**2. Neurocognitive impairments and hepatitis C virus**

The evidence of CNS infection is supported by the detection of replicative intermediate forms of HCV RNA and viral proteins within the CNS. Additional mechanisms, involved in neurological dysfunction, are possibly related to the consequence of circulating inflammatory cytokines and chemokines in the brain tissues through altered sites of the blood–brain barrier [14–17]. HCV ribonucleic acid (RNA) has been detected in peripheral blood mononuclear cells, cerebrospinal fluid (CSF), and the brain of chronically infected patients with neuropathological abnormalities. The majority of reports supporting HCV in the CNS have used PCR-based approaches to detect viral genomes in brain tissue and CSF. The presence of HCV in the brain was demonstrated using immunostaining and Western blot techniques. The presence of RNA negative strand intermediate is considered as a direct evidence of HCV replication. Until now, it is not clear which cells are involved. Some authors demonstrated that HCV infects microglia/macrophages, astrocytes, brain microvascular endothelial cells, neuroepithelioma cells, and neuroblastoma cells. More recent studies showed that CSF was found to be HCV positive in more than 50% of patients with HCV [18–23].

A variety of mechanisms have been hypothesized to explain the biological abnormalities in the brain:

**a.** direct infection of the brain,

(HIV), atherosclerosis, chronic kidney disease, mixed cryoglobulinemia, insulin resistance, and several cardiovascular diseases [1, 2]. The extrahepatic manifestation is secondary to HCV-related inflammatory responses and autoimmune reactions. According to a recent metaanalysis, the most frequent extrahepatic manifestation occurring in HCV-infected persons is

The issue of a direct relationship between hepatitis C virus (HCV) infection and neuropsychiatric symptoms was raised for some years. Initially, the psychiatric and neurocognitive complaints were considered as the results of impairments in liver function. About 50% of the patients com-

Meanwhile, it has been shown that the reduction of global health-related quality of life (HRQoL) and development of psychiatric and neurocognitive impairments are not correlated

Data point to an increasing evidence to support central nervous system (CNS) change in HCV patients. Several studies detected HCV in cerebrospinal fluid and brain. Further evidence was provided by studies using imaging techniques like magnetic resonance spectroscopy (MRS), positron emission tomography (PET), and single photon emission computed tomography

The mechanisms through which HCV entries and replicates in the brain are not fully elucidated yet, but evidences point to microstructural changes, and cerebral metabolite abnormali-

Historically, the treatment of hepatitis C with interferon (IFN) was burdensome, complicated, and often was associated with neurocognitive abnormalities, depression, anxiety, and

This chapter aims to analyze the current data about the relation between chronic HCV infection, depression, and neurocognitive impairments. Also, the effects of pharmacologic viral

The evidence of CNS infection is supported by the detection of replicative intermediate forms of HCV RNA and viral proteins within the CNS. Additional mechanisms, involved in neurological dysfunction, are possibly related to the consequence of circulating inflammatory cytokines and chemokines in the brain tissues through altered sites of the blood–brain barrier [14–17]. HCV ribonucleic acid (RNA) has been detected in peripheral blood mononuclear cells, cerebrospinal fluid (CSF), and the brain of chronically infected patients with neuropathological abnormalities. The majority of reports supporting HCV in the CNS have used PCR-based approaches to detect viral genomes in brain tissue and CSF. The presence of HCV in the brain was demonstrated using immunostaining and Western blot techniques. The presence of RNA negative strand intermediate is considered as a direct evidence of HCV replication. Until now, it is not clear which cells are involved. Some authors demonstrated that HCV infects microglia/macrophages, astrocytes, brain microvascular endothelial cells,

clearance on cognitive dysfunction and psychiatric features will be discussed.

**2. Neurocognitive impairments and hepatitis C virus**

depression, irrespective of alcohol and drug abuse or antiviral treatment [3].

with the level of hepatic alterations [9, 10].

204 Liver Research and Clinical Management

(SPECT).

ties [11–13].

psychosis.

plain of chronic fatigue, deficits in attention, memory, learning, and depression [4–8].


#### **2.1. Neuroimaging studies**

The imaging techniques that have been used to determine the biological abnormalities in HCV patients were: magnetic resonance spectroscopy, positron emission tomography, single photon computed tomography (SPECT), magnetic resonance-perfusion weighted imaging, and diffusion tensor imaging (DTI).

MRS provides noninvasive measures to evidence the metabolite abnormalities concentration in specific brain regions: myoinositol (mI), choline-containing compounds (Cho), creatine and phosphocreatine (Cr), glutathione, and N-acetyl aspartate (NAA). These metabolites are sensitive to changes in neuronal and glial state and density.

