Next Article in Journal
Effect of Mowing on Wheat Growth at Seeding Stage
Next Article in Special Issue
HCV and HCC Tango—Deciphering the Intricate Dance of Disease: A Review Article
Previous Article in Journal
Vaping-Induced Proteolysis Causes Airway Surface Dehydration
Previous Article in Special Issue
Hepatocellular Carcinoma Prevention in the Era of Hepatitis C Elimination
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 24
Issue 20
10.3390/ijms242015351
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Depression and Cognitive Dysfunction in Patients with Chronic Hepatitis C: Correlation with Viral Replication in the Peripheral Blood Mononuclear Cells and Cytokines in Serum

by
Marek Radkowski
1,
Tomasz Kryczka
2,
Bogna Szymańska-Kotwica
3,
Hanna Berak
3,
Andrzej Horban
4,
Tomasz Pawłowski
5,
Karol Perlejewski
1 and
Tomasz Laskus
4,*
1
Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 02-106 Warsaw, Poland
2
Department of Development of Nursing and Social and Medical Sciences, Medical University of Warsaw, 01-445 Warsaw, Poland
3
Outpatient Clinic, Warsaw Hospital for Infectious Diseases, 01-201 Warsaw, Poland
4
Department of Adult Infectious Diseases, Medical University of Warsaw, 01-201 Warsaw, Poland
5
Department of Psychiatry, Wroclaw Medical University, 50-367 Wroclaw, Poland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(20), 15351; https://doi.org/10.3390/ijms242015351
Submission received: 17 September 2023 / Revised: 13 October 2023 / Accepted: 16 October 2023 / Published: 19 October 2023
(This article belongs to the Special Issue Hepatitis C Virus: Pathogenetic Mechanisms, Residual Problems after Cure and Hopes for Elimination)
Browse Figures
Versions Notes

Abstract

:
Chronic hepatitis C virus (HCV) infection is commonly associated with depression and cognitive dysfunction, the cause of which could be related to the HCV neuroinvasion and/or state of chronic inflammation. Viral sequences and proteins were previously detected in the brain and since blood leukocytes can cross the blood–brain barrier, they could provide viral access to the CNS. Eighty chronic hepatitis C patients were tested for viral replication in PBMCs (detection of the HCV RNA-negative strand) and serum cytokines. Depression was assessed by the Beck Depression Inventory (BDI), neuroticism by the Eysenck Personality Inventory (N/EPO-R), and anxiety by the State-Trait Anxiety Inventory (STAI) while neurocognitive testing included the Wisconsin Card Sorting Test (WCST), Ruff Figural Fluency Test (RFFT), California Verbal Learning Test (CVLT), and Grooved Pegboard Test (GPT). The HCV RNA-negative strand was detected in PBMCs from 24 (30%) patients and these patients had significantly higher BDI scores (median 12.5 [IQR] 6.3–20.5 vs. median 8.00 [IQR] 3–12; p = 0.013). Both depression and anxiety correlated positively with IL-8 while cognitive flexibility, executive function, problem-solving skills, memory, and motor functioning correlated negatively with some proinflammatory cytokines. Our findings suggest that due to chronic HCV infection, the brain function is negatively affected by both viral replication in PBMCs and by the immune activation state.

1. Introduction

Chronic hepatitis C virus (HCV) infection is commonly associated with depression and cognitive dysfunction [1,2,3]. The cause of these problems was largely attributed to liver dysfunction and the awareness of chronic illness until Forton and colleagues provided evidence for the likely biological basis of HCV-related brain effects. In proton magnetic-resonance spectroscopy (1H MRS), patients with hepatitis C demonstrated elevations in choline/creatine ratios in basal ganglia and white matter, which were not present in patients with hepatitis of another etiology or healthy controls [2,4]; notably, in hepatic encephalopathy, the choline ratios were depressed [5]. Similar findings were since reported by other groups, strengthening the argument that depression and neurocognitive disturbances are directly related to HCV infection and not secondary to liver disease [6,7]. Importantly, many of the same changes are encountered in HIV-infected patients [8,9] and HIV is known to directly infect and injure the central nervous system (CNS), leading to a wide spectrum of neuropsychiatric symptoms (so-called neuroAIDS), including a plethora of neurocognitive disorders, such as dementia, minor neurocognitive disorder, depression, and anxiety [10].
The results of these studies, and some similarities to the effects of HIV infection, led to speculation that HCV could be neuroinvasive and neurotropic; this suspicion was confirmed when negative-strand HCV RNA, which is a viral replicative intermediate, was detected in an autopsy of brain tissue [11] and two subsequent studies demonstrated the presence of HCV proteins in brain tissue by Western Blotting and/or immunostaining [12,13]. Similarly to findings in HIV-infected patients, brain-derived HCV variants could represent a separate compartment as they are often distinct from those circulating in the blood [11,14]. Furthermore, some studies demonstrated a close relationship between the HCV sequences present in the CNS and those found in peripheral blood mononuclear cells (PBMCs) and lymph nodes [11,14,15], which suggests that the virus could gain access via infected leucocytes in a process similar to the one postulated for HIV infection (the so-called ‘Trojan horse’ phenomenon) [16]. HCV is considered to be lymphotropic—several groups of researchers have detected viral replicative forms in PBMCs, lymph nodes, and bone marrow and it was also demonstrated that viral genomic sequences present in extrahepatic sites often differ from those found in the serum and liver [17,18,19]. In chimpanzees, the same minor variants of the HCV strain H77, which were selected in lymphoblastoid cells in vitro, were found to be replicating in vivo in PBMCs when the animals were inoculated with the same parental strain [20].
The aim of this study was to determine whether depression and neurocognitive deficiencies in chronic HCV infection correlate with the presence of replication in PBMCs. Furthermore, since there is mounting evidence that chronic inflammation in the brain and body may contribute to the development and maintenance of depressive symptoms [21], we tested the serum levels of a number of cytokines. Viral extrahepatic replication was determined by the detection of viral negative strand and cytokines were measured by a commercially available assay.

