d) CSF lactate was elevated (PLR 23.0) or (e) sIL-2R was elevated (PLR>8.0). The combination of (a) one of three following basic CSF parameters, i.e., (a.1.) CSF WCC >30/ul, or (a.2.) QAlb >10 × 10-3, or (a.3.) absence of CSF-specific OCB, and (b) absence of positive MRZ reaction showed the best diagnostic accuracy (sensitivity and specificity each >92%; PLR 12.8 and NLR 0.08). Conclusion Combined evaluation of basic CSF parameters and MRZ reaction is powerful in differentiating neurosarcoidosis from MS, with moderate to severe pleocytosis and QAlb elevation and absence of intrathecal IgG synthesis as useful rule-in parameters and positive MRZ reaction as a rule-out parameter for neurosarcoidosis.
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Affiliation(s)
- Benjamin Vlad
- Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
- Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Stephan Neidhart
- Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
- Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Marc Hilty
- Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
- Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Mario Ziegler
- Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
- Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Ilijas Jelcic
- Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
- Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
- *Correspondence: Ilijas Jelcic
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Lim N, Festa M, Lade S, Britton P. Multiple Complications of Typhoid in a Returned Child Traveler. Clin Pediatr (Phila) 2022; 61:741-744. [PMID: 35686371 DOI: 10.1177/00099228221103083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Natalie Lim
- Department of General Medicine, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Marino Festa
- Paediatric Intensive Care Unit, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Samantha Lade
- Department of General Medicine, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Philip Britton
- Department of Infectious Diseases and Microbiology, The Children's Hospital at Westmead, Sydney, NSW, Australia.,Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
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Pamies D, Sartori C, Schvartz D, González-Ruiz V, Pellerin L, Nunes C, Tavel D, Maillard V, Boccard J, Rudaz S, Sanchez JC, Zurich MG. Neuroinflammatory Response to TNFα and IL1β Cytokines Is Accompanied by an Increase in Glycolysis in Human Astrocytes In Vitro. Int J Mol Sci 2021; 22:4065. [PMID: 33920048 PMCID: PMC8071021 DOI: 10.3390/ijms22084065] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/02/2021] [Accepted: 04/06/2021] [Indexed: 01/11/2023] Open
Abstract
Astrogliosis has been abundantly studied in rodents but relatively poorly in human cells due to limited access to the brain. Astrocytes play important roles in cerebral energy metabolism, and are also key players in neuroinflammation. Astroglial metabolic and inflammatory changes as a function of age have been reported, leading to the hypothesis that mitochondrial metabolism and inflammatory responses are interconnected in supporting a functional switch of astrocytes from neurotrophic to neurotoxic. This study aimed to explore the metabolic changes occurring in astrocytes during their activation. Astrocytes were derived from human ReN cell neural progenitors and characterized. They were activated by exposure to tumor necrosis factor alpha (TNFα) or interleukin 1β (IL1β) for 24 h. Astrocyte reaction and associated energy metabolic changes were assessed by immunostaining, gene expression, proteomics, metabolomics and extracellular flux analyses. ReN-derived astrocytes reactivity was observed by the modifications of genes and proteins linked to inflammation (cytokines, nuclear factor-kappa B (NFκB), signal transducers and activators of transcription (STATs)) and immune pathways (major histocompatibility complex (MHC) class I). Increased NFκB1, NFκB2 and STAT1 expression, together with decreased STAT3 expression, suggest an activation towards the detrimental pathway. Strong modifications of astrocyte cytoskeleton were observed, including a glial fibrillary acidic protein (GFAP) decrease. Astrogliosis was accompanied by changes in energy metabolism characterized by increased glycolysis and lactate release. Increased glycolysis is reported for the first time during human astrocyte activation. Astrocyte activation is strongly tied to energy metabolism, and a possible association between NFκB signaling and/or MHC class I pathway and glycolysis is suggested.
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Affiliation(s)
- David Pamies
- Department of Biomedical Sciences, University of Lausanne, CH-1005 Lausanne, Switzerland; (D.P.); (C.S.); (L.P.); (C.N.); (D.T.); (V.M.)
- Swiss Centre for Applied Human Toxicology (SCAHT), 4055 Basel, Switzerland; (D.S.); (V.G.-R.); (J.B.); (S.R.); (J.-C.S.)
| | - Chiara Sartori
- Department of Biomedical Sciences, University of Lausanne, CH-1005 Lausanne, Switzerland; (D.P.); (C.S.); (L.P.); (C.N.); (D.T.); (V.M.)
| | - Domitille Schvartz
- Swiss Centre for Applied Human Toxicology (SCAHT), 4055 Basel, Switzerland; (D.S.); (V.G.-R.); (J.B.); (S.R.); (J.-C.S.)
- Translational Biomarker Group, Department of Internal Medicine Specialties, University of Geneva, CH-1211 Genève, Switzerland
| | - Víctor González-Ruiz
- Swiss Centre for Applied Human Toxicology (SCAHT), 4055 Basel, Switzerland; (D.S.); (V.G.-R.); (J.B.); (S.R.); (J.-C.S.)
- Analytical Sciences, Institute of Pharmaceutical Sciences of Western Switzerland and School of Pharmaceutical Sciences, University of Geneva, CH-1211 Genève, Switzerland
| | - Luc Pellerin
- Department of Biomedical Sciences, University of Lausanne, CH-1005 Lausanne, Switzerland; (D.P.); (C.S.); (L.P.); (C.N.); (D.T.); (V.M.)
- INSERM U1082, Faculté de Médecine et de Pharmacie, Université de Poitiers, F-86021 Poitiers, France
| | - Carolina Nunes
- Department of Biomedical Sciences, University of Lausanne, CH-1005 Lausanne, Switzerland; (D.P.); (C.S.); (L.P.); (C.N.); (D.T.); (V.M.)
- Swiss Centre for Applied Human Toxicology (SCAHT), 4055 Basel, Switzerland; (D.S.); (V.G.-R.); (J.B.); (S.R.); (J.-C.S.)
| | - Denise Tavel
- Department of Biomedical Sciences, University of Lausanne, CH-1005 Lausanne, Switzerland; (D.P.); (C.S.); (L.P.); (C.N.); (D.T.); (V.M.)
- Swiss Centre for Applied Human Toxicology (SCAHT), 4055 Basel, Switzerland; (D.S.); (V.G.-R.); (J.B.); (S.R.); (J.-C.S.)
| | - Vanille Maillard
- Department of Biomedical Sciences, University of Lausanne, CH-1005 Lausanne, Switzerland; (D.P.); (C.S.); (L.P.); (C.N.); (D.T.); (V.M.)
- Swiss Centre for Applied Human Toxicology (SCAHT), 4055 Basel, Switzerland; (D.S.); (V.G.-R.); (J.B.); (S.R.); (J.-C.S.)
| | - Julien Boccard
- Swiss Centre for Applied Human Toxicology (SCAHT), 4055 Basel, Switzerland; (D.S.); (V.G.-R.); (J.B.); (S.R.); (J.-C.S.)
- Analytical Sciences, Institute of Pharmaceutical Sciences of Western Switzerland and School of Pharmaceutical Sciences, University of Geneva, CH-1211 Genève, Switzerland
| | - Serge Rudaz
- Swiss Centre for Applied Human Toxicology (SCAHT), 4055 Basel, Switzerland; (D.S.); (V.G.-R.); (J.B.); (S.R.); (J.-C.S.)
- Analytical Sciences, Institute of Pharmaceutical Sciences of Western Switzerland and School of Pharmaceutical Sciences, University of Geneva, CH-1211 Genève, Switzerland
| | - Jean-Charles Sanchez
- Swiss Centre for Applied Human Toxicology (SCAHT), 4055 Basel, Switzerland; (D.S.); (V.G.-R.); (J.B.); (S.R.); (J.-C.S.)
