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Dirks M, Hennemann A, Grosse GM, Beer A, Pflugrad H, Haag K, Schuppner R, Deterding K, Cornberg M, Wedemeyer H, Weissenborn K. Long-Term Follow-Up of Neuropsychiatric Symptoms After Sustained Virological Response to Interferon-Free and Interferon-Based Hepatitis C Virus Treatment. J Viral Hepat 2025; 32:e14033. [PMID: 39503158 PMCID: PMC11883457 DOI: 10.1111/jvh.14033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 10/02/2024] [Accepted: 10/18/2024] [Indexed: 03/08/2025]
Abstract
Chronic hepatitis C virus (HCV) infection can be associated with neuropsychiatric symptoms like fatigue and cognitive impairment, independent of the liver status. The present study aims to assess changes in the pattern and extent of neuropsychological symptoms after successful treatment with interferon (IFN)-based and IFN-free therapy. HCV-infected patients who underwent neuropsychological assessment in previous studies were invited to a follow-up examination. Patients were grouped according to the treatment status: Sustained virological response (SVR) after IFN treatment (IFN SVR, n = 14) or after therapy with direct acting antivirals (DAA SVR, n = 28) or ongoing HCV infection (HCV RNA+, n = 11). A group of 33 healthy controls served as reference. Patients completed self-report questionnaires addressing health-related quality of life (HRQoL), mood and sleep quality and a neuropsychological test battery including tests of memory and attention (Luria's list of words, PSE test, cancelling "d" test, Word-Figure-Memory Test and computer-based test battery for the assessment of attention [TAP]). At baseline, all three patient groups had worse fatigue, depression, anxiety and HRQoL scores compared to healthy controls. Longitudinal analysis revealed that fatigue and mood slightly improved in all patient groups over time, while HRQoL improved in SVR patients but not in HCV RNA+ patients. Memory test results improved significantly in all patient groups, irrespective of their virological status. In contrast, the attention test results showed no clear change from baseline to follow-up. Our data can be considered as a hint that HCV eradication-independent of therapy regimen-does not substantially ameliorate neuropsychiatric symptoms in HCV-afflicted patients.
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Affiliation(s)
- Meike Dirks
- Department of NeurologyHannover Medical SchoolHannoverGermany
| | | | | | - Anika Beer
- Department of NeurologyHannover Medical SchoolHannoverGermany
| | | | - Kim Haag
- Department of NeurologyHannover Medical SchoolHannoverGermany
| | | | - Katja Deterding
- Department of Gastroenterology, Hepatology, Infectious Diseases and EndocrinologyHannover Medical SchoolHannoverGermany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology, Infectious Diseases and EndocrinologyHannover Medical SchoolHannoverGermany
- Centre for Individualised Infection Medicine (CiiM)HannoverGermany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and EndocrinologyHannover Medical SchoolHannoverGermany
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Su FH, Su MJ, Yu MZ, Maliko M, Yeh CC. Association of Cognitive Impairment With Chronic Viral Hepatitis Among Older Adults in Taiwan. Am J Geriatr Psychiatry 2024; 32:180-191. [PMID: 37838541 DOI: 10.1016/j.jagp.2023.09.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 09/10/2023] [Accepted: 09/11/2023] [Indexed: 10/16/2023]
Abstract
OBJECTIVE To evaluate the risk of cognitive impairment among patients with chronic viral hepatitis. DESIGN A cross-sectional study. SETTING Population-based. PARTICIPANTS Individuals 60 years or older were enrolled from the Taiwan Biobank database from 2012. EXPOSURE Hepatitis B virus and hepatitis C virus infections. MEASUREMENT Cognitive impairment was evaluated using the mini-mental state examination (MMSE). Logistic regression models were used to calculate odds ratios and 95% confidence intervals (CIs). The effects of APOE ε4 polymorphisms on the association between viral hepatitis and the risk of cognitive impairment were also investigated. RESULTS We recruited 912 participants with cognitive impairment and 22 869 participants without cognitive impairment. The adjusted odds ratio (aOR) for cognitive impairment was 1.38 (95% CI: 1.03-1.85, p = 0.033) among participants with hepatitis C virus infection and 1.14 (95% CI: 0.91-1.43, p = 0.257) among participants with hepatitis B virus infection. Participants with hepatitis C virus infection and without hepatitis B virus infection had a higher risk of cognitive impairment (aOR: 1.52, 95% CI: 1.13-2.04, p = 0.006). The MMSE subcategories most associated with hepatitis C virus infection were orientation and design copying. The association between hepatitis C virus infection and cognitive impairment was higher among participants with ε4 alleles of the APOE gene than among those without alleles (aOR: 2.18, 95% CI: 1.21-3.91, p = 0.009). CONCLUSIONS Our findings suggest that individuals 60 years or older with chronic hepatitis C virus infection are at increased risk of cognitive impairment.
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Affiliation(s)
- Fu-Hsiung Su
- Department of Family Medicine (F-HS), Cardinal Tien Hospital, Fu Jen Catholic University, New Taipei City, Taiwan; School of Medicine (F-HS), College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Ming-Jang Su
- School of Public Health (M-JS, M-ZY, MM, C-CY), College of Public Health, Taipei Medical University, New Taipei City, Taiwan; Department of Laboratory Medicine (M-JS), Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Ming-Zhen Yu
- School of Public Health (M-JS, M-ZY, MM, C-CY), College of Public Health, Taipei Medical University, New Taipei City, Taiwan
| | - Moreen Maliko
- School of Public Health (M-JS, M-ZY, MM, C-CY), College of Public Health, Taipei Medical University, New Taipei City, Taiwan
| | - Chih-Ching Yeh
- School of Public Health (M-JS, M-ZY, MM, C-CY), College of Public Health, Taipei Medical University, New Taipei City, Taiwan; Cancer Center (C-CY), Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan; Department of Public Health (C-CY), College of Public Health, China Medical University, Taichung, Taiwan; Master Program in Applied Epidemiology (C-CY), College of Public Health, Taipei Medical University, New Taipei City, Taiwan.
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3
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Zahr N, Sullivan E, Pfefferbaum A. [WITHDRAWN] Serum biomarkers of liver fibrosis identify changes in striatal metabolite levels. RESEARCH SQUARE 2024:rs.3.rs-2729490. [PMID: 37034697 PMCID: PMC10081358 DOI: 10.21203/rs.3.rs-2729490/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
The full text of this preprint has been withdrawn by the authors due to author disagreement with the posting of the preprint. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.
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Carvalho TL, Mertens Brainer de Queiroz Lima AC, de Araújo NS, de Sousa Fernandes MS, Lira GB, de Melo MMM, Vasconcelos LRS, de Moura PMMF, da Cunha Correia C. Aspects of cognitive assessments and spectroscopic magnetic resonance imaging in people with chronic hepatitis C: a systematic review. PSYCHOL HEALTH MED 2023; 28:1013-1029. [PMID: 35075963 DOI: 10.1080/13548506.2022.2029915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Extrahepatic manifestations are common in people with hepatitis C virus (HCV). Cognitive changes are pointed out, but the mechanisms are still uncertain. The aim of this systematic review was to analyze studies involving spectroscopic magnetic resonance in people infected with HCV, which also included cognitive tests. The research occurred in six databases (Directory of Open Access Journals, Lilacs, Medcaribe, Medline, Scielo and ScienceDirect) and the selection of studies was carried out in two stages: search for titles and abstracts, then reading of the full articles, excluding those that did not meet the eligibility criteria. 12,888 titles and abstracts were selected, but only 6 articles were included in the review. Impairments in attention, concentration, speed of information processing, memory, verbal fluency and executive functions were identified as well as an increase in the Cho/Cr and mI/Cr ratios and a reduction in the NAA/Cr ratio in some included studies. Longitudinal studies, with more homogeneous samples and methods, as well as with better controlled confounding factors, are necessary to adequately identify the effect of HCV on the brain.
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Affiliation(s)
- Tatiana Lins Carvalho
- Hospital Universitário Oswaldo Cruz, Pós-Graduação em Ciências da Saúde, Universidade de Pernambuco (UPE), Recife, Brazil
| | | | | | - Matheus Santos de Sousa Fernandes
- Departamento de Fisiologia e Farmacologia, Pós-graduação Em Neuropsiquiatria e Ciências do Comportamento, Universidade Federal de Pernambuco (UFPE), Recife, Brazil
| | - Gabriela Barza Lira
- Programa de Pós-graduação de Saúde da Criança e do Adolescente, Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil
| | | | | | | | - Carolina da Cunha Correia
- Professor of Neurology and Post Graduate Course in Health Sciences, Universidade de Pernambuco (UPE), Recife, PE, Brazil
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5
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Bungert AD, Urbantat RM, Jelgersma C, Bekele BM, Mueller S, Mueller A, Felsenstein M, Dusatko S, Blank A, Ghori A, Boehm-Sturm P, Koch SP, Vajkoczy P, Brandenburg S. Myeloid cell subpopulations compensate each other for Ccr2-deficiency in glioblastoma. Neuropathol Appl Neurobiol 2023; 49:e12863. [PMID: 36346010 DOI: 10.1111/nan.12863] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 08/07/2022] [Accepted: 10/09/2022] [Indexed: 11/11/2022]
Abstract
AIMS Glioblastomas are high-grade brain tumours that are characterised by the accumulation of brain-resident microglia and peripheral macrophages. Recruitment of these myeloid cells can be facilitated by CCR2/CCL2 signalling. Besides the well-known CCR2+ macrophages, we have identified microglia expressing CCR2 in glioma tissues. Thus, we investigated how Ccr2-deficiency of one of the myeloid cell populations affects the other population and tumour biology. METHODS We generated four chimeric groups to analyse single and combined Ccr2-deficiency of microglia and macrophages. On day 21 after tumour cell implantation (GL261), we conducted flow cytometry, immunofluorescence and real-time polymerase chain reaction analyses. Tumour volume and metabolism were determined by magnetic resonance imaging and magnetic resonance spectroscopy. Moreover, in vitro studies were performed with primary microglia and bone marrow-derived macrophages. RESULTS We demonstrated reduced infiltration of macrophages and microglia depending on the lack of Ccr2. However, the total number of myeloid cells remained constant except for the animals with dual Ccr2-knockout. Both microglia and macrophages with Ccr2-deficiency showed impaired expression of proinflammatory molecules and altered phagocytic activity. Despite the altered immunologic phenotype caused by Ccr2-deficiency, glioma progression and metabolism were hardly affected. Alterations were detected solely in apoptosis and proliferation of tumours from animals with specific Ccr2-deficient microglia, whereas vessel stability was increased in mice with Ccr2-knockout in both cell populations. CONCLUSION These results indicate that microglia and macrophages provide a homoeostatic balance within glioma tissue and compensate for the lack of the corresponding counterpart. Moreover, we identified that the CCR2/CCL2 axis is involved in the immunologic function of microglia and macrophages beyond its relevance for migration.
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Affiliation(s)
- Alexander D Bungert
- Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Ruth M Urbantat
- Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Claudius Jelgersma
- Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Biniam M Bekele
- Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Susanne Mueller
- Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Center for Stroke Research Berlin, Berlin, Germany
| | - Annett Mueller
- Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Matthäus Felsenstein
- Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Silke Dusatko
- Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Anne Blank
- Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Adnan Ghori
- Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Philipp Boehm-Sturm
- Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Center for Stroke Research Berlin, Berlin, Germany
| | - Stefan P Koch
- Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Peter Vajkoczy
- Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Susan Brandenburg
- Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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6
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Reichardt JL, Dirks M, Wirries AK, Pflugrad H, Nösel P, Haag K, Lanfermann H, Wedemeyer H, Potthoff A, Weissenborn K, Ding XQ. Brain metabolic and microstructural alterations associated with hepatitis C virus infection, autoimmune hepatitis and primary biliary cholangitis. Liver Int 2022; 42:842-852. [PMID: 34719118 DOI: 10.1111/liv.15093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 10/24/2021] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS Neuropsychiatric symptoms in hepatitis C (HCV) patients resemble those of patients with autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC), whilst the mechanisms behind them are unknown. Here we looked for cerebral metabolic and/or microstructural alterations in patients with HCV, AIH or PBC as possible causes behind these symptoms. METHODS Patients with HCV infection (n = 17), AIH (n = 14) or PBC (n = 11) and age-adjusted healthy controls (n = 18) underwent brain magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and psychometric assessment of memory and attention. Brain relative proton density (PD) and T2 relaxation time (T2) were determined in 17 regions of interest (ROIs), as were the concentrations of N-acetyl-aspartate, choline, creatine, myo-inositol and glutamine + glutamate in frontal- (fWM) and parietal white matter (pWM). One-way analysis of variance and Kruskal-Wallis tests were used for group comparison. Correlations between altered neuropsychological findings and MRI/MRS observations were estimated with the Spearman ρ test. RESULTS HCV, AIH and PBC patients revealed similar alterations in brain PD and metabolites compared to controls: significantly decreased PD in 7/17 ROIs in the HCV group, 16/17 ROIs in the PBC group and 14/17 ROIs in the AIH group, significantly increased N-acetyl-aspartate in fWM in all patients, significantly increased choline in the PBC group in both fWM and pWM, in the AIH group only in pWM and with a trend in the HCV group in pWM. Correlation analysis did not reveal significant associations between MRI/MRS alterations and neuropsychological dysfunction. CONCLUSION The findings suggest similar pathophysiological mechanisms behind neuropsychiatric symptoms associated with HCV infection, AIH and PBC.
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Affiliation(s)
- Jan-Luca Reichardt
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Meike Dirks
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | | | - Henning Pflugrad
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Patrick Nösel
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Kim Haag
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Heinrich Lanfermann
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Andrej Potthoff
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | - Xiao-Qi Ding
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
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7
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Danilescu CM, Sandulescu DL, Pirlog MC, Streba CT, Rogoveanu I. Depressive and Anxious Symptoms in Hepatitis C Virus Infected Patients Receiving DAA-Based Therapy. Diagnostics (Basel) 2021; 11:2237. [PMID: 34943472 PMCID: PMC8700570 DOI: 10.3390/diagnostics11122237] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/26/2021] [Accepted: 11/27/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) represents the most important etiologic factor for advanced fibrosis/cirrhosis and hepatocellular carcinoma associated with a psychological dimension. Our study aims to assess, on a sample comprising of 90 HCV-infected subjects (96.67% F3-F4 METAVIR), the relationship between Direct-Acting Antiviral (DAA) therapies and the psychological effects of the liver disease, focused on the anxious and depressive symptoms. The comprehensive evaluation was done before starting the DAA treatment (BSL), after 12 weeks (End of Treatment-EOT), respectively after another 12 weeks (Sustained Viral Response-SVR). Presumable depressive and/or anxious symptoms were evaluated by Hospital Anxiety and Depression Scale (HADS). The reported depressive symptoms decreased from 21.11% (BSL) to 1.11% (SVR) (p < 0.00001), while the anxious ones dropped from 43.34% (BSL) to 4.44% (SVR) (p < 0.00001), without a clear evolutionary pattern. We identified no statistically significant interaction between comorbidities (anemia, CKD, obesity) over HADS scores evolution (p > 0.05), while the DAAs side-effects (fatigue, headache, pruritus) significantly influenced the anxious and depressive symptoms (p < 0.05). During and after the DAA-based therapy, patients with HCV infection presented a significantly reduced rate of the associated depressive and anxious relevant symptoms.
