Showing posts with label Brain. Show all posts
Showing posts with label Brain. Show all posts

Monday, March 4, 2019

NIH study of brain energy patterns provides new insights into alcohol effects

NIH scientists present a new method for combining measures of brain activity (left) and glucose consumption (right) to study regional specialization and to better understand the effects of alcohol on the human brain.
Dr. Ehsan Shokri Kojori, NIAAA

NIH study of brain energy patterns provides new insights into alcohol effects
Assessing the patterns of energy use and neuronal activity simultaneously in the human brain improves our understanding of how alcohol affects the brain, according to new research by scientists at the National Institutes of Health. The new approach for characterizing brain energetic patterns could also be useful for studying other neuropsychiatric diseases. A report of the findings is now online in Nature Communications.

“The brain uses a lot of energy compared to other body organs, and the association between brain activity and energy utilization is an important marker of brain health,” said George F. Koob, Ph.D., director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of NIH, which funded the study. “This study introduces a new way of characterizing how brain activity is related to its consumption of glucose, which could be very useful in understanding how the brain uses energy in health and disease.”

The research was led by Dr. Ehsan Shokri-Kojori and Dr. Nora D. Volkow of the NIAAA Laboratory of Neuroimaging. Dr. Volkow is also the director of the National Institute on Drug Abuse at NIH. In previous studies they and their colleagues have shown that alcohol significantly affects brain glucose metabolism, a measure of energy use, as well as regional brain activity, which is assessed through changes in blood oxygenation.

“The findings from this study highlight the relevance of energetics for ensuring normal brain function and reveal how it is disrupted by excessive alcohol consumption,” says Dr. Volkow.

In their new study, the researchers combined human brain imaging techniques for measuring glucose metabolism and neuronal activity to derive new measures, which they termed power and cost.

“We measured power by observing to what extent brain regions are active and use energy,” explained Dr. Shokri-Kojori. “We measured cost of brain regions by observing to what extent their energy use exceeds their underlying activity.”

In a group of healthy volunteers, the researchers showed that different brain regions that serve distinct functions have notably different power and different cost. They then investigated the effects of alcohol on these new measures by assessing a group of people that included light drinkers and heavy drinkers and found that both acute and chronic exposure to alcohol affected power and cost of brain regions.

“In heavy drinkers, we saw less regional power for example in the thalamus, the sensory gateway, and frontal cortex of the brain, which is important for decision making,” said Dr. Shokri-Kojori. “These decreases in power were interpreted to reflect toxic effects of long-term exposure to alcohol on the brain cells.”

The researchers also found a decrease in power during acute alcohol exposure in the visual regions, which was related to disruption of visual processing. At the same time, visual regions had the most significant decreases in cost of activity during alcohol intoxication, which is consistent with the reliance of these regions on alternative energy sources such as acetate, a byproduct of alcohol metabolism.

They conclude that despite widespread decreases in glucose metabolism in heavy drinkers compared to light drinkers, heavy drinking shifts the brain toward less efficient energetic states. Future studies are needed to investigate the mechanisms contributing to this relative inefficiency.

“Studying energetic signatures of brain regions in different neuropsychiatric diseases is an important future direction, as the measures of power and cost may provide new multimodal biomarkers for such disorders,” says Dr. Shokri-Kojori.

The National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health, is the primary U.S. agency for conducting and supporting research on the causes, consequences, prevention, and treatment of alcohol use disorder. NIAAA also disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at:

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit

Shokri-Kojori E, Tomasi D, Alipanahi B, Wiers CE, Wang GJ, Volkow ND (2019). Correspondence between cerebral glucose metabolism and BOLD reveals relative power and cost in human brain. Nat Commun. 10(1):690.

Saturday, December 22, 2018

Hepatitis C - Impact of treatment with direct-acting antivirals on anxiety and depression

Impact of treatment with direct-acting antivirals on anxiety and depression in chronic hepatitis C 
Marta Gallach , Mercedes Vergara, Joao Pedro da Costa, Mireia Miquel, Meritxell Casas, Jordi Sanchez-Delgado, Blai Dalmau, Núria Rudi, Isabel Parra, Teresa Monllor, Meritxell Sanchez-Lloansí, Angelina Dosal, Oliver Valero, Xavier Calvet
Published: December 19, 2018

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Background and aim
Treatment of hepatitis C with direct-acting antiviral agents (DAA) has few side effects. Although pivotal studies suggested that DAA were safe in patients with psychiatric diseases who could not be treated with previous antiviral therapies, their effects on anxiety and depression have not yet been analysed in clinical practice. The aim of our study was to analyse anxiety and depression in the setting of DAA treatment in a clinical practice series.

All patients starting DAA treatment between November 1, 2014 and October 31, 2015 were eligible. Patients completed the Hospital Anxiety and Depression scale at different times during treatment. The results were plotted on line graphs and evaluated using a linear regression model with repeated measures.

One hundred and forty-five patients were included (11% with major psychiatric disorders; 32% on psychiatric treatment). Sustained virologic response (SVR) was achieved in 97.3% of cases. Anxiety and depression measures did not differ between time points. No differences between patients on psychiatric treatment or with advanced fibrosis or cirrhosis were found at any time point analysed.

DAA treatment had no impact on anxiety or depression during or after chronic hepatitis C infection treatment, even in high-risk patients with major psychiatric disorders.
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Wednesday, September 12, 2018

Neuropsychiatric symptoms associated with hepatitis C virus (HCV)

September 12, 2018 
HCV Neuropsychiatric Symptoms Likely Linked to Virus' Effects on Brain Function
The neuropsychiatric symptoms associated with hepatitis C virus (HCV) infection are likely caused by the body's response to the virus' effects on brain function, according to a study recently published in the Journal of Viral Hepatitis. This neuro-inflammatory and systemic response is akin to that observed in patients with autoimmune diseases of the liver.

Dirks M, Haag K, Pflugrad H, et al. 
[published online August 18, 2018]. J Viral Hepat. doi: 10.1111/jvh.12979

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 aims to prove that HCV patients feature similar to those with autoimmune liver disease but contrary to HBV patients regarding neuropsychiatric symptoms.

132 non‐cirrhotic 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.

Saturday, March 17, 2018

Hep C Compounds Alcoholism’s Effect on Brain Volume

JAMA Psychiatry Published March 14, 2018
Full Text Article: The Role of Aging, Drug Dependence, and Hepatitis C Comorbidity in Alcoholism Cortical Compromise
This combined cross-sectional/longitudinal study evaluated magnetic resonance imaging data collected during 14 years in 199 control and 222 alcohol-dependent participants. Findings revealed frontally distributed cortical volume deficits in individuals with alcohol dependence, accelerated age-dependent decline, and compounded deficits with drug dependence or hepatitis C virus infection comorbidity.

These findings raise concern for heightened risk of accelerated cortical aging with alcohol dependence even when alcohol misuse develops later in life.

In The Media
Hep C Compounds Alcoholism’s Effect on Brain Volume
Last Updated: March 16, 2018.
Media Source - DoctorsLounge

FRIDAY, March 16, 2018 (HealthDay News) -- Alcohol dependence has deleterious effects on frontal cortical volumes that are compounded by hepatitis C virus (HCV) infection and drug dependence, according to a study published online March 14 in JAMA Psychiatry.

Edith V. Sullivan, Ph.D., from the Stanford University School of Medicine in California, and colleagues examined cortical volume deficits using 826 structural magnetic resonance images from 222 individuals with alcohol dependence and 199 age-matched control participants. Longitudinal data were available for 116 participants with alcoholism and 96 controls.