- Translational Biomarker Group, Department of Internal Medicine Specialties, University of Geneva, CH-1211 Genève, Switzerland
| | - Marie-Gabrielle Zurich
- Department of Biomedical Sciences, University of Lausanne, CH-1005 Lausanne, Switzerland; (D.P.); (C.S.); (L.P.); (C.N.); (D.T.); (V.M.)
- Swiss Centre for Applied Human Toxicology (SCAHT), 4055 Basel, Switzerland; (D.S.); (V.G.-R.); (J.B.); (S.R.); (J.-C.S.)
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12
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Klaus F, Guetter K, Schlegel R, Seifritz E, Rassi A, Thöny B, Cathomas F, Kaiser S. Peripheral biopterin and neopterin in schizophrenia and depression. Psychiatry Res 2021; 297:113745. [PMID: 33524773 DOI: 10.1016/j.psychres.2021.113745] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 01/19/2021] [Indexed: 01/21/2023]
Abstract
Increasing evidence points to a causal involvement of inflammation in the pathogenesis of neuropsychiatric disorders, including major depressive disorder (MDD) and schizophrenia (SZ). Neopterin and biopterin may link peripheral immune system activation and central neurotransmitter alterations. However, it is not fully established whether these alterations are transdiagnostic or disorder-specific and whether they are associated with reward-related psychopathologies. We investigated group differences in neopterin and biopterin in the plasma of healthy comparison (HC) (n=19), SZ (n=45) and MDD (n=43) participants. We then correlated plasma proteins with CRP as a measure for inflammation. Lastly, plasma proteins were correlated with the reward-related psychopathological domain apathy. We found a trend-level difference in biopterin levels and no significant difference in neopterin levels between groups. Within both patient groups, but not HC, we show a significant positive correlation of CRP with neopterin but not with biopterin. Further, we observed no significant correlations of plasma proteins with reward-related psychopathology in HC, MDD or SZ. While our study shows trend-level alterations of biopterin with relevance for future research, it does not support the hypothesis that peripheral neopterin or biopterin are associated with reward-related psychopathology.
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Affiliation(s)
- Federica Klaus
- Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Lenggstrasse 31, 8032 Zurich, Switzerland; Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, San Diego, USA.
| | - Karoline Guetter
- Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Lenggstrasse 31, 8032 Zurich, Switzerland
| | - Rebecca Schlegel
- Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Lenggstrasse 31, 8032 Zurich, Switzerland
| | - Erich Seifritz
- Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Lenggstrasse 31, 8032 Zurich, Switzerland
| | - Anahita Rassi
- Divisions of Metabolism and of Clinical Chemistry and Biochemistry and Children's Research Center, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland
| | - Beat Thöny
- Divisions of Metabolism and of Clinical Chemistry and Biochemistry and Children's Research Center, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032 Zurich, Switzerland
| | - Flurin Cathomas
- Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Lenggstrasse 31, 8032 Zurich, Switzerland; Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy P, New York, USA
| | - Stefan Kaiser
- Division of Adult Psychiatry, Department of Psychiatry, Geneva University Hospitals, Chemin du Petit-Bel-Air, 1225 Chêne-Bourg, Switzerland
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Loeffler DA, Aasly JO, LeWitt PA, Coffey MP. What Have We Learned from Cerebrospinal Fluid Studies about Biomarkers for Detecting LRRK2 Parkinson's Disease Patients and Healthy Subjects with Parkinson's-Associated LRRK2 Mutations? JOURNAL OF PARKINSONS DISEASE 2020; 9:467-488. [PMID: 31322581 PMCID: PMC6700639 DOI: 10.3233/jpd-191630] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known cause of autosomal dominant Parkinson’s disease (PD) and sporadic PD (sPD). The clinical presentation of LRRK2 PD is similar to sPD, and except for genetic testing, no biochemical or imaging markers can differentiate LRRK2 PD from sPD. Discovery of such biomarkers could indicate neuropathological mechanisms that are unique to or increased in LRRK2 PD. This review discusses findings in 17 LRRK2 - related CSF studies found on PubMed. Most of these studies compared analyte concentrations between four diagnostic groups: LRRK2 PD patients, sPD patients, asymptomatic control subjects carrying PD-associated LRRK2 mutations (LRRK2 CTL), and healthy control subjects lacking LRRK2 mutations (CTL). Analytes examined in these studies included Aβ1-42, tau, α-synuclein, oxidative stress markers, autophagy-related proteins, pteridines, neurotransmitter metabolites, exosomal LRRK2 protein, RNA species, inflammatory cytokines, mitochondrial DNA (mtDNA), and intermediary metabolites. FINDINGS: Pteridines, α-synuclein, mtDNA, 5-hydroxyindolacetic acid, β-D-glucose, lamp2, interleukin-8, and vascular endothelial growth factor were suggested to differentiate LRRK2 PD from sPD patients; 8-hydroxy-2’-deoxyguanosine (8-OHdG), 8-isoprostane (8-ISO), 2-hydroxybutyrate, mtDNA, lamp2, and neopterin may differentiate between LRRK2 CTL and LRRK2 PD subjects; and soluble oligomeric α-synuclein, 8-OHdG, and 8-ISO might differentiate LRRK2 CTL from CTL subjects. CONCLUSIONS: The low numbers of investigations of each analyte, small sample sizes, and methodological differences limit conclusions that can be drawn from these studies. Further investigations are indicated to determine the validity of the analytes identified in these studies as possible biomarkers for LRRK2 PD patients and/or LRRK2 CTL subjects.
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Affiliation(s)
- David A Loeffler
- Department of Neurology, Beaumont Hospital-Royal Oak, Beaumont Health, Royal Oak, MI, USA
| | - Jan O Aasly
- Department of Neurology, St. Olav's Hospital, Trondheim, Norway
| | - Peter A LeWitt
- Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.,Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Mary P Coffey
- Department of Biostatistics, Beaumont Hospital-Royal Oak, Beaumont Health, Royal Oak, MI, USA
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14
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Alterations in the reduced pteridine contents in the cerebrospinal fluids of LRRK2 mutation carriers and patients with Parkinson's disease. J Neural Transm (Vienna) 2017; 125:45-52. [PMID: 28864907 DOI: 10.1007/s00702-017-1784-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2017] [Accepted: 08/26/2017] [Indexed: 01/16/2023]
Abstract
Tetrahydrobiopterin (BH4) is a cofactor for tyrosine hydroxylase that is essential for the biosynthesis of dopamine. Parkinson's disease (PD) is characterized by a progressive degeneration of nigrostriatal dopaminergic neurons, and biomarkers reflecting the degree of neurodegeneration are important not only for basic research but also for clinical diagnosis and the treatment of the disease. Although the total neopterin and biopterin levels in the cerebrospinal fluids (CSF) of the patients with PD were reported, alterations in the composition of reduced and oxidized forms of pteridine compounds have not been examined. In this study, we first examined the time-dependent alterations in BH4 and other reduced pteridine compounds in the CSF of an MPTP-treated monkey as a primate PD model. We found that the CSF levels of BH4 and dihydroneopterin, an intermittent metabolite of BH4-biosynthesis, altered inversely with progression of neurodegeneration, whereas those of dihydrobiopterin and neopterin were relatively low and constant. Next, we assayed the amounts of reduced pteridine compounds in the CSF of 36 pre-symptomatic LRRK2-mutation (N1437H or G2019S) carriers (LRRK2-carrier), 13 patients with PD symptoms (LRRK2-PD), 46 patients with sporadic PD (sPD), and 26 non-PD individuals. The BH4 levels were significantly lower in both the LRRK2-PD and sPD patients, and the LRRK2-carriers exhibited higher BH4 levels compared with the sPD patients. The total neopterin levels in the CSF of the LRRK2-PD were significantly higher than those in the sPD and non-PD individuals, which indicated greater inflammatory responses in the brains of LRRK2-PD patients. The present results suggest that detailed analyses of pteridine levels in the CSF might be useful for understanding the pathophysiology of familial PD and for monitoring PD progression.