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Affiliation(s)
| | - Daniela Larisa Sandulescu
- Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.L.S.); (I.R.)
| | - Mihail Cristian Pirlog
- Department of Medical Sociology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Costin Teodor Streba
- Department of Scientific Research Methodology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Ion Rogoveanu
- Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.L.S.); (I.R.)
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Moretti R, Giuffrè M, Merli N, Caruso P, Di Bella S, Tiribelli C, Crocè LS. Hepatitis C Virus-Related Central and Peripheral Nervous System Disorders. Brain Sci 2021; 11:1569. [PMID: 34942871 PMCID: PMC8699483 DOI: 10.3390/brainsci11121569] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatitis C Virus (HCV), despite being a hepatotropic virus, is the causative agent of many systemic disorders, such as vasculitis, autoimmune diseases, lymphoproliferative disorders, and a broad spectrum of neurological and psychiatric manifestations. Although symptoms have been misdiagnosed or underdiagnosed, only recently, evidence of direct (inflammatory) or indirect (immune-mediated) HCV-dependent cerebral effects has been established. HCV infection can promote acute inflammatory response, pro-coagulative status and ischemic disorders, and neurodegeneration. These effects rely on cerebral HCV replication, possibly mediated by blood-brain barrier alterations. Further study is needed to better understand the HCV-related mechanisms of brain damage.
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Affiliation(s)
- Rita Moretti
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | - Mauro Giuffrè
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | - Nicola Merli
- Department Neurological Sciences, University of Ferrara, 44121 Ferrara, Italy;
| | - Paola Caruso
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | - Stefano Di Bella
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | | | - Lory Saveria Crocè
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
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9
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Xing F, Marsili L, Truong DD. Parkinsonism in viral, paraneoplastic, and autoimmune diseases. J Neurol Sci 2021; 433:120014. [PMID: 34629181 DOI: 10.1016/j.jns.2021.120014] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 09/27/2021] [Accepted: 09/29/2021] [Indexed: 12/13/2022]
Abstract
Secondary parkinsonism, namely parkinsonism due to causes other than idiopathic neurodegeneration, may have multiple etiologies. Common secondary etiologies of parkinsonism such as drug-induced or vascular etiologies are well documented. Other secondary causes of parkinsonism such as infectious (mainly viral and prion-like diseases), autoimmune (systemic/drug-induced) and paraneoplastic etiologies are rare but are a topic of increasing interest. Older examples from the existing literature demonstrate the intricacies of viral infection from the last pandemic of the 20th century on the development of hypokinetic symptoms experienced in post-encephalitic patients. Viral and prion-like infections are only part of a complex interplay between the body's immune response and aberrant cell cycle perturbations leading to malignancy. In addition to the classic systemic autoimmune diseases (mainly systemic lupus erythematosus - SLE, and Sjögren syndrome), there have been new developments in the context of the current COVID-19 pandemic as well as more prominent use of immunotherapies such as immune checkpoint inhibitors in the treatment of solid tumors. Both of these developments have deepened our understanding of the underlying pathophysiologic process. Increased awareness and understanding of these rarer etiologies of parkinsonism is crucial to the modern diagnostic evaluation of a patient with parkinsonian symptoms as the potential treatment options may differ from the conventional levodopa-based therapeutic regimen of idiopathic Parkinson's disease. This review article aims to give an up-to-date review of the current literature on parkinsonian symptoms, their pathogenesis, diagnostic methods, and available treatment options. Many potential future directions in the field of parkinsonian conditions remain to be explored. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna.
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Affiliation(s)
- Frank Xing
- Truong Neuroscience Institute, Orange Coast Memorial Medical Center, Fountain Valley, CA, USA
| | - Luca Marsili
- Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH, USA
| | - Daniel D Truong
- Truong Neuroscience Institute, Orange Coast Memorial Medical Center, Fountain Valley, CA, USA; Department of Neurosciences, UC Riverside, Riverside, CA, USA.
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Zahr NM, Pohl KM, Kwong AJ, Sullivan EV, Pfefferbaum A. Preliminary Evidence for a Relationship between Elevated Plasma TNFα and Smaller Subcortical White Matter Volume in HCV Infection Irrespective of HIV or AUD Comorbidity. Int J Mol Sci 2021; 22:ijms22094953. [PMID: 34067023 PMCID: PMC8124321 DOI: 10.3390/ijms22094953] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 02/08/2023] Open
Abstract
Classical inflammation in response to bacterial, parasitic, or viral infections such as HIV includes local recruitment of neutrophils and macrophages and the production of proinflammatory cytokines and chemokines. Proposed biomarkers of organ integrity in Alcohol Use Disorders (AUD) include elevations in peripheral plasma levels of proinflammatory proteins. In testing this proposal, previous work included a group of human immunodeficiency virus (HIV)-infected individuals as positive controls and identified elevations in the soluble proteins TNFα and IP10; these cytokines were only elevated in AUD individuals seropositive for hepatitis C infection (HCV). The current observational, cross-sectional study evaluated whether higher levels of these proinflammatory cytokines would be associated with compromised brain integrity. Soluble protein levels were quantified in 86 healthy controls, 132 individuals with AUD, 54 individuals seropositive for HIV, and 49 individuals with AUD and HIV. Among the patient groups, HCV was present in 24 of the individuals with AUD, 13 individuals with HIV, and 20 of the individuals in the comorbid AUD and HIV group. Soluble protein levels were correlated to regional brain volumes as quantified with structural magnetic resonance imaging (MRI). In addition to higher levels of TNFα and IP10 in the 2 HIV groups and the HCV-seropositive AUD group, this study identified lower levels of IL1β in the 3 patient groups relative to the control group. Only TNFα, however, showed a relationship with brain integrity: in HCV or HIV infection, higher peripheral levels of TNFα correlated with smaller subcortical white matter volume. These preliminary results highlight the privileged status of TNFα on brain integrity in the context of infection.
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Affiliation(s)
- Natalie M. Zahr
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; (K.M.P.); (A.P.)
- Neuroscience Program, SRI International, Menlo Park, CA 94025, USA;
- Correspondence: ; Tel.: +1-650-859-5243
| | - Kilian M. Pohl
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; (K.M.P.); (A.P.)
- Neuroscience Program, SRI International, Menlo Park, CA 94025, USA;
| | - Allison J. Kwong
- Gastroenterology and Hepatology Medicine, Stanford University School of Medicine, Stanford, CA 94350, USA;
| | | | - Adolf Pfefferbaum
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; (K.M.P.); (A.P.)
- Neuroscience Program, SRI International, Menlo Park, CA 94025, USA;
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11
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Britton MK, Porges EC, Bryant V, Cohen RA. Neuroimaging and Cognitive Evidence for Combined HIV-Alcohol Effects on the Central Nervous System: A Review. Alcohol Clin Exp Res 2021; 45:290-306. [PMID: 33296091 PMCID: PMC9486759 DOI: 10.1111/acer.14530] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 11/29/2020] [Indexed: 12/27/2022]
Abstract
Alcohol use disorder (AUD) among people living with HIV (PLWH) is a significant public health concern. Despite the advent of effective antiretroviral therapy, up to 50% of PLWH still experience worsened neurocognition, which comorbid AUD exacerbates. We report converging lines of neuroimaging and neuropsychological evidence linking comorbid HIV/AUD to dysfunction in brain regions linked to executive function, learning and memory, processing speed, and motor control, and consequently to impairment in daily life. The brain shrinkage, functional network alterations, and brain metabolite disruption seen in individuals with HIV/AUD have been attributed to several interacting pathways: viral proteins and EtOH are directly neurotoxic and exacerbate each other's neurotoxic effects; EtOH reduces antiretroviral adherence and increases viral replication; AUD and HIV both increase gut microbial translocation, promoting systemic inflammation and HIV transport into the brain by immune cells; and HIV may compound alcohol's damaging effects on the liver, further increasing inflammation. We additionally review the neurocognitive effects of aging, Hepatitis C coinfection, obesity, and cardiovascular disease, tobacco use, and nutritional deficiencies, all of which have been shown to compound cognitive changes in HIV, AUD, and in their comorbidity. Finally, we examine emerging questions in HIV/AUD research, including genetic and cognitive protective factors, the role of binge drinking in HIV/AUD-linked cognitive decline, and whether neurocognitive and brain functions normalize after drinking cessation.
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Affiliation(s)
- Mark K. Britton
- University of Florida, Department of Clinical and Health Psychology, Center for Cognitive Aging and Memory, Cognitive Aging and Memory Clinical Translational Research Program; 1225 Center Drive, Gainesville, Florida 32607
| | - Eric C. Porges
- University of Florida, Department of Clinical and Health Psychology, Center for Cognitive Aging and Memory, Cognitive Aging and Memory Clinical Translational Research Program; 1225 Center Drive, Gainesville, Florida 32607
| | - Vaughn Bryant
- University of Florida, Department of Clinical and Health Psychology, Center for Cognitive Aging and Memory, Cognitive Aging and Memory Clinical Translational Research Program; 1225 Center Drive, Gainesville, Florida 32607
- University of Florida, Department of Epidemiology, 2004 Mowry Road, Gainesville, FL 32610
| | - Ronald A. Cohen
- University of Florida, Department of Clinical and Health Psychology, Center for Cognitive Aging and Memory, Cognitive Aging and Memory Clinical Translational Research Program; 1225 Center Drive, Gainesville, Florida 32607
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12
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Peculiarities of the Expression of Immunohistochemical Marker HCV nS3 in the Autopsy Brain of the Patients Died in the Outcome of Chronic Infection, Caused by Hepatitis C Virus. ACTA BIOMEDICA SCIENTIFICA 2020. [DOI: 10.29413/abs.2020-5.2.3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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13
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Neuroimaging Findings in Chronic Hepatitis C Virus Infection: Correlation with Neurocognitive and Neuropsychiatric Manifestations. Int J Mol Sci 2020; 21:ijms21072478. [PMID: 32252497 PMCID: PMC7177498 DOI: 10.3390/ijms21072478] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/26/2020] [Accepted: 03/31/2020] [Indexed: 01/18/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is commonly associated with neurocognitive dysfunction, altered neuropsychological performance and neuropsychiatric symptoms. Quantifiable neuropsychological changes in sustained attention, working memory, executive function, verbal learning and recall are the hallmark of HCV-associated neurocognitive disorder (HCV-AND). This constellation is at variance with the neuropsychological complex that is seen in minimal hepatic encephalopathy, which is typified by an array of alterations in psychomotor speed, selective attention and visuo-constructive function. Noncognitive symptoms, including sleep disturbances, depression, anxiety and fatigue, which are less easily quantifiable, are frequently encountered and can dominate the clinical picture and the clinical course of patients with chronic HCV infection. More recently, an increased vulnerability to Parkinson’s disease among HCV-infected patients has also been reported. The degree to which neurocognitive and neuropsychiatric changes are due to HCV replication within brain tissues or HCV-triggered peripheral immune activation remain to be determined. Without absolute evidence that clearly exonerates or indicts HCV, our understanding of the so-called “HCV brain syndrome”, relies primarily on clinical and neuropsychological assessments, although other comorbidities and substance abuse may impact on neurocognitive function, thus confounding an appropriate recognition. In recent years, a number of functional and structural brain imaging studies have been of help in recognizing possible biological markers of HCV-AND, thus providing a rationale for guiding and justifying antiviral therapy in selected cases. Here, we review clinical, neuroradiological, and therapeutic responses to interferon-based and interferon-free regimens in HCV-related cognitive and neuropsychiatric disorder.
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14
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The Many Difficulties and Subtleties in the Cognitive Assessment of Chronic Hepatitis C Infection. Int J Hepatol 2020; 2020:9675235. [PMID: 32257447 PMCID: PMC7106929 DOI: 10.1155/2020/9675235] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 02/27/2020] [Accepted: 03/10/2020] [Indexed: 12/30/2022] Open
Abstract
Since the discovery of HCV in 1989, several diseases have been related to chronic infection by this virus. Often, patients with hepatitis C virus (HCV) complain of cognitive impairment even before the development of hepatic cirrhosis, which they described as "brain fog." Several studies have proposed a link between chronic HCV infection and the development of cognitive alterations, but the inclusion of confounding factors in their samples significantly limits the analysis of the results. In this article, we will give an overview about cognitive dysfunction in patients with HCV.
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15
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Nardelli S, Riggio O, Rosati D, Gioia S, Farcomeni A, Ridola L. Hepatitis C virus eradication with directly acting antivirals improves health-related quality of life and psychological symptoms. World J Gastroenterol 2019; 25:6928-6938. [PMID: 31908396 PMCID: PMC6938730 DOI: 10.3748/wjg.v25.i48.6928] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 12/13/2019] [Accepted: 12/22/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Alterations in health-related quality of life (HRQoL) and neuropsychological disorders were described in the hepatitis C virus (HCV) patients. Although several studies investigated the modifications of HRQoL after HCV eradication, no data exists on the modifications of neuropsychological symptoms. AIM To investigate the effect of directly acting antivirals (DAAs) treatment on HRQoL and neuropsychological symptoms. METHODS Thirty nine patients with HCV infection underwent a neuropsychological assessment, including Zung-Self Depression-Rating-Scale, Spielberg State-Trait Anxiety Inventory Y1-Y2 and the Toronto-Alexithymia Scale-20 items before and after DAAs treatment. HRQoL was detected by Short-Form-36 (SF-36). RESULTS All HRQoL domains, but role limitation physical and bodily pain, significantly improved after treatment. Interestingly, after DAAs treatment, all domains of HRQoL returned similar to those of controls. Each neuropsychological test significantly improved after HCV eradication. A significant correlation was observed among each psychological test and the summary components of SF-36. At multiple linear regression analysis including each psychological test as possible covariates, Zung-Self Depression Rating Scale (Zung-SDS) score was independently and significantly related to summary components of the SF-36 in the basal state and the difference between Zung-SDS score before and after treatment was the only variable significantly and independently related to the modification of HRQoL induced by the treatment. CONCLUSION Neuropsychological symptoms strongly influenced HRQoL in HCV patients and there was a significant improvement of neuropsychological tests and HRQoL after DAAs treatment.