The researchers found that participants with alcohol dependence had volume deficits in frontal, temporal, parietal, cingulate, and insular cortices; the deficits were prominent in fontal subregions and were not dependent on sex. In the frontal cortex and precentral and superior gyri, accelerated aging occurred; this could not be attributed to the amount of alcohol consumed, which was greater in younger- versus older-onset participants with alcoholism. Smaller frontal volumes were seen for alcohol plus cocaine and alcohol plus opiate groups versus drug-dependence-free alcoholism groups. Greater deficits were seen in those with versus those without HCV infection in frontal, precentral, superior, and orbital volumes; in uninfected participants with alcoholism, total frontal, insular, parietal, temporal, and precentral volume deficits persisted compared with control participants with known HCV status.

"We speculate that age-alcohol interactions notable in frontal cortex put older adults at heightened risk for age-associated neurocompromise even if alcohol misuse is initiated later in life," the authors write.

Abstract/Full Text

Thursday, January 18, 2018

Editorial: direct-acting antivirals significantly improve quality of life in patients with HCV


Editorial: direct-acting antivirals significantly improve quality of life in patients with hepatitis C virus infection 
Authors S. Sanagapalli, M. Danta

First published: 17 January 2018
DOI: 10.1111/apt.14467

Linked Content
This article is linked to Younossi et al and Younossi papers. To view these articles visit and

The effect of direct-acting antiviral chronic Hepatitis C (HCV) therapies on patients’ quality of life has been a topic of minor attention compared with their impressive effects on virological endpoints. Yet, therapeutic benefits on quality of life are important to patients, and knowledge regarding such benefits may be an important tool in improving compliance in real-world scenarios.[1] For this reason, Younossi and colleagues are to be commended for their study, which describes clinically significant improvements in almost all measured physical and mental health-related quality of life outcomes following therapy with sofosbuvir and velpatasvir with or without voxilaprevir.[2] This replicates findings from other direct-acting antiviral regimens, but also confirms our own observations from clinical experience using these drugs.

Comparison with quality of life data from the interferon era may help us to tease out the mechanisms behind these findings. First, impairments in both mental and physical aspects of quality of life have long been described in chronic HCV, with or without cirrhosis, using the SF-36, one of the four instruments used in this study.[3] Second, very similar improvements in quality of life parameters were described 24 weeks after completion of interferon-based therapy, with the benefit confined only to those with sustained virological response.[4] More recent data comparing interferon-containing to interferon-free regimens clearly demonstrates that while both regimens result in equivalent improvements in quality of life (in responders) post therapy, the interferon-containing treatments are associated with significant worsening of quality of life during therapy. In contrast, quality of life seems to be improved early during interferon-free therapy and improves further following completion of successful treatment.[5, 6] Taken cumulatively we can infer that virological clearance plays a key role in improvement of quality of life, but cannot be the only factor, since improvement continues long after the virus has completely cleared from the serum.

What might such other factors be? The authors propose that improvement of liver function may play a role, though this still fails to explain the persistent improvement in benefit in non-cirrhotics post therapy. On the other hand, cerebral inflammation due to chronic HCV may explain some of the findings. Magnetic resonance spectroscopy and positron emission tomography scanning have demonstrated significant metabolic abnormalities in the brains of noncirrhotics with HCV, implying a low-grade inflammatory state, with the microglial cells being a focus of activation.[7, 8] In a small study, Byrnes and colleagues demonstrated that successful treatment with pegylated interferon and ribavirin led to normalisation of these central nervous system metabolic changes. Crucially, however, normalisation occurred gradually and improvement in metabolic abnormalities continued until 12 weeks post therapy, implying that the neuroinflammatory process may take time to settle after HCV therapy.[9] While the underlying mechanisms for improved quality of life are of interest, this study adds to the weight of evidence for the overall benefits of direct-acting antiviral therapies for HCV.

Editorial: direct-acting antivirals significantly improve quality of life in patients with hepatitis C virus infection—Author's reply
Z. M. Younossi

First published: 17 January 2018
DOI: 10.1111/apt.14481

Linked Content
This article is linked to Younossi et al and Sanagapalli and Danta papers. To view these articles visit and

We appreciate the Editorial comments by Drs. Sanagapalli and Danta about our recent study reporting patient-reported outcomes in patients with hepatitis C virus infection who were treated with sofosbuvir (SOF), velpatasvir (VEL) with or without voxilaprevir (VOX).[1, 2] We agree with their comments and would like to emphasise the importance of these findings in the context of the “comprehensive benefit” of HCV cure.

To fully understand the comprehensive benefit of HCV treatment, we believe it is important to assess the comprehensive impact of HCV infection including all the pertinent clinical consequences (hepatic and extrahepatic manifestations of HCV infection), the impact on patient-reported outcomes (health-related quality of life or HRQL) and the economic burden of HCV (resource utilisation and cost of illness).[3] Similarly, the benefit of anti-HCV treatment must be assessed in this comprehensive manner.[3] The most clinically relevant endpoint of HCV treatment is achieving sustained virologic response (SVR), a surrogate of improving survival by reducing the hepatic and extrahepatic complications.[3] Another important endpoint of HCV treatment should be its positive impact on patient-reported outcomes, a surrogate of HCV patients' experience.[4] Finally, we must assess the impact of anti-HCV treatment on important economic outcomes (resource utilisation, cost of illness, cost-effectiveness of treatment) must also be assessed.[5] Although the total impact of HCV infection has been well established,[3, 6] the comprehensive benefit of “HCV cure” has only recently been recognised.[1-6] In this context, our study provides additional evidence that the new regimen of SOF/VEL+/-VOX not only has superior clinical outcomes (high SVR) but also improves patient-reported outcomes during treatment and after SVR.[2]

In their Editorial, the authors have reflected about the mechanism of patient-reported outcome improvement post-SVR-12; we agree that this improvement is partly related to viral eradication. It is plausible that the additional patient-reported benefits of SVR may be related to the amelioration of the inflammatory environment of chronic hepatitis, which takes longer to resolve. This “inflammatory milieu” of HCV infection may exert its influence on the brain or the periphery of the infected patients. In fact, HCV has been associated with a number of extrahepatic manifestations such as neuropsychiatric diseases, chronic fatigue and others.[7, 8] In this context, neurocognition, fatigue and their changes after SVR may be differentially affected which in turn can influence changes in patient-reported outcome scores.[7, 8] In fact, the impact of SVR on fatigue has been recently substantiated and the data have shown that while most patients with HCV improve fatigue scores post-SVR, some do not improve.[9] Furthermore, these subjects who continue to report disabling fatigue post-SVR seem to have significant comorbidities such as depression, anxiety, type 2 diabetes.[9] Nevertheless, in the majority of HCV subjects with SVR, fatigue continues to improve and seems to maximise by post-treatment week 48.[10]

In summary, we believe that the initial patient-reported outcome improvements are due to viral eradication. The subsequent improvement may be due to a number of post-SVR changes including improvement of the inflammatory milieu and its impact of HCV on the brain and other extrahepatic targets. In contrast, patients with HCV who continue to show residual patient-reported outcome impairments post-SVR seem to have other comorbidities, which will require other treatment modalities to optimise their well-being. In this context, we believe that patient-reported outcomes must be a routine part of assessment of any chronic liver disease. These assessments will complement the clinical outcomes and provide evidence for the comprehensive impact of treatment on the patients and the society.

Monday, November 27, 2017

Listen To The Health Report - Non-alcoholic fatty liver disease & the brain

Today on Health Report, a radio program based in Australia, host Norman Swan interviews Sudha Seshadri, lead author of a study investigating an association between non-alcoholic fatty liver disease with total brain size. The program clearly points out what you need to know about fatty liver disease, very interesting.
Listen here...

Program Summary
November 27, 2017
Fatty liver disease and your overall brain volume
When fat's deposited in the liver, it triggers metabolic changes — and the brain's not immune from those changes, as a new study indicates.