In general, metabolites are reported as a ratio to creatine. The evidence of neuroinflammation in HCV-positive patients is underlined by choline/creatine ratios. The cholinecontaining compound (Cho) peak is considered a marker for cell turnover and membrane metabolism. They were significantly higher in the basal ganglia (BG) and white matter of HCV positive patients. This data was associated with elevated myoinositol/creatine ratios (a marker of glial density). Myoinositol is a cerebral osmolyte and considered a marker for gliosis. Increases are thought to reflect microglial activation and are associated with CNS inflammation. Choline and myoinositol were significantly higher in the BG. N-acetyl aspartate (NAA) is considered a marker for neurons/axons. NAA and N-acetyl-glutamate were also significantly higher in BG.

Alterations in brain metabolism and neurotransmission are presented in **Table 1**.

In spite of the fact that the results vary greatly in the areas of the brain most affected, HCV positive patients with mild liver disease are characterized on MRS by higher mI (or mI/Cr), higher Cho (or Cho/Cr), and often lower NAA (or NAA/Cr). Those results are considered to represent the results of neuronal dysfunction and immune activation of microglia cells.

The main limitations of these studies are represented by:



severe, the patients could present word finding difficulties, anomia, and significant deficits in attention performance. In general, constructional abilities and nonverbal recall are intact in these patients. Many studies suggest that approximately 30% of patients with chronic HCV exhibit cognitive dysfunctions even in the absence of cirrhosis. It seems that the cognitive performances are unrelated to viral load or viral genotype. The imaging studies showed significant reduction in striatal and midbrain dopamine availability and reduced metabolism in limbic, frontal, parietal, and temporal cortices. Thus, a crucial role of impaired dopaminergic transmission in causing cognitive impairment in HCV-infected patients was suggested. Moreover, pathologic cerebral serotonin and dopamine transporter binding were observed. Emerging lines of evidence suggest that the profile of neuropsychological dysfunction in

HCV and healthy controls

all subcortical areas assessed (caudate, thalamus, pallidum) but in no cortical areas Journal of Hepatology [27]

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Neurocognitive Impairments and Depression and Their Relationship...

Neurology Neuroimmunology Neuroinflammation [28]

207

Journal of Viral Hepatitis [29]

Journal of Viral Hepatitis [30]

Journal of Viral Hepatitis [34]

Journal of Clinical and Experimental Neuropsychology [35]

**Author Year Technique Findings Journal**

Thames et al. 2015 DTI Increased FA in striatum, thalamus, and insula

Grover VPB 2012 PET Significantly higher binding potential in

Pflugrad et al. 2016 PET No differences between patients with mild

2013 DTI Decreased FA in all white matter areas measured

Several cognitive impairments demonstrated in patient with HCV are presented in **Table 3**.

Weissenborn et al. 2004 Impaired executive function Journal of Hepatology [31] Karaivazoglou et al. 2007 Impairment of verbal learning and memory Liver international [32] Fontana et al. 2007 Impairment in verbal recall and working memory Hepatology [33]

attention, spatial orientation, age identification, and

**Table 3.** Summary of major cognitive dysfunctions observed in patients with chronic hepatitis C virus infection.

**Author Year Domains Journal**

delayed auditory recognition

Lowry et al. 2010 Alterations in memory, sustained attention, and

working memory

Ibrahim et al. 2016 Worse performance in nonverbal reasoning,

HCV-infected patients is characterized by impairment in:

**a.** executive function, **b.** sustained attention,

Bladowska et al.

**c.** working memory, and

**d.** verbal learning and verbal recall.

**Table 2.** Neuroimaging findings in HCV patients.

**Table 1.** Neuroimaging findings.

Diffusion tensor imaging (DTI) is a technique of magnetic resonance imaging that provides metrics for the speed and direction of water diffusion along the white matter tracts in the brain. DTI is a sensible method for detecting microscopic differences in tissue properties. The common DTI measures are mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (Dr), and axial diffusivity (Da). Mean diffusivity (MD) is an averaged measure of speed of diffusion in the three main directions. Fractional anisotropy (FA) measures the degree to which diffusion is faster in one direction than others. FA is used to highlight the microstructural changes, but it seems to be not very specific to the type of changes. Reductions in FA and elevations in MD seem to indicate impaired white matter integrity. Microglial state is also assessed using the positron emission tomography (PET) ligand PK11195, which binds to the mitochondrial membrane translocator protein (TPSO) present in endothelial, astroglial, and microglial cells. It is considered a marker for microglial activation. The most important neuroimaging findings are presented in **Table 2**.

#### **2.2. Cognitive impairments**

Approximately more than 50% of patients with chronic HCV infection complain of:


Despite its potential clinical significance, cognitive impairments are often missed in patients evaluated for HCV, unless the manifestations are overt or interfere with the functionality, leading to impairments in health-related quality of life. When the symptomatology is very


**Table 2.** Neuroimaging findings in HCV patients.

severe, the patients could present word finding difficulties, anomia, and significant deficits in attention performance. In general, constructional abilities and nonverbal recall are intact in these patients. Many studies suggest that approximately 30% of patients with chronic HCV exhibit cognitive dysfunctions even in the absence of cirrhosis. It seems that the cognitive performances are unrelated to viral load or viral genotype. The imaging studies showed significant reduction in striatal and midbrain dopamine availability and reduced metabolism in limbic, frontal, parietal, and temporal cortices. Thus, a crucial role of impaired dopaminergic transmission in causing cognitive impairment in HCV-infected patients was suggested. Moreover, pathologic cerebral serotonin and dopamine transporter binding were observed.