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Affiliation(s)
- Silvia Nardelli
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Oliviero Riggio
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Davide Rosati
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Stefania Gioia
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Alessio Farcomeni
- Department of Economics & Finance, University of Rome “Tor Vergata”, Rome 00185, Italy
| | - Lorenzo Ridola
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
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16
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Lin WY, Lin MS, Weng YH, Yeh TH, Lin YS, Fong PY, Wu YR, Lu CS, Chen RS, Huang YZ. Association of Antiviral Therapy With Risk of Parkinson Disease in Patients With Chronic Hepatitis C Virus Infection. JAMA Neurol 2019; 76:1019-1027. [PMID: 31168563 DOI: 10.1001/jamaneurol.2019.1368] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Importance Epidemiologic evidence suggests that hepatitis C virus (HCV) could be a risk factor for Parkinson disease (PD), but treatment for HCV infection has never been considered in these studies; hence, the association between antiviral therapy and PD incidence has remained unclear. Understanding this association may help in developing strategies to reduce PD occurrence. Objective To identify the risk of PD development in patients with HCV infection receiving antiviral treatment and in patients not receiving this treatment. Design, Setting, and Participants This cohort study obtained claims data from the Taiwan National Health Insurance Research Database. Adult patients with a new HCV diagnosis with or without hepatitis per International Classification of Diseases, Ninth Revision, Clinical Modification codes and anti-PD medications from January 1, 2003, to December 31, 2013, were selected for inclusion. After excluding participants not eligible for analysis, the remaining patients (n = 188 152) were categorized into treated and untreated groups according to whether they received antiviral therapy. Propensity score matching was performed to balance the covariates across groups for comparison of main outcomes. This study was conducted from July 1, 2017, to December 31, 2017. Main Outcomes and Measures Development of PD was the main outcome. A Cox proportional hazards regression model was used to compare the risk of PD, and the hazard ratio (HR) was calculated at 1 year, 3 years, and 5 years after the index date and at the end of the cohort. Results A total of 188 152 patients were included in the analysis. An equal number (n = 39 936) and comparable characteristics of participants were retained in the treated group (with 17 970 female [45.0%] and a mean [SD] age of 52.8 [11.4] years) and untreated group (with 17 725 female [44.4%] and a mean [SD] age of 52.5 [12.9] years) after matching. The incidence density of PD was 1.00 (95% CI, 0.85-1.15) in the treated group and 1.39 (95% CI, 1.21-1.57) per 1000 person-years in the untreated group. The advantage of antiviral therapy reached statistical significance at the 5-year follow-up (HR, 0.75; 95% CI, 0.59-0.96), and this advantage continued to increase until the end of follow-up (HR, 0.71; 95% CI, 0.58-0.87). Conclusions and Relevance Evidence suggested that the PD incidence was lower in patients with chronic HCV infection who received interferon-based antiviral therapy; this finding may support the hypothesis that HCV could be a risk factor for PD.
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Affiliation(s)
- Wey-Yil Lin
- Department of Neurology, Landseed International Hospital, Taoyuan, Taiwan.,Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Ming-Shyan Lin
- Department of Cardiology, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Yi-Hsin Weng
- Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,School of Medicine, Chang Gung University, Taoyuan, Taiwan.,Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Tu-Hsueh Yeh
- Department of Neurology, Taipei Medical University Hospital, Taipei, Taiwan.,School of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yu-Sheng Lin
- Department of Cardiology, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Po-Yu Fong
- Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yih-Ru Wu
- Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chin-Song Lu
- Department of Neurology, Landseed International Hospital, Taoyuan, Taiwan.,Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,School of Medicine, Chang Gung University, Taoyuan, Taiwan.,Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Rou-Shayn Chen
- Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ying-Zu Huang
- Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,School of Medicine, Chang Gung University, Taoyuan, Taiwan.,Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan.,Institute of Cognitive Neuroscience, National Central University, Taoyuan, Taiwan
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17
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Talwar P, Gupta R, Kushwaha S, Agarwal R, Saso L, Kukreti S, Kukreti R. Viral Induced Oxidative and Inflammatory Response in Alzheimer's Disease Pathogenesis with Identification of Potential Drug Candidates: A Systematic Review using Systems Biology Approach. Curr Neuropharmacol 2019; 17:352-365. [PMID: 29676229 PMCID: PMC6482477 DOI: 10.2174/1570159x16666180419124508] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 03/19/2018] [Accepted: 04/10/2018] [Indexed: 02/07/2023] Open
Abstract
Alzheimer's disease (AD) is genetically complex with multifactorial etiology. Here, we aim to identify the potential viral pathogens leading to aberrant inflammatory and oxidative stress response in AD along with potential drug candidates using systems biology approach. We retrieved protein interactions of amyloid precursor protein (APP) and tau protein (MAPT) from NCBI and genes for oxidative stress from NetAge, for inflammation from NetAge and InnateDB databases. Genes implicated in aging were retrieved from GenAge database and two GEO expression datasets. These genes were individually used to create protein-protein interaction network using STRING database (score≥0.7). The interactions of candidate genes with known viruses were mapped using virhostnet v2.0 database. Drug molecules targeting candidate genes were retrieved using the Drug- Gene Interaction Database (DGIdb). Data mining resulted in 2095 APP, 116 MAPT, 214 oxidative stress, 1269 inflammatory genes. After STRING PPIN analysis, 404 APP, 109 MAPT, 204 oxidative stress and 1014 inflammation related high confidence proteins were identified. The overlap among all datasets yielded eight common markers (AKT1, GSK3B, APP, APOE, EGFR, PIN1, CASP8 and SNCA). These genes showed association with hepatitis C virus (HCV), Epstein- Barr virus (EBV), human herpes virus 8 and Human papillomavirus (HPV). Further, screening of drugs targeting candidate genes, and possessing anti-inflammatory property, antiviral activity along with a suggested role in AD pathophysiology yielded 12 potential drug candidates. Our study demonstrated the role of viral etiology in AD pathogenesis by elucidating interaction of oxidative stress and inflammation causing candidate genes with common viruses along with the identification of potential AD drug candidates.
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Affiliation(s)
- Puneet Talwar
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Delhi, India
| | - Renu Gupta
- Institute of Human Behaviour & Allied Sciences (IHBAS), Dilshad Garden, Delhi 110 095, India
| | - Suman Kushwaha
- Institute of Human Behaviour & Allied Sciences (IHBAS), Dilshad Garden, Delhi 110 095, India
| | - Rachna Agarwal
- Institute of Human Behaviour & Allied Sciences (IHBAS), Dilshad Garden, Delhi 110 095, India
| | - Luciano Saso
- Department of Physiology and Pharmacology, Sapienza University of Rome, Italy
| | | | - Ritushree Kukreti
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Delhi, India
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18
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Amirsardari Z, Rahmani F, Rezaei N. Cognitive impairments in HCV infection: From pathogenesis to neuroimaging. J Clin Exp Neuropsychol 2019; 41:987-1000. [PMID: 31405320 DOI: 10.1080/13803395.2019.1652728] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Extrahepatic manifestations of hepatitis C virus (HCV) infection, in particular cognitive impairments, can be present in the absence of clinical liver dysfunction. Executive memory, attention, and concentration are cognitive domains that are most frequently affected. Microstructural and functional changes in cortical gray matter and basal ganglia associate these neuropsychiatric changes in early HCV infection. No study has covered the relationship between imaging features of HCV-related cognitive impairment and HCV pathology. Herein we summarize evidence suggesting a direct pathology of HCV in microglia, astrocytes, and microvascular endothelial cells, and a neuroinflammatory response in HCV-related cognitive decline. Lipoproteins and their receptors mediate HCV infectivity in the central nervous system and confer susceptibility to HCV-related cognitive decline. Magnetic resonance spectroscopy has revealed changes compatible with reactive gliosis and microglial activation in basal ganglia, frontal and occipital white matter, in the absence of cirrhosis or hepatic encephalopathy. Similarly, diffusion imaging shows evidence of structural disintegrity in the axonal fibers of white matter tracts associated with temporal and frontal cortices. We also discuss the cognitive benefits and side-effects of the two most popular therapeutic protocols interferon-based therapy and interferon-free therapy using direct acting anti-virals. Evidences support a network-based pattern of disruption in functional connectivity in HCV patients and a common neuronal substrate for HCV-related and interferon-therapy-associated cognitive decline. These evidences might help identify patients who benefit from either interferon-based or interferon-free treatment regimen.
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Affiliation(s)
- Zahra Amirsardari
- Student's Scientific Research Center (SSRC), Tehran University of Medical Sciences , Tehran , Iran.,NeuroImaging Network (NIN), Universal Scientific Education and Research Network (USERN) , Tehran , Iran
| | - Farzaneh Rahmani
- Student's Scientific Research Center (SSRC), Tehran University of Medical Sciences , Tehran , Iran.,NeuroImaging Network (NIN), Universal Scientific Education and Research Network (USERN) , Tehran , Iran
| | - Nima Rezaei
- NeuroImaging Network (NIN), Universal Scientific Education and Research Network (USERN) , Tehran , Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences , Tehran , Iran
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19
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Dirks M, Haag K, Pflugrad H, Tryc AB, Schuppner R, Wedemeyer H, Potthoff A, Tillmann HL, Sandorski K, Worthmann H, Ding X, Weissenborn K. Neuropsychiatric symptoms in hepatitis C patients resemble those of patients with autoimmune liver disease but are different from those in hepatitis B patients. J Viral Hepat 2019; 26:422-431. [PMID: 30120896 DOI: 10.1111/jvh.12979] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Revised: 08/03/2018] [Accepted: 08/07/2018] [Indexed: 12/14/2022]
Abstract
Chronic fatigue, mood alterations and cognitive impairment are frequent accessory symptoms of HCV infection. Fatigue and mood alterations have also been observed in autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), but not in hepatitis B virus (HBV)-infection, thus indicating an autoimmune response as possible cause of HCV infection-associated encephalopathy. Data, however, are sparse. This study aimed to prove that HCV patients feature similar to those with autoimmune liver disease but contrary to HBV patients regarding neuropsychiatric symptoms. A total of 132 noncirrhotic patients (HCV: 46, HBV: 22, AIH: 27, PBC: 29, AIH/PBC: 8) completed questionnaires addressing the domains mentioned above. Eighty-eight underwent a comprehensive neuropsychological assessment. Patient groups were compared among each other and to 33 healthy controls. Fatigue, anxiety and depression scores were significantly increased, and the SF-36 mental score significantly decreased in all patient groups compared to controls. Fatigue was significantly more pronounced in HCV than in HBV patients. HCV patients scored significantly worse than HBV patients but not AIH and PBC patients in the SF-36. HCV, AIH and PBC but not HBV patients did significantly worse than controls in word learning. Recognition of words was impaired in HCV, AIH and PBC patients and recognition of figures in HCV patients, exclusively (P ≤ 0.002). HCV patients did also worse than controls and HBV patients concerning alertness and working memory (P ≤ 0.001). The neuropsychiatric profiles of HCV patients are similar to those of AIH and PBC patients but differ from those of HBV patients, suggesting an autoimmune response as a possible cause for these differences.
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Affiliation(s)
- Meike Dirks
- Clinic for Neurology, Hannover Medical School, Hannover, Germany
| | - Kim Haag
- Clinic for Neurology, Hannover Medical School, Hannover, Germany
| | - Henning Pflugrad
- Clinic for Neurology, Hannover Medical School, Hannover, Germany
| | - Anita B Tryc
- Clinic for Neurology, Hannover Medical School, Hannover, Germany
| | - Ramona Schuppner
- Clinic for Neurology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Andrej Potthoff
- Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Hans L Tillmann
- Division of Gastroenterology, Hepatology & Nutrition, East Carolina University, Greenville, North Carolina
| | | | - Hans Worthmann
- Clinic for Neurology, Hannover Medical School, Hannover, Germany
| | - Xiaoqi Ding
- Institute for Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
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20
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Yuan G, Rong L, Liu J, Zhang Z, Hu C, Chen M, Ma L, Zhang YY, Li YP, Zhou Y. Serum‑derived hepatitis C virus can infect human glioblastoma cell line SF268 and activate the PI3K‑Akt pathway. Mol Med Rep 2019; 19:4441-4448. [PMID: 30896873 DOI: 10.3892/mmr.2019.10063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 02/08/2019] [Indexed: 11/06/2022] Open
Abstract
Extra‑hepatic manifestations are frequently observed in hepatitis C virus (HCV)‑infected patients; however the underlying mechanisms remain largely unknown. In the present study, the human glioblastoma SF268 cell line (the precise origin of the cell type is not clear) was infected with HCV using HCV‑positive serum, and viral replication was assessed by immunofluorescence, reverse transcription‑polymerase chain reaction (PCR), quantitative PCR and western blotting following infection. HCV core protein and HCV RNA were detected in HCV‑positive serum‑infected SF268 cells at day 4 post‑infection, while no infection was observed in cells exposed to HCV‑negative serum. The mean HCV RNA levels at day 4 post‑infection were up to 5.00 IU/ml log10; however, HCV RNA and immunostaining for core protein were negative when cultured to day 6 or longer. The data suggest that human glioblastoma SF268 cells were transiently infected with HCV. AKT serine/threonine kinase phosphorylation was also detected in HCV‑infected SF268 cells at day 4 post‑infection. To the best of our knowledge, this is the first demonstration that a human glioblastoma cell line can be infected with serum‑derived HCV. The results provide evidence that HCV infection can occur in cells of the central nervous system. Neurological disorder‑associated phosphoinositide 3‑kinase‑AKT signaling pathway was activated in parallel with HCV infection, suggesting that SF268 may serve as an in vitro model for investigating HCV‑nervous system cell interactions.
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Affiliation(s)
- Guosheng Yuan
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Liang Rong
- Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Junwei Liu
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Zhenzhen Zhang
- Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Chengguang Hu
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Mingxiao Chen
- Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Ling Ma
- Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | | | - Yi-Ping Li
- Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Yuanping Zhou
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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21
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Abo Hagar A, Ashour Y, Negm M, Abdelfatah M, Gad KA, Hashish E. Brain magnetic resonance spectroscopy and cognitive impairment in chronic hepatitis C patients. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2018; 54:43. [PMID: 30613130 PMCID: PMC6302099 DOI: 10.1186/s41983-018-0046-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 12/04/2018] [Indexed: 01/18/2023] Open
Abstract
Background Cognitive dysfunction in patients with chronic hepatitis C virus (HCV) infection may appear long before the development of severe liver cirrhosis. These alterations are not ascribed to hepatic encephalopathy; however, early detection is always difficult. Objective The aim of this study was to assess the changes of magnetic resonance spectroscopy (MRS) metabolites among chronic hepatitis C virus patients with and without cognitive impairment. Patients and methods A cross-sectional study was conducted in Suez Canal University Hospital. Forty-six HCV patients was included and divided into two groups: patients with and without cognitive impairment. Assessment of cognitive function was done using mini-mental state examination and Wechsler Memory Scale - Revised. Both groups were subjected to single-voxel MRS to evaluate metabolites in three brain regions: the basal ganglia, hippocampus, and posterior cingulate gyrus. Results The CHO/Cr was significantly higher, and NAA/Cr was significantly lower in group with cognitive impairment in the basal ganglia and posterior cingulate gyrus. Mini-mental state score had negative significant correlation with PCR of HCV. Mini-mental state score had significant negative and positive correlation with CHO/Cr and NAA/Cr, respectively, in the basal ganglia. All values of the Wechsler Memory Scale were statistically higher in the group without cognitive impairment except verbal memory score. Conclusion There were changes at brain metabolites associated with cognitive impairment in chronic hepatitis C patients regarding a decrease of NAA/Cr ratio and an increase of CHO/Cr ratio at the basal ganglia.