2. Results

The HCV RNA-negative strand was detected in PBMCs from 24 (30%) out of 80 analyzed patients. Patients in whom the viral negative strand was detected did not differ from those in whom it was not detected with respect to viral load (median 1.07 × 106, interquartile range [IQR] 2.56 × 105–2.7 × 106 vs. median 9.91 × 105 [IQR] 1.58 × 105–2.9 × 106) but were less likely to have advanced liver disease as the METAVIR score F3/F4 was found in 35% of patients in the former and 53% of patients in the latter group. However, this difference did not reach statistical significance (p = 0.26). Interestingly, patients with evidence of HCV replication in their PBMCs had significantly higher IL-8 serum levels (median 26.3 [IQR] 19.0–50.1 vs. median 22.5 [IQR] 14.8–31.9; p = 0.025).
The two groups of patients did not differ with respect to the results of any of the cognitive tests, nor with respect to the level of neuroticism or anxiety. However, there was a significant difference regarding the depression scores (median 12.5 [IQR] 6.3–20.5 vs. median 8.00 [IQR] 3–12; p = 0.013) in these two groups (Figure 1).
Correlations between the scores for depression, anxiety, and neuroticism and the levels of cytokines in serum are shown in Table 1 and Figure 2. The BDI scores showed a moderate correlation with IL-8 (r = 0.29; p = 0.012) and borderline with GM-CSF (r = 0.21; p = 0.08); meanwhile, anxiety correlated with IL-8 (r = 0.30; p = 0.009) and borderline with IFN-gamma (r = 0.21; p = 0.06) and MCP-1 (r = 0.23; p = 0.051). When neuroticism levels were correlated with the cytokines’ concentrations, statistically significant relationships were found for IL-4 (r = 0.27; p = 0.02), IL-7 (r = 0.24; p = 0.046), and Eotaxin (r = 0.25; p = 0.03).
Correlations between the cytokine levels and neurocognitive scores are presented in Table 2 and Figure 3. The RFFT, which was analyzed only with respect to the number of unique designs, showed a weak negative correlation with IP-10 (r = −0.25; p = 0.034) only; meanwhile, CVLT scores representing the sum of immediate recall from Trial-1 to Trial-5 correlated with MIP-1alpha (r = −0.25; p = 0.025). Motor functioning, as assessed by the Grooved Pegboard Test (GPT) time, correlated with IFN-gamma (r = 0.24; p = 0.41) and MCP-1 (r = 0.28; p = 0.016). When the results of the WCST were correlated with cytokine levels, the numbers of correct responses showed a moderate negative correlation with IL-1ra (r = −0.24; p = 0.042) and MCP-1 (r = −0.25; p = 0.035) while other responses (errors, perseverative responses, nonperseverative errors) did not show any statistically significant correlations
To further analyze factors affecting depression, multiple linear regression was performed, taking into account the presence of the viral negative strand in PBMCs, IL-8, and GM-CSF. The presence of the viral negative strand in PBMCs and the level of IL-8 showed statistically significant relationships with the BDI scores (regression coefficient 3.89 [95% CI] 0.53–7.25; p = 0.024) and 0.037 [95% CI] 0.007 to 0.066; p = 0.016, respectively). Multicollinearity was small (R2 with other variables was 0.10 for the presence of a negative strand and 0.07 for IL-8 concentration).