Emerging lines of evidence suggest that the profile of neuropsychological dysfunction in HCV-infected patients is characterized by impairment in:

**a.** executive function,

Diffusion tensor imaging (DTI) is a technique of magnetic resonance imaging that provides metrics for the speed and direction of water diffusion along the white matter tracts in the brain. DTI is a sensible method for detecting microscopic differences in tissue properties. The common DTI measures are mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (Dr), and axial diffusivity (Da). Mean diffusivity (MD) is an averaged measure of speed of diffusion in the three main directions. Fractional anisotropy (FA) measures the degree to which diffusion is faster in one direction than others. FA is used to highlight the microstructural changes, but it seems to be not very specific to the type of changes. Reductions in FA and elevations in MD seem to indicate impaired white matter integrity. Microglial state is also assessed using the positron emission tomography (PET) ligand PK11195, which binds to the mitochondrial membrane translocator protein (TPSO) present in endothelial, astroglial, and microglial cells. It is considered a marker for microglial activation. The most important neuroimaging findings are presented in **Table 2**.

**Author Year Technique Findings Journal**

Cr) ratio in the basal ganglia and

(NAA)/Cr ratio in the frontal gray

concentrations in basal ganglia and

Increased Cr, NAA, and N-acetylaspartyl-glutamate in basal ganglia

Increased myoinositol and

no changes of the Cho/Cr ratio

Lancet [24]

[12]

Gut [25]

Hepatology [10]

Journal of Hepatology

International Journal of Hepatology [26]

frontal white matter

white matter

white matter

glutathione

matter

Forton et al. 2001 MRS Elevated choline/creatine (Cho/

Forton et al. 2002 MRS Higher choline in basal ganglia,

Weissenborn et al 2004 MRS Decrease of the N-acetyl-aspartate

Bokemeyer et al. 2011 MRS Increased Cho and myoinositol

dimensional correlated spectroscopy (L-COSY)

Approximately more than 50% of patients with chronic HCV infection complain of:

Despite its potential clinical significance, cognitive impairments are often missed in patients evaluated for HCV, unless the manifestations are overt or interfere with the functionality, leading to impairments in health-related quality of life. When the symptomatology is very

**2.2. Cognitive impairments**

Nagarajan et al. 2012 Localized two-

**Table 1.** Neuroimaging findings.

206 Liver Research and Clinical Management

• impaired attention, and

• poor memory,

• fatigue.


Several cognitive impairments demonstrated in patient with HCV are presented in **Table 3**.


**Table 3.** Summary of major cognitive dysfunctions observed in patients with chronic hepatitis C virus infection.

There is evidence that cognitive dysfunctions in HCV patients have some impact in the reduction of health-related quality of life, chronic fatigue, and impaired functionality. The literature demonstrates evidence of neurocognitive impairment in patients with chronic HCV infection. However, until now, it is not clear that these dysfunctions can be linked, wholly or in part, to the virus itself. The longitudinal evaluation of the cognitive functioning could provide valuable information regarding the persistence of symptoms after the clearance of virus in the periphery.

**3.1. Psychosocial factors involved in development of depression**

nificantly associated with the appearance of depressive symptoms [41–46].

**Table 4.** Psychosocial factors associated with the development of depression in HCV patients.

The most commonly used coping styles by HCV patients are:

• problem-solving behavior,

• depressive coping.

Fear of transmitting the disease

Illness perception

Functional disability Impaired quality of life

Fatigue severity Personality disorders

Low income Social stigma Coping styles Social support

• distraction and self-revalorization, • religiousness and search for meaning,

• cognitive avoidance and dissimulation, and

Risk of cirrhosis/cancer and other health-related worries

Concerns about the complications of disease/treatment

development of depression are illustrated in **Table 4**.

It is very important to distinguish between psychological reactions to the knowledge that one has been infected with HCV and the direct effects of the virus itself. Learning that one has contracted HCV infection represents a significant life stressor and will produce emotional stress in most patients, and psychiatric disorder in many. The psychological reasons for the development of depression are illustrated in **Table 4**. The psychosocial factors involved in the

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Stigma negatively affects the HRQOL, mental health, and social life of the patients, and leads to difficulties with receiving or accepting treatment. Poor social and work adjustment, lower acceptance of the illness, and higher subjective complaints are other problems associated with stigmatization. Researches showed that women generally are prone to experience more stigmatization. The social stigma may cause some HCV individuals to refuse to disclose their HCV diagnosis. Furthermore, HCV-related stigma is an important stressor that leads to poor treatment adherence. In some cases, HCV-infected individuals tend to isolate themselves to prevent stigma-related negative attitudes. Low income is also a socio-demographic factor sig-