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Affiliation(s)
| | - Youssri Ashour
- Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Mohamed Negm
- Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | | | - Khaled A Gad
- Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Ehab Hashish
- Faculty of Medicine, Suez Canal University, Ismailia, Egypt
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22
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Fath-Elbab HK, Ahmed E, Mansour DF, Soliman WT. Event-related evoked potential versus clinical tests in assessment of subclinical cognitive impairment in chronic hepatitis C virus. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2018; 54:35. [PMID: 30532514 PMCID: PMC6245136 DOI: 10.1186/s41983-018-0034-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Accepted: 10/19/2018] [Indexed: 01/01/2023] Open
Abstract
Context Chronic infection by hepatitis C virus causes impairment in neurocognitive function in up to 50% of patients which may not be detected by clinical tests. Aim Early detection of neurocognitive impairment in chronic hepatitis C patients and investigating the cognitive function in HCV patient by p300 and clinical test. Materials and methods The study included 60 patients with chronic hepatitis C and 30 healthy controls. Participants were subjected to a biochemical, hematological assessment, mini-mental state examination, Montreal Cognitive Assessment, P300, polymerase chain reaction (PCR), and fibroscan made for hepatitis C patients. Results The digit span, attention, concentration, and memory were significantly lower in patients than controls. The delayed P300 peak latency and the reduction of its amplitude were significantly evident in patients with liver fibrosis than the controls and patients without fibrosis. These abnormalities were significantly higher with increasing the grade of fibrosis. All patients with cognitive impairment (reduced mini-mental state score) had abnormal P300-evoked responses. P300 could detect neurocognitive impairment in some patients with normal neurocognitive functions by clinical test. P300 had sensitivity (100%), specificity (59.26), positive predictive value (75%), negative predictive value (100%), and accuracy (81.67) in the detection of neurocognitive impairment in HCV patient. Conclusion Patients with chronic hepatitis C infection had significant impairment in their cognitive functions. This impairment increases with the increase in grade of hepatic fibrosis. P300 can detect minimal and subclinical impairment of cognitive function at early stages of chronic hepatitis with accuracy (81.67). Trial registration PACTR on 19 march 2018 retrospectively. Identification number for the registry is PACTR201804003215168.
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Affiliation(s)
| | - Elham Ahmed
- Minia University Faculty of Medicine, Minia, Egypt
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23
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Li WW, Yang Y, Dai QG, Lin LL, Xie T, He LL, Tao JL, Shan JJ, Wang SC. Non-invasive urinary metabolomic profiles discriminate biliary atresia from infantile hepatitis syndrome. Metabolomics 2018; 14:90. [PMID: 30830373 DOI: 10.1007/s11306-018-1387-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 06/14/2018] [Indexed: 12/26/2022]
Abstract
INTRODUCTION Neonatal cholestatic disorders are a group of hepatobiliary diseases occurring in the first 3 months of life. The most common causes of neonatal cholestasis are infantile hepatitis syndrome (IHS) and biliary atresia (BA). The clinical manifestations of the two diseases are too similar to distinguish them. However, early detection is very important in improving the clinical outcome of BA. Currently, a liver biopsy is the only proven and effective method used to differentially diagnose these two similar diseases in the clinic. However, this method is invasive. Therefore, sensitive and non-invasive biomarkers are needed to effectively differentiate between BA and IHS. We hypothesized that urinary metabolomics can produce unique metabolite profiles for BA and IHS. OBJECTIVES The aim of this study was to characterize urinary metabolomic profiles in infants with BA and IHS, and to identify differences among infants with BA, IHS, and normal controls (NC). METHODS Urine samples along with patient characteristics were obtained from 25 BA, 38 IHS, and 38 NC infants. A non-targeted gas chromatography-mass spectrometry (GC-MS) metabolomics method was used in conjunction with orthogonal partial least squares discriminant analysis (OPLS-DA) to explore the metabolomic profiles of BA, IHS, and NC infants. RESULTS In total, 41 differentially expressed metabolites between BA vs. NC, IHS vs. NC, and BA vs. IHS were identified. N-acetyl-D-mannosamine and alpha-aminoadipic acid were found to be highly accurate at distinguishing between BA and IHS. CONCLUSIONS BA and IHS infants have specific urinary metabolomic profiles. The results of our study underscore the clinical potential of metabolomic profiling to uncover metabolic changes that could be used to discriminate BA from IHS.
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Affiliation(s)
- Wei-Wei Li
- Department of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yan Yang
- TCM Department, Beijing Children's Hospital Affiliated to Capital Medical University, Beijing, China
| | - Qi-Gang Dai
- Department of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Li-Li Lin
- Department of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, China
| | - Tong Xie
- Department of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, China
| | - Li-Li He
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jia-Lei Tao
- Department of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jin-Jun Shan
- Department of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
- Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, China.
| | - Shou-Chuan Wang
- Department of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
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24
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Interferon-free therapy in hepatitis C virus (HCV) monoinfected and HCV/HIV coinfected patients: effect on cognitive function, fatigue, and mental health. J Neurovirol 2018; 24:557-569. [PMID: 29785584 DOI: 10.1007/s13365-018-0647-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 03/27/2018] [Accepted: 04/26/2018] [Indexed: 12/13/2022]
Abstract
The efficacy and safety of interferon-free therapies for hepatitis C virus (HCV) infection have been reported. Considering the accumulating evidence for a direct central nervous system infection by HCV, we aim to evaluate the effect of direct acting antivirals (DAA) therapy on cognitive function in HCV patients. We conducted a longitudinal analysis of the cognitive performance of 22 patients (8 HCV+, 14 HCV+/HIV+) who completed neuropsychological testing at baseline and at week 12 after DAA therapy. In 20 patients, we analyzed specific attention parameters derived from an experimental testing based on the Theory of Visual Attention (TVA). Depression, fatigue, and mental health were assessed as patient reported outcomes. At baseline, 54.5% of the patients met the criteria for cognitive impairment and 40% showed impairment in TVA parameters. Follow-up analysis revealed significant improvements in the domains of visual memory/learning, executive functions, verbal fluency, processing speed, and motor skills but not in verbal learning and attention/working memory. We did not observe significant improvement in visual attention measured by TVA. Fatigue and mental health significantly improved at follow-up. Our findings indicate that successful DAA treatment leads to cognitive improvements in several domains measured by standard neuropsychological testing. The absence of improvement in TVA parameters and of significant improvement in the domain of attention/working memory might reflect the persistence of specific cognitive deficits after HCV eradication. In summary, DAA treatment seems to have a positive effect on some cognitive domains and leads to an improvement in mental health and fatigue in HCV-infected patients.
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25
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Oriolo G, Egmond E, Mariño Z, Cavero M, Navines R, Zamarrenho L, Solà R, Pujol J, Bargallo N, Forns X, Martin-Santos R. Systematic review with meta-analysis: neuroimaging in hepatitis C chronic infection. Aliment Pharmacol Ther 2018. [PMID: 29536563 DOI: 10.1111/apt.14594] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Chronic hepatitis C is considered a systemic disease because of extra-hepatic manifestations. Neuroimaging has been employed in hepatitis C virus-infected patients to find in vivo evidence of central nervous system alterations. AIMS Systematic review and meta-analysis of neuroimaging research in chronic hepatitis C treatment naive patients, or patients previously treated without sustained viral response, to study structural and functional brain impact of hepatitis C. METHODS Using PRISMA guidelines a database search was conducted from inception up until 1 May 2017 for peer-reviewed studies on structural or functional neuroimaging assessment of chronic hepatitis C patients without cirrhosis or encephalopathy, with control group. Meta-analyses were performed when possible. RESULTS The final sample comprised 25 studies (magnetic resonance spectroscopy [N = 12], perfusion weighted imaging [N = 1], positron emission tomography [N = 3], single-photon emission computed tomography [N = 4], functional connectivity in resting state [N = 1], diffusion tensor imaging [N = 2] and structural magnetic resonance imaging [N = 2]). The whole sample was of 509 chronic hepatitis C patients, with an average age of 41.5 years old and mild liver disease. A meta-analysis of magnetic resonance spectroscopy studies showed increased levels of choline/creatine ratio (mean difference [MD] 0.12, 95% confidence interval [CI] 0.06-0.18), creatine (MD 0.85, 95% CI 0.42-1.27) and glutamate plus glutamine (MD 1.67, 95% CI 0.39-2.96) in basal ganglia and increased levels of choline/creatine ratio in centrum semiovale white matter (MD 0.13, 95% CI 0.07-0.19) in chronic hepatitis C patients compared with healthy controls. Photon emission tomography studies meta-analyses did not find significant differences in PK11195 binding potential in cortical and subcortical regions of chronic hepatitis C patients compared with controls. Correlations were observed between various neuroimaging alterations and neurocognitive impairment, fatigue and depressive symptoms in some studies. CONCLUSIONS Patients with chronic hepatitis C exhibit cerebral metabolite alterations and structural or functional neuroimaging abnormalities, which sustain the hypothesis of hepatitis C virus involvement in brain disturbances.
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Affiliation(s)
- G Oriolo
- Department of Psychiatry and Psychology, Hospital Clinic, Institut d'Investigació Biomèdica Arthur Pi I Sunyer (IDIBAPS), Centro Investigación Biomédica en Red de Salud Mental (CIBERSAM), University of Barcelona, Barcelona, Spain.,Department of Medicine, Institute of Neuroscience, University of Barcelona, Barcelona, Spain
| | - E Egmond
- Department of Psychiatry and Psychology, Hospital Clinic, Institut d'Investigació Biomèdica Arthur Pi I Sunyer (IDIBAPS), Centro Investigación Biomédica en Red de Salud Mental (CIBERSAM), University of Barcelona, Barcelona, Spain.,Department of Medicine, Institute of Neuroscience, University of Barcelona, Barcelona, Spain.,Department of Health and Clinical Psychology, Faculty of Psychology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Z Mariño
- Liver Unit, Hospital Clinic, IDIBAPS, Centro Investigación Biomédica en Red de Enfermedades hepáticas y digestivas, (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - M Cavero
- Department of Psychiatry and Psychology, Hospital Clinic, Institut d'Investigació Biomèdica Arthur Pi I Sunyer (IDIBAPS), Centro Investigación Biomédica en Red de Salud Mental (CIBERSAM), University of Barcelona, Barcelona, Spain.,Department of Medicine, Institute of Neuroscience, University of Barcelona, Barcelona, Spain
| | - R Navines
- Department of Psychiatry and Psychology, Hospital Clinic, Institut d'Investigació Biomèdica Arthur Pi I Sunyer (IDIBAPS), Centro Investigación Biomédica en Red de Salud Mental (CIBERSAM), University of Barcelona, Barcelona, Spain.,Department of Medicine, Institute of Neuroscience, University of Barcelona, Barcelona, Spain
| | - L Zamarrenho
- Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto - Universidade de São Paulo (USP), Ribeirão Preto (SP), Brazil
| | - R Solà
- Liver Unit, Parc de Salut Mar, Universitat Autonoma de Barcelona, Barcelona, Spain
| | - J Pujol
- MRI Research Unit, Department of Radiology, Hospital del Mar, CIBERSAM, Barcelona, Spain
| | - N Bargallo
- Center of Diagnostic Image (CDIC), Hospital Clinic, Magnetic Resonance Image Core Facility, IDIBAPS, Barcelona, Spain
| | - X Forns
- Liver Unit, Hospital Clinic, IDIBAPS, Centro Investigación Biomédica en Red de Enfermedades hepáticas y digestivas, (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - R Martin-Santos
- Department of Psychiatry and Psychology, Hospital Clinic, Institut d'Investigació Biomèdica Arthur Pi I Sunyer (IDIBAPS), Centro Investigación Biomédica en Red de Salud Mental (CIBERSAM), University of Barcelona, Barcelona, Spain.,Department of Medicine, Institute of Neuroscience, University of Barcelona, Barcelona, Spain.,Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto - Universidade de São Paulo (USP), Ribeirão Preto (SP), Brazil
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26
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Zahr NM. The Aging Brain With HIV Infection: Effects of Alcoholism or Hepatitis C Comorbidity. Front Aging Neurosci 2018; 10:56. [PMID: 29623036 PMCID: PMC5874324 DOI: 10.3389/fnagi.2018.00056] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 02/20/2018] [Indexed: 12/11/2022] Open
Abstract
As successfully treated individuals with Human Immunodeficiency Virus (HIV)-infected age, cognitive and health challenges of normal aging ensue, burdened by HIV, treatment side effects, and high prevalence comorbidities, notably, Alcohol Use Disorders (AUD) and Hepatitis C virus (HCV) infection. In 2013, people over 55 years old accounted for 26% of the estimated number of people living with HIV (~1.2 million). The aging brain is increasingly vulnerable to endogenous and exogenous insult which, coupled with HIV infection and comorbid risk factors, can lead to additive or synergistic effects on cognitive and motor function. This paper reviews the literature on neuropsychological and in vivo Magnetic Resonance Imaging (MRI) evaluation of the aging HIV brain, while also considering the effects of comorbidity for AUD and HCV.
