Neuroimaging abnormalities, neurocognitive function, and fatigue in patients with hepatitis C

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Neuroimaging abnormalities, neurocognitive function, and fatigue in patients with hepatitis C

April D. Thames, PhD, Steven A. Castellon, PhD, Elyse J. Singer, MD, Rajakumar Nagarajan, PhD, Manoj K. Sarma, PhD, Jason Smith, PharmD, Nicholas S. Thaler, PhD, Jonathan Hien Truong, MD, Daniel Schonfeld, BS, M. Albert Thomas, PhD and Charles H. Hinkin, PhD

Published online January 14, 2015 doi: 10.1212/NXI.0000000000000059Neurol Neuroimmunol Neuroinflamm February 2015 vol. 2 no. 1 e59

Abstract

Objective: This study examined neurologic abnormalities (as measured by proton magnetic resonance spectroscopy imaging and diffusion tensor imaging), neurocognitive performance, and fatigue among a sample of adults with hepatitis C virus (HCV). We hypothesized that HCV+ individuals would demonstrate structural brain abnormalities and neurocognitive compromise consistent with frontostriatal dysfunction as well as increased fatigue compared to controls.

Method: Participants were 76 individuals diagnosed with HCV and 20 controls who underwent a comprehensive neurocognitive evaluation and clinical assessments. A subset of the HCV+ participants (n = 29) and all controls underwent MRI.

Results: Individuals diagnosed with chronic HCV infection demonstrated greater fractional anisotropy in the striatum as well as greater mean diffusivity in the fronto-occiptal fasciculus and external capsule compared to HCV− controls. HCV+ participants also demonstrated lower levels of N-acetylaspartate in bilateral parietal white matter and elevations in myo-inosital (mI) in bilateral frontal white matter compared to HCV− controls (all p values < 0.05). HCV+ participants also demonstrated significantly poorer neuropsychological performance, particularly in processing speed and verbal fluency. HCV+ patients reported higher levels of fatigue than controls, and fatigue was significantly correlated with diffusivity in the superior fronto-occipital fasciculus, elevations in mI in frontal white matter, and overall cognitive performance.

Conclusions: Our results suggest that HCV-associated neurologic complications disrupt frontostriatal structures, which may result in increased fatigue and poorer cognitive performance, particularly in those cognitive domains regulated by frontostriatal regions.

DISCUSSION ONLY

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The current study examined the effects of chronic HCV infection on microstructural brain abnormalities, cerebral metabolites, fatigue, and neurocognitive performance. Major strengths of the current investigation include the use of DTI and MRSI in combination with measures of neurocognitive functioning and fatigue, and the use of a control group for comparison. As hypothesized based on prior literature, we observed microstructural abnormalities in such areas as the striatum, external capsule, and fronto-occipital fasciculus, which is consistent with previous DTI studies of HCV^9,10 and findings among individuals with HIV infection.^28,29

We observed greater FA in gray matter regions of the striatum in HCV+ patients compared to healthy volunteers. Higher FA in the striatum has been found among patients with Huntington disease³² and is thought to be due to degeneration of efferent pathways that increase the coherence of gray matter structures. In a study of patients with chronic subdural hematoma, increased FA was found in the striatum, which reduced following surgical intervention.³³ Therefore, our findings are consistent with other investigations of neuropathology in regions that are affected in HCV.

Increased diffusivity in the fronto-occipital tract and external capsule was also found in the HCV+ group compared to controls. The fronto-occipital tract has been suggested as modulating frontal lobe–related inhibitory control and occipital lobe–related sensory inputs.³⁴ Alterations of this tract may interfere with integrating sensory information and inhibiting control over impulses and emotion, which is problematic among drug abusers. The external capsule contains a variety of different nerve bundles and pathways connecting the cerebral cortex to subcortical nuclei as well as connecting different parts of the cortex to each other. Therefore, disruption to fibers of the external capsule may result in dysfunction of frontal-subcortical circuitry.