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15
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Hall S, Arora D, Anoopkumar-Dukie S, Grant GD. Effect of Coffee in Lipopolysaccharide-Induced Indoleamine 2,3-Dioxygenase Activation and Depressive-like Behavior in Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2016; 64:8745-8754. [PMID: 27690418 DOI: 10.1021/acs.jafc.6b03568] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Research has identified a potential inverse correlation between coffee consumption and the risk of depression. The aim of this study was to investigate the effects of caffeinated coffee on lipopolysaccharide-induced depressive-like behaviors and inflammatory biomarkers in an in vivo model of depression in a C57BL/6J mouse model. The behavioral studies showed that caffeinated coffee decreased immobility time in both the tail suspension test (caffeinated coffee 56.60 ± 9.17; p < 0.0001) and the forced swimming test (caffeinated coffee 28.80 ± 5.93; p < 0.0001), suggesting antidepressant-like activity. The effects of caffeinated coffee on the inflammatory biomarkers associated with depression supported the results observed in the behavioral studies. Statistically significant decreases in indoleamine 2,3-dioxygenase activity (p < 0.001) and the neopterin/biopterin ratio (p < 0.001) were observed in animals pretreated with caffeinated coffee 24 h post-lipopolysaccharide exposure in comparison to the lipopolysaccharide control group. In conclusion, this study has provided evidence to suggest that caffeinated coffee has antidepressant-like activities; however, further studies are required to fully investigate these effects.
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Affiliation(s)
- Susan Hall
- Menzies Health Institute Queensland, Griffith University , Queensland 4222, Australia
- School of Pharmacy, Griffith University , Queensland 4222, Australia
| | - Devinder Arora
- Menzies Health Institute Queensland, Griffith University , Queensland 4222, Australia
- School of Pharmacy, Griffith University , Queensland 4222, Australia
| | - Shailendra Anoopkumar-Dukie
- Menzies Health Institute Queensland, Griffith University , Queensland 4222, Australia
- School of Pharmacy, Griffith University , Queensland 4222, Australia
| | - Gary D Grant
- Menzies Health Institute Queensland, Griffith University , Queensland 4222, Australia
- School of Pharmacy, Griffith University , Queensland 4222, Australia
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16
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Engin A, Gonul II, Engin AB, Karamercan A, Sepici Dincel A, Dursun A. Relationship between indoleamine 2,3-dioxygenase activity and lymphatic invasion propensity of colorectal carcinoma. World J Gastroenterol 2016; 22:3592-601. [PMID: 27053851 PMCID: PMC4814645 DOI: 10.3748/wjg.v22.i13.3592] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 01/31/2016] [Accepted: 03/02/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate whether serum and tumor indoleamine 2,3-dioxygenase activities can predict lymphatic invasion (LI) or lymph node metastasis in colorectal carcinoma. METHODS The study group consisted of 44 colorectal carcinoma patients. The patients were re-grouped according to the presence or absence of LI and lymph node metastasis. Forty-three cancer-free subjects without any metabolic disturbances were included into the control group. Serum neopterin was measured by enzyme linked immunosorbent assay. Urinary neopterin and biopterin, serum tryptophan (Trp) and kynurenine (Kyn) concentrations of all patients were determined by high performance liquid chromatography. Kyn/Trp was calculated and its correlation with serum neopterin was determined to estimate the serum indoleamine 2,3-dioxygenase activity. Tissue sections from the studied tumors were re-examined histopathologically and were stained by immunohistochemistry with indoleamine-2,3-dioxygenase antibodies. RESULTS Neither serum nor urinary neopterin was significantly different between the patient and control groups (both P > 0.05). However, colorectal carcinoma patients showed a significant positive correlation between the serum neopterin levels and Kyn/Trp (r = 0.450, P < 0.01). Urinary biopterin was significantly higher in cancer cases (P < 0.05). Serum Kyn/Trp was significantly higher in colorectal carcinoma patients (P < 0.01). Lymphatic invasion was present in 23 of 44 patients, of which only 12 patients had lymph node metastasis. Eleven patients with LI had no lymph node metastasis. Indoleamine-2,3-dioxygenase intensity score was significantly higher in LI positive cancer group (44.56% ± 6.11%) than negative colorectal cancer patients (24.04% ± 6.90%), (P < 0.05). Indoleamine 2,3-dioxygenase expression correlated both with the presence of LI and lymph node metastasis (P < 0.01 and P < 0.05, respectively). A significant difference between the accuracy of diagnosis by using either total indoleamine-2,3-dioxygenase immunostaining score or of lymph node metastasis was found during the evaluation of cancer patients. CONCLUSION Indoleamine-2,3-dioxygenase expression may predict the presence of unrecognized LI and lymph node metastasis and may be included in the histopathological evaluation of colorectal carcinoma cases.
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Viaccoz A, Ducray F, Tholance Y, Barcelos GK, Thomas-Maisonneuve L, Ghesquières H, Meyronet D, Quadrio I, Cartalat-Carel S, Louis-Tisserand G, Jouanneau E, Guyotat J, Honnorat J, Perret-Liaudet A. CSF neopterin level as a diagnostic marker in primary central nervous system lymphoma. Neuro Oncol 2015; 17:1497-503. [PMID: 26014047 DOI: 10.1093/neuonc/nov092] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 05/01/2015] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND The diagnosis of primary central nervous system lymphoma (PCNSL) can be challenging. PCNSL lesions are frequently located deep within the brain, and performing a cerebral biopsy is not always feasible. The aim of this study was to investigate the diagnostic value of CSF neopterin, a marker of neuroinflammation, in immunocompetent patients with suspected PCNSL. METHODS We retrospectively reviewed the characteristics of 124 patients with brain tumor (n = 82) or an inflammatory CNS disorder (n = 42) in whom CSF neopterin levels were assessed. Twenty-eight patients had PCNSL, 54 patients had another type of brain tumor (glioma n = 36, metastasis n = 13, other n = 5), and 13 patients had a pseudotumoral inflammatory brain lesion. RESULTS CSF neopterin levels were significantly higher in the patients with PCNSL than in those with other brain tumors (41.8 vs 5.1 nmol/L, P < .001), those with pseudotumoral inflammatory brain lesions (41.8 vs 4.3 nmol/L, P < .001), and those with nontumefactive inflammatory CNS disorders (41.8 vs 3.8 nmol/L, P < .001). In the 95 patients with space-occupying brain lesions, at a cutoff of 10 nmol/L, the sensitivity of this approach was 96% and the specificity was 93% for the diagnosis of PCNSL. The positive and negative predictive values were 84% and 98%, respectively. CONCLUSION Assessing CSF neopterin levels in patients with a suspected brain tumor might be helpful for the positive and differential diagnosis of PCNSL. A prospective study is warranted to confirm these results.