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Affiliation(s)
- Natalie M Zahr
- Neuroscience Program, SRI International, Menlo Park, CA, United States.,Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford University, Stanford, CA, United States
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27
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Ene L. Human Immunodeficiency Virus in the Brain-Culprit or Facilitator? Infect Dis (Lond) 2018; 11:1178633717752687. [PMID: 29467577 PMCID: PMC5815409 DOI: 10.1177/1178633717752687] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 12/15/2017] [Indexed: 01/21/2023] Open
Abstract
Introduction: Human immunodeficiency virus (HIV) enters the brain early, where it can persist, evolve, and become compartmentalized. Central nervous system (CNS) disease can be attributed to HIV alone or to the complex interplay between the virus and other neurotropic pathogens. Aim: The current review aims to describe the direct impact of HIV on the brain as well as its relationship with other pathogens from a practitioner’s perspective, to provide a general clinical overview, brief workup, and, whenever possible, treatment guidance. Methods: A review of PubMed was conducted to identify studies on neuropathogenesis of HIV in relation to host responses. Furthermore, the interaction between the CNS pathogens and the host damage responses were revised in the setting of advanced and also well-controlled HIV infection. Results: Similar to other pathogens, HIV leads to CNS immune activation, inflammation, and viral persistence. Therefore, almost half of the infected individuals present with neurocognitive disorders, albeit mild. Compartmentalized HIV in the CNS can be responsible in a minority of cases for the dramatic presentation of symptomatic HIV escape. Disruption of the immune system secondary to HIV may reactivate latent infections or allow new pathogens to enter the CNS. Opportunistic infections with an inflammatory component are associated with elevated HIV loads in the cerebrospinal fluid and also with greater cognitive impairment. The inflammatory immune reconstitution syndrome associated with CNS opportunistic infections can be a life-threatening condition, which needs to be recognized and managed by efficiently controlling the pathogen burden and timely balanced combination antiretroviral therapy. Latent neurotropic pathogens can reactivate in the brain and mimic HIV-associated severe neurological diseases or contribute to neurocognitive impairment in the setting of stable HIV infection. Conclusions: As HIV can be responsible for considerable brain damage directly or by facilitating other pathogens, more effort is needed to recognize and manage HIV-associated CNS disorders and to eventually target HIV eradication from the brain.
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Affiliation(s)
- Luminita Ene
- HIV Department, "Dr. Victor Babes" Hospital for Infectious and Tropical Diseases, Bucharest, Romania
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28
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Forton D, Weissenborn K, Bondin M, Cacoub P. Expert opinion on managing chronic HCV in patients with neuropsychiatric manifestations. Antivir Ther 2018; 23:47-55. [PMID: 30451150 DOI: 10.3851/imp3245] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2018] [Indexed: 10/27/2022]
Abstract
Neurological manifestations of HCV infection appear to be under-recognized in clinical practice despite the majority of HCV-infected patients experiencing symptoms such as fatigue, depression and cognitive dysfunction. There is also growing evidence for a link between HCV infection and an increased risk of Parkinson's disease. The mechanism underpinning the association between HCV and these neuropsychiatric syndromes still requires further investigation. Here we review the pre-clinical and clinical evidence for a link between HCV and effects on the central nervous system leading to neuropsychiatric syndromes. Lastly, we describe how improvements in neuropsychiatric manifestations of HCV following treatment have been observed, which is subsequently reflected in an overall improvement in health-related quality of life.
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Affiliation(s)
- Daniel Forton
- Department of Gastroenterology and Hepatology, St George's Hospital London, London, UK
- St George's University of London, London, UK
| | | | | | - Patrice Cacoub
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France
- INSERM, UMR_S 959, Paris, France
- CNRS, FRE3632, F-75005, Paris, France
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France
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29
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Barbosa MED, Zaninotto AL, de Campos Mazo DF, Pessoa MG, de Oliveira CPMS, Carrilho FJ, Farias AQ. Hepatitis C virus eradication improves immediate and delayed episodic memory in patients treated with interferon and ribavirin. BMC Gastroenterol 2017; 17:122. [PMID: 29178838 PMCID: PMC5702148 DOI: 10.1186/s12876-017-0679-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 11/15/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Chronic hepatitis C virus (HCV) infection is associated with impairment of cognitive function and mood disorders. Our aim was to evaluate the impact of sustained virological response (SVR) on cognitive function and mood disorders. METHOD A prospective exploratory one arm study was conducted. Adult clinically compensated HVC patients were consecutively recruited before treatment with interferon and ribavirin for 24 to 48 weeks, according to HCV genotype. Clinical, neurocognitive and mood assessments using the PRIME-MD and BDI instruments were performed at baseline, right after half of the expected treatment has been reached and 6 months after the end of antiviral treatment. Exclusion criteria were the use of illicit psychotropic substances, mental confusion, hepatic encephalopathy, hepatocellular carcinoma, severe anemia, untreated hypothyroidism, Addison syndrome and major depression before treatment. RESULTS Thirty six patients were enrolled and 21 completed HCV treatment (n = 16 with SVR and n = 5 without). Regardless of the viral clearance at the end of treatment, there was a significant improvement in the immediate verbal episodic memory (p = 0.010), delayed verbal episodic memory (p = 0.007), selective attention (p < 0.001) and phonemic fluency (p = 0.043). Patients with SVR displayed significant improvement in immediate (p = 0.045) and delayed verbal episodic memory (p = 0.040) compared to baseline. The baseline frequency of depression was 9.5%, which rose to 52.4% during treatment, and returned to 9.5% 6 months after the end of treatment, without significant difference between patients with and without SVR. Depressive symptoms were observed in 19.1% before treatment, 62% during (p = 0.016) and 28.6% 6 months after the end of treatment (p = 0.719). CONCLUSIONS Eradication of HCV infection improved cognitive performance but did not affect the frequency of depressive symptoms at least in the short range.
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Affiliation(s)
- Mary Ellen Dias Barbosa
- Division of Psychology, Clinics Hospital, University of Sao Paulo School of Medicine, Avenida Dr. Eneas Carvalho de Aguiar, 255, São Paulo, 05403-900 Brazil
- Division of Clinical Gastroenterology and Hepatology, Clinics Hospital, Department of Gastroenterology, University of São Paulo School of Medicine, Avenida Dr. Eneas Carvalho de Aguiar, 255, sala 9159, São Paulo, 05403-900 Brazil
- Department of Gastroenterology, University of Sao Paulo School of Medicine, Av. Dr. Enéas de Carvalho Aguiar n° 255, São Paulo, 05403-000 Brazil
| | - Ana Luiza Zaninotto
- Division of Psychology, Clinics Hospital, University of Sao Paulo School of Medicine, Avenida Dr. Eneas Carvalho de Aguiar, 255, São Paulo, 05403-900 Brazil
| | - Daniel Ferraz de Campos Mazo
- Division of Clinical Gastroenterology and Hepatology, Clinics Hospital, Department of Gastroenterology, University of São Paulo School of Medicine, Avenida Dr. Eneas Carvalho de Aguiar, 255, sala 9159, São Paulo, 05403-900 Brazil
- Division of Gastroenterology, School of Medical Sciences, University of Campinas, Rua Carlos Chagas, 420, Campinas, 13083-878 Brazil
| | - Mario Guimarães Pessoa
- Division of Clinical Gastroenterology and Hepatology, Clinics Hospital, Department of Gastroenterology, University of São Paulo School of Medicine, Avenida Dr. Eneas Carvalho de Aguiar, 255, sala 9159, São Paulo, 05403-900 Brazil
| | - Cláudia Pinto Marques Souza de Oliveira
- Division of Clinical Gastroenterology and Hepatology, Clinics Hospital, Department of Gastroenterology, University of São Paulo School of Medicine, Avenida Dr. Eneas Carvalho de Aguiar, 255, sala 9159, São Paulo, 05403-900 Brazil
| | - Flair José Carrilho
- Division of Clinical Gastroenterology and Hepatology, Clinics Hospital, Department of Gastroenterology, University of São Paulo School of Medicine, Avenida Dr. Eneas Carvalho de Aguiar, 255, sala 9159, São Paulo, 05403-900 Brazil
| | - Alberto Queiroz Farias
- Division of Clinical Gastroenterology and Hepatology, Clinics Hospital, Department of Gastroenterology, University of São Paulo School of Medicine, Avenida Dr. Eneas Carvalho de Aguiar, 255, sala 9159, São Paulo, 05403-900 Brazil
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30
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Kumar A, Deep A, Gupta RK, Atam V, Mohindra S. Brain Microstructural Correlates of Cognitive Dysfunction in Clinically and Biochemically Normal Hepatitis C Virus Infection. J Clin Exp Hepatol 2017; 7:198-204. [PMID: 28970706 PMCID: PMC5620352 DOI: 10.1016/j.jceh.2017.03.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Accepted: 03/14/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIMS This study examined correlates of the brain's neurocognitive performance among clinically and biochemically normal adult patient with hepatitis C virus (HCV). We hypothesized that anti-HCV positive individuals would demonstrate structural brain abnormalities and neurocognitive dysfunction as well as the changes in cell component and extracellular space in the white matter regions of brain in asymptomatic HCV infection by using diffusion tensor tractrography (DTT) metrics. METHODS Anti-HCV positive patient (n = 40), and healthy controls (n = 31), fulfilling inclusion criteria (incidentally detected anti-HCV positive) and able to provide informed consent were screened and recruited for the study. All these subjects and controls underwent subjective assessment of their quality of life related symptoms, neuropsychometric tests (NPT) and magnetic resonance imaging. RESULTS The patients were subjected to neuroimaging as well as psychological testing. There was no significant difference in basic laboratory parameters in these two groups. Independent t-test reveals significantly lower neuropsychological functioning as compared to healthy control. A significantly decreased FA values and myoinsitol were observed in HCV subjects on sensory, inferior longitudinal fascicules, and STR fiber bundles as compared to healthy control. Bivariate correlation analysis reveals that neuropsychological scores are significantly positive. CONCLUSION Our result show that HCV positive individuals would demonstrate structural brain abnormalities and neurocognitive dysfunction as well as the changes in cell component and extracellular space in the white matter regions of brain in asymptomatic HCV infection by using DTT metrics.
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Key Words
- BD, block design
- CC, central cortex
- Cho, choline
- DS, digit symbol
- DTT, diffusion tensor tractrography
- FA, fractional anisotrophy
- FCA, figure connection test A
- FCB, figure connection test B
- Gln, glutamine
- Glx, glutamate
- ILF, inferior longitudinal fascicules
- Ins, inositol
- MD, mean diffusivity
- MRI
- NAA, N-acetylaspartate
- OA, object assembly
- PA, picture arrangement
- PC, picture completion
- QOL, quality of life
- SLF, superior longitudinal fascicules
- STR fiber bundles
- STR, superior thalamic radiations
- hepatitis C virus
- myoinsitol
- neuropsychometric tests
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Affiliation(s)
- Ajay Kumar
- Department of Medical Gastroenterology, King George's Medical University, Lucknow 226003, India,Address for correspondence: Ajay Kumar, Assistant Prof, Department of Medical Gastroenterology, K.G. Medical University, Lucknow, UP 226003, India. Tel.: +91 9455519306.Department of Medical Gastroenterology, K.G. Medical UniversityLucknowUP226003India
| | - Amar Deep
- Department of Medical Gastroenterology, King George's Medical University, Lucknow 226003, India,Experimental and Public Health Lab, Department of Zoology, University of Lucknow, 226003, India
| | - Rakesh K. Gupta
- Department of Radiodiagnosis, SGPGIMS, Lucknow 226003, India
| | - Virendra Atam
- Department of Medicine, King George's Medical University, India
| | - Samir Mohindra
- Department of Gastroenterology, SGPGIMS, Lucknow, UP, India
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31
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Abstract
The extrahepatic manifestations of hepatitis C include effects on the central nervous system, which have been associated with the ability of hepatitis C virus (HCV) to replicate in microglial and endothelial cells and the chronic inflammation induced by HCV. HCV can induce impaired neurocognition, which is clinically manifested by impaired quality of life, fatigue, and brain fog. These cognitive defects can be present even in patients with mild histologic HCV and have been confirmed by neurocognitive testing and brain imaging by magnetic resonance spectroscopy. Neurocognitive defects include loss of functioning memory and subtle changes in attention and processing speed.
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Affiliation(s)
- Sentia Iriana
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, 110 Francis Street, Boston, MA 02125, USA
| | - Michael P Curry
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, 110 Francis Street, Boston, MA 02125, USA
| | - Nezam H Afdhal
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, 110 Francis Street, Boston, MA 02125, USA.
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32
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Kharabian Masouleh S, Herzig S, Klose L, Roggenhofer E, Tenckhoff H, Kaiser T, Thöne-Otto A, Wiese M, Berg T, Schroeter ML, Margulies DS, Villringer A. Functional connectivity alterations in patients with chronic hepatitis C virus infection: A multimodal MRI study. J Viral Hepat 2017; 24:216-225. [PMID: 27813284 DOI: 10.1111/jvh.12634] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 10/05/2016] [Indexed: 12/13/2022]
Abstract
Chronic hepatitis C virus (HCV) infection is associated with fatigue and depression. Cognitive impairments are also reported in a smaller number of HCV-positive patients. Recent studies linked HCV to low-grade inflammation in brain. Here, we test the hypothesis that chronic HCV is associated with 3T-neuroimaging-derived grey matter volume (GMV) and functional connectivity alterations in a sample of chronic HCV (1b), without severe liver disease. Regional GMV and resting-state fMRI-derived eigenvector centrality (EC) were compared between 19 HCV-positive patients and 23 healthy controls (all females, 50-69 and 52-64 years, respectively), controlling for white matter hyperintensities and age. Standard tests were used to assess fatigue, depression and cognitive performance. Also, liver fibrosis stage and viral load were quantified among patients. In comparison with controls, HCV-positive patients had higher scores in fatigue and depression, and worse alertness scores. The groups performed similarly in other cognitive domains. We report higher EC in a cluster in the right anterior superior parietal lobule in patients, while no differences are found in GMV. Post hoc functional connectivity analysis showed increased connectivity of this cluster with primary and secondary somatosensory cortex, and temporal and occipital lobes in patients. Higher mean EC in the superior parietal cluster, adjusted for mean framewise displacement, was associated with better memory and attention performance, but not with fatigue, depression, viral load or level of liver fibrosis, among patients. These results suggest a compensatory mechanism in chronic hepatitis C and explain equivocal results in the literature about cognitive deficits in infected persons. Further studies should define the relation of these connectivity changes to the brain's inflammatory activity.