In the research, non-alcoholic fatty liver disease was associated with a reduction in total brain volume. That could have implications for your risk of stroke or dementia.
Listen here...

Related On This Blog
"Fatty liver can be prevented by conducting appropriate lifestyle and diet," Weinstein added. "In turn, if one retains a healthy liver, his/her risk for other diseases, such as diabetes and heart diseases, is also reduced. In this study, we show that keeping a healthy liver may also be linked with a healthier brain."

Sunday, November 26, 2017

Hepatitis C - Impact of SVR on cognitive performance

BMC Gastroenterology
Hepatitis C virus eradication improves immediate and delayed episodic memory in patients treated with interferon and ribavirin
Mary Ellen Dias Barbosa, Ana Luiza Zaninotto, Daniel Ferraz de Campos Mazo, Mario Guimarães Pessoa, Cláudia Pinto Marques Souza de Oliveira, Flair José Carrilho and Alberto Queiroz Farias
Received: 26 June 2017 Accepted: 15 November 2017 Published: 25 November 2017

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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.

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.


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).

Eradication of HCV infection improved cognitive performance but did not affect the frequency of depressive symptoms at least in the short range.

Cognition Memory Attention Neuropsychology Hepatitis C Depression

Friday, November 24, 2017

Nonalcoholic Fatty Liver Disease - Liver fat may have a direct association with brain aging

Original Investigation
JAMA Neurol. Published online November 20, 2017. doi:10.1001/jamaneurol.2017.3229
View Abstract - Association of Nonalcoholic Fatty Liver Disease With Lower Brain Volume in Healthy Middle-Aged Adults in the Framingham Study

Reuters Health Reports
Fatty liver linked to a shrinking brain
By Will Boggs MD
Last Updated: 2017-11-23

"Liver fat may have a direct association with brain aging," lead author Galit Weinstein from School of Public Health at the University of Haifa in Israel said in an email.

Reuters Health - Fatty liver disease that is not related to excess drinking is associated with greater brain shrinkage than normally happens with age, researchers say.

The reduced brain volume linked to non-alcoholic fatty liver disease (NAFLD) is equivalent to an extra 4.2 years of aging for people in their 60s and early 70s, or an extra 7.3 years of aging for people under age 60, researchers report in JAMA Neurology November 20.
Continue to article -

Wednesday, August 2, 2017

Persistent Neuropsychiatric Impairment in HCV Patients Despite Clearance of the Virus?!

Persistent Neuropsychiatric Impairment in HCV Patients Despite Clearance of the Virus?!
Original article was published 9 February 2017 in Journal of Viral Hepatitis, the research article is open access over at Medscape, patient-friendly commentary published at Infectious Disease Advisor, discussion only provided below.

Many patients with HCV infection report disabling chronic fatigue--even after viral clearance. Might HCV be implicated in a virus infection-associated chronic fatigue syndrome?

Persistent Neuropsychiatric Impairment in HCV Patients Despite Clearance of the Virus?!
M. Dirks; H. Pflugrad; K. Haag; H. L. Tillmann; H. Wedemeyer; D. Arvanitis; H. Hecker; A. Tountopoulou; A. Goldbecker; H. Worthmann; K. Weissenborn
J Viral Hepat. 2017;24(7):541-550. 

Discussion Only
Full text article published @ Medscape 
To our knowledge the present study is the largest study concerning neuropsychiatric symptoms in PCR-positive and PCR-negative HCV-afflicted patients with only mild liver disease that combined the assessment of health-related quality of life with the assessment of chronic fatigue, mood disturbances and cognition.

The results of our study can be summarized as follows: (i) PCR+ and PCR− HCV-afflicted patients with only mild liver disease but neuropsychiatric symptoms do not differ with regard to the features and extent of these symptoms, (ii) chronic fatigue is the most frequent neuropsychiatric symptom and has the most significant impact on the patients' health-related quality of life, (iii) significant cognitive dysfunction is present in about one-third of the patients with neuropsychiatric symptoms and (iv) is not feigned by the presence of depression.

So far, the largest population sample related to cognitive function in HCV-afflicted patients was published by Fontana et al.[31] They analysed cognitive function in PCR−positive patients with advanced liver fibrosis (Ishak fibrosis score 3–6), who took part in the HALT-C trial—a prospective, randomized, controlled study of long-term pegylated interferon for chronic hepatitis C patients with advanced fibrosis who were nonresponders to prior interferon therapy. Two hundred and one patients were included of whom 38% had developed liver cirrhosis. Fifty-two per cent of their patients met DSM-IV criteria for a lifetime diagnosis of an alcohol use disorder, and 39% of subjects met DSM-IV criteria for a lifetime diagnosis of a drug use disorder. In analogy to our findings Fontana and co-workers reported that about 33% of their patients showed evidence of mild cognitive dysfunction. Domains predominantly affected were verbal recall and working memory. Of note and in line with our data, they did not find evidence for a significant effect of neither liver function nor grade of liver fibrosis or of former alcohol or drug abuse upon their neuropsychological results. Interestingly, the domains affected were congruent with those described in other studies upon cognitive dysfunction in HCV-afflicted patients but incongruent with the characteristic neuropsychological pattern of hepatic encephalopathy associated with liver cirrhosis.[32] Thus, there was clear evidence that cognitive dysfunction in the patients in Fontana's study was not due to hepatic encephalopathy, but instead probably due to HCV infection.

Our study included patients with mild liver disease, exclusively, thereby even further eliminating the confounding of advanced liver disease on brain function. Nevertheless, we found deficits in the recognition of words or figures in 45% and attention deficits in 30% of the patients. About 77% showed chronic fatigue, and 50%-60% mild to moderate anxiety and depression. Health-related quality of life correlated negatively with fatigue, as did the patients' attention ability. Of note, the patients' cognitive function was independent from their mood status. The significant correlation between attention test sum score and the fatigue and depression scores would indicate otherwise on the first view, multiple regression analysis, however, identified the extent of fatigue as the main and single independent predictor of attention deficit. The positive correlation between the attention test sum score and the LLW sum score relates to the fact that LLW tests working memory and learning ability and thus attentional function. Memory function in our patients did not show a correlation with either fatigue or depression scores and was even independent from the attention test performance, thus also indicating that cognitive dysfunction in the patients is independent from mood alterations.

Of note, we did not find a fundamental difference in the neuropsychiatric symptom profile considering the PCR status or treatment history.

Chronic fatigue has been identified as the most frequent complication of HCV infection years ago.[2] For a long time, however, the patients' complaints about disabling fatigue have not directly been linked to the virus. Symptoms were classified as reaction to the knowledge of being infected or as a consequence of advanced liver disease. Patients showing sustained response to antiviral therapy were and are still in general considered to be cured. Our data, however, show that the neuropsychiatric symptoms, if present, feature identical in PCR-positive and PCR-negative HCV-afflicted patients. Former studies showed similar alterations of brain metabolite levels, cerebral glucose utilization and dopaminergic neurotransmission in PCR-positive and PCR-negative patients, as well as a relationship between these parameters and the patients' cerebral function.[33–35] This indicates that clearance of the virus in the periphery is not equivalent to cure from neuropsychiatric sequelae of HCV infection. It has still to be clarified, for example, if quasispecies of the virus are able to persist within the brain after successful clearance in the periphery, or if the virus induces a neuroinflammatory response that carries on independent of the presence or absence of the virus. Recently, HCV RNA was detected in peripheral blood mononuclear cells (PBMCs) in patients with sustained viral response (SVR) 52–66 months after pegylated IFN and ribavirin therapy.[36] In addition, it has been shown that cure of HCV infection does not lead to complete restoration of the altered cytokine and chemokine milieu. According to a recent paper by Hengst and colleagues, several soluble inflammatory mediators that are suppressed in HCV patients before successful antiviral therapy remain suppressed thereafter.[37]

Patients in both PCR-negative groups were more impaired than those in the PCR-positive groups in this study. This, however, can reflect a selection bias, because PCR-negative patients without any further symptoms are less likely to present in a hepatitis outpatient clinic or to seek support in a patient support group and to take part in a study upon neuropsychiatric symptoms than PCR-negative patients with symptoms. The same aspect holds true of course also for PCR-positive patients and might lead to an overestimation of the frequency of neuropsychiatric symptoms in HCV patients.