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Affiliation(s)
- Aurélien Viaccoz
- Neuro-oncology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (A.V., F.D., L.T.-M., S.C.-C., J.H.); INSERM U1028/CNRS UMR 5292, Lyon Neuroscience Research Center, Lyon, France (A.V., F.D., Y.T., G.K.B., L.T.-M., D.M., I.Q., J.H., A.P.-L.); Université de Lyon, Université Claude-Bernard Lyon 1, Lyon, France (A.V., F.D., L.T.-M., J.H.); Neurochemistry Unit, Biochemistry Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (Y.T., I.Q., A.P.-L.); Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, Switzerland (G.K.B.); Hematology Department, Centre Léon Bérard, Lyon, France (H.G.); Neuroradiology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (G.L.-T.); Neurosurgery Department B, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (E.J.); Neurosurgery Department D, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (J.G.)
| | - François Ducray
- Neuro-oncology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (A.V., F.D., L.T.-M., S.C.-C., J.H.); INSERM U1028/CNRS UMR 5292, Lyon Neuroscience Research Center, Lyon, France (A.V., F.D., Y.T., G.K.B., L.T.-M., D.M., I.Q., J.H., A.P.-L.); Université de Lyon, Université Claude-Bernard Lyon 1, Lyon, France (A.V., F.D., L.T.-M., J.H.); Neurochemistry Unit, Biochemistry Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (Y.T., I.Q., A.P.-L.); Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, Switzerland (G.K.B.); Hematology Department, Centre Léon Bérard, Lyon, France (H.G.); Neuroradiology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (G.L.-T.); Neurosurgery Department B, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (E.J.); Neurosurgery Department D, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (J.G.)
| | - Yannick Tholance
- Neuro-oncology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (A.V., F.D., L.T.-M., S.C.-C., J.H.); INSERM U1028/CNRS UMR 5292, Lyon Neuroscience Research Center, Lyon, France (A.V., F.D., Y.T., G.K.B., L.T.-M., D.M., I.Q., J.H., A.P.-L.); Université de Lyon, Université Claude-Bernard Lyon 1, Lyon, France (A.V., F.D., L.T.-M., J.H.); Neurochemistry Unit, Biochemistry Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (Y.T., I.Q., A.P.-L.); Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, Switzerland (G.K.B.); Hematology Department, Centre Léon Bérard, Lyon, France (H.G.); Neuroradiology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (G.L.-T.); Neurosurgery Department B, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (E.J.); Neurosurgery Department D, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (J.G.)
| | - Gleicy Keli Barcelos
- Neuro-oncology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (A.V., F.D., L.T.-M., S.C.-C., J.H.); INSERM U1028/CNRS UMR 5292, Lyon Neuroscience Research Center, Lyon, France (A.V., F.D., Y.T., G.K.B., L.T.-M., D.M., I.Q., J.H., A.P.-L.); Université de Lyon, Université Claude-Bernard Lyon 1, Lyon, France (A.V., F.D., L.T.-M., J.H.); Neurochemistry Unit, Biochemistry Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (Y.T., I.Q., A.P.-L.); Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, Switzerland (G.K.B.); Hematology Department, Centre Léon Bérard, Lyon, France (H.G.); Neuroradiology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (G.L.-T.); Neurosurgery Department B, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (E.J.); Neurosurgery Department D, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (J.G.)
| | - Laure Thomas-Maisonneuve
- Neuro-oncology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (A.V., F.D., L.T.-M., S.C.-C., J.H.); INSERM U1028/CNRS UMR 5292, Lyon Neuroscience Research Center, Lyon, France (A.V., F.D., Y.T., G.K.B., L.T.-M., D.M., I.Q., J.H., A.P.-L.); Université de Lyon, Université Claude-Bernard Lyon 1, Lyon, France (A.V., F.D., L.T.-M., J.H.); Neurochemistry Unit, Biochemistry Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (Y.T., I.Q., A.P.-L.); Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, Switzerland (G.K.B.); Hematology Department, Centre Léon Bérard, Lyon, France (H.G.); Neuroradiology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (G.L.-T.); Neurosurgery Department B, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (E.J.); Neurosurgery Department D, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (J.G.)
| | - Hervé Ghesquières
- Neuro-oncology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (A.V., F.D., L.T.-M., S.C.-C., J.H.); INSERM U1028/CNRS UMR 5292, Lyon Neuroscience Research Center, Lyon, France (A.V., F.D., Y.T., G.K.B., L.T.-M., D.M., I.Q., J.H., A.P.-L.); Université de Lyon, Université Claude-Bernard Lyon 1, Lyon, France (A.V., F.D., L.T.-M., J.H.); Neurochemistry Unit, Biochemistry Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (Y.T., I.Q., A.P.-L.); Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, Switzerland (G.K.B.); Hematology Department, Centre Léon Bérard, Lyon, France (H.G.); Neuroradiology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (G.L.-T.); Neurosurgery Department B, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (E.J.); Neurosurgery Department D, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (J.G.)
| | - David Meyronet
- Neuro-oncology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (A.V., F.D., L.T.-M., S.C.-C., J.H.); INSERM U1028/CNRS UMR 5292, Lyon Neuroscience Research Center, Lyon, France (A.V., F.D., Y.T., G.K.B., L.T.-M., D.M., I.Q., J.H., A.P.-L.); Université de Lyon, Université Claude-Bernard Lyon 1, Lyon, France (A.V., F.D., L.T.-M., J.H.); Neurochemistry Unit, Biochemistry Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (Y.T., I.Q., A.P.-L.); Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, Switzerland (G.K.B.); Hematology Department, Centre Léon Bérard, Lyon, France (H.G.); Neuroradiology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (G.L.-T.); Neurosurgery Department B, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (E.J.); Neurosurgery Department D, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (J.G.)
| | - Isabelle Quadrio
- Neuro-oncology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (A.V., F.D., L.T.-M., S.C.-C., J.H.); INSERM U1028/CNRS UMR 5292, Lyon Neuroscience Research Center, Lyon, France (A.V., F.D., Y.T., G.K.B., L.T.-M., D.M., I.Q., J.H., A.P.-L.); Université de Lyon, Université Claude-Bernard Lyon 1, Lyon, France (A.V., F.D., L.T.-M., J.H.); Neurochemistry Unit, Biochemistry Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (Y.T., I.Q., A.P.-L.); Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, Switzerland (G.K.B.); Hematology Department, Centre Léon Bérard, Lyon, France (H.G.); Neuroradiology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (G.L.-T.); Neurosurgery Department B, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (E.J.); Neurosurgery Department D, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (J.G.)
| | - Stéphanie Cartalat-Carel
- Neuro-oncology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (A.V., F.D., L.T.-M., S.C.-C., J.H.); INSERM U1028/CNRS UMR 5292, Lyon Neuroscience Research Center, Lyon, France (A.V., F.D., Y.T., G.K.B., L.T.-M., D.M., I.Q., J.H., A.P.-L.); Université de Lyon, Université Claude-Bernard Lyon 1, Lyon, France (A.V., F.D., L.T.-M., J.H.); Neurochemistry Unit, Biochemistry Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (Y.T., I.Q., A.P.-L.); Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, Switzerland (G.K.B.); Hematology Department, Centre Léon Bérard, Lyon, France (H.G.); Neuroradiology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (G.L.-T.); Neurosurgery Department B, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (E.J.); Neurosurgery Department D, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (J.G.)
| | - Guy Louis-Tisserand
- Neuro-oncology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (A.V., F.D., L.T.-M., S.C.-C., J.H.); INSERM U1028/CNRS UMR 5292, Lyon Neuroscience Research Center, Lyon, France (A.V., F.D., Y.T., G.K.B., L.T.-M., D.M., I.Q., J.H., A.P.-L.); Université de Lyon, Université Claude-Bernard Lyon 1, Lyon, France (A.V., F.D., L.T.-M., J.H.); Neurochemistry Unit, Biochemistry Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (Y.T., I.Q., A.P.-L.); Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, Switzerland (G.K.B.); Hematology Department, Centre Léon Bérard, Lyon, France (H.G.); Neuroradiology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (G.L.-T.); Neurosurgery Department B, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (E.J.); Neurosurgery Department D, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (J.G.)