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Affiliation(s)
- S Kharabian Masouleh
- Department of Neurology, Max Planck Institute for Cognitive and Brain Sciences, Leipzig, Germany
| | - S Herzig
- Clinic for Cognitive Neurology, University of Leipzig, Leipzig, Germany
| | - L Klose
- Clinic for Cognitive Neurology, University of Leipzig, Leipzig, Germany
| | - E Roggenhofer
- Department of Neurology, Max Planck Institute for Cognitive and Brain Sciences, Leipzig, Germany.,LREN, Department for Clinical Neurosciences, CHUV, University of Lausanne, Lausanne, Switzerland
| | - H Tenckhoff
- Section of Hepatology, Department of Gastroenterology and Rheumatology, University Hospital, Leipzig, Germany
| | - T Kaiser
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - A Thöne-Otto
- Clinic for Cognitive Neurology, University of Leipzig, Leipzig, Germany
| | - M Wiese
- Section of Hepatology, Department of Gastroenterology and Rheumatology, University Hospital, Leipzig, Germany
| | - T Berg
- Section of Hepatology, Department of Gastroenterology and Rheumatology, University Hospital, Leipzig, Germany
| | - M L Schroeter
- Department of Neurology, Max Planck Institute for Cognitive and Brain Sciences, Leipzig, Germany.,Clinic for Cognitive Neurology, University of Leipzig, Leipzig, Germany
| | - D S Margulies
- Max Planck Research Group for Neuroanatomy and Connectivity, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
| | - A Villringer
- Department of Neurology, Max Planck Institute for Cognitive and Brain Sciences, Leipzig, Germany.,Clinic for Cognitive Neurology, University of Leipzig, Leipzig, Germany
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Fialho R, Pereira M, Rusted J, Whale R. Depression in HIV and HCV co-infected patients: a systematic review and meta-analysis. PSYCHOL HEALTH MED 2017; 22:1089-1104. [PMID: 28100073 DOI: 10.1080/13548506.2017.1280177] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The aim of this study was to carry out a systematic review and meta-analysis of the differences in the prevalence of depression and presence of depressive symptoms between HIV/HCV co-infection, HIV mono-infection, and hepatitis C virus (HCV) mono-infection. A systematic electronic search of bibliographic databases was performed to locate articles published from the earliest available online until December 2014. Outcomes of depression were based on clinical interviews and validated self-reported measures of depression/depressive symptoms. Of the 188 records initially screened, 29 articles were included in the descriptive systematic review and six were included in the meta-analysis. The meta-analytic results indicated that, as measured by self-reported measures of depression, HIV/HCV co-infected patients were significantly more likely to report depressive symptoms than either HIV (SMD = .24, 95% CI: .03-.46, p = .02) or HCV mono-infected (SMD = .55, 95% CI: .17-.94, p = .005) patients. The variability of the results of the reviewed studies, largely dependent on the samples' characteristics and the methods of assessment of depression, suggests that a clear interpretation of how depression outcomes are affected by the presence of HIV/HCV co-infection is still needed. Failing to diagnose depression or to early screen depressive symptoms may have a significant impact on patients' overall functioning and compromise treatments' outcomes.
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Affiliation(s)
- Renata Fialho
- a School of Psychology , University of Sussex , Brighton , UK.,b Sussex Partnership NHS Foundation Trust , Brighton , UK
| | - Marco Pereira
- c Faculty of Psychology and Educational Sciences , University of Coimbra , Coimbra , Portugal
| | - Jennifer Rusted
- a School of Psychology , University of Sussex , Brighton , UK
| | - Richard Whale
- b Sussex Partnership NHS Foundation Trust , Brighton , UK.,d Brighton and Sussex Medical School , Brighton , UK
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D'Mello C, Swain MG. Immune-to-Brain Communication Pathways in Inflammation-Associated Sickness and Depression. Curr Top Behav Neurosci 2017; 31:73-94. [PMID: 27677781 DOI: 10.1007/7854_2016_37] [Citation(s) in RCA: 129] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2023]
Abstract
A growing body of evidence now highlights a key role for inflammation in mediating sickness behaviors and depression. Systemic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and chronic liver disease have high comorbidity with depression. How the periphery communicates with the brain to mediate changes in neurotransmission and thereby behavior is not completely understood. Traditional routes of communication between the periphery and the brain involve neural and humoral pathways with TNFα, IL-1β, and IL-6 being the three main cytokines that have primarily been implicated in mediating signaling via these pathways. However, in recent years communication via peripheral immune-cell-to-brain and the gut-microbiota-to-brain routes have received increasing attention for their ability to modulate brain function. In this chapter we discuss periphery-to-brain communication pathways and their potential role in mediating inflammation-associated sickness behaviors and depression.
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Affiliation(s)
- Charlotte D'Mello
- Immunology Research Group, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, 3280 Hospital Dr. NW, Calgary, AB, Canada, T2N 4N1
| | - Mark G Swain
- Immunology Research Group, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, 3280 Hospital Dr. NW, Calgary, AB, Canada, T2N 4N1.
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Grover VPB, Southern L, Dyson JK, Kim JU, Crossey MME, Wylezinska‐Arridge M, Patel N, Fitzpatrick JA, Bak‐Bol A, Waldman AD, Alexander GJ, Mells GF, Chapman RW, Jones DEJ, Taylor‐Robinson SD. Early primary biliary cholangitis is characterised by brain abnormalities on cerebral magnetic resonance imaging. Aliment Pharmacol Ther 2016; 44:936-945. [PMID: 27604637 PMCID: PMC5082539 DOI: 10.1111/apt.13797] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 06/09/2016] [Accepted: 08/19/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Brain change can occur in primary biliary cholangitis (PBC), potentially as a result of cholestatic and/or inflammatory processes. This change is linked to systemic symptoms of fatigue and cognitive impairment. AIM To identify whether brain change occurs early in PBC. If the change develops early and is progressive, it may explain the difficulty in treating these symptoms. METHODS Early disease brain change was explored in 13 patients with newly diagnosed biopsy-proven precirrhotic PBC using magnetisation transfer, diffusion-weighted imaging and 1 H magnetic resonance spectroscopy. Results were compared to 17 healthy volunteers. RESULTS Cerebral magnetisation transfer ratios were reduced in early PBC, compared to healthy volunteers, in the thalamus, putamen and head of caudate with no greater reduction in patients with greater symptom severity. Mean apparent diffusion coefficients were increased in the thalamus only. No 1 H magnetic resonance spectroscopy abnormalities were seen. Serum manganese levels were elevated in all PBC patients, but no relationship was seen with imaging or symptom parameters. There were no correlations between neuroimaging data, laboratory data, symptom severity scores or age. CONCLUSIONS This is the first study to be performed in this precirrhotic patient population, and we have highlighted that neuroimaging changes are present at a much earlier stage than previously demonstrated. The neuroimaging abnormalities suggest that the brain changes seen in PBC occur early in the pathological process, even before significant liver damage has occurred. If such changes are linked to symptom pathogenesis, this could have important implications for the timing of second-line-therapy use.
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Affiliation(s)
- V. P. B. Grover
- Liver UnitDivision of Diabetes, Endocrinology and MetabolismDepartment of MedicineImperial College LondonLondonUK,Robert Steiner MRI UnitImaging Sciences DepartmentMRC Clinical Sciences CentreImperial College LondonLondonUK
| | - L. Southern
- Liver UnitDivision of Diabetes, Endocrinology and MetabolismDepartment of MedicineImperial College LondonLondonUK
| | - J. K. Dyson
- Institute of Cellular MedicineNewcastle UniversityNewcastle‐upon‐TyneUK
| | - J. U. Kim
- Liver UnitDivision of Diabetes, Endocrinology and MetabolismDepartment of MedicineImperial College LondonLondonUK
| | - M. M. E. Crossey
- Liver UnitDivision of Diabetes, Endocrinology and MetabolismDepartment of MedicineImperial College LondonLondonUK
| | - M. Wylezinska‐Arridge
- Robert Steiner MRI UnitImaging Sciences DepartmentMRC Clinical Sciences CentreImperial College LondonLondonUK
| | - N. Patel
- Robert Steiner MRI UnitImaging Sciences DepartmentMRC Clinical Sciences CentreImperial College LondonLondonUK
| | - J. A. Fitzpatrick
- Liver UnitDivision of Diabetes, Endocrinology and MetabolismDepartment of MedicineImperial College LondonLondonUK,Robert Steiner MRI UnitImaging Sciences DepartmentMRC Clinical Sciences CentreImperial College LondonLondonUK
| | - A. Bak‐Bol
- Liver UnitDivision of Diabetes, Endocrinology and MetabolismDepartment of MedicineImperial College LondonLondonUK
| | - A. D. Waldman
- Robert Steiner MRI UnitImaging Sciences DepartmentMRC Clinical Sciences CentreImperial College LondonLondonUK
| | - G. J. Alexander
- Cambridge Hepatobiliary ServiceAddenbrookes Hospital. Hills RoadCambridgeUK
| | - G. F. Mells
- Cambridge Hepatobiliary ServiceAddenbrookes Hospital. Hills RoadCambridgeUK
| | - R. W Chapman
- Nuffield Department of MedicineOxford UniversityJohn Radcliffe HospitalOxfordUK
| | - D. E. J. Jones
- Institute of Cellular MedicineNewcastle UniversityNewcastle‐upon‐TyneUK
| | - S. D. Taylor‐Robinson
- Liver UnitDivision of Diabetes, Endocrinology and MetabolismDepartment of MedicineImperial College LondonLondonUK
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Affiliation(s)
- Daniel M Forton
- Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, London, UK
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Yarlott L, Heald E, Forton D. Hepatitis C virus infection, and neurological and psychiatric disorders - A review. J Adv Res 2016; 8:139-148. [PMID: 28149649 PMCID: PMC5272938 DOI: 10.1016/j.jare.2016.09.005] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 09/09/2016] [Accepted: 09/09/2016] [Indexed: 02/06/2023] Open
Abstract
An association between hepatitis C virus infection and neuropsychiatric symptoms has been proposed for some years. A variety of studies have been undertaken to assess the nature and severity of these symptoms, which range from fatigue and depression to defects in attention and verbal reasoning. There is evidence of mild neurocognitive impairment in some patients with HCV infection, which is not fully attributable to liver dysfunction or psychosocial factors. Further evidence of a biological cerebral effect has arisen from studies using magnetic resonance spectroscopy; metabolic abnormalities correlate with cognitive dysfunction and resemble the patterns of neuroinflammation that have been described in HIV infection. Recent research has suggested that, in common with HIV infection, HCV may cross the blood brain barrier leading to neuroinflammation. Brain microvascular endothelial cells, astrocytes and microglia may be minor replication sites for HCV. Importantly, patient reported outcomes improve following successful antiviral therapy. Further research is required to elucidate the molecular basis for HCV entry and replication in the brain, and to clarify implications and recommendations for treatment.
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Affiliation(s)
- Lydia Yarlott
- Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, Blackshaw Rd, London SW17 0QT, United Kingdom
| | - Eleanor Heald
- Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, Blackshaw Rd, London SW17 0QT, United Kingdom
| | - Daniel Forton
- Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, Blackshaw Rd, London SW17 0QT, United Kingdom; St George's, University of London, Cranmer Terrace, London SW17 0RE, United Kingdom
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Hjerrild S, Renvillard SG, Leutscher P, Sørensen LH, Østergaard L, Eskildsen SF, Videbech P. Reduced cerebral cortical thickness in Non-cirrhotic patients with hepatitis C. Metab Brain Dis 2016; 31:311-9. [PMID: 26530221 DOI: 10.1007/s11011-015-9752-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 10/21/2015] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection is associated with fatigue, depression, and cognitive impairment even in the absence of severe liver fibrosis or cirrhosis. HCV has been hypothesised to cause neurodegenerative changes through low-grade neuroinflammation. Our aim was to examine whether cortical thickness (CTh) differs between chronic HCV patients and healthy controls, suggestive of cortical atrophy. In this case-control study 43 HCV patients without severe liver fibrosis, substance abuse, or comorbid HIV or hepatitis B virus infection, and 43 age and sex matched controls underwent MRI. Cortical thickness was measured using a surface based approach. Participants underwent semi-structured psychiatric interview and fatigue was assessed using the fatigue severity scale. HCV was associated with higher fatigue scores, and 58 % of HCV patients suffered from significant fatigue (p < 0.0001). Depression was observed in 16 % of patients. Areas of significantly reduced CTh were found in both left and right occipital cortex and in the left frontal lobe after correction for multiple comparisons (p < 0.05). No association between fatigue, former substance abuse, or psychotropic medication and CTh was found. No overall difference in cerebral white and grey matter volume was found. The findings support the hypothesis that HCV is associated with neurodegenerative changes.
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Affiliation(s)
- Simon Hjerrild
- Department for Affective Disorders, Aarhus University Hospital, Skovagervej 2, 8240, Risskov, Denmark.
- Center of Functionally Integrative Neuroscience (CFIN), Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
| | - Signe Groth Renvillard
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
- Department for Affective Disorders, Aarhus University Hospital, Skovagervej 2, 8240, Risskov, Denmark
| | - Peter Leutscher
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
| | | | - Leif Østergaard
- Center of Functionally Integrative Neuroscience (CFIN), Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Simon Fristed Eskildsen
- Center of Functionally Integrative Neuroscience (CFIN), Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Poul Videbech
- Department for Affective Disorders, Aarhus University Hospital, Skovagervej 2, 8240, Risskov, Denmark
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Infectious disease burden and cognitive function in young to middle-aged adults. Brain Behav Immun 2016; 52:161-168. [PMID: 26598104 DOI: 10.1016/j.bbi.2015.10.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 10/23/2015] [Accepted: 10/23/2015] [Indexed: 11/20/2022] Open
Abstract
Prior research has suggested an association between exposure to infectious disease and neurocognitive function in humans. While most of these studies have explored individual viral, bacterial, and even parasitic sources of infection, few have considered the potential neurocognitive burden associated with multiple infections. In this study, we utilized publically available data from a large dataset produced by the Centers for Disease Control and Prevention that included measures of neurocognitive function, sociodemographic variables, and serum antibody data for several infectious diseases. Specifically, immunoglobulin G antibodies for toxocariasis, toxoplasmosis, hepatitis A, hepatitis B, and hepatitis C, cytomegalovirus, and herpes 1 and 2 were available in 5662 subjects. We calculated an overall index of infectious-disease burden to determine if an aggregate measure of exposure to infectious disease would be associated with neurocognitive function in adults aged 20-59 years. The index predicted processing speed and learning and memory but not reaction time after controlling for age, sex, race-ethnicity, immigration status, education, and the poverty-to-income ratio. Interactions between the infectious-disease index and some sociodemographic variables were also associated with neurocognitive function. In summary, an index aggregating exposure to several infectious diseases was associated with neurocognitive function in young- to middle-aged adults.
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40
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Wozniak MA, Lugo Iparraguirre LM, Dirks M, Deb-Chatterji M, Pflugrad H, Goldbecker A, Tryc AB, Worthmann H, Gess M, Crossey MME, Forton DM, Taylor-Robinson SD, Itzhaki RF, Weissenborn K. Apolipoprotein E-ε4 deficiency and cognitive function in hepatitis C virus-infected patients. J Viral Hepat 2016; 23:39-46. [PMID: 26306786 DOI: 10.1111/jvh.12443] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 07/16/2015] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) causes not only liver damage in certain patients but can also lead to neuropsychiatric symptoms. Previous studies have shown that the type 4 allele of the gene for apolipoprotein E (APOE) is strongly protective against HCV-induced damage in liver. In this study, we have investigated the possibility that APOE genotype is involved in the action of HCV in brain. One hundred HCV-infected patients with mild liver disease underwent a neurological examination and a comprehensive psychometric testing of attention and memory function. In addition, patients completed questionnaires for the assessment of fatigue, health-related quality of life and mood disturbances. Apolipoprotein E gene genotyping was carried out on saliva using buccal swabs. The APOE-ε4 allele frequency was significantly lower in patients with an impairment of working memory, compared to those with a normal working memory test result (P = 0.003). A lower APOE-ε4 allele frequency was also observed in patients with definitely altered attention ability (P = 0.008), but here, the P-value missed the level of significance after application of the Bonferroni correction. Our data suggest that the APOE-ε4 allele is protective against attention deficit and especially against poor working memory in HCV-infected subjects with mild liver disease. Considering the role of apolipoprotein E in the life cycle of the virus, the findings shed interesting new light upon possible pathomechanisms behind the development of neuropsychiatric symptoms in hepatitis C infection.