3. Discussion

Ours is the first study suggesting the potential role of extrahepatic replication in HCV-associated depression. There is strong evidence that the HCV can be neurotropic, as demonstrated in postmortem studies finding viral replicative forms and viral proteins in brain tissue [11,12,13]. Furthermore, brain-derived HCV variants are often distinct from those circulating in the blood and may even contain tissue-specific adaptations in the internal ribosomal entry site (IRES) [11,14]. The cells harboring the HCV were identified by two independent groups as astrocytes and macrophages/microglia cells [12,13] and it was subsequently shown that the infected cells were activated [22]. In the latter study, which analyzed CD68+ cells isolated from autopsy brain tissue, it was found that mRNA transcripts for key immune activation cytokines were higher in HCV-positive patients than in HCV-negative control patients and even in HCV-positive compared to HCV-negative CD68 cells in the same patient. Within the population of PBMCs, the cells harboring the replicating virus have been identified mainly as monocytes/macrophages and B cells; although, T-cells can be infected as well, particularly in terms of long-lasting infections [23,24]. Since some monocyte family members are constantly being replaced as part of normal physiology [25,26] and all basic groups of leukocytes have the ability to enter the brain under certain conditions [27], it is highly probable that infected PBMCs constitute the vehicle for the transmission of the HCV from the periphery to the brain; thus, the presence of the viral negative strand in these cells could constitute a surrogate marker of viral replication in the CNS.
Our findings that the BDI score was higher in the presence of extrahepatic viral replication in PBMCs and correlated with the IL-8 serum levels are compatible with the inflammatory theory of depression. There is mounting evidence that any chronic inflammatory process could affect the neurotransmission, neuroplasticity, and neurogenesis of mood-regulating brain regions [21,28]. The proinflammatory cytokines can increase cortisol synthesis by activating the hypothalamic–pituitary–adrenal axis and can also activate the tryptophan–kynurenine pathway, leading to the synthesis of the neurotoxic N-methyl-D-aspartate (NMDA) glutamate agonist quinolinic acid and 3-hydroxykynurenine [28]. The distribution of the tryptophan–kynurenine pathway in the brain is concentrated mainly in the astrocytes and microglia [29]. Increased inflammatory cytokines in microglial cells can also influence the neuronal reuptake of monoamine neurotransmitters by regulating neuronal mitogen-activated protein kinase (MAPK), leading to an increased surface expression of monoamine transporters on neurons [30]. Furthermore, there is experimental evidence that the widely used and effective selective serotonin reuptake inhibitor (SSRI) antidepressants have yet another biological effect as they reduce the release of cytokines from activated macrophages and microglia [31] and non-steroidal anti-inflammatory drugs, such as the cyclooxygenase-2 inhibitor celecoxib, can enhance the response to standard antidepressant treatment [32]. Similarly, a tetracycline antibiotic, minocycline, an inhibitor of microglial inflammatory activation, has shown promising antidepressant activity in the treatment-resistant depression patients [33].
Increased proinflammatory cytokines in circulation have the propensity to repress the expression of several tight-junction proteins of the blood–brain barrier (BBB), thus promoting the passage of circulating proinflammatory cytokines and depression-like behaviors in mice [34]. However, although increased levels of proinflammatory cytokines in the plasma and CSF of depressed patients have been reported, the discriminative power of cytokine concentrations between depressed and non-depressed people is weak and they have also been shown to be altered in other psychiatric disorders [35,36]. Confusingly, the same cytokine can be produced by multiple cell types and the same cell can produce various cytokines. Importantly, many patients suffering from Major Depressive Disorder (MDD) have no evidence of increased inflammatory cytokine activity and most people with evidence of increased inflammation do not suffer from depression [37,38]. While the exogenous administration of cytokines such as interferon-alpha can trigger depression, the majority of treated patients remain unaffected [39]. These observations led to speculation that there may be a specific subtype of depression (so-called inflammatory cytokine-associated depression) that is uniquely associated with inflammatory cytokines and which may even require different treatment [37].
There is ample literature demonstrating evidence of neurocognitive defects in patients with the chronic HCV infection, usually in the form of the mild impairment of attention, concentration, and working memory [40]. However, it is difficult to determine whether these impairments are attributed to the virus itself or are secondary to liver injury, an inflammatory state, awareness of chronic disease, or possibly to a mixture of several factors. A particular problem is posed by minimal hepatic encephalopathy (MHE), which can affect the results of neurocognitive testing. Hilsabeck and colleagues reported that cognitive test performance was associated with the fibrosis stage on liver biopsy and, thus, was likely influenced by MHE; however, impairments in attention and concentration were evident, even in patients with minor hepatic injury [41]. Weissenborn et al. [6] reported that in comparison to the healthy controls, the patients with the HCV infection showed evidence of cognitive impairment, primarily attention, higher executive functions, higher levels of anxiety, and depression; these results were associated with MRS changes, thus eliminating the possibility of the confounding effect of MHE. In another study limited to patients with histologically mild liver disease, selective impairments of concentration and working memory were reported that were not seen to the same degree in patients who had recovered from HCV infection [2]. In yet another study conducted on a very homogenous cohort of iatrogenically infected women, PCR-positive women had impaired memory and attention compared to normal controls and the PCR-negative group [42]. However, some other studies have found no association between HCV infection and impaired cognitive function [3,43].
In contrast to these previous studies, our analysis did not address the question of whether HCV-infected patients have neurocognitive deficits, nor were our patients compared to controls; however, we correlated the neurocognitive test results with serum cytokine levels and the presence of extrahepatic HCV replication in PBMCs. Our findings suggest that the inflammatory process, as reflected by the cytokine levels, has some impact on neurocognitive function in chronic hepatitis C. However, while clinically overt encephalopathy was excluded, MHE was likely to be a factor since a large proportion of our patients had advanced liver fibrosis. The association between cytokines and neurocognitive dysfunction has been most extensively studied in the setting of mild cognitive impairment (MCI), which is a common precursor of Alzheimer’s disease (AD). In their comprehensive overview of 118 research articles on cytokine and other inflammation-associated protein levels in the plasma, serum, and cerebrospinal fluid (CSF) of patients with AD and MCI, Brosseron et al. [44] concluded that while increased levels of several cytokines are possible indicators of neuroinflammation, many reports are controversial or inconclusive. However, several studies reported on the increased levels of IFN-gamma, IP-10, MCP-1, and MIP-1alpha and these very cytokines correlated negatively with neurocognitive function among our patients.
In a previous study [45], we found a correlation between the PBMC activation state, as reflected by the levels of mRNA transcripts of several cytokines, and depression and neuroticism in patients after treatment with pegylated interferon and ribavirin. However, this study was limited to 24 patients and neither the viral negative-strand nor neurocognitive function were analyzed. Furthermore, the administration of interferon could have affected the results as it could have activated inflammatory responses in the brain [46].
The effect of HCV infection on the brain is still hypothetical but could share some similarities with HIV, which infects the same types of cells: brain macrophages and microglia. These cells, in turn, secrete proinflammatory cytokines, which are believed to play an important role in the pathogenesis of neuroAIDS [47].
The finding of higher IL-8 serum levels in patients with HCV replication in the PBMCs was not unexpected as we have previously reported that the infection of primary human macrophages with the hepatitis C virus in vitro results in the induction of IL-8 [48]. It was shown that the core protein strongly upregulates IL-8 transcription through the activation of NF-κB and that naturally occurring amino acid changes in the C terminus of the core protein affect this ability [49,50]. Thus, it is likely that the infected lymphoid cells were the source of elevated IL-8 in our patients.
In summary, we found a correlation between the level of depression and the presence of HCV replication in PBMCs and between neurocognitive function and cytokine serum levels. These findings suggest that in patients with the chronic HCV infection, brain function is influenced by both viral replication in PBMCs and by the overall immune activation state.

4. Materials and Methods

4.1. Patients

The current analysis included 80 patients who were being evaluated at the Outpatient Clinic of the Municipal Hospital for Infectious Diseases between January 2019 and February 2020 as candidates for antiviral treatment. Eligible patients for this study were at least 18 years old, had detectable plasma HCV RNA levels, and were required to have no history of decompensated liver disease and/or liver encephalopathy. Furthermore, patients who were active alcohol or drug abusers were excluded from this study. Enrolled patients underwent psychological testing and biological samples, consisting of sera and peripheral blood mononuclear cells (PBMCs); they were collected at the same time point. All testing preceded the initiation of antiviral therapy and separated PBMCs and serum samples were kept at −80 °C until analysis.
There were 39 women (49%) and 41 men (51%), their median age was 46.5 years (range 28–83 years) and the median duration of infection was 6.0 years (range 1–43 years). The median pretreatment HCV viral load was 9.94 × 105 IU/mL (range 1.32 × 102–1.09 × 107). Liver fibrosis was assessed by FibroScan and a 5-point METAVIR scale grading where F0/F1 represents no or minimal fibrosis, F2 moderate fibrosis, F3 severe fibrosis, and F4 cirrhosis [51]. Among the 64 patients with whom this analysis was conducted, 23 were classified as F0/F1, 10 as F2, 10 as F3, and 21 as F4.
Informed consent was obtained from each patient included in this study and the study protocol followed the ethical guidelines of the 2013 Declaration of Helsinki and was approved by the Bioethical Committee of the Medical University of Warsaw (Approval Number KB/77/A/2015).