| | - Emmanuel Jouanneau
- Neuro-oncology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (A.V., F.D., L.T.-M., S.C.-C., J.H.); INSERM U1028/CNRS UMR 5292, Lyon Neuroscience Research Center, Lyon, France (A.V., F.D., Y.T., G.K.B., L.T.-M., D.M., I.Q., J.H., A.P.-L.); Université de Lyon, Université Claude-Bernard Lyon 1, Lyon, France (A.V., F.D., L.T.-M., J.H.); Neurochemistry Unit, Biochemistry Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (Y.T., I.Q., A.P.-L.); Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, Switzerland (G.K.B.); Hematology Department, Centre Léon Bérard, Lyon, France (H.G.); Neuroradiology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (G.L.-T.); Neurosurgery Department B, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (E.J.); Neurosurgery Department D, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (J.G.)
| | - Jacques Guyotat
- Neuro-oncology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (A.V., F.D., L.T.-M., S.C.-C., J.H.); INSERM U1028/CNRS UMR 5292, Lyon Neuroscience Research Center, Lyon, France (A.V., F.D., Y.T., G.K.B., L.T.-M., D.M., I.Q., J.H., A.P.-L.); Université de Lyon, Université Claude-Bernard Lyon 1, Lyon, France (A.V., F.D., L.T.-M., J.H.); Neurochemistry Unit, Biochemistry Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (Y.T., I.Q., A.P.-L.); Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, Switzerland (G.K.B.); Hematology Department, Centre Léon Bérard, Lyon, France (H.G.); Neuroradiology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (G.L.-T.); Neurosurgery Department B, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (E.J.); Neurosurgery Department D, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (J.G.)
| | - Jérôme Honnorat
- Neuro-oncology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (A.V., F.D., L.T.-M., S.C.-C., J.H.); INSERM U1028/CNRS UMR 5292, Lyon Neuroscience Research Center, Lyon, France (A.V., F.D., Y.T., G.K.B., L.T.-M., D.M., I.Q., J.H., A.P.-L.); Université de Lyon, Université Claude-Bernard Lyon 1, Lyon, France (A.V., F.D., L.T.-M., J.H.); Neurochemistry Unit, Biochemistry Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (Y.T., I.Q., A.P.-L.); Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, Switzerland (G.K.B.); Hematology Department, Centre Léon Bérard, Lyon, France (H.G.); Neuroradiology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (G.L.-T.); Neurosurgery Department B, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (E.J.); Neurosurgery Department D, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (J.G.)
| | - Armand Perret-Liaudet
- Neuro-oncology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (A.V., F.D., L.T.-M., S.C.-C., J.H.); INSERM U1028/CNRS UMR 5292, Lyon Neuroscience Research Center, Lyon, France (A.V., F.D., Y.T., G.K.B., L.T.-M., D.M., I.Q., J.H., A.P.-L.); Université de Lyon, Université Claude-Bernard Lyon 1, Lyon, France (A.V., F.D., L.T.-M., J.H.); Neurochemistry Unit, Biochemistry Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (Y.T., I.Q., A.P.-L.); Department of Anesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, Switzerland (G.K.B.); Hematology Department, Centre Léon Bérard, Lyon, France (H.G.); Neuroradiology Department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (G.L.-T.); Neurosurgery Department B, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (E.J.); Neurosurgery Department D, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (J.G.)
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Molero-Luis M, Fernández-Ureña S, Jordán I, Serrano M, Ormazábal A, Garcia-Cazorla À, Artuch R. Cerebrospinal fluid neopterin analysis in neuropediatric patients: establishment of a new cut off-value for the identification of inflammatory-immune mediated processes. PLoS One 2013; 8:e83237. [PMID: 24367586 PMCID: PMC3867431 DOI: 10.1371/journal.pone.0083237] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Accepted: 11/01/2013] [Indexed: 12/02/2022] Open
Abstract
Objective A high level of cerebrospinal fluid (CSF) neopterin is a marker of central nervous system inflammatory-immune mediated processes. We aimed to assess data from 606 neuropediatric patients, describing the clinical and biochemical features of those neurological disorders presenting CSF neopterin values above a new cut-off value that was defined in our laboratory. Methods To establish the new CSF neopterin cut-off value, we studied two groups of patients: Group 1 comprised 68 patients with meningoencephalitis, and Group 2 comprised 52 children with a confirmed peripheral infection and no central nervous system involvement. We studied 606 CSF samples from neuropediatric patients who were classified into 3 groups: genetic diagnosis (A), acquired/unknown etiologic neurologic diseases (B) and inflammatory-immune mediated processes (C). Results The CSF neopterin cut-off value was 61 nmol/L. Out of 606 cases, 56 presented a CSF neopterin level above this value. Group C had significantly higher CSF neopterin, protein and leukocyte values than the other groups. Sixteen of twenty-three patients in this group had a CSF neopterin level above the cut-off, whereas three and seven patients presented increased leukocyte and protein values, respectively. A significant association was found among CSF neopterin, proteins and leukocytes in the 606 patients. White matter disturbances were associated with high CSF neopterin concentrations. Conclusions Although children with inflammatory-immune mediated processes presented higher CSF neopterin values, patients with other neurological disorders also showed increased CSF neopterin concentrations. These results stress the importance of CSF neopterin analysis for the identification of inflammatory-immune mediated processes.
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Affiliation(s)
- Marta Molero-Luis
- Clinical Biochemistry and Neuropediatrc Departments, University Hospital Sant Joan de Déu, and Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain
- * E-mail:
| | - Sergio Fernández-Ureña
- Intensive Pediatric Care Unit Service, University Hospital Saint Joan de Déu, Barcelona, Spain
| | - Iolanda Jordán
- Intensive Pediatric Care Unit Service, University Hospital Saint Joan de Déu, Barcelona, Spain
| | - Mercedes Serrano
- Clinical Biochemistry and Neuropediatrc Departments, University Hospital Sant Joan de Déu, and Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain
| | - Aida Ormazábal
- Clinical Biochemistry and Neuropediatrc Departments, University Hospital Sant Joan de Déu, and Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain
| | - Àngels Garcia-Cazorla
- Clinical Biochemistry and Neuropediatrc Departments, University Hospital Sant Joan de Déu, and Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain
| | - Rafael Artuch
- Clinical Biochemistry and Neuropediatrc Departments, University Hospital Sant Joan de Déu, and Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain
| | - the Neopterin working group
- Clinical Biochemistry and Neuropediatrc Departments, University Hospital Sant Joan de Déu, and Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain
- Intensive Pediatric Care Unit Service, University Hospital Saint Joan de Déu, Barcelona, Spain
- Molecular Microbiology Department, Microbiology Service, University Hospital Sant Joan de Déu, Barcelona, Spain
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19
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Kuehne LK, Reiber H, Bechter K, Hagberg L, Fuchs D. Cerebrospinal fluid neopterin is brain-derived and not associated with blood-CSF barrier dysfunction in non-inflammatory affective and schizophrenic spectrum disorders. J Psychiatr Res 2013; 47:1417-22. [PMID: 23790260 DOI: 10.1016/j.jpsychires.2013.05.027] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Revised: 05/16/2013] [Accepted: 05/23/2013] [Indexed: 11/26/2022]
Abstract
Many psychiatric patients have a minor blood-CSF barrier dysfunction and increased Cerebrospinal fluid (CSF) neopterin concentrations. The source of normal CSF neopterin, a biomarker in inflammatory and non-inflammatory neurological diseases, has never been shown explicitly, a precondition for sensitive detection of pathologically increased CSF neopterin. Neopterin concentrations (ELISA) in CSF and serum of normal controls (n = 26) are evaluated by inter-individual variation propagation. Normal CSF neopterin is brain-derived: The inter-individual variation of CSF neopterin in the control group does not depend on serum neopterin concentration variation (coefficient of variation, CV-CSF = 9.7% < CV-serum = 24.5%). Additionally individual normal CSF neopterin concentrations are invariant to the variation of the albumin quotient, QAlb, i.e. CSF neopterin does not derive from leptomeninges. Subsequently CSF neopterin was interpreted with reference to its absolute concentration in CSF (cut off = 5.5 nmol/l). Patients (N = 44), retrospectively selected from a larger group with schizophrenic and affective spectrum disorder, are characterized by the absence of any clinical and neurochemical signs of inflammation. In this group 30% had an increased CSF neopterin concentration and 30% had an increased QAlb with only 7% combined pathologies. Increased CSF neopterin did not correlate with the blood-CSF barrier dysfunction. In the discussion we point to possible sources of both independent pathologies, connected either with reduced CSF flow rate (QAlb) or microglial activation (neopterin). With CSF neopterin analysis earlier in vitro studies about microglia activation in schizophrenic spectrum disorders or corresponding therapeutic efforts could get a more direct, in-vivo analytical tool.