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Affiliation(s)
- M A Wozniak
- Faculty of Life Sciences, University of Manchester, Manchester, UK
| | | | - M Dirks
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - M Deb-Chatterji
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - H Pflugrad
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - A Goldbecker
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - A B Tryc
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - H Worthmann
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - M Gess
- Department of Gastroenterology and Hepatology, St George's Hospital and Medical School, London, UK
| | - M M E Crossey
- Department of Medicine, St Mary's Hospital Campus, Imperial College London, London, UK
| | - D M Forton
- Department of Gastroenterology and Hepatology, St George's Hospital and Medical School, London, UK
| | - S D Taylor-Robinson
- Department of Medicine, St Mary's Hospital Campus, Imperial College London, London, UK
| | - R F Itzhaki
- Faculty of Life Sciences, University of Manchester, Manchester, UK
| | - K Weissenborn
- Department of Neurology, Hannover Medical School, Hannover, Germany
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41
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Monaco S, Mariotto S, Ferrari S, Calabrese M, Zanusso G, Gajofatto A, Sansonno D, Dammacco F. Hepatitis C virus-associated neurocognitive and neuropsychiatric disorders: Advances in 2015. World J Gastroenterol 2015; 21:11974-11983. [PMID: 26576086 PMCID: PMC4641119 DOI: 10.3748/wjg.v21.i42.11974] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 09/11/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
Since its identification in 1989, hepatitis C virus (HCV) has emerged as a worldwide health problem with roughly 185 million chronic infections, representing individuals at high risk of developing cirrhosis and liver cancer. In addition to being a frequent cause of morbidity and mortality due to liver disease, HCV has emerged as an important trigger of lymphoproliferative disorders, owing to its lymphotropism, and of a wide spectrum of extra-hepatic manifestations (HCV-EHMs) affecting different organ systems. The most frequently observed HCV-EHMs include mixed cryoglobulinemia and cryoglobulinemic vasculitis, B-cell non-Hodgkin’s lymphoma, nephropathies, thyreopathies, type 2 diabetes mellitus, cardiovascular diseases, and several neurological conditions. In addition, neuropsychiatric disorders and neurocognitive dysfunction are reported in nearly 50% of patients with chronic HCV infection, which are independent of the severity of liver disease or HCV replication rates. Fatigue, sleep disturbance, depression and reduced quality of life are commonly associated with neurocognitive alterations in patients with non-cirrhotic chronic HCV infection, regardless of the stage of liver fibrosis and the infecting genotype. These manifestations, which are the topic of this review, typically occur in the absence of structural brain damage or signal abnormalities on conventional brain magnetic resonance imaging (MRI), although metabolic and microstructural changes can be detected by in vivo proton magnetic resonance spectroscopy, perfusion-weighted and diffusion tensor MRI, and neurophysiological tests of cognitive processing. Several lines of evidence, including comparative and longitudinal neuropsychological assessments in patients achieving spontaneous or treatment-induced viral clearance, support a major pathogenic role for HCV in neuropsychiatric and neurocognitive disorders.
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Changes in the NMR Metabolic Profile of Live Human Neuron-Like SH-SY5Y Cells Exposed to Interferon-α2. J Neuroimmune Pharmacol 2015; 11:142-52. [DOI: 10.1007/s11481-015-9641-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 10/27/2015] [Indexed: 12/29/2022]
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Negro F, Forton D, Craxì A, Sulkowski MS, Feld JJ, Manns MP. Extrahepatic morbidity and mortality of chronic hepatitis C. Gastroenterology 2015; 149:1345-60. [PMID: 26319013 DOI: 10.1053/j.gastro.2015.08.035] [Citation(s) in RCA: 271] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Revised: 08/14/2015] [Accepted: 08/17/2015] [Indexed: 12/17/2022]
Abstract
Chronic hepatitis C virus (HCV) infection is associated with several extrahepatic manifestations. Patients with HCV may develop mixed cryoglobulinemia and its sequelae, ranging from cutaneous and visceral vasculitis to glomerulonephritis and B-cell non-Hodgkin lymphoma. HCV-infected patients have increased rates of insulin resistance, diabetes, and atherosclerosis, which may lead to increased cardiovascular morbidity and mortality. Neurological manifestations of HCV infection include fatigue and cognitive impairment. The mechanisms causing the extrahepatic effects of HCV infection are likely multifactorial and may include endocrine effects, HCV replication in extrahepatic cells, or a heightened immune reaction with systemic effects. Successful eradication of HCV with interferon alfa and ribavirin was shown to improve some of these extrahepatic effects; sustained virological response is associated with resolution of complications of cryoglobulinemia, reduced levels of insulin resistance, reduced incidence of diabetes and stroke, and improved fatigue and cognitive functioning. The availability of new interferon-free, well-tolerated anti-HCV treatment regimens is broadening the spectrum of patients available for therapy, including those in whom interferon was contraindicated, and will likely result in greater improvements in the extrahepatic manifestations of HCV. If these regimens are shown to confer significant benefit in the metabolic, cardiovascular, or neuropsychiatric conditions associated with HCV infection, extrahepatic manifestations of HCV may become a major indication for treatment even in the absence of liver disease.
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Affiliation(s)
- Francesco Negro
- Division of Gastroenterology and Hepatology and Division of Clinical Pathology, University Hospital, Geneva, Switzerland
| | - Daniel Forton
- Department of Gastroenterology and Hepatology, St George's Hospital, London, England
| | - Antonio Craxì
- Gastroenterology and Internal Medicine, University of Palermo, Palermo, Italy
| | - Mark S Sulkowski
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jordan J Feld
- Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, University of Toronto, Toronto, Ontario, Canada
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Hannover, Germany.
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Sheppard DP, Woods SP, Bondi MW, Gilbert PE, Massman PJ, Doyle KL. Does Older Age Confer an Increased Risk of Incident Neurocognitive Disorders Among Persons Living with HIV Disease? Clin Neuropsychol 2015; 29:656-77. [PMID: 26367342 DOI: 10.1080/13854046.2015.1077995] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
OBJECTIVE This study aimed to determine the combined effects of age and HIV infection on the risk of incident neurocognitive disorders. METHOD A total of 146 neurocognitively normal participants were enrolled at baseline into one of four groups based on age (≤ 40 years and ≥ 50 years) and HIV serostatus resulting in 24 younger HIV-, 27 younger HIV+, 39 older HIV-, and 56 older HIV+ individuals. All participants were administered a standardized clinical neuropsychological battery at baseline and 14.3 ± .2 months later. RESULTS A logistic regression predicting incident neurocognitive disorders from HIV, age group, and their interaction was significant (χ(2)[4] = 13.56, p = .009), with a significant main effect of HIV serostatus (χ(2)[1] = 5.01, p = .025), but no main effect of age or age by HIV interaction (ps > .10). Specifically, 15.7% of the HIV+ individuals had an incident neurocognitive disorder as compared to 3.2% of the HIV- group (odds ratio = 4.8 [1.2, 32.6]). Among older HIV+ adults, lower baseline cognitive reserve, prospective memory, and verbal fluency each predicted incident neurocognitive disorders at follow-up. CONCLUSIONS Independent of age, HIV infection confers a nearly fivefold risk for developing a neurocognitive disorder over approximately one year. Individuals with lower cognitive reserve and mild weaknesses in higher-order neurocognitive functions may be targeted for closer clinical monitoring and preventative measures.
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Affiliation(s)
- David P Sheppard
- a Department of Psychology , The University of Houston , Houston , TX , USA
| | - Steven Paul Woods
- a Department of Psychology , The University of Houston , Houston , TX , USA.,b Department of Psychiatry , The HIV Neurobehavioral Research Program, University of California , San Diego , CA , USA
| | - Mark W Bondi
- c Psychology Service , VA San Diego Healthcare System , San Diego , CA , USA.,d Department of Psychiatry , University of California , San Diego , CA , USA
| | - Paul E Gilbert
- e Department of Psychology , San Diego State University , San Diego , CA , USA
| | - Paul J Massman
- a Department of Psychology , The University of Houston , Houston , TX , USA
| | - Katie L Doyle
- f SDSU/UCSD Joint Doctoral Program in Clinical Psychology , San Diego , CA , USA
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Anderson AM, Fennema-Notestine C, Umlauf A, Taylor MJ, Clifford DB, Marra CM, Collier AC, Gelman BB, McArthur JC, McCutchan JA, Simpson DM, Morgello S, Grant I, Letendre SL. CSF biomarkers of monocyte activation and chemotaxis correlate with magnetic resonance spectroscopy metabolites during chronic HIV disease. J Neurovirol 2015; 21:559-67. [PMID: 26069183 DOI: 10.1007/s13365-015-0359-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 05/09/2015] [Accepted: 06/01/2015] [Indexed: 02/07/2023]
Abstract
Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) persist despite combination antiretroviral therapy (cART), supporting the need to better understand HIV neuropathogenesis. Magnetic resonance spectroscopy (MRS) of the brain has demonstrated abnormalities in HIV-infected individuals despite cART. We examined the associations between MRS metabolites and selected cerebrospinal fluid (CSF) biomarkers reflecting monocyte/macrophage activation and chemotaxis. A multicenter cross-sectional study involving five sites in the USA was conducted. The following CSF biomarkers were measured: soluble CD14 (sCD14), monocyte chemotactic protein-1 (MCP-1), interferon inducible protein 10 (IP-10), and stromal cell-derived growth factor 1 alpha (SDF-1α). The following MRS metabolites were measured from basal ganglia (BG), frontal white matter (FWM), and frontal gray matter (FGM): N-acetylaspartate (NAA), myo-inositol (MI), choline (Cho), and creatine (Cr). CSF biomarkers were compared to absolute MRS metabolites as well as metabolite/Cr ratios using linear regression. Eighty-three HIV-infected individuals were included, 78 % on cART and 37 % with HAND. The most robust positive correlations were between MCP-1 and Cho in BG (R (2) 0.179, p < 0.001) as well as MCP-1 and MI in FWM (R (2) 0.137, p = 0.002). Higher Cr levels in FWM were associated with MCP-1 (R (2) 0. 075, p = 0.01) and IP-10 (R (2) 0.106, p = 0.003). Comparing biomarkers to MRS metabolite/Cr ratios impacted some relationships, e.g., higher sCD14 levels were associated with lower Cho/Cr ratios in FGM (R (2) 0.224, p < 0.001), although higher MCP-1 levels remained associated with Cho/Cr in BG. These findings provide evidence that monocyte activation and chemotaxis continue to contribute to HIV-associated brain abnormalities in cART-treated individuals.
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Affiliation(s)
| | - Christine Fennema-Notestine
- University of California, San Diego, La Jolla, CA, USA
- HIV Neurobehavioral Research Center and Antiviral Research Center, University of California, San Diego, 220 Dickinson Street, Suite A, San Diego, CA, 92103, USA
| | - Anya Umlauf
- University of California, San Diego, La Jolla, CA, USA
- HIV Neurobehavioral Research Center and Antiviral Research Center, University of California, San Diego, 220 Dickinson Street, Suite A, San Diego, CA, 92103, USA
| | - Michael J Taylor
- University of California, San Diego, La Jolla, CA, USA
- HIV Neurobehavioral Research Center and Antiviral Research Center, University of California, San Diego, 220 Dickinson Street, Suite A, San Diego, CA, 92103, USA
| | - David B Clifford
- Washington University School of Medicine, Washington University, St. Louis, MO, USA
| | | | | | - Benjamin B Gelman
- University of Texas Medical Branch, University of Texas System, Galveston, TX, USA
| | - Justin C McArthur
- John Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - J Allen McCutchan
- University of California, San Diego, La Jolla, CA, USA
- HIV Neurobehavioral Research Center and Antiviral Research Center, University of California, San Diego, 220 Dickinson Street, Suite A, San Diego, CA, 92103, USA
| | | | | | - Igor Grant
- University of California, San Diego, La Jolla, CA, USA
- HIV Neurobehavioral Research Center and Antiviral Research Center, University of California, San Diego, 220 Dickinson Street, Suite A, San Diego, CA, 92103, USA
| | - Scott L Letendre
- University of California, San Diego, La Jolla, CA, USA.
- HIV Neurobehavioral Research Center and Antiviral Research Center, University of California, San Diego, 220 Dickinson Street, Suite A, San Diego, CA, 92103, USA.
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Vassallo M, Durant J, Lebrun-Frenay C, Fabre R, Ticchioni M, Andersen S, DeSalvador F, Harvey-Langton A, Dunais B, Cohen-Codar I, Montagne N, Cua E, Fredouille-Heripret L, Laffon M, Cottalorda J, Dellamonica P, Pradier C. Virologically suppressed patients with asymptomatic and symptomatic HIV-associated neurocognitive disorders do not display the same pattern of immune activation. HIV Med 2015; 16:431-40. [PMID: 25981452 DOI: 10.1111/hiv.12246] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/10/2014] [Indexed: 12/31/2022]
Abstract
OBJECTIVES Inversion of the CD4:CD8 ratio is a marker of immune activation and age-associated disease. We measured the CD4:CD8 ratio as a marker of cognitive impairment in HIV-infected patients and explored differences according to clinical severity. METHODS Post hoc analysis of data from two prospective cohorts of HIV-infected patients randomly selected to undergo neuropsychological tests was performed. Test scores were adjusted for age, gender and education. Inclusion criteria were undetectable viral load and stable treatment for at least 6 months. Subjects with HIV-associated dementia were excluded. Patients were divided into an unimpaired group, a group with asymptomatic neurocognitive disorder (ANI) and a group with symptomatic HIV-associated neurocognitive disorder (sHAND), represented by mild neurocognitive disorder (MND). Demographic and background parameters, immune activation markers and the CD4:CD8 ratio were recorded. RESULTS Two hundred patients were included in the study. The mean age was 52 years, 78% were male, the mean CD4 count was 624 cells/μL, the mean nadir CD4 count was 240 cells/μL, 27% were hepatitis C virus (HCV)-coinfected, the mean duration of HIV infection was 16 years, and the mean time on current combination antiretroviral therapy (cART) was 2.9 years. Twenty-nine per cent of subjects had HAND (21% had ANI and 8% had MND). In multivariate analysis, a CD4:CD8 ratio < 1 was associated with a nadir CD4 count < 200 cells/μL [odds ratio (OR) 3.68] and with the presence of CD4(+) CD38(+) HLA(+) cells (OR 1.23). Multinominal logistic regression showed that, in comparison with the unimpaired group, diagnosis of sHAND was associated with a CD4:CD8 ratio < 1 (OR 10.62), longer HIV infection (OR 1.15) and longer current cART (OR 1.34), while the ANI group differed from the unimpaired group only for education level. CONCLUSIONS Aviraemic patients with sHAND did not display the same pattern of immune activation as subjects with ANI, suggesting that the underlying pathophysiological mechanisms could be different.