Recent therapeutic studies were able to show that virus eradication results in clinically meaningful improvements in several HRQoL domains.[11–14] These studies also showed that improvement was likely to be achieved in physical but not in mental health scores. Based on these findings Bonkovsky et al.[14] suggested that HCV infection per se has an effect on emotional states. Accompanying cognitive deficits in HCV-infected patients, however, was suggested to result from underlying conditions such as anxiety and depression or use of psychotropic medications rather than from HCV infection itself.[14] This explanation is disproved by our findings as we did not observe a significant correlation between cognitive function and anxiety or depression and had excluded patients on psychotropic drugs. Comparing the results of patients who had been interferon/ribavirin exposed to those who had never been treated, we were able to show that the neuropsychiatric symptoms in formerly treated HCV-afflicted patients cannot be ascribed to interferon/ribavirin therapy.

Today we have growing evidence for HCV invasion into and replication within the brain.[38–42] Interestingly, evidence for virus replication was found in about 50% of the samples studied. That is nearly identical with the percentage of HCV patients with neuropsychiatric symptoms in population studies.[2,18,43] In a recent autopsy study, microglia and astrocytes were identified as host cells for the virus.[42] The alterations of magnetic resonance spectra of the brain of HCV patients suggested a neuroinflammatory response to the virus.[8–10,35] This assumption was supported by the finding of an activation of brain microglia cells in autopsy brain tissue from HCV-positive patients.[44] Therefore, evidence for microglia activation in patients with HCV−associated encephalopathy was searched using 11C- PK11195 positron emission tomography. 11C-PK11195 binds to the translocator protein (TSPO) which is located amongst others on the outer mitochondrial membrane of microglia, and which is expressed especially in activated microglia.[45,46] Indeed, microglia activation was observed compared to controls both in PCR-positive and in PCR-negative patients.[47,48] Differences in 11C-PK11195 binding, however, were found between patients with and without cognitive dysfunction. Preserved cognitive function was associated with significantly increased microglia activation indicating a neuroprotective role of microglia activation in the HCV−exposed patients.[48]

In our study, PCR+ and PCR− patients scored similarly in all assessed domains, while both patient groups scored significantly worse than the healthy controls. The data clearly show that neither the HRQOL, nor the extent of fatigue, nor cognitive or mental function in HCV-exposed patients depend on their PCR status. This finding is in line with earlier studies including large and representative cohorts of women infected through anti-D prophylaxis. In both cohorts, from Ireland[49] and from Germany,[43] fatigue was a frequently observed phenomenon, but unrelated to liver disease and virological status.

The observation that the neuropsychiatric syndrome in HCV-exposed patients is independent of the virus replication state as measured in the patients' blood is in favour of the hypothesis that the symptoms are unrelated to HCV infection. However, the development of an HCV infection triggered autoimmune process, which continues after clearance of the virus, or—alternatively—the possibility of a virus variant persisting in the brain should seriously be discussed. Considering the data upon virus infection-associated chronic fatigue syndrome HCV just appears to be more capable to induce this disorder than other viruses, while the clinical features are similar irrespective of the underlying cause.[50] It will be of outmost interest to observe whether sustained response to the new direct acting antivirals will be more effective with regard to neuropsychiatric manifestations of HCV than the interferon/ribavirin combination therapy.

Continue to full text article published @ Medscape
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Friday, July 14, 2017

Extrahepatic manifestations of HCV & Treatment

If you are interested in reading full text articles about the treatment and management of HCV I highly suggest you follow Henry E. Chang on Twitter.

Latest Tweets By @HenryEChang on the extrahepatic manifestations of HCV.

July 14, 2017
Extrahepatic manifestations of HCV: The role of direct acting antivirals
María Laura Polo and *Natalia Laufer
Expert Review of Anti-infective Therapy DOI: 10.1080/14787210.2017.1354697

Hepatitis C virus (HCV) represents a major health concern, as nearly 3 million people become newly infected by this pathogen annually. The majority of infected individuals fail to clear the virus, and chronicity is established. Chronic HCV patients are at high risk for liver disease, ranging from mild fibrosis to cirrhosis and severe hepatocellular carcinoma. Over the last few years, the development of multiple direct acting antivirals (DAA) have revolutionized the HCV infection treatment, demonstrating cure rates higher than 90%, and showing less side effects than previous interferon-based regimens. Areas covered: Besides liver, HCV infection affects a variety of organs, therefore inducing diverse extrahepatic manifestations.

This review covers clinical, experimental, and epidemiological publications regarding systemic manifestations of HCV, as well as recent studies focused on the effect of DAA in such conditions.  Expert commentary: Though further research is needed; available data suggest that HCV eradication is often associated with the improvement of extrahepatic symptoms. Therefore, the emergence of DAA would offer the opportunity to treat both HCV infection and its systemic manifestations, requiring shorter treatment duration and driving minor adverse effects.
Link - Download Full Text Article.......

Clinics in Liver Disease, Volume 21, Issue 3

Chronic Hepatitis C Virus Infection and Depression
Luigi Elio Adinolfi, Riccardo Nevola, Luca Rinaldi, Ciro Romano, Mauro Giordano

HCV Depression Quality of life


Depression is an extrahepatic manifestation of chronic hepatitis C virus (HCV) infection reported in one-third of patients.

The prevalence of depression in patients with HCV has been estimated to be 1.5 to 4.0 times higher than that observed in the general population.

Direct HCV neuro-invasion, induction of local and systemic inflammation, neurotransmission, and metabolic derangements are the hypothesized pathogenic mechanisms of depression.

Depression considerably impacts health-related quality of life of HCV-positive patients.

Clearance of HCV by antiviral treatments is associated with an improvement of both depression and quality of life.
Link - Download Full Text PDF

Metabolic Manifestations of Hepatitis C Virus
Lawrence Serfaty

Hepatitis C Steatosis Hypobetalipoproteinemia Microsomal triglyceride transfer protein Insulin resistance. Tumor necrosis factor


Out of excessive alcohol consumption, steatosis should be classified into 2 types according to hepatitis C virus (HCV) genotypes: metabolic steatosis, which is associated with features of metabolic syndrome and insulin resistance in patients infected with nongenotype 3, and viral steatosis, which is correlated with viral load and hyperlipemia in patients infected with genotype 3.

HCV interacts with host lipid metabolism by several mechanisms, such as promotion of lipogenesis, reduction of fatty acid oxidation, and decreases of lipids export, leading to hepatic steatosis and hypolipidemia.

A strong link between HCV infection and diabetes mellitus has been found in subjectbased studies and, to a lesser degree, in population-based studies.

HCV-mediated insulin resistance may be promoted through multiple pathogenic mechanisms, such as direct inhibition of insulin signaling pathway by HCV core protein in the liver, overproduction of tumor necrosis factor-alpha, oxidative stress, modulation of incretins, or pancreatic ß-cells dysfunction.
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Neurologic manifestations of hepatitis C virus infection
Sentia Iriana, MD, Michael P. Curry, MD, Nezam H. Afdhal, MD, DSc

Hepatitis C Fatigue Neurocognition MR spectroscopy Interferon Ledipasvir/sofosbuvir Cerebrovascular disease

The extrahepatic manifestations of hepatitis C virus (HCV) in the brain include neurocognitive dysfunction, which is manifested by subtle changes in memory, attention, and processing speed.