4.2. Detection of the HCV RNA-Negative Strand in PBMC

Peripheral blood mononuclear cells (PBMCs) (3 × 105–106 cells) were isolated from the blood by centrifugation over a density gradient and RNA was extracted by a modified guanidinium thiocyanate-phenol/chloroform technique using a commercially available kit (TRIZOL LS, Gibco/BRL, Mississauga, ON, Canada). The strand specificity of RT-PCR was assured by conducting the reverse transcription step at 65 °C with the help of the thermostable enzyme Tth, as described previously [17,52]. This assay was found to be capable of detecting approximately 100 genomic equivalent (eq) molecules of the correct strand while unspecifically detecting ≥107–108 genomic eq of the incorrect strand.

4.3. Detection of Cytokines and Chemokines in Serum

Serum samples were tested for the concentration of a panel of cytokines reflecting the immune system activation status; commercially available assay was used (Bio-Plex Pro Human Cytokine 27-plex Assay; Bio-Rad Laboratories Inc., Hercules, CA, USA).

4.4. Psychological Evaluation

The patients’ mental states were assessed by psychological clinical examination and psychometric tests. Depression was measured by the self-administered multiple-choice Beck Depression Inventory (BDI) [53] and neuroticism was evaluated by the Eysenck Personality Inventory (N/EPO-R), which is also a self-assessment test [54]. Anxiety was assessed by the State-Trait Anxiety Inventory (STAI), which is a commonly used measure of trait and state anxiety [55] while cognitive function was assessed by the Wisconsin Card Sorting Test (WCST) [56], Ruff Figural Fluency Test (RFFT) [57], and California Verbal Learning Test (CVLT) [58]. The WCST measures cognitive flexibility, executive function, and problem-solving skills; responses are classified in various ways: (A) correct; (B) errors; (C) perseverative responses; and (D) nonperseverative errors. The RFFT, which assesses non-verbal fluency within the domain of executive functioning, was recorded as a number of unique designs and the CVLT, which assesses verbal learning and memory, was recorded as the sum of immediate recall from Trial-1 to Trial-5 (the total score is the sum of correct responses to the five presentations). Motor functioning was assessed by the Grooved Pegboard Test (GPT) [59]; however, some research indicates that performance on this test may also reflect cognitive factors, particularly attention and executive functioning.

4.5. Statistical Analysis

Continuous variables were summarized as medians and categorical as frequencies and percentages. The Mann–Whitney U test was used to compare continuous variables among independent groups and correlations were calculated using Spearman’s correlation test or Pearson’s correlation test if data passed the D’Agostino-Pearson test for normality. When p ≤ 0.05, this was considered to be statistically significant. In addition, p-values corrected for the false discovery rate (FDR) were calculated using the Benjamini–Hochberg procedure (q-value ≤ 0.1). Calculations were performed using GraphPad Prism version 9.50 for Windows (GraphPad Software, San Diego, CA, USA).

Author Contributions

Individual contributions: Conceptualization, M.R. and T.L.; Methodology, T.K., K.P. and B.S.-K.; Validation, T.K. and A.H.; Formal Analysis, B.S.-K. and T.L.; Investigation B.S.-K., H.B., T.P. and A.H.; Resources, M.R. and A.H.; Data Curation, H.B. and T.L.; Writing—Original Draft Preparation, T.L. and M.R.; Writing—Review and Editing, T.L. and T.P.; Visualization, K.P.; Supervision, T.L. and M.R.; Project Administration, M.R. and T.L.; Funding Acquisition, T.L. All authors have read and agreed to the published version of the manuscript.

Funding

Grant 2014/15/B/NZ6/02378 from Narodowe Centrum Nauki.

Institutional Review Board Statement

This study was approved by the Bioethical Committee of the Medical University of Warsaw (1.38/2018)).