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Affiliation(s)
- Leonie K Kuehne
- Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innrain 80, A-6020 Innsbruck, Austria
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Yilmaz A, Yiannoutsos CT, Fuchs D, Price RW, Crozier K, Hagberg L, Spudich S, Gisslén M. Cerebrospinal fluid neopterin decay characteristics after initiation of antiretroviral therapy. J Neuroinflammation 2013; 10:62. [PMID: 23664008 PMCID: PMC3657550 DOI: 10.1186/1742-2094-10-62] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 04/22/2013] [Indexed: 11/29/2022] Open
Abstract
Background Neopterin, a biomarker of macrophage activation, is elevated in the cerebrospinal fluid (CSF) of most HIV-infected individuals and decreases after initiation of antiretroviral therapy (ART). We studied decay characteristics of neopterin in CSF and blood after commencement of ART in HIV-infected subjects and estimated the set-point levels of CSF neopterin after ART-mediated viral suppression. Methods CSF and blood neopterin were longitudinally measured in 102 neurologically asymptomatic HIV-infected subjects who were treatment-naïve or had been off ART for ≥ 6 months. We used a non-linear model to estimate neopterin decay in response to ART and a stable neopterin set-point attained after prolonged ART. Seven subjects with HIV-associated dementia (HAD) who initiated ART were studied for comparison. Results Non-HAD patients were followed for a median 84.7 months. Though CSF neopterin concentrations decreased rapidly after ART initiation, it was estimated that set-point levels would be below normal CSF neopterin levels (<5.8 nmol/L) in only 60/102 (59%) of these patients. Pre-ART CSF neopterin was the primary predictor of set-point (P <0.001). HAD subjects had higher baseline median CSF neopterin levels than non-HAD subjects (P <0.0001). Based on the non-HAD model, only 14% of HAD patients were predicted to reach normal levels. Conclusions After virologically suppressive ART, abnormal CSF neopterin levels persisted in 41% of non-HAD and the majority of HAD patients. ART is not fully effective in ameliorating macrophage activation in CNS as well as blood, especially in subjects with higher pre-ART levels of immune activation.
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Affiliation(s)
- Aylin Yilmaz
- Department of Infectious Diseases, University of Gothenburg, Journalvagen 10, Gothenburg, 416 50, Sweden.
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Koshiba S, Tokuoka H, Yokoyama T, Horiuchi E, Ichinose H, Hasegawa K. Biopterin levels in the cerebrospinal fluid of patients with PARK8 (I2020T). J Neural Transm (Vienna) 2011; 118:899-903. [PMID: 21290151 DOI: 10.1007/s00702-011-0587-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2010] [Accepted: 01/16/2011] [Indexed: 11/28/2022]
Abstract
PARK8 is the most common form of familial Parkinson's disease (PD). We measured biopterin and monoamine metabolite levels in the cerebrospinal fluids of 7 PARK8 patients (I2020T mutation in leucine-rich repeat kinase 2), 2 asymptomatic mutation carriers, and 21 sporadic PD patients. The biopterin levels in PARK8 patients were significantly higher than those in sporadic PD patients, although the symptoms were comparable in both groups, suggesting that PARK8 patients exhibit parkinsonian symptoms with higher biopterin levels than sporadic PD patients.
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Affiliation(s)
- Shoko Koshiba
- Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259-B7 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan
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Stoeck K, Zerr I. Cellular immune activation markers neopterin and β2-microglobulin are not elevated in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. J Neuroimmunol 2011; 233:228-32. [PMID: 21232804 DOI: 10.1016/j.jneuroim.2010.12.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2010] [Revised: 11/05/2010] [Accepted: 12/05/2010] [Indexed: 10/18/2022]
Abstract
In prion diseases, neuroimmunological responses include activation of microglia, astrocytosis and release of pro- and anti-inflammatory cytokines, which might substantially contribute to the neurodegenerative process. In this study we investigated neopterin and beta(β)2-microglobulin, as markers of cellular immune activation, in the cerebrospinal fluid (CSF) of patients with Creutzfeldt-Jakob disease (CJD) and of patients with other neurological and non-neurological diseases. CSF samples from CJD patients were collected in the framework of the German CJD Surveillance study. Concentrations of neopterin and β2-microglobulin were determined in CSF using ELISA. We could not obtain significant changes in CSF levels of neopterin and β2-microglobulin in CJD patients when compared to other neurological and non-neurological controls. In a subanalysis of CJD patients only, we could find significant elevated neopterin levels in patients with MV genotype, potentially reflecting a distinct disease pathology. Since autoimmune inflammatory disorders are important differential diagnoses in CJD, additional biomarker might be helpful in clinical setting.
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Affiliation(s)
- Katharina Stoeck
- Department of Neurology, University of Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany
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Durukan AH, Hurmeric V, Akgul EO, Kilic S, Bayraktar MZ. Urinary Neopterin Levels in Uveitis: Is It a New Activity Marker? Ocul Immunol Inflamm 2009; 15:303-8. [PMID: 17763127 DOI: 10.1080/09273940701344374] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
PURPOSE Neopterin is an immunologic marker for the activation of the cell-mediated immune system and it is found to be elevated in autoimmune diseases. We aimed in this study to investigate the relationship between urinary neopterin levels and disease activity in patients with uveitis. METHODS 31 patients with active uveitis and 13 patients with inactive uveitis were compared with 27 age and sex matched controls. Disease activity was evaluated by clinical examination and fundus florescein angiography findings. Samples were studied with High Performance Liquid Chromatography. RESULTS Urinary neopterin levels in patients with active uveitis, inactive uveitis and control subjects were 274 +/- 98, 179 +/- 61 and 166 +/- 38 micromol/mol creatinine respectively (p < 001). The difference between active uveitis, inactive uveitis and control groups were statistically significant (p < 001). CONCLUSIONS Urinary neopterin levels are found to be increased in patients with active uveitis. Neopterin can be used as a biochemical activity marker to support the clinical findings in patients with uveitis.
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Affiliation(s)
- Ali H Durukan
- Department of Ophthalmology, Gulhane Military Medical Academy, Ankara, Turkey.