Neurocognitive defects are independent of the histologic stage of disease and may be induced by a direct effect of HCV on microglial cells or mediated by systemic cytokines crossing the blood-brain barrier.

Magnetic resonance spectroscopy demonstrates abnormal metabolism in basal ganglia and prefrontal and frontal cortex, which has been associated with fatigue and abnormal neurocognitive testing. Interferon and direct-acting antiviral therapy can improve cerebral metabolism and neurocognition if a sustained virologic response is obtained.

Cerebrovascular events and mortality are increased in patients with HCV and may be through an increased risk of carotid artery disease and plaque formation.
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Rheumatologic manifestations of hepatitis C virus
Patrice Cacoub, Cloé Comarmond, Anne Claire Desbois, David Saadoun

Hepatitis C (HCV) Rheumatic disorders Arthritis Vasculitis Arthralgia Sicca syndrome

Main rheumatologic manifestations reported with hepatitis C virus (HCV) chronic infection include arthralgia, myalgia, cryoglobulinemia vasculitis, and sicca syndrome.

Immunologic factors predisposing to developsuch manifestations include stimulation of B cells, expansion of B-cell–producing immunoglobulin M with rheumatoid factor activity and of clonal marginal zone, like B cells, and a decrease of regulatory T cells.

The treatment of HCV infection with interferon alpha has been contraindicated for a long time in many rheumatologic autoimmune/inflammatory disorders.

New oral interferon-free combinations now offer an opportunity for patients with HCV extrahepatic manifestations, including rheumatologic autoimmune/inflammatory disorders, to be cured with a high efficacy rate and a low risk of side effects.
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Other EHM of HCV infection (pulmonary, idiopathic thrombocytopenic purpura, nondiabetes endocrine disorders
Daniel Segna, Jean-François DuFour

Hepatitis C Extrahepatic manifestations Pulmonary Endocrine Idiopathic thrombocytopenic purpura


Hepatitis C Virus (HCV) infection may increase the risk for obstructive, interstitial, and vascular lung disease, lung cancer, and mortality in HCV-infected lung transplant recipients.

HCV infection may increase the risk of idiopathic thrombocytopenic purpura, nonresponse to corticosteroids during the treatment, and higher rates of splenectomy.

HCV infection may increase the risk of autoimmune thyroiditis, infertility, growth hormone and adrenal deficiency, osteoporosis, and low-trauma fractures.

Targeted prospective cohorts may confirm these results mostly obtained from small casecontrol studies with different study populations and low level of evidence.
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Hepatitis C Virus–Associated Non-Hodgkin Lymphomas
Gabriele Pozzato, Cesare Mazzaro, Valter Gattei

Hepatitis C virus Marginal zone lymphoma Non-Hodgkin lymphoma Direct antiviral agents

Eradication of hepatitis C virus (HCV) in indolent non-Hodgkin lymphomas (NHLs), especially in marginal zone lymphomas(MZLs), determines the regression of the hematological disorder in a significant fraction of cases.

Because direct antiviral agents (DAAs) show an excellent profile in terms of efficacy, safety, and rapid onset of action, these drugs can be used in any clinical situation and the presence of any comorbidities.

To avoid the progression of the NHL, despite HCV eradication, antiviral therapy should be provided as soon as the viral infection is discovered; before that, the chronic antigenic stimulation determines the irreversible proliferation of neoplastic B cells.
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Dermatologic manifestations of chronic hepatitis C
Mehmet Sayiner, Pegah Golabi, Freba Farhat, Zobair M. Younossi

Hepatitis C Extrahepatic manifestation Dermatologic manifestation Cryoglobulinemia Porphyria Lichen planus

HCV infection is associated with several dermatologic diseases, such as symptomatic mixed cryoglobulinemia, lichen planus, porphyria cutanea tarda, and necrolytic acral erythema.

Most of the dermatologic manifestations may be caused by immune complexes. In the interferon and ribavirin era, treatment was associated with dermatologic side effects.

The new generation of interferon-free and ribavirin-free anti-HCV regimens is devoid of dermatologic side effects.
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Hepatitis C Infection - A systematic disease
Zobair M. Younossi
Hepatitis C virus Hepatic complications Extrahepatic complications

It is critical to recognize that hepatitis C virus (HCV) infection is a multifaceted systemic disease with both hepatic and extrahepatic complications.

The comprehensive burden of HCV should not only include its clinical burden, but also its burden on the economic and patient-reported outcomes.

It is only through this comprehensive approach to HCV infection that we can fully appreciate its true burden, and understand the full benefit of curing HCV for the patient and the society.
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Thank you Henry E. Chang

Wednesday, June 7, 2017

Improvements in brain and behavior following eradication of hepatitis C

Update June 26, 2017
Full Text
The effect of SVR on the risk of extrahepatic manifestations of HCV infection
 Compared with HCV-infected individuals who did not receive treatment, SVR attainment was associated with a reduced risk of mixed cryoglobulinaemia, glomerulonephritis, porphyria cutanea tarda, non-Hodgkin's lymphoma, diabetes mellitus and stroke, but not lichen planus or coronary heart disease. Risk reductions were also observed when patients with SVR were compared with treated patients without SVR for mixed cryoglobulinaemia, glomerulonephritis, porphyria cutanea tarda and diabetes.
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Journal of NeuroVirology, Inc. 2017
First Online: 30 May 2017
Improvements in brain and behavior following eradication of hepatitis C
Taylor Kuhn1,2 & Philip Sayegh3 & Jacob D. Jones1,2 & Jason Smith2 & Manoj K. Sarma1 & A. Ragin1 & Elyse J. Singer4 & M. Albert Thomas1 & April D. Thames1 & Steven A. Castellon1,2 & Charles H. Hinkin1,2

Despite recent advances in treatment, hepatitis C remains a significant public health problem. The hepatitis C virus(HCV) is known to infiltrate the brain, yet findings from studies on associated neurocognitive and neuropathological changes are mixed. Furthermore, it remains unclear if HCV eradication improves HCV-associated neurological compromise. This study examined the longitudinal relationship between neurocognitive and neurophysiologic markers among healthy HCV− controls and HCV+ adults following successful HCV eradication. We hypothesized that neurocognitive outcomes following treatment would be related to both improved cognition and white matter integrity. Participants included 57 HCV+ participants who successfully cleared the virus at the end of treatment (sustained virologic responders [SVRs]) and 22 HCV− controls. Participants underwent neuropsychological testing and, for a nested subset of participants, neuroimaging (diffusion tensor imaging) at baseline and 12 weeks following completion of HCV therapy. Contrary to expectation, group-level longitudinal analyses did not reveal significant improvement in neurocognitive performance in the SVRs compared to the control group. However, a subgroup of SVRs demonstrated a significant improvement in cognition relative to controls, which was related to improved white matter integrity. Indeed, neuroimaging data revealed beneficial effects associated with clearing the virus, particularly in the posterior corona radiata and the superior longitudinal fasciculus. Findings suggest that a subgroup of HCV+ patients experienced improvements in cognitive functioning following eradication of HCV, which appears related to positive changes in white matter integrity. Future research should examine whether any additional improvements in neurocognition and white matter integrity among SVRs occur with longer follow-up periods.

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Links Provided By Henry E. Chang via Twitter

Tuesday, February 21, 2017

Neuropsychiatric Symptoms in Patients With HCV Cured of Infection

Neuropsychiatric Symptoms in Patients With HCV Cured of Infection

Disabling chronic fatigue is reported in approximately 60% of patients with confirmed hepatitis C virus (HCV) infection,1,2 as well as decreased quality of life (QoL)3,4 and cognitive dysfunction (eg, deficits in attention and verbal learning).5,6 While these neuropsychiatric symptoms may be expected in patients with ongoing HCV infection, it is questionable whether these effects are also present in HCV-exposed patients who currently are cured of the infection (polymerase chain reaction-negative [PCR-]).