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Affiliation(s)
- M Vassallo
- Department of Infectious Diseases, L'Archet Hospital, University of Nice, Nice, France.,Department of Internal Medicine, Cannes General Hospital, Cannes, France
| | - J Durant
- Department of Infectious Diseases, L'Archet Hospital, University of Nice, Nice, France
| | - C Lebrun-Frenay
- Department of Neurology, Pasteur Hospital, University of Nice, Nice, France
| | - R Fabre
- Department of Public Health, L'Archet Hospital, University of Nice, Nice, France
| | - M Ticchioni
- Immunology Laboratory Unit, L'Archet Hospital, University of Nice, Nice, France
| | - S Andersen
- Department of Infectious Diseases, L'Archet Hospital, University of Nice, Nice, France
| | - F DeSalvador
- Department of Infectious Diseases, L'Archet Hospital, University of Nice, Nice, France
| | - A Harvey-Langton
- Department of Infectious Diseases, L'Archet Hospital, University of Nice, Nice, France
| | - B Dunais
- Department of Infectious Diseases, L'Archet Hospital, University of Nice, Nice, France.,Department of Public Health, L'Archet Hospital, University of Nice, Nice, France
| | | | - N Montagne
- Department of Internal Medicine, Cannes General Hospital, Cannes, France
| | - E Cua
- Department of Infectious Diseases, L'Archet Hospital, University of Nice, Nice, France.,Department of Internal Medicine, Cannes General Hospital, Cannes, France
| | | | - M Laffon
- Department of Neurology, Pasteur Hospital, University of Nice, Nice, France
| | - J Cottalorda
- Virology Laboratory Unit, L'Archet Hospital, University of Nice, Nice, France
| | - P Dellamonica
- Department of Infectious Diseases, L'Archet Hospital, University of Nice, Nice, France
| | - C Pradier
- Department of Public Health, L'Archet Hospital, University of Nice, Nice, France
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Solinas A, Piras MR, Deplano A. Cognitive dysfunction and hepatitis C virus infection. World J Hepatol 2015; 7:922-925. [PMID: 25954475 PMCID: PMC4419096 DOI: 10.4254/wjh.v7.i7.922] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2015] [Revised: 02/23/2015] [Accepted: 03/18/2015] [Indexed: 02/06/2023] Open
Abstract
Cognitive dysfunction in patients with chronic hepatitis C virus (HCV) infection is a distinct form of minimal hepatic encephalopathy (MHE). In fact, the majority of HCV-positive patients, irrespective of the grading of liver fibrosis, display alterations of verbal learning, attention, executive function, and memory when they are evaluated by suitable neuropsychological tests. Similarities between the cognitive dysfunction of HCV patients and MHE of patients with different etiologies are unclear. It is also unknown how the metabolic alterations of advanced liver diseases interact with the HCV-induced cognitive dysfunction, and whether these alterations are reversed by antiviral therapies. HCV replication in the brain may play a role in the pathogenesis of neuroinflammation. HCV-related brain dysfunction may be associated with white matter neuronal loss, alterations of association tracts and perfusion. It is unclear to what extent, in patients with cirrhosis, HCV triggers an irreversible neurodegenerative brain damage. New insights on this issue will be provided by longitudinal studies using the protocols established by the diagnostic and statistical manual of mental disorders fifth edition for cognitive disorders. The domains to be evaluated are complex attention; executive functions; learning and memory; perceptual motor functions; social cognition. These evaluations should be associated with fluorodeoxyglucose positron emission tomography and magnetic resonance imaging (MRI) protocols for major cognitive disorders including magnetic resonance spectroscopy, diffusion tensor imaging, magnetic resonance perfusion, and functional MRI. Also, the characteristics of portal hypertension, including the extent of liver blood flow and the type of portal shunts, should be evaluated.
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Matinella A, Lanzafame M, Bonometti MA, Gajofatto A, Concia E, Vento S, Monaco S, Ferrari S. Neurological complications of HIV infection in pre-HAART and HAART era: a retrospective study. J Neurol 2015; 262:1317-1327. [PMID: 25877836 DOI: 10.1007/s00415-015-7713-8] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2014] [Revised: 03/15/2015] [Accepted: 03/16/2015] [Indexed: 02/02/2023]
Abstract
The introduction of highly active anti-retroviral therapy (HAART) led to a radical change in the natural history of HIV infection and of the associated neurological opportunistic infections. However, the mortality of central nervous system (CNS) complications and opportunistic infections is still high in untreated HIV-infected individuals or in patients unaware of their HIV infection. We describe the outcome of HIV-infected patients followed at a single center for AIDS-related neurological syndromes in the 16 years following the introduction of HAART, and compare the findings with those in patients admitted up to 1996. We have conducted a retrospective study of patients with HIV infection or AIDS (based on WHO criteria and classified according to the 1993 CDC criteria) admitted during 20 years (January 1992 to March 2012) to the Infectious Diseases Unit of the University of Verona for the presence of focal or widespread CNS lesion on neuroimaging. Clinical history, CD4 cell count, HIV-RNA level, neurological examination, imaging, cerebrospinal fluid examination and eventual cerebral biopsy results were reviewed as well as the final neurological diagnosis and the treatment. The survival time from the clinical onset of the neurologic syndrome to death was calculated for each patient who died. A statistical analysis was performed comparing data collected up to and after 1996, i.e., before and after HAART introduction. Among 1043 patients with HIV infection or AIDS admitted to the Infectious Diseases Unit of the University of Verona between January 1992 and March 2012, 114 had a CNS lesion. The following diseases were observed: neurotoxoplasmosis (NT), progressive multifocal leukoencephalopathy), primary central nervous system lymphoma (PCNSL), the severe form of HIV-associated neurocognitive disorder, cryptococcal encephalitis (CE) and lesions of undetermined origin. The follow-up period was 4 weeks to 72 months both in the pre-HAART and HAART era. Cerebral lesions were detected in 53/243 patients (21.8%) in the pre-HAART era and in 61/801 patients (7.6%) in the HAART era (p < 0.001). Most patients who developed a neurological complication in the HAART period (40/59, 67.8%) were untreated or did not know to be HIV-infected; in particular, 27.9% of patients with a CNS lesion in the HAART era were unaware of their HIV infection vs 13.2% in the pre-HAART era (p < 0.05). Some patients were not virologically suppressed (14/59, 23.7%) or were immunological non-responders (undetectable viral load, with CD4 count <200 cells/μL; 4/59, 6.8%). Other statistically significant data were the mean age at the onset of neurological complications (32.6 ± 5.4 years in the pre-HAART, 40.3 ± 9.5 in the HAART group, p < 0.001) and the mean CD4 cell count at the onset of illness (median of 38 cells/µL (2-215) in the pre-HAART, 77 cells/µL (2-752) in the HAART group; p < 0.001). In the HAART era a reduction of PCNSL and NT was observed. Our results, while confirming a decrease in the incidence of opportunistic infections of the CNS in the HAART era, show that late presentation of patients with HIV infection remains an important issue in our catchment area.
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Affiliation(s)
- Angela Matinella
- Section of Neurology, Department of Neurological and Movement Sciences, "G.B. Rossi" University Hospital, University of Verona, Verona, Italy,
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Thames AD, Castellon SA, Singer EJ, Nagarajan R, Sarma MK, Smith J, Thaler NS, Truong JH, Schonfeld D, Thomas MA, Hinkin CH. Neuroimaging abnormalities, neurocognitive function, and fatigue in patients with hepatitis C. NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION 2015; 2:e59. [PMID: 25610883 PMCID: PMC4299885 DOI: 10.1212/nxi.0000000000000059] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 11/21/2014] [Indexed: 12/11/2022]
Abstract
OBJECTIVE This study examined neurologic abnormalities (as measured by proton magnetic resonance spectroscopy imaging and diffusion tensor imaging), neurocognitive performance, and fatigue among a sample of adults with hepatitis C virus (HCV). We hypothesized that HCV+ individuals would demonstrate structural brain abnormalities and neurocognitive compromise consistent with frontostriatal dysfunction as well as increased fatigue compared to controls. METHOD Participants were 76 individuals diagnosed with HCV and 20 controls who underwent a comprehensive neurocognitive evaluation and clinical assessments. A subset of the HCV+ participants (n = 29) and all controls underwent MRI. RESULTS Individuals diagnosed with chronic HCV infection demonstrated greater fractional anisotropy in the striatum as well as greater mean diffusivity in the fronto-occiptal fasciculus and external capsule compared to HCV- controls. HCV+ participants also demonstrated lower levels of N-acetylaspartate in bilateral parietal white matter and elevations in myo-inosital (mI) in bilateral frontal white matter compared to HCV- controls (all p values < 0.05). HCV+ participants also demonstrated significantly poorer neuropsychological performance, particularly in processing speed and verbal fluency. HCV+ patients reported higher levels of fatigue than controls, and fatigue was significantly correlated with diffusivity in the superior fronto-occipital fasciculus, elevations in mI in frontal white matter, and overall cognitive performance. CONCLUSIONS Our results suggest that HCV-associated neurologic complications disrupt frontostriatal structures, which may result in increased fatigue and poorer cognitive performance, particularly in those cognitive domains regulated by frontostriatal regions.
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Affiliation(s)
- April D Thames
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - Steven A Castellon
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - Elyse J Singer
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - Rajakumar Nagarajan
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - Manoj K Sarma
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - Jason Smith
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - Nicholas S Thaler
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - Jonathan Hien Truong
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - Daniel Schonfeld
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - M Albert Thomas
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
| | - Charles H Hinkin
- David Geffen School of Medicine (A.D.T., S.A.C., E.J.S., R.N., M.K.S., N.S.T., M.A.T., C.H.H.), University of California, Los Angeles; Greater Los Angeles VA Healthcare System (S.A.C., J.S., D.S., C.H.H.); and Department of Infectious Disease (J.H.T.), Kaiser Permanente Antelope Valley, Lancaster, CA
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Sarkar S, Sarkar R, Berg T, Schaefer M. Sadness and mild cognitive impairment as predictors for interferon-alpha-induced depression in patients with hepatitis C. Br J Psychiatry 2015; 206:45-51. [PMID: 25359924 DOI: 10.1192/bjp.bp.113.141770] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Antiviral therapy with interferon-alpha (IFN-α) for hepatitis C virus (HCV) infection is associated with increased risk for depression. AIMS To identify clinical predictors for IFN-α-induced depression during antiviral therapy for HCV infection. METHOD Depression (defined with the Montgomery-Åsberg Depression Rating Scale (MADRS)) was evaluated before and during antiviral treatment in 91 people with chronic HCV infection without a history of psychiatric disorders. Cognitive function was evaluated using the Trail Making Test A/B (TMT A/B). (Trial registration at ClinicalTrials.gov: NCT00136318.) RESULTS Depression during antiviral therapy was significantly associated with a baseline MADRS score of 3 or higher (P = 0.006). In total, 89% (n = 16) of patients who had a baseline score >0 for the single item sadness developed depression. Poor baseline performance in the TMT A (P = 0.027) and TMT B (P = 0.033) was predictive for severe depression. CONCLUSIONS Pre-treatment screening for subthreshold depressive and cognitive symptoms will help to identify those at risk for IFN-α-associated depression among patients with chronic hepatitis C.
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Affiliation(s)
- Susanne Sarkar
- Susanne Sarkar, PhD, Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Charité, Mitte, Berlin, and Department and Outpatient Clinic of Medical Psychology, Center of Psychosocial Medicine, University Medical Center Hamburg-Eppendorf, Hamburg; Rahul Sarkar, MD, Department of Psychiatry and Psychotherapy, Asklepios Westklinikum Hamburg-Klinikum, Hamburg; Thomas Berg, MD, Department of Gastroenterology und Rheumatology, Section of Hepatology, Universitätsklinikum, Leipzig; Martin Schaefer, MD, Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Charité, Mitte, Berlin, and Department of Psychiatry, Psychotherapy and Addiction Medicine, Kliniken Essen-Mitte, Essen, Germany
| | - Rahul Sarkar
- Susanne Sarkar, PhD, Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Charité, Mitte, Berlin, and Department and Outpatient Clinic of Medical Psychology, Center of Psychosocial Medicine, University Medical Center Hamburg-Eppendorf, Hamburg; Rahul Sarkar, MD, Department of Psychiatry and Psychotherapy, Asklepios Westklinikum Hamburg-Klinikum, Hamburg; Thomas Berg, MD, Department of Gastroenterology und Rheumatology, Section of Hepatology, Universitätsklinikum, Leipzig; Martin Schaefer, MD, Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Charité, Mitte, Berlin, and Department of Psychiatry, Psychotherapy and Addiction Medicine, Kliniken Essen-Mitte, Essen, Germany
| | - Thomas Berg
- Susanne Sarkar, PhD, Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Charité, Mitte, Berlin, and Department and Outpatient Clinic of Medical Psychology, Center of Psychosocial Medicine, University Medical Center Hamburg-Eppendorf, Hamburg; Rahul Sarkar, MD, Department of Psychiatry and Psychotherapy, Asklepios Westklinikum Hamburg-Klinikum, Hamburg; Thomas Berg, MD, Department of Gastroenterology und Rheumatology, Section of Hepatology, Universitätsklinikum, Leipzig; Martin Schaefer, MD, Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Charité, Mitte, Berlin, and Department of Psychiatry, Psychotherapy and Addiction Medicine, Kliniken Essen-Mitte, Essen, Germany
| | - Martin Schaefer
- Susanne Sarkar, PhD, Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Charité, Mitte, Berlin, and Department and Outpatient Clinic of Medical Psychology, Center of Psychosocial Medicine, University Medical Center Hamburg-Eppendorf, Hamburg; Rahul Sarkar, MD, Department of Psychiatry and Psychotherapy, Asklepios Westklinikum Hamburg-Klinikum, Hamburg; Thomas Berg, MD, Department of Gastroenterology und Rheumatology, Section of Hepatology, Universitätsklinikum, Leipzig; Martin Schaefer, MD, Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Campus Charité, Mitte, Berlin, and Department of Psychiatry, Psychotherapy and Addiction Medicine, Kliniken Essen-Mitte, Essen, Germany
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