Informed Consent Statement

Informed consent was obtained from each patient included in this study and the study protocol followed the ethical guidelines of the 2013 Declaration of Helsinki.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Barkhuizen, A.; Rosen, H.R.; Wolf, S.; Flora, K.; Benner, K.; Bennett, R.M. Musculoskeletal pain and fatigue are associated with chronic hepatitis C: A report of 239 hepatology clinic patients. Am. J. Gastroenterol. 1999, 94, 1355–1360. [Google Scholar] [CrossRef] [PubMed]
  2. Forton, D.M.; Thomas, H.C.; Murphy, C.A.; Allsop, J.M.; Foster, G.R.; Main, J.; Wesnes, K.A.; Taylor-Robinson, S.D. Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. Hepatology 2002, 35, 433–439. [Google Scholar] [CrossRef] [PubMed]
  3. Hilsabeck, R.C.; Perry, W.; Hassanein, T.I. Neuropsychological impairment in patients with chronic hepatitis C. Hepatology 2002, 35, 440–446. [Google Scholar] [CrossRef] [PubMed]
  4. Forton, D.M.; Allsop, J.M.; Main, J.; Foster, G.R.; Thomas, H.C.; Taylor-Robinson, S.D. Evidence for a cerebral effect of the hepatitis C virus. Lancet 2001, 358, 38–39. [Google Scholar] [CrossRef]
  5. Taylor-Robinson, S.D. Applications of magnetic resonance spectroscopy to chronic liver disease. Clin. Med. 2001, 1, 54–60. [Google Scholar] [CrossRef]
  6. Weissenborn, K.; Krause, J.; Bokemeyer, M.; Hecker, H.; Schuler, A.; Ennen, J.C.; Ahl, B.; Manns, M.P.; Boker, K.W. Hepatitis C virus infection affects the brain-evidence from psychometric studies and magnetic resonance spectroscopy. J. Hepatol. 2004, 41, 845–851. [Google Scholar] [CrossRef]
  7. McAndrews, M.P.; Farcnik, K.; Carlen, P.; Damyanovich, A.; Mrkonjic, M.; Jones, S.; Heathcote, E.J. Prevalence and significance of neurocognitive dysfunction in hepatitis C in the absence of correlated risk factors. Hepatology 2005, 41, 801–808. [Google Scholar] [CrossRef] [PubMed]
  8. Marcus, C.D.; Taylor-Robinson, S.D.; Sargentoni, J.; Ainsworth, J.G.; Frize, G.; Easterbrook, P.J.; Shaunak, S.; Bryant, D.J. 1H MR spectroscopy of the brain in HIV-1-seropositive subjects: Evidence for diffuse metabolic abnormalities. Metab. Brain Dis. 1998, 13, 123–136. [Google Scholar] [CrossRef]
  9. Meyerhoff, D.J.; Bloomer, C.; Cardenas, V.; Norman, D.; Weiner, M.W.; Fein, G. Elevated subcortical choline metabolites in cognitively and clinically asymptomatic HIV+ patients. Neurology 1999, 52, 995–1003. [Google Scholar] [CrossRef]
  10. McCombe, J.A.; Noorbakhsh, F.; Buchholz, C.; Trew, M.; Power, C. NeuroAIDS: A watershed for mental health and nervous system disorders. J. Psychiatry Neurosci. 2009, 34, 83–85. [Google Scholar]
  11. Radkowski, M.; Wilkinson, J.; Nowicki, M.; Adair, D.; Vargas, H.; Ingui, C.; Rakela, J.; Laskus, T. Search for hepatitis C virus negative-strand RNA sequences and analysis of viral sequences in the central nervous system: Evidence of replication. J. Virol. 2002, 76, 600–608. [Google Scholar] [CrossRef]
  12. Wilkinson, J.; Radkowski, M.; Laskus, T. Hepatitis C virus neuroinvasion: Identification of infected cells. J. Virol. 2009, 83, 1312–1319. [Google Scholar] [CrossRef]
  13. Letendre, S.; Paulino, A.D.; Rockenstein, E.; Adame, A.; Crews, L.; Cherner, M.; Heaton, R.; Ellis, R.; Everall, I.P.; Grant, I.; et al. Pathogenesis of hepatitis C virus coinfection in the brains of patients infected with HIV. J. Infect. Dis. 2007, 196, 361–370. [Google Scholar] [CrossRef] [PubMed]
  14. Forton, D.M.; Karayiannis, P.; Mahmud, N.; Taylor-Robinson, S.D.; Thomas, H.C. Identification of unique hepatitis C virus quasispecies in the central nervous system and comparative analysis of internal translational efficiency of brain, liver, and serum variants. J. Virol. 2004, 78, 5170–5183. [Google Scholar] [CrossRef] [PubMed]
  15. Laskus, T.; Radkowski, M.; Bednarska, A.; Wilkinson, J.; Adair, D.; Nowicki, M.; Nikolopoulou, G.B.; Vargas, H.; Rakela, J. Detection and analysis of hepatitis C virus sequences in cerebrospinal fluid. J. Virol. 2002, 76, 10064–10068. [Google Scholar] [CrossRef] [PubMed]
  16. Zheng, J.; Gendelman, H.E. The HIV-1 associated dementia complex: A metabolic encephalopathy fueled by viral replication in mononuclear phagocytes. Curr. Opin. Neurol. 1997, 10, 319–325. [Google Scholar] [CrossRef] [PubMed]
  17. Laskus, T.; Radkowski, M.; Wang, L.F.; Nowicki, M.; Rakela, J. Uneven distribution of hepatitis C virus quasispecies in tissues from subjects with end-stage liver disease: Confounding effect of viral adsorption and mounting evidence for the presence of low-level extrahepatic replication. J. Virol. 2000, 74, 1014–1017. [Google Scholar] [CrossRef]
  18. Lerat, H.; Rumin, S.; Habersetzer, F.; Berby, F.; Trabaud, M.A.; Trepo, C.; Inchauspe, G. In vivo tropism of hepatitis C virus genomic sequences in hematopoietic cells: Influence of viral load, viral genotype, and cell phenotype. Blood 1998, 91, 3841–3849. [Google Scholar] [CrossRef]
  19. Navas, S.; Martin, J.; Quiroga, J.A.; Castillo, I.; Carreno, V. Genetic diversity and tissue compartmentalization of the hepatitis C virus genome in blood mononuclear cells, liver, and serum from chronic hepatitis C patients. J. Virol. 1998, 72, 1640–1646. [Google Scholar] [CrossRef]
  20. Shimizu, Y.K.; Igarashi, H.; Kanematu, T.; Fujiwara, K.; Wong, D.C.; Purcell, R.H.; Yoshikura, H. Sequence analysis of the hepatitis C virus genome recovered from serum, liver, and peripheral blood mononuclear cells of infected chimpanzees. J. Virol. 1997, 71, 5769–5773. [Google Scholar] [CrossRef]
  21. Afridi, R.; Suk, K. Neuroinflammatory Basis of Depression: Learning From Experimental Models. Front. Cell Neurosci. 2021, 15, 691067. [Google Scholar] [CrossRef] [PubMed]