A study7 recently published in the Journal of Viral Hepatitis found no evidence linking the presence of HCV infection with these neuropsychiatric symptoms. Instead, researchers suggest that the fatigue and impairment in health-related quality of life (HRQoL) and cognitive and mental function commonly found in HCV-exposed patients may be explained by either an HCV infection-triggered autoimmune response persisting beyond virus clearance or the development of a virus variant in the brain.7

Tuesday, January 8, 2013

Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C

Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C

  1. Michael R Kraus1,2,†,
  2. Arne Schäfer1,‡,*,
  3. Gerlinde Teuber3,
  4. Heiner Porst4,
  5. Kathrin Paul3,
  6. Sven Wollschläger4,
  7. Christian Keicher1,
  8. Michael Scheurlen1
DOI: 10.1002/hep.26229

hepatitis c;
interferon alfa;
neurocognitive performance;
long-term follow-up;
SVR – sustained virologic response

Earlier studies have suggested neurocognitive impairment in patients with chronic hepatitis C virus (HCV) infection even before liver cirrhosis has developed. Since these deficits might be reversible after successful antiviral therapy, we analyzed the long-term course of neurocognitive parameters in HCV patients with and without successful virus elimination by an interferon-based antiviral treatment.
In a multicenter study including 168 HCV patients receiving antiviral therapy (peginterferon alfa-2b and ribavirin) we performed a long-term follow-up of neurocognitive performance before and after treatment.
Neurocognitive function was psychometrically assessed using the computer-aided TAP (Test Battery of Attentional Performance).
When tested at least 12 months after termination of antiviral treatment, patients with sustained virologic response (SVR) had improved significantly as compared to their pretreatment performance in three of five TAP subtasks (vigilance, P<0.001; shared attention – optical task, P<0.001; working memory, P<0.001).
Patients who failed to eradicate the virus, however, showed no significant long-term changes in neurocognitive performance in all five subtasks assessed (0.194 < P < 0.804).
In the post-treatment evaluation, neurocognitive function was significantly better in responders to the antiviral therapy as compared to non-responders.
Successful eradication of HCV leads to a significant improvement of relevant aspects of attentional and neurocognitive performance, indicating that the neurocognitive impairment caused by chronic HCV infection is potentially reversible. This therefore suggests an added therapeutic benefit of antiviral treatment in HCV infection. Improvement of neurocognitive function may be an additional treatment indication in patients with HCV.

Sunday, September 30, 2012

Poster - "Fatigue, Cognitive Function, and Sleep Quality in Patients with Chronic Hepatitis C

Bailey Presents at 2012 State of the Science Congress on Nursing Research

September 30, 2012
Friday, September 28, 2012

Chip Bailey presented a poster entitled "Fatigue, Cognitive Function, and Sleep Quality in Patients with Chronic Hepatitis C (CHC)" at the Council for the Advancement of Nursing Science 2012 State of the Science Congress on Nursing Research in Washington, D.C., September 13-15. He co-authored the abstract with Shelly Epps, Trina Walker, Justin Levens, Karin Weissenborn, Richard Keefe, and Hans L. Tillmann.

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Fatigue, Cognitive Function, and Sleep Quality in Patients with Chronic Hepatitis C (CHC)

Donald E. Bailey, Jr. 1
Shelly Epps 2
Trina Walker 3
Justin Levens 2
Karin Weissenborn 4
Richard Keefe 3
Hans L. Tillmann 3

1 Duke University School of Nursing, Durham, NC;
2 Duke Office of Clinical Research, Durham, NC;
3 Duke University School of Medicine, Durham, NC;
4 Department of Neurology, Medizinische Hochschule, Hannover, Germany

Fatigue is a frequent complaint in CHC patients. CHC patients also often experience problems with cognitive function: difficulties with attention, concentration, memory.

Study Aims
Describe cognitive processing difficulties in adults with CHC. Explore relationship of cognitive function in these patients with fatigue, sleep quality, and disease stage.

Sample (n=29)
Adult patients with CHC:
*18 with fatigue
*11with no fatigue
*Convenience sample
* Recruited at Duke University Medical Center, Gastroenterology Clinic
*Baseline data for sample demographic and clinical characteristics are shown in tables

Fatigue: Revised Piper Fatigue Scale (PFS).
*22-item scale (each item scaled 0-10); use summary score.
*Summary score scaled 0-10 (higher score indicates more fatigue).
*Administered only to patients reporting fatigue (n=18)

Sleep Quality:
*Sleep Timing & Sleep Quality Screening Questionnaire: 1 item
Disease Stage and Disease Grade :
*Clinical data abstracted from medical record

Measures of Cognitive Function
*Brief Assessment of Cognition (BAC) includes 6 tasks:
List Learning -- Verbal Memory
Digit Sequencing Task -- Working Memory
Token Motor Task – Motor Spped Verbal Fluency
Semantic/Letter Fluency Tower of London
Reasoning & Problem Solving / Executive Function Symbol Coding
Attention and Processing Speed

B. Continuous Phase Trials – Identical Pairs (CPT – IP)
Measures Sustained Attention and Vigilance

* Standardized z-scores calculated for BAC cognitive function test (based on comparisons with normative healthy control sample). Separate z-scores for each of the 6 BAC measures; BAC composite z-score

*Means, 95% CI for BAC task & composite scores calculated for:
CHC patients with fatigue (n=18) vs. without fatigue (n=11) Patients at each disease grade (0-3; measures inflammation) Patients at each disease stage (I-IV; measures fibrosis)

*Mann-Whitney rank sum test used to compare z-scores on BAC and CPT-IP score for CHC patients with vs. without fatigue.

*Pearson correlation used to evaluate relationships between BAC z-scores and PFS fatigue scores, sleep quality ratings.


HCV patients in this study showed significant impairment independent of fatigue for 3 of the 6 BAC tasks.

In the graphs below, z-score for healthy controls on each task = 0.0 (shown in graphs below as a red dotted line)

Mean z-scores for all HCV patients were significantly lower than healthy control scores (no overlap of 95% CI with control line) for the 3 tasks identified by red star

These findings suggest HCV-related impairment of cognitive function in the 3 domains of verbal memory, working memory, reasoning/problem solving.


*No significant differences between HCV patients with fatigue vs. without fatigue on BAC composite scores (cognitive function) or CPT–IP (attention/vigilance).

*BAC composite scores of HCV patients lower than those of healthy controls.

*Disease stage (fibrosis) had no effect on BAC composite scores.

*Higher disease grade (liver inflammation) may be weakly associated with poorer cognitive function in patients with HCV.

Pearson correlation analysis of relationships between scores on 6 individual BAC tasks and: Level of Fatigue, Quality of Sleep:
Piper Fatigue Scale summary score (level of fatigue): No correlation with scores on any BAC cognitive task.

Sleep Quality Item: Poor sleep quality (high scores) was significantly correlated with impairment on three BAC tasks: Digit Sequencing, Symbol Coding, and Tower of London.

Examples below shows Pearson correlation analyses for symbol coding:

Findings of this study support previous reports of cognitive processing difficulty in patients with CHC. Differences in cognitive processing between CHC patients with vs. without fatigue at baseline were not significant in this sample, but merit further study in a larger sample.

This study was supported by a research grant from the National Institute of Nursing Research (NIH/NINR: 1 R15 NR 008794-01A1, Bailey, PI) and by a small grant from the Duke University School of Nursing Office of Research Affairs (Bailey, PI).