HCV+ participants demonstrated lower levels of NAA in bilateral parietal white matter and elevations of mI in bilateral frontal white matter compared to controls, which was associated with poorer performance in the cognitive domains of processing speed and verbal/language fluency. Further, there was a correspondence between our DTI and MRSI measures. Specifically, higher NAA in parietal white matter was significantly correlated with lower diffusivity in the fronto-occipital fasciculus, whereas greater frontal white matter mI was significantly correlated with higher diffusivity in the fronto-occipital fasciculus.

That stated, our MRSI results were generally consistent with previous MRSI studies of HCV+ cohorts,^8,12,35 although we did not observe abnormal cerebral metabolite levels in basal ganglia as was expected.

However, in the current study we were careful to exclude participants with medical (e.g., cirrhosis) and psychiatric conditions that potentially could have confounded interpretation of the neuroimaging findings. Through this process we may have excluded HCV+ individuals with more severe neurologic impairments and neuropathologic changes in subcortical structures that are detectable by H-MRS. Although HCV+ patients demonstrated poorer global neurocognitive performance than controls, examination of performance data suggests normal range of performance (i.e., T > 40). Again, because of the use of stringent inclusion/exclusion criteria, this group may not be fully representative of the general HCV+ population. Despite the potential recruitment of higher-functioning HCV+ individuals, we still found the poorer performance in the cognitive domains of processing speed and verbal fluency (relative to controls) that has been reported across other studies,^4,5,13,15,16 and this performance was independent of such factors as liver fibrosis and history of substance abuse.

HCV+ participants also reported greater fatigue than controls, which was associated with abnormalities in frontal white matter, whereas poorer cognitive performance was associated with abnormalities in both frontal white matter and subcortical structures. These results suggest that HCV-associated neurologic complications that are specific to changes in frontal-subcortical structures give rise to both reduced cognitive performance and fatigue. The specific cognitive deficits observed in verbal/language fluency and information processing speed are all regulated by frontal-striatal structures.³⁶ In our sample, verbal fluency demonstrated the greatest degree of performance difference between HCV+ and control groups and the strongest correlation with elevated levels of mI in frontal white matter.

There are limitations to the current study. First, while structural neuroimaging methods are helpful in identifying microstructural pathology that may not be detected on standard MRI, they do not provide a clear understanding about the functions of these neural circuits. Hence, existing disruptions in a neural circuit may make a patient more vulnerable to developing symptoms such as fatigue. Second, although we attempted to control for a number of demographic variables between HCV patients and controls, we recognize that there are a myriad of psychosocial differences (e.g., stress, past drug use) that may account for the reduced cognitive performance and structural brain differences that were observed in the current study. For instance, we were unable to examine past drug abuse differences between our HCV+ and control groups because information on past drug abuse was not collected from the controls. We recognize that in order to precisely rule out the effects of past drug abuse we would have needed to recruit a sample of past drug abusers who were HCV−. However, considering that 61% of our HCV+ patients reported a lifetime history of cocaine or opiate use, we attempted to address this concern by examining the effects of past drug abuse within this subgroup. While we did not find significant differences in our neuroimaging or neurocognitive data as a function of past drug abuse (all p values > 0.10), we cannot rule out the residual confounding effects of distant substance use on neurologic function.

Despite these limitations, the current study represents a significant extension of the extant literature on HCV's effects on neurologic and neurobehavioral functioning by demonstrating how abnormalities in frontal/parietal and subcortical structures have independent and overlapping relationships with cognitive performance and fatigue.

It has long been known that HCV is hepatotoxic; increasingly there is reason to believe that it is neurotoxic as well. While the precise pathophysiologic mechanism remains unclear, findings from the current study as well as others have demonstrated that HCV infection is associated with neurophysiologic and neurobehavioral abnormality. While advances in the pharmacologic treatment of HCV hold incredible promise, there remain millions of HCV-infected adults in the United States and approximately 100 million worldwide. Continued study of the neurologic effects of HCV is needed. 

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