  22. Wilkinson, J.; Radkowski, M.; Eschbacher, J.M.; Laskus, T. Activation of brain macrophages/microglia cells in hepatitis C infection. Gut 2010, 59, 1394–1400. [Google Scholar] [CrossRef] [PubMed]
  23. Laskus, T.; Radkowski, M.; Piasek, A.; Nowicki, M.; Horban, A.; Cianciara, J.; Rakela, J. Hepatitis C Virus in Lymphoid Cells of Patients Coinfected with Human Immunodeficiency Virus Type 1: Evidence of Active Replication in Monocytes/Macrophages and Lymphocytes. J. Infect. Dis. 2000, 181, 442–448. [Google Scholar] [CrossRef]
  24. Ducoulombier, D.; Roque-Afonso, A.M.; Di Liberto, G.; Penin, F.; Kara, R.; Richard, Y.; Dussaix, E.; Feray, C. Frequent compartmentalization of hepatitis C virus variants in circulating B cells and monocytes. Hepatology 2004, 39, 817–825. [Google Scholar] [CrossRef]
  25. Hickey, W.F.; Vass, K.; Lassmann, H. Bone marrow-derived elements in the central nervous system: An immunohistochemical and ultrastructural survey of rat chimeras. J. Neuropathol. Exp. Neurol. 1992, 51, 246–256. [Google Scholar] [CrossRef]
  26. Unger, E.R.; Sung, J.H.; Manivel, J.C.; Chenggis, M.L.; Blazar, B.R.; Krivit, W. Male donor-derived cells in the brains of female sex-mismatched bone marrow transplant recipients: A Y-chromosome specific in situ hybridization study. J. Neuropathol. Exp. Neurol. 1993, 52, 460–470. [Google Scholar] [CrossRef]
  27. Hickey, W.F. Leukocyte traffic in the central nervous system: The participants and their roles. Semin. Immunol. 1999, 11, 125–137. [Google Scholar] [CrossRef]
  28. Leonard, B.E. Inflammation and depression: A causal or coincidental link to the pathophysiology? Acta Neuropsychiatr. 2018, 30, 1–16. [Google Scholar] [CrossRef]
  29. Grant, R.S.; Kapoor, V. Murine glial cells regenerate NAD, after peroxide-induced depletion, using either nicotinic acid, nicotinamide, or quinolinic acid as substrates. J. Neurochem. 1998, 70, 1759–1763. [Google Scholar] [CrossRef] [PubMed]
  30. Zhu, C.B.; Lindler, K.M.; Owens, A.W.; Daws, L.C.; Blakely, R.D.; Hewlett, W.A. Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters. Neuropsychopharmacology 2010, 35, 2510–2520. [Google Scholar] [CrossRef]
  31. Horikawa, H.; Kato, T.A.; Mizoguchi, Y.; Monji, A.; Seki, Y.; Ohkuri, T.; Gotoh, L.; Yonaha, M.; Ueda, T.; Hashioka, S.; et al. Inhibitory effects of SSRIs on IFN-gamma induced microglial activation through the regulation of intracellular calcium. Prog. Neuropsychopharmacol. Biol. Psychiatry 2010, 34, 1306–1316. [Google Scholar] [CrossRef] [PubMed]
  32. Muller, N.; Schwarz, M.J.; Dehning, S.; Douhe, A.; Cerovecki, A.; Goldstein-Muller, B.; Spellmann, I.; Hetzel, G.; Maino, K.; Kleindienst, N.; et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: Results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol. Psychiatry 2006, 11, 680–684. [Google Scholar] [CrossRef] [PubMed]
  33. Nettis, M.A.; Lombardo, G.; Hastings, C.; Zajkowska, Z.; Mariani, N.; Nikkheslat, N.; Worrell, C.; Enache, D.; McLaughlin, A.; Kose, M.; et al. Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: Results from a double-blind randomised clinical trial. Neuropsychopharmacology 2021, 46, 939–948. [Google Scholar] [CrossRef] [PubMed]
  34. Dudek, K.A.; Dion-Albert, L.; Lebel, M.; LeClair, K.; Labrecque, S.; Tuck, E.; Ferrer Perez, C.; Golden, S.A.; Tamminga, C.; Turecki, G.; et al. Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression. Proc. Natl. Acad. Sci. USA 2020, 117, 3326–3336. [Google Scholar] [CrossRef] [PubMed]
  35. Martinez, J.M.; Garakani, A.; Yehuda, R.; Gorman, J.M. Proinflammatory and “resiliency” proteins in the CSF of patients with major depression. Depress. Anxiety 2012, 29, 32–38. [Google Scholar] [CrossRef]
  36. Himmerich, H.; Patsalos, O.; Lichtblau, N.; Ibrahim, M.A.A.; Dalton, B. Cytokine Research in Depression: Principles, Challenges, and Open Questions. Front. Psychiatry 2019, 10, 30. [Google Scholar] [CrossRef]
  37. Lotrich, F.E. Inflammatory cytokine-associated depression. Brain Res. 2015, 1617, 113–125. [Google Scholar] [CrossRef]
  38. Marques-Deak, A.H.; Neto, F.L.; Dominguez, W.V.; Solis, A.C.; Kurcgant, D.; Sato, F.; Ross, J.M.; Prado, E.B. Cytokine profiles in women with different subtypes of major depressive disorder. J. Psychiatr. Res. 2007, 41, 152–159. [Google Scholar] [CrossRef]
  39. Dieperink, E.; Willenbring, M.; Ho, S.B. Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: A review. Am. J. Psychiatry 2000, 157, 867–876. [Google Scholar] [CrossRef]
  40. Yarlott, L.; Heald, E.; Forton, D. Hepatitis C virus infection, and neurological and psychiatric disorders—A review. J. Adv. Res. 2017, 8, 139–148. [Google Scholar] [CrossRef]
  41. Hilsabeck, R.C.; Hassanein, T.I.; Carlson, M.D.; Ziegler, E.A.; Perry, W. Cognitive functioning and psychiatric symptomatology in patients with chronic hepatitis C. J. Int. Neuropsychol. Soc. 2003, 9, 847–854. [Google Scholar] [CrossRef]
  42. Lowry, D.; Coughlan, B.; McCarthy, O.; Crowe, J. Investigating health-related quality of life, mood and neuropsychological test performance in a homogeneous cohort of Irish female hepatitis C patients. J. Viral Hepat. 2010, 17, 352–359. [Google Scholar] [CrossRef] [PubMed]
  43. Cordoba, J.; Flavia, M.; Jacas, C.; Sauleda, S.; Esteban, J.I.; Vargas, V.; Esteban, R.; Guardia, J. Quality of life and cognitive function in hepatitis C at different stages of liver disease. J. Hepatol. 2003, 39, 231–238. [Google Scholar] [CrossRef]
  44. Brosseron, F.; Krauthausen, M.; Kummer, M.; Heneka, M.T. Body fluid cytokine levels in mild cognitive impairment and Alzheimer’s disease: A comparative overview. Mol. Neurobiol. 2014, 50, 534–544. [Google Scholar] [CrossRef] [PubMed]