Monday, May 21, 2012

Hepatitis C Virus and the Brain

From Journal of Viral Hepatitis

Hepatitis C Virus and the Brain

N. F. Fletcher and J. A. McKeating

Authors and Disclosures
N. F. Fletcher and J. A. McKeating
Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, B15 2TT, UK
Nicola F. Fletcher, Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, B15 2TT, UK. E-mail:

Posted: 05/21/2012; J Viral Hepat. 2012;19(5):301-306. © 2012 Blackwell Publishing

Abstract and Introduction

Hepatitis C virus (HCV) is an enveloped, positive-strand RNA virus of the family Flaviviridae that primarily infects hepatocytes, causing acute and chronic liver disease. HCV is also associated with a variety of extrahepatic symptoms including central nervous system (CNS) abnormalities, cognitive dysfunction, fatigue and depression. These symptoms do not correlate with the severity of liver disease and are independent of hepatic encephalopathy. HCV RNA has been associated with CNS tissue, and reports of viral sequence diversity between brain and liver tissue suggest independent viral evolution in the CNS and liver. This review will explore the data supporting HCV infection of the CNS and how this fits into our current understanding of HCV pathogenesis.

Hepatitis C virus (HCV) is a positive stranded virus, which is classified in its own genus, Hepacivirus, within the Flaviviridae family. Approximately 170 million individuals are infected with HCV worldwide, and infection leads to a progressive liver disease including hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC).[1] HCV is a leading cause for liver transplantation, and the number of patients requiring transplantation for chronic hepatitis C is increasing. HCV infects the newly transplanted liver in all cases, resulting in a more rapidly progressive disease.[2] HCV re-infection of the allograft is frequently associated with a shift in the viral quasispecies, leading several authors to suggest that extra-hepatic sites of HCV replication exist. Monitoring the HCV quasispecies in the plasma at the time of transplantation and identifying infecting strain(s) have led several authors to conclude that up to 4% of circulating virions are of extra-hepatic origin.[3-5]

Hepatocytes represent the major target for infection; however, HCV RNA has been detected in peripheral blood mononuclear cells, cerebrospinal fluid and the brain of chronically infected patients with neuropathological abnormalities.[6–8] Fatigue is the most commonly reported neurological symptom, with between 65% and 80% of chronically infected patients complaining of fatigue that is independent of liver dysfunction.[9,10] However, more recent studies using in vivo proton magnetic resonance spectroscopy demonstrate altered brain metabolism and cognitive dysfunction in HCV-infected patients without cirrhosis.[11,12] HCV-infected subjects perform significantly worse on various neuropsychological tasks than patients with liver disease of other causes.[11,13] Recent research efforts have investigated whether these abnormalities result from direct infection of the CNS or peripheral disease.

HCV RNA Association With Brain Tissue
The majority of reports supporting HCV in the CNS have used PCR-based approaches to detect viral genomes in brain tissue and cerebral spinal fluid (CSF).[14–21] However, the detection of viral RNA alone does not reflect active sites of replication and may simply represent viral carriage from the periphery. More recently, several authors have reported negative-strand HCV RNA, a replicative intermediate, in the CNS suggesting viral replication.[15,16,22] However, many studies include small numbers of patients, making it difficult to ascertain the frequency of HCV in brain tissue. A recent study quantified the levels of HCV RNA in multiple samples from the brain and liver of HCV-infected patients,[19] demonstrating between 1000 and 10 000-fold lower amounts of HCV RNA in brain tissue compared with liver, consistent with mild neuropathologies observed in HCV-infected patients. In summary, care is needed when interpreting the physiological relevance of HCV RNA genomes in brain tissue, where viral RNA could be a result of blood contamination and not direct evidence of viral replication.

There is some evidence of genetic diversity between viral strains isolated from brain tissue, PBMC, serum and liver biopsies from the same patient; Radkowski et al. observed that HCV NS3 sequences isolated from a variety of brain regions were similar to those isolated from lymph nodes but differed from serum-derived virus, suggesting independent viral evolution in the brain.[15] This study failed to detect negative-strand HCV RNA in the serum, leading the authors to conclude that viral sequences detected in the brain were not a result of blood contamination.[15] Similarly, variability in the HCV internal ribosomal entry site (IRES) was reported in brain tissue from two HCV-infected patients, compared with liver sequences.[20] More recently, a study of 13 HCV-infected patients, of which four had detectable HCV signals in brain tissue, used single nucleotide polymorphism analysis to identify a brain-specific mutation that constituted approximately 10% of HCV sequences in the cerebellum and medulla, whereas this mutation was undetectable in the liver and plasma of the same patients.[19] Taken together, these studies strengthen the evidence that HCV may replicate in the brain, raising questions on which cell types within the CNS support HCV infection.

HCV Infection is Associated With Immune Responses in the Brain
Recent studies have suggested that HCV infection is associated with inflammatory responses in the brain. The brain metabolites choline, creatine and inositol were significantly increased in HCV-infected patients compared with healthy controls,[23,24] yet those patients with low levels of fatigue had higher levels of choline than those with severe fatigue. Nevertheless, these results suggest activation of microglia and possibly astrocytes in HCV-infected patients with fatigue.[24] A recent study of treatment-naïve subjects with mild chronic HCV infection revealed microglial and brain macrophage activation using a combination of proton magnetic resonance spectroscopy and positron emission tomography (PET) with a ligand for neuroinflammation, which was not observed in HCV seronegative subjects.[25] This immune activation was associated with HCV viraemia and altered cerebral metabolism, demonstrating altered basal ganglia myoinositol/creatinine and choline/creatine ratios in HCV-infected patients,[25] putative biomarkers of glial cell inflammation and activation.[23,26] This observation was reported in a group of 22 HCV-infected patients, of which 15 were treated with pegylated interferon and ribavirin, and seven were untreated HCV-positive controls.[27] In the treated group, the patients who responded to therapy had lower cerebral metabolite measurements (reductions in choline and myoinositol) than non-responders or untreated controls, and the reduction in metabolites associated with improved neurocognitive performance.[27] A further study of postmortem tissue demonstrated that brain tissue from HCV-infected subjects expressed significantly increased levels of proinflammatory cytokines IL-1, TNF-α, IL-12, and IL-18,[28] which could explain glial cell activation reported in several studies. Astrogliosis and demyelination were reported in rare cases of HCV infection with severe neuropathology;[17,28,29] however, this is not observed in the majority of patients. These results demonstrate that higher viral load and lower neurocognitive performance correlate with increased immune activation in the CNS of HCV-infected individuals; further large-scale studies are required to ascertain the extent to which this phenomenon occurs in chronic hepatitis C.

Identifying HCV Permissive Brain Cells
Visualizing HCV antigen-expressing hepatocytes in the liver has been technically challenging, most likely reflecting the low viral burden at a cellular level.[30,31] Given the low levels of HCV RNA reported in the brain, it will be technically challenging to identify viral antigen-expressing cells. Previous studies have reported the presence of viral RNA in microglia and astrocytes isolated using laser capture microdissection.[22,32] However, recent immunohistochemical studies show that astrocytes and microglia do not express the viral receptors required for HCV entry.[33,34] A recent screen of neural cells for their ability to support HCV infection demonstrated that two independent neuroepithelioma cell lines support HCV entry and replication, and both lines expressed all of the cellular molecules required for virus entry: scavenger receptor B-I (SR-BI); tetraspanin CD81 and tight junction proteins claudin-1 and occludin.[33,35] Neuroepithelioma cell lines supported high level entry of retroviral particles pseudotyped with HCV glycoproteins in a receptor-dependent manner.[33,35] These observations contrast with a recent report showing limited evidence for HCV entry or replication in various immune cell types.[36] These studies were the first to demonstrate productive HCV entry in non-hepatic cells that were not engineered to express the viral receptors.[37] However, these results are unlikely to correspond to HCV infection of neurons in vivo. Neuroepitheliomas are peripheral tumours derived from neural crest-derived neuroepithelium, which represent a less differentiated aspect of the neural lineage[38] and are unlikely to correspond to any cell type in normal CNS. Moreover, in the same study, neuronal cell lines failed to support HCV entry.[33] However, the expression of SR-BI, CD81, claudin-1 and occludin in neuroepithelioma cells demonstrates that HCV receptor expression is not exclusive to hepatocytes and infection may not be solely restricted to the liver.