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Dale RC, Brilot F, Fagan E, Earl J. Cerebrospinal fluid neopterin in paediatric neurology: a marker of active central nervous system inflammation. Dev Med Child Neurol 2009; 51:317-23. [PMID: 19191826 DOI: 10.1111/j.1469-8749.2008.03225.x] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
AIM Cerebrospinal fluid (CSF) neopterin production is increased by interferon-gamma stimulation and appears to act as a marker of intrathecal immune activation. We aimed to test the usefulness of elevated CSF neopterin as a biological marker of central nervous system (CNS) inflammation. METHOD We retrospectively reviewed CSF neopterin in 158 children (89 males, 69 females, mean age 4y 1mo, SD 3y 11mo, range 1mo-15y). RESULTS CSF neopterin levels in children with chronic static CNS disorders (n=105) were predominantly low, suggesting that inflammation is rare in these patients. We created an upper value of normal (chronic static group 95th centile 27.4 nmol/l). CSF neopterin was elevated in all 10 patients with acute encephalitis and in 10 of 12 patients with other acute inflammatory CNS disorders (demyelination, post-infectious ataxia, myelitis). CSF neopterin was also significantly elevated in patients with chronic progressive disorders of inflammatory origin. Interestingly, CSF neopterin was elevated in four of six patients with chronic static disorders who were tested during a febrile exacerbation of seizures or dystonia, suggesting that intrathecal immune activation may be important in this setting. INTERPRETATION Neopterin has a short half-life and was useful for monitoring inflammation activity in a patient with relapsing-remitting encephalitis. CSF neopterin is a useful marker of inflammation in a broad range of acute and chronic CNS disorders, and is a significantly more sensitive marker of inflammation than CSF pleocytosis.
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Affiliation(s)
- Russell C Dale
- Neuroinflammation Group, Discipline of Paediatrics and Child Health, Children's Hospital at Westmead, University of Sydney, NSW, Australia
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Persistent intrathecal immune activation in HIV-1-infected individuals on antiretroviral therapy. J Acquir Immune Defic Syndr 2008; 47:168-73. [PMID: 17971711 DOI: 10.1097/qai.0b013e31815ace97] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Neopterin is a well-established marker of macrophage activation. The cerebrospinal fluid (CSF) neopterin levels are elevated in most HIV-1-infected individuals and decrease significantly after initiation of antiretroviral therapy (ART). Unexpectedly, CSF concentrations often remain mildly abnormal even in patients treated for a long time with suppressive ART. The aims of this study were to analyze if persistently elevated CSF neopterin levels were associated with the type of antiretroviral regimen or with low-level CSF HIV-1 concentrations and to evaluate if plasma HIV-1 RNA levels correlated to lingering CSF neopterin concentrations in patients with effective ART. METHODS One hundred fifty-seven chronically HIV-1-infected patients with stable ART for > or =6 months and no neurologic symptoms were included, and 193 HIV-1-infected patients without ART served as controls. Neopterin was analyzed with a radioimmunoassay or an enzyme-linked immunosorbent assay. HIV-1 RNA quantification was performed with the Roche Amplicor assay (version 1.5; Hoffman-La Roche, Basel, Switzerland). Two quantitative HIV-1 RNA assays with sensitivities < or =2.5 copies/mL were used in 40 samples. RESULTS As anticipated, HIV-1 RNA and CSF neopterin levels were markedly lower in patients on ART compared with untreated controls. No significant difference in CSF neopterin concentrations was found between those treated with protease inhibitor- and nonnucleoside reverse transcriptase inhibitor-based regimens in combination with 2 nucleoside analogues. Subjects with CSF HIV-1 RNA loads <2.5 copies/mL had the lowest CSF neopterin levels. Plasma viral load had no impact on intrathecal immune activation in cases with CSF viral loads <50 copies/mL. CONCLUSION The persistent intrathecal cell-mediated immune response was associated with CSF viral load but not with treatment regimen in individuals on ART.
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Cinque P, Brew BJ, Gisslen M, Hagberg L, Price RW. Cerebrospinal fluid markers in central nervous system HIV infection and AIDS dementia complex. HANDBOOK OF CLINICAL NEUROLOGY 2007; 85:261-300. [PMID: 18808988 DOI: 10.1016/s0072-9752(07)85017-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- Paola Cinque
- Clinic of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
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Abstract
INTRODUCTION One of the main problems in Behçet's disease is the lack of an original laboratory marker that can reflect clinical activity. In this study, laboratory parameters that could be used as indicators of active disease are investigated. MATERIALS AND METHODS The study included a total of 40 patients with Behçet's disease, 25 of whom were active and 15 inactive, who applied to Firat University, Firat Medical Center Dermatology, Rheumatology, Physiotherapy, and Ophthalmology outpatient clinics and a control group composed of 30 healthy volunteers. Serum neopterin, C-reactive protein (CRP), and sedimentation rate (ESR) levels were determined in all patients and healthy controls. RESULTS Serum neopterin, CRP, and ESR levels in active Behçet's disease patients were significantly higher than those in both the inactive group and healthy controls (p<0.001). CONCLUSIONS It was contemplated that together with serum CRP and ESR, neopterin could be a useful laboratory parameter in patients in whom disease activation could not be determined.
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Affiliation(s)
- Basak Coskun
- Department of Dermatology, Firat University, Faculty of Medicine, TR 23119 Elazig, Turkey.
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Pranzatelli MR, Hyland K, Tate ED, Arnold LA, Allison TJ, Soori GS. Evidence of cellular immune activation in children with opsoclonus-myoclonus: cerebrospinal fluid neopterin. J Child Neurol 2004; 19:919-24. [PMID: 15704863 DOI: 10.1177/08830738040190120201] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
To evaluate cellular immune activation in opsoclonus-myoclonus syndrome, we measured the inflammatory marker neopterin in the cerebrospinal fluid of 16 children with opsoclonus-myoclonus and neuroblastoma, 24 children with opsoclonus-myoclonus but no tumor, and 19 age-matched controls. The mean concentration in opsoclonus-myoclonus was 2.3-fold higher than in controls (P = .008). Neopterin was greatly elevated in four of the most neurologically severe cases, up to 8.3-fold above the highest control level. Thirteen of the 40 children with opsoclonus-myoclonus but no controls had a neopterin concentration >2 SD above the control mean (P = .005). In this high neopterin subgroup, neurologic severity was significantly greater and the duration of neurologic symptoms was less. In 16 children re-examined on immunotherapy, including adrenocorticotropic hormone (ACTH) combination therapy, treatment was associated with a significant reduction in both neopterin and neurologic severity. Neopterin did not differ significantly between the tumor and non-tumor opsoclonus-myoclonus etiologies. No abnormalities of tetrahydrobiopterin were found. Although cerebrospinal fluid neopterin lacked the sensitivity to be a biomarker of disease activity in opsoclonus-myoclonus, elevated concentrations do support a role for T-cell activation and cell-mediated immunity in its pathophysiology.
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Affiliation(s)
- Michael R Pranzatelli
- National Pediatric Myoclonus Center, Southern Illinois University School of Medicine, P.O. Box 19643, Springfield, IL 62702, USA
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Dhondt JL. Difficulties in establishing reference intervals for special fluids: the example of 5-hydroxyindoleacetic acid and homovanillic acid in cerebrospinal fluids. ACTA ACUST UNITED AC 2004; 42:833-41. [PMID: 15327020 DOI: 10.1515/cclm.2004.137] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
AbstractBiochemical measurements in “special fluids” are complicated with the problem of reference intervals. Reference intervals are difficult to establish for these types of samples since they are usually only collected in patients with clinical suspicion of disease. Determination of neurotransmitter metabolites in cerebrospinal fluid illustrates this difficulty. This paper will review the factors and circumstances that have been identified or are suspected to modifythe concentration of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid. In addition to obvious parameters such as age-related variation that can affect the concentration of 5-HIAA and HVA in cerebrospinal fluid, a varietyof other factors can explain the wide range of “control” group sizes reported in the literature. Reference intervals must take into account the purpose of cerebrospinal fluid examinations, whether they be prospective studies to explore physio-pathologic relationships or for diagnostic purposes. In the latter case, certain neurological disorders cannot be excluded if a single measured value is within the reference interval.