  45. Pawlowski, T.; Radkowski, M.; Malyszczak, K.; Inglot, M.; Zalewska, M.; Jablonska, J.; Laskus, T. Depression and neuroticism in patients with chronic hepatitis C: Correlation with peripheral blood mononuclear cells activation. J. Clin. Virol. 2014, 60, 105–111. [Google Scholar] [CrossRef]
  46. Raison, C.L.; Borisov, A.S.; Majer, M.; Drake, D.F.; Pagnoni, G.; Woolwine, B.J.; Vogt, G.J.; Massung, B.; Miller, A.H. Activation of central nervous system inflammatory pathways by interferon-alpha: Relationship to monoamines and depression. Biol. Psychiatry 2009, 65, 296–303. [Google Scholar] [CrossRef]
  47. Brabers, N.A.; Nottet, H.S. Role of the pro-inflammatory cytokines TNF-alpha and IL-1beta in HIV-associated dementia. Eur. J. Clin. Investig. 2006, 36, 447–458. [Google Scholar] [CrossRef]
  48. Radkowski, M.; Bednarska, A.; Horban, A.; Stanczak, J.; Wilkinson, J.; Adair, D.M.; Nowicki, M.; Rakela, J.; Laskus, T. Infection of primary human macrophages with hepatitis C virus in vitro: Induction of tumour necrosis factor-alpha and interleukin 8. J. Gen. Virol. 2004, 85 Pt 1 Pt 1, 47–59. [Google Scholar] [CrossRef]
  49. Kato, N.; Yoshida, H.; Ono-Nita, S.K.; Kato, J.; Goto, T.; Otsuka, M.; Lan, K.; Matsushima, K.; Shiratori, Y.; Omata, M. Activation of intracellular signaling by hepatitis B and C viruses: C-viral core is the most potent signal inducer. Hepatology 2000, 32, 405–412. [Google Scholar] [CrossRef]
  50. Hoshida, Y.; Kato, N.; Yoshida, H.; Wang, Y.; Tanaka, M.; Goto, T.; Otsuka, M.; Taniguchi, H.; Moriyama, M.; Imazeki, F.; et al. Hepatitis C virus core protein and hepatitis activity are associated through transactivation of interleukin-8. J. Infect. Dis. 2005, 192, 266–275. [Google Scholar] [CrossRef] [PubMed]
  51. Foucher, J.; Chanteloup, E.; Vergniol, J.; Castera, L.; Le Bail, B.; Adhoute, X.; Bertet, J.; Couzigou, P.; de Ledinghen, V. Diagnosis of cirrhosis by transient elastography (FibroScan): A prospective study. Gut 2006, 55, 403–408. [Google Scholar] [CrossRef] [PubMed]
  52. Laskus, T.; Radkowski, M.; Jablonska, J.; Kibler, K.; Wilkinson, J.; Adair, D.; Rakela, J. Human immunodeficiency virus facilitates infection/replication of hepatitis C virus in native human macrophages. Blood 2004, 103, 3854–3859. [Google Scholar] [CrossRef] [PubMed]
  53. Beck, A.T.; Ward, C.H.; Mendelson, M.; Mock, J.; Erbaugh, J. An inventory for measuring depression. Arch. Gen. Psychiatry 1961, 4, 561–571. [Google Scholar] [CrossRef] [PubMed]
  54. Eysenck, H.J.; Eysenck, S.B.J. Manual of the Eysenck Personality Inventory; Hodder&Stoughton: London, UK, 1975; pp. 390–401. [Google Scholar]
  55. Spielberger, C.D.; Gorsuch, R.L.; Lushene, R.; Vagg, P.R.; Jacobs, G.A. Manual for the State-Trait Anxiety Inventory; Consulting Psychologist Press: Palo Alto, CA, USA, 1983. [Google Scholar]
  56. Grant, D.A.; Berg, E.A. A behavioral analysis of degree of reinforcement and ease of shifting to new responses in a Weigl-type card-sorting problem. J. Exp. Psychol. 1948, 38, 404–411. [Google Scholar] [CrossRef] [PubMed]
  57. Ruff, R.M. Ruff Figural Fluency Test; Odessa, F.L., Ed.; Psychological Assessment Resources: Lutz, FL, USA, 2011. [Google Scholar]
  58. Delis, D.C.; Kramer, J.H.; Kaplan, E.; Ober, B.A. California Verbal Learning Test—Second Edition (CVLT–II) [Database Record]; PsycTESTS; American Psychological Association: Washington, DC, USA, 1987–2000. [Google Scholar]
  59. Matthews, C.G.; Klove, K. Instruction Manual for the Adult Neuropsychology Test Battery; University of Wisconsin Medical School: Madison, WI, USA, 1964. [Google Scholar]
Ijms 24 15351 g001
Figure 1. Depression in patients with the chronic HCV infection in relation to the presence or absence of the HCV RNA-negative strand in the PBMCs. Depression was measured by the Beck Depression Index (BDI) and the HCV RNA-negative strand (viral replicative form) was detected by a strand-specific assay in 24 out of 80 patients. Horizontal lines represent median values. Data were compared using the nonparametric Mann–Whitney U test.
Figure 1. Depression in patients with the chronic HCV infection in relation to the presence or absence of the HCV RNA-negative strand in the PBMCs. Depression was measured by the Beck Depression Index (BDI) and the HCV RNA-negative strand (viral replicative form) was detected by a strand-specific assay in 24 out of 80 patients. Horizontal lines represent median values. Data were compared using the nonparametric Mann–Whitney U test.
Ijms 24 15351 g001
Ijms 24 15351 g002
Figure 2. Correlation between the cytokine/chemokine levels in the serum and depression, anxiety, and neuroticism. Neuroticism was assessed by the Revised Eysenck Personality Test while depression and anxiety were measured by the Beck Depression Index (BDI) and State-Trait Anxiety Inventory (STAI), respectively.Detailed comparisons are shown in Table 1 and only correlations that were statistically significant are shown in the figure. Correlation coefficients r and statistical significance are provided in the panels. Cytokines are provided as pg/mL.
Figure 2. Correlation between the cytokine/chemokine levels in the serum and depression, anxiety, and neuroticism. Neuroticism was assessed by the Revised Eysenck Personality Test while depression and anxiety were measured by the Beck Depression Index (BDI) and State-Trait Anxiety Inventory (STAI), respectively.Detailed comparisons are shown in Table 1 and only correlations that were statistically significant are shown in the figure. Correlation coefficients r and statistical significance are provided in the panels. Cytokines are provided as pg/mL.
Ijms 24 15351 g002
Ijms 24 15351 g003