A recent study reported that brain microvascular endothelial cells (BMEC), the major component of the blood/brain barrier, support HCV infection in vitro.[39] Two independently derived brain microvascular endothelial cell lines, hCMEC/D3 and HBMEC, expressed all of the HCV entry factors and supported HCV pseudoparticle entry and HCVcc infection. Furthermore, immunochemical staining of human brain sections revealed that microvascular endothelium express all four receptors required for HCV entry. Notably, SR-BI expression was restricted to brain microvascular endothelium,[33] suggesting that HCV tropism for the brain may be restricted to these cells. HCVpp expressing diverse glycoproteins infected BMEC, and entry was neutralized by anti-receptor and anti-HCV E2 antibodies, demonstrating a common entry pathway to that reported for hepatocytes.[33] HCVpp infection was restricted to brain-derived endothelial cells, with endothelial cells isolated from liver sinusoids or umbilical vein endothelium failing to support HCV infection. Importantly, BMEC was permissive for cell culture-derived HCV (HCVcc), showing a spreading infection and release of particles that were infectious for Huh-7 hepatoma cells. Viral infection persisted in Huh-7 cells, whereas infection declined in BMEC after 120 h and was associated with cytopathic effects, suggesting an acute lytic infection compared with the chronic infection observed in hepatoma cells. Apoptosis was observed in BMEC cultures infected with HCV, and endothelial barrier activity reduced following infection; this was reversed by the addition of HCV-positive patient serum.[39]

Endothelial cells of the blood/brain barrier (BBB) differ from endothelial cells elsewhere in the body in a number of respects. Tight junctions in brain endothelium are more complex than those of peripheral endothelium, leading to epithelial-like polarity.[40] These tight junctions exclude the passage of large, water-soluble substances into the brain from the bloodstream. Passage of large and lipophilic substances into the brain across the BBB typically occurs via receptor-mediated endocytosis, and some substances are transported via transport proteins such as the GLUT-1 glucose transporter.[40] Brain microvascular endothelial cells are surrounded by astrocyte end feet and pericytes that help maintain barrier integrity[40] (Fig. 1). Our in vitro studies showing HCV-infected BMEC apoptosis suggest that HCV may disrupt BBB integrity in vivo. This could allow the influx of inflammatory cytokines and virus to the brain parenchyma, which could give rise to the relatively mild neurological symptoms observed in patients. HCV replication and assembly of infectious particles in BMEC suggests that the brain may contribute to HCV pathogenesis via direct viral infection of the BBB (Fig. 2), which raises questions on the potential efficacy of therapies currently in development, such as protease and polymerase inhibitors,[41] as they may achieve low drug levels in the brain because of the expression of efficient drug efflux pumps at the BBB such as P-glycoprotein. There may be difficulties in delivering these drugs to the CNS, similar to those reported in HIV infection where reservoirs of infection develop in immune-privileged sites such as the brain.[42]

Figure 1.
The blood/brain barrier (BBB) in vivo. The BBB is formed by brain microvascular endothelial cells, which polarize and form tight junctions, thereby limiting the passage of substances into the central nervous system (CNS). Endothelial cells are surrounded by a basal lamina and astrocytic endfeet, which secrete factors that help to maintain the endothelial cell phenotype. Pericytes also surround the endothelium, and recent evidence suggests that these cells contribute to the maintenance of barrier function. These cells, together with surrounding neurons, form a 'neurovascular unit', which function to regulate cerebral blood flow [40].

Figure 2.
Proposed neuropathogenesis of HCV infection. The chronically infected liver produces approximately 1012 viral particles per day, which are released into the bloodstream and encounter brain microvascular endothelial cells of the BBB. Brain microvascular endothelial cells express all of the receptors required for viral entry, together with LDL-R and Apolipoprotein E. Direct viral infection of BBB endothelial cells may occur, resulting in apoptosis and BBB breakdown that could allow entry of inflammatory cytokines, viral particles and other neurotoxic substances that may potentiate neurological symptoms and activate microglial cells and astrocytes. Infection of brain microvascular endothelium is likely to impact upon astrocyte homoeostasis, and some studies have suggested that HCV infects astrocytes. Productive infection of brain microvascular endothelium and the release of infectious viral particles could contribute to viral persistence.

HIV is a Frequent Co-pathogen With HCV
Owing to similar modes of transmission, an estimated 30% of HIV positive individuals are co-infected with HCV in the USA and Europe.[43] In high risk groups, the rate of co-infection rises and HCV is found in 50–70% of HIV-infected intravenous drug users.[43] HCV co-infection with HIV leads to accelerated hepatic fibrosis progression and increased rates of cirrhosis and liver failure compared with HCV mono-infected individuals.[44] HIV is known to enter the brain early after infection and can infect microglia, perivascular macrophages and astrocytes (for reviews, see [45,46] HIV infection can cause severe HIV-associated dementia in untreated individuals; however, even in the setting of optimally treated HIV infection, brain replication persists and gives rise to minor cognitive motor disorder (MCMD) in a significant number of patients, because of poor brain penetration of therapies across the BBB.[46] HCV-HIV co-infected individuals perform worse in neurocognitive tests compared with HIV-monoinfected individuals[47] and are more likely to be diagnosed with HIV-associated dementia.[47] A study of co-infected individuals performed both pre- and postmortem suggested an association between poorly controlled HIV infection and the presence of HCV in the brain, and patients with detectable HCV in the brain had higher plasma HIV viral loads.[18] Although the study only assessed small numbers of patients, there was a trend towards increased levels of cognitive deficits in co-infected patients with detectable brain HCV, compared with mono-infected patients or those with HCV restricted to systemic locations.[18] Further studies of co-infected patients has suggested that successful HIV therapy may reduce the levels of increased cognitive impairment attributed to HCV infection, although correlation of cognitive impairment with detectable levels of virus in the brain was not investigated.[48–50] White matter abnormalities were recently reported in co-infected patients,[51,52] suggesting neuropathological processes directly related to the presence of HCV in the brain. Furthermore, plasma cytokine IL-6, IL-16 and MIP-1β levels in co-infected patients associate with neurocognitive abnormalities,[53] suggesting that the interplay of HIV, HCV and inflammatory host responses may contribute to neuropathology in co-infected individuals. These clinical and translational reports warrant further studies to determine the interactions of these viruses in the central nervous system, and the mechanisms by which they contribute to neural dysfunction in infected individuals.

Hepatitis C is a member of the Flaviviridae, whose members include a number of neurovirulent viruses, including Japanese encephalitis virus, West Nile virus and Tick-borne encephalitis virus.[54] Neurological symptoms associated with HCV infection have been reported many times; however, it has been unclear whether these symptoms are a function of liver disease, peripheral inflammation or direct infection of the CNS. The detection of HCV RNA in brain tissue, together with evidence to suggest independent viral evolution within the CNS, has suggested that the neurological symptoms reported in patients may result from direct infection of the brain. Recent advances in the tools available to study HCV have allowed researchers to address the question of whether HCV replicates in brain-derived cells. The recent observation that HCV can replicate in brain endothelial cells, and that neuroinflammation is a feature of HCV infection, may provide a mechanism for the neurological symptoms observed in a significant number of infected patients.

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