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Nikkilä HV, Ahokas A, Wahlbeck K, Rimón R, Andersson LC. Neopterin and macrophage inflammatory protein-1alpha in the cerebrospinal fluid of schizophrenic patients: no evidence of intrathecal inflammation. Neuropsychobiology 2003; 46:169-72. [PMID: 12566931 DOI: 10.1159/000067805] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Numerous reports support the idea that inflammatory and/or immunological processes contribute to the etiopathogenesis of schizophrenia. Most of the data are, however, based on findings from body compartments outside the central nervous system (CNS). We measured the concentrations of the inflammatory marker neopterin and the chemokine macrophage inflammatory protein-alpha (MIP-1alpha) in the cerebrospinal fluid (CSF) of acutely psychotic schizophrenic patients and of healthy controls. METHODS The concentration of neopterin was measured in the CSF of 11 schizophrenic patients by radioimmunoassay, and of MIP-1alpha in the CSF from 8 patients using ELISA. Control CSF was collected from 10 and 8 healthy individuals. RESULTS No statistically significant differences in CSF neopterin or MIP-1alpha were detected between patients and controls or between the patient samples obtained on hospital admission and after the treatment period associated with clinical improvement. CONCLUSIONS These findings argue against the hypothesis that active inflammatory processes are part of the pathophysiology of acute psychotic episodes in schizophrenia. The possible mechanisms explaining the previously reported aberrations of mononuclear cells and cytokines in schizophrenia are discussed.
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Andersson LM, Hagberg L, Fuchs D, Svennerholm B, Gisslén M. Increased blood-brain barrier permeability in neuro-asymptomatic HIV-1-infected individuals--correlation with cerebrospinal fluid HIV-1 RNA and neopterin levels. J Neurovirol 2001; 7:542-7. [PMID: 11704886 DOI: 10.1080/135502801753248123] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
The objective of this study was to assess the frequency of blood-brain barrier (BBB) impairment, as measured by the albumin ratio, in neuro-asymptomatic HIV-1-infected individuals without antiretroviral treatment and the correlation between BBB disruption and intrathecal immune activation and HIV-1 RNA levels. Serum and cerebrospinal fluid (CSF) albumin, neopterin, and HIV-1 RNA levels were analysed in 110 neuro-asymptomatic HIV-1-infected individuals at different stages of disease; 63 classified as CDC A, 25 as CDC B, and 22 as CDC C. Increased BBB permeability was found in 17 of 110 (15%) of HIV-1-infected individuals. This proportion was sustained throughout the CDC stages. The albumin ratio was correlated with the CSF neopterin levels (r(s) = 0.36, P < 0.001), the serum neopterin levels (r(s) = 0.37, P < 0.001), and the CSF HIV-1 RNA levels (r(s) = 0.26, P < 0.01), but not with the plasma HIV-1 RNA levels. The correlations between the albumin ratio and the CSF and serum neopterin concentrations and the CSF HIV-1 RNA levels indicate that immune activation and, possibly, intrathecal HIV-1 virus replication are important factors associated with increased BBB permeability in HIV-1 infection.
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Affiliation(s)
- L M Andersson
- Institute of Internal Medicine, Department of Infectious Diseases, Sahlgrenska University Hospital, S-416 85 Göteborg, Sweden.
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Furukawa Y, Shimadzu M, Rajput AH, Shimizu Y, Tagawa T, Mori H, Yokochi M, Narabayashi H, Hornykiewicz O, Mizuno Y, Kish SJ. GTP-cyclohydrolase I gene mutations in hereditary progressive amd dopa-responsive dystonia. Ann Neurol 1996; 39:609-17. [PMID: 8619546 DOI: 10.1002/ana.410390510] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Recently, mutations of the GTP-cyclohydrolase I (GTP-CH I) gene, which catalyzes the first step in the tetrahydrobiopterin (BH4) biosynthesis, were discovered in Japanese patients with hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD). However, it has not been confirmed that non-Japanese patients also contain mutations in the same gene, or whether these mutations are specific to HPD/DRD. In this study, two novel nonsense mutations in exon I of the GTP-CH I gene and a new mutation at the splice acceptor site of intron I were identified in an autopsied case of English-Irish descent and 2 Japanese patients with HPD/DRD. In the latter, cerebrospinal fluid (CSF) neopterin levels (which may reflect the GTP-CH I activity in the brain) were reduced to 18% and 37% of controls. A therapeutic trial of oral BH4 was ineffective, however, in a genetically proven patient. In contrast, no mutations in any exons of the GTP-CH I gene were found in 2 patients with early-onset parkinsonism with dystonia (EOP-D) who developed dopa-responsive parkinsonism and dystonia at 6 and 8 years old, respectively. Neopterin levels in CSF were well preserved in 6 EOP-D patients. These data suggest that, among patients of different racial backgrounds, the pathogenesis of HPD/DRD, unlike EOP-D, involves partial reduction of the brain GTP-CH I activity consequent to mutations in the GTP-CH I gene. Measurement of CSF neopterin concentration may be useful for the differential diagnosis between HPD/DRD and EOP-D.
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Affiliation(s)
- Y Furukawa
- Department of Neurology, Juntendo University School of Medicine, Japan
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Shaw CE, Dunbar PR, Macaulay HA, Neale TJ. Measurement of immune markers in the serum and cerebrospinal fluid of multiple sclerosis patients during clinical remission. J Neurol 1995; 242:53-8. [PMID: 7707089 DOI: 10.1007/bf00887815] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Magnetic resonance imaging of multiple sclerosis (MS) patients often shows active inflammatory lesions despite clinical remission. No immunological marker of disease activity has been identified in these patients. Concentrations of neopterin, interleukin-2 (IL-2), soluble interleukin-2 receptor (sIL-2R) and tumour necrosis factor-alpha (TNF-alpha) were measured in the serum and cerebrospinal fluid of 19 clinically-inactive MS patients and compared with those of 19 non-inflammatory controls. Cerebrospinal fluid (CSF) neopterin concentrations were significantly higher in the MS group than in controls (mean 9.1 mM vs 3.4 nM, P < 0.01) and 10 of 19 MS patients had levels above the control range. This finding provides evidence of ongoing T-cell-directed and interferon-gamma-mediated macrophage activation in the central nervous system. Analysis of IL-2, sIL-2R and TNF-alpha concentrations revealed no significant differences between MS patients and controls. We conclude that CSF neopterin concentration may correlate with disease activity in asymptomatic patients.
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Affiliation(s)
- C E Shaw
- Department of Medicine, Wellington School of Medicine, New Zealand
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Candito M, Nagatsu T, Chambon P, Chatel M. High-performance liquid chromatographic measurement of cerebrospinal fluid tetrahydrobiopterin, neopterin, homovanillic acid and 5-hydroxindoleacetic acid in neurological diseases. JOURNAL OF CHROMATOGRAPHY. B, BIOMEDICAL APPLICATIONS 1994; 657:61-6. [PMID: 7524948 DOI: 10.1016/0378-4347(94)80070-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Cerebrospinal fluid (CSF) samples from patients with a variety of neurological disorders were assayed to determine the concentrations of tetrahydrobiopterin (BH4), the active cofactor of hydroxylases. Dihydroneopterin (NH2) and neopterin (N), which are linked with BH4 synthesis and are inflammatory biochemical markers, were also measured simultaneously in a number of patients. 5-Hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), the main products of serotonin and dopamine breakdown, were analyzed in parallel whenever possible. As BH4 and NH2 are difficult to analyze owing to their instability, CSF samples were collected under special conditions to preserve the reduced BH4 and NH2. Liquid chromatographic assays and detection of the various substances measured also required particular precautions. BH4 concentrations were elevated in patients with neurological disorders such as syphilis and lupus-like disease and especially in an AIDS patient with neurological complications with an increased N/BH4 ratio.
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Affiliation(s)
- M Candito
- Laboratoire de Biochimie, Hôpital Pasteur, Nice, France
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