Figure 3. Correlation between the cytokine/chemokine levels in serum and the results of Ruff Figural Fluency Test (RFFT), California Verbal Learning Test (CVLT), Grooved Pegboard and Wisconsin Card Sorting Tests (WCST). The RFFT is shown as a number of unique designs and CVLT represents sum of immediate recall from Trial-1 to Trial-5. The results of The Grooved Pegboard Test are shown in seconds while the WCST is represented as the total number of correct responses. Detailed comparisons are shown in Table 2 and only correlations that were statistically significant are shown in the figure. Correlation coefficients r and statistical significance are provided in the panels. Cytokines are provided as pg/mL.
Figure 3. Correlation between the cytokine/chemokine levels in serum and the results of Ruff Figural Fluency Test (RFFT), California Verbal Learning Test (CVLT), Grooved Pegboard and Wisconsin Card Sorting Tests (WCST). The RFFT is shown as a number of unique designs and CVLT represents sum of immediate recall from Trial-1 to Trial-5. The results of The Grooved Pegboard Test are shown in seconds while the WCST is represented as the total number of correct responses. Detailed comparisons are shown in Table 2 and only correlations that were statistically significant are shown in the figure. Correlation coefficients r and statistical significance are provided in the panels. Cytokines are provided as pg/mL.
Ijms 24 15351 g003
Table 1. Correlation between the Beck Depression Index (BDI) scores, anxiety levels assessed by the State-Trait Anxiety Inventory (STAI), neuroticism levels assessed by the Eysenck Personality Inventory (N/EPO-R), and the serum levels of various cytokines in 80 patients with chronic hepatitis C.
Table 1. Correlation between the Beck Depression Index (BDI) scores, anxiety levels assessed by the State-Trait Anxiety Inventory (STAI), neuroticism levels assessed by the Eysenck Personality Inventory (N/EPO-R), and the serum levels of various cytokines in 80 patients with chronic hepatitis C.
Cytokine/
Chemokine		BDISTAINeuroticism
Correlation CoefficientStatistical
Significance a		Correlation
Coefficient		Statistical
Significance		Correlation
Coefficient		Statistical
Significance
IL-1ra−0.06NS0.10NS−0.19NS
IL-1β−0.08NS−0.02NS−0.14NS
IL-2−0.10NS−0.01NS−0.13NS
IL-4−0.05NS−0.04NS0.270.02 (0.37) b
IL-70.02NS−0.05NS0.240.046 (0.38)
IL-80.290.012 (0.28)0.300.009 (0.21)0.18NS
IL-9−0.04NS0.14NS0.08NS
IL-13−0.10NS−0.12NS−0.06NS
IL-17−0.12NS−0.12NS0.10NS
TNF-α−0.13NS−0.11NS0.04NS
IFN-γ0.13NS0.210.06 (0.51)−0.03NS
IP-10/CXCL10−0.07NS0.09NS−0.05NS
GM-CSF0.210.080.06NS0.03NS
G-CSF−0.04NS0.07NS0.15NS
FGF-basic0.16NS0.07NS−0.01NS
PDGF-BB−0.10NS−0.04NS−0.06NS
MCP-1/CCL20.11NS0.230.05 (0.51)−0.02NS
MIP-1α/CCL30.029NS0.09NS0.12NS
MIP-1β/CCL40.12NS0.06NS0.00NS
RANTES/CCL5−0.14NS−0.03NS−0.07NS
Eotaxin−0.04NS−0.10NS0.250.03 (0.37)
a Only p values ≤ 0.1 are listed, p values ≤ 0.05 are shown in bold. b The p values corrected for the false discovery rate are shown in parentheses.
Table 2. Correlation between the results of the Ruff Figural Fluency Test (RFFT), California Verbal Learning Test (CVLT), Grooved Pegboard Test and levels of various cytokines in 80 Patients with chronic hepatitis C.
Table 2. Correlation between the results of the Ruff Figural Fluency Test (RFFT), California Verbal Learning Test (CVLT), Grooved Pegboard Test and levels of various cytokines in 80 Patients with chronic hepatitis C.
Cytokine/
Chemokine		RFFT aCVLT 1–5 bGrooved Pegboard Test
Correlation
Coefficient		Statistical
Significance c		Correlation CoefficientStatistical
Significance		Correlation CoefficientStatistical
Significance
IL-1ra−0.06NS−0.10NS−0.07NS
IL-1β−0.08NS0.16NS0.09NS
IL-20.01NS−0.12NS0.13NS
IL-40.10NS0.05NS−0.07NS
IL-70.01NS0.08NS0.00NS
IL-8−0.18NS−0.08NS0.13NS
IL-90.05NS−0.02NS−0.05NS
IL-13−0.19NS−0.17NS−0.03NS
IL-17−0.12NS−0.13NS−0.05NS
TNF-α0.03NS−0.05NS−0.13NS
IFN-γ0.10NS0.17NS0.240.041 (0.48) d
IP-10/CXCL10−0.250.034 (0.74)−0.09NS0.10NS
GM-CSF0.06NS0.17NS0.02NS
G-CSF−0.02NS−0.16NS0.02NS
FGF-basic−0.15NS−0.05NS0.04NS
PDGF-BB0.05NS0.05NS−0.19NS
MCP-1/CCL2−0.16NS−0.04NS0.280.016 (0.36)
MIP-1α/CCL3−0.14NS−0.250.025 (0.56)0.00NS
MIP-1β/CCL40.01NS0.04NS−0.17NS
RANTES/CCL5−0.07NS0.04NS−0.08NS
Eotaxin0.04NS0.02NS−0.03NS
a A unique design number. b Sum of immediate recall from Trial-1 to Trial-5. c Only p values ≤ 0.1 are listed, p values ≤ 0.05 are shown in bold. d The p values corrected for the false discovery rate are shown in parentheses.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Radkowski, M.; Kryczka, T.; Szymańska-Kotwica, B.; Berak, H.; Horban, A.; Pawłowski, T.; Perlejewski, K.; Laskus, T. Depression and Cognitive Dysfunction in Patients with Chronic Hepatitis C: Correlation with Viral Replication in the Peripheral Blood Mononuclear Cells and Cytokines in Serum. Int. J. Mol. Sci. 2023, 24, 15351. https://doi.org/10.3390/ijms242015351

AMA Style

Radkowski M, Kryczka T, Szymańska-Kotwica B, Berak H, Horban A, Pawłowski T, Perlejewski K, Laskus T. Depression and Cognitive Dysfunction in Patients with Chronic Hepatitis C: Correlation with Viral Replication in the Peripheral Blood Mononuclear Cells and Cytokines in Serum. International Journal of Molecular Sciences. 2023; 24(20):15351. https://doi.org/10.3390/ijms242015351

Chicago/Turabian Style

Radkowski, Marek, Tomasz Kryczka, Bogna Szymańska-Kotwica, Hanna Berak, Andrzej Horban, Tomasz Pawłowski, Karol Perlejewski, and Tomasz Laskus. 2023. "Depression and Cognitive Dysfunction in Patients with Chronic Hepatitis C: Correlation with Viral Replication in the Peripheral Blood Mononuclear Cells and Cytokines in Serum" International Journal of Molecular Sciences 24, no. 20: 15351. https://doi.org/10.3390/ijms242015351

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop