Abstract
Hepatitis C virus (HCV) infection is associated with fatigue, depression, and cognitive impairment even in the absence of severe liver fibrosis or cirrhosis. HCV has been hypothesised to cause neurodegenerative changes through low-grade neuroinflammation. Our aim was to examine whether cortical thickness (CTh) differs between chronic HCV patients and healthy controls, suggestive of cortical atrophy. In this case–control study 43 HCV patients without severe liver fibrosis, substance abuse, or comorbid HIV or hepatitis B virus infection, and 43 age and sex matched controls underwent MRI. Cortical thickness was measured using a surface based approach. Participants underwent semi-structured psychiatric interview and fatigue was assessed using the fatigue severity scale. HCV was associated with higher fatigue scores, and 58 % of HCV patients suffered from significant fatigue (p < 0.0001). Depression was observed in 16 % of patients. Areas of significantly reduced CTh were found in both left and right occipital cortex and in the left frontal lobe after correction for multiple comparisons (p < 0.05). No association between fatigue, former substance abuse, or psychotropic medication and CTh was found. No overall difference in cerebral white and grey matter volume was found. The findings support the hypothesis that HCV is associated with neurodegenerative changes.
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References
Anthony IC, Bell PJE (2008) The neuropathology of HIV/AIDS. Int Rev Psychiatry 20:15–24. doi:10.1080/09540260701862037
Aubert-Broche B, Fonov VS, García-Lorenzo D et al (2013) A new method for structural volume analysis of longitudinal brain MRI data and its application in studying the growth trajectories of anatomical brain structures in childhood. Neuroimage 82:393–402. doi:10.1016/j.neuroimage.2013.05.065
Bladowska J, Zimny A, Knysz B et al (2013) Evaluation of early cerebral metabolic, perfusion and microstructural changes in HCV-positive patients: a pilot study. J Hepatol. doi:10.1016/j.jhep.2013.05.008
Bladowska J, Knysz B, Zimny A et al (2014) Value of perfusion-weighted MR imaging in the assessment of early cerebral alterations in neurologically asymptomatic HIV-1-positive and HCV-positive patients. PLoS One 9:e102214. doi:10.1371/journal.pone.0102214
Bokemeyer M, Ding XQ, Goldbecker A et al (2011) Evidence for neuroinflammation and neuroprotection in HCV infection-associated encephalopathy. Gut 60:370–377. doi:10.1136/gut.2010.217976
Cardinale F, Chinnici G, Bramerio M et al (2014) Validation of FreeSurfer-estimated brain cortical thickness: comparison with Histologic measurements. Neuroinformatics. doi:10.1007/s12021-014-9229-2
Chiu W-C, Tsan Y-T, Tsai SL et al (2014) Hepatitis C viral infection and the risk of dementia. Eur J Neurol 21:1068–e59. doi:10.1111/ene.12317
Collins DL, Evans AC (1997) ANIMAL: validation and applications of non-linear registration-based segmentation. Int J Pattern Recognit Artif Intell 11:1271–1294
Collins DL, Neelin P, Peters TM, Evans AC (1994) Automatic 3D intersubject registration of MR volumetric data in standardized talairach space. J Comput Assist Tomogr 18:192–205
Collins DL, Zijdenbos AP, Baare WFC, Evans AC (1999) ANIMAL + INSECT: improved cortical structure segmentation. In: Kuba A (ed) IPMI. pp 210–223
Coupe P, Yger P, Prima S et al (2008) An optimized blockwise nonlocal means denoising filter for 3-D magnetic resonance images. IEEE Trans Med Imaging 27:425–441. doi:10.1109/TMI.2007.906087
Coupé P, Manjón JV, Gedamu E et al (2010) Robust Rician noise estimation for MR images. Med Image Anal 14:483–493. doi:10.1016/j.media.2010.03.001
Dittner AJ, Wessely SC, Brown RG (2004) The assessment of fatigue: a practical guide for clinicians and researchers. J Psychosom Res 56:157–170. doi:10.1016/S0022-3999(03)00371-4
Eskildsen SF, Østergaard LR (2006) Active surface approach for extraction of the human cerebral cortex from MRI. Med Image Comput Comput Assist Interv 9:823–830
Eskildsen SF, Østergaard LR (2007) Quantitative comparison of two cortical surface extraction methods using MRI phantoms. Med Image Comput Comput Assist Interv 10:409–416
Eskildsen SF, Østergaard LR (2008) Evaluation of five algorithms for mapping brain cortical surfaces. Computer graphics and image processing, 2008 SIBGRAPI ′08 XXI Brazilian symposium on 137–144.
Eskildsen SF, Uldahl M, Østergaard LR (2005) Extraction of the cerebral cortical boundaries from MRI for measurement of cortical thickness. In: Fitzpatrick JM, Reinhardt JM (eds) Proc. SPIE 5747, Medical Imaging 2005: Image processing. pp 1400–1410
Eskildsen SF, Coupé P, Fonov V et al (2012) BEaST: brain extraction based on nonlocal segmentation technique. Neuroimage 59:2362–2373. doi:10.1016/j.neuroimage.2011.09.012
Eskildsen SF, Coupé P, García-Lorenzo D et al (2013) Prediction of Alzheimer’s disease in subjects with mild cognitive impairment from the ADNI cohort using patterns of cortical thinning. Neuroimage 65C:511–521. doi:10.1016/j.neuroimage.2012.09.058
Fishman SL, Murray JM, Eng FJ et al (2008) Molecular and bioinformatic evidence of hepatitis C virus evolution in brain. J Infect Dis 197:597–607. doi:10.1086/526519
Fletcher NF, McKeating JA (2012) Hepatitis C virus and the brain. J Viral Hepat 19:301–306. doi:10.1111/j.1365-2893.2012.01591.x
Fonov V, Evans AC, Botteron K et al (2011) Unbiased average age-appropriate atlases for pediatric studies. Neuroimage 54:313–327. doi:10.1016/j.neuroimage.2010.07.033
Forton DM, Allsop JM, Main J et al (2001) Evidence for a cerebral effect of the hepatitis C virus. Lancet 358:38–39. doi:10.1016/S0140-6736(00)05270-3
Forton DM, Karayiannis P, Mahmud N et al (2004) Identification of unique hepatitis C virus quasispecies in the central nervous system and comparative analysis of internal translational efficiency of brain, liver, and serum variants. J Virol 78:5170–5183
Forton DM, Hamilton G, Allsop JM et al (2008) Cerebral immune activation in chronic hepatitis C infection: a magnetic resonance spectroscopy study. J Hepatol 49:316–322. doi:10.1016/j.jhep.2008.03.022
Golden J, O’Dwyer AM, Conroy RM (2005) Depression and anxiety in patients with hepatitis C: prevalence, detection rates and risk factors. Gen Hosp Psychiatry 27:431–438. doi:10.1016/j.genhosppsych.2005.06.006
Grover VP, Pavese N, Koh SB et al (2012) Cerebral microglial activation in patients with hepatitis c: in vivo evidence of neuroinflammation. J Viral Hepat 19:e89–96. doi:10.1111/j.1365-2893.2011.01510.x
Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62
Hassoun Z, Willems B, Deslauriers J et al (2002) Assessment of fatigue in patients with chronic hepatitis C using the fatigue impact scale. Dig Dis Sci 47:2674–2681
Kallianpur KJ, Kirk GR, Sailasuta N et al (2012) Regional cortical thinning associated with detectable levels of HIV DNA. Cereb Cortex 22:2065–2075. doi:10.1093/cercor/bhr285
Kleinman L, Zodet MW, Hakim Z et al (2000) Psychometric evaluation of the fatigue severity scale or use in chronic hepatitis C. Qual Life Res 9:499–508
Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD (1989) The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 46:1121–1123
Laskus T, Radkowski M, Adair DM et al (2005) Emerging evidence of hepatitis C virus neuroinvasion. AIDS 19(Suppl 3):S140–4
Lerdal A, Wahl A, Rustøen T et al (2005) Fatigue in the general population: a translation and test of the psychometric properties of the Norwegian version of the fatigue severity scale. Scand J Public Health 33:123–130. doi:10.1080/14034940410028406
Maes M, Berk M, Goehler L et al (2012) Depression and sickness behavior are janus-faced responses to shared inflammatory pathways. BMC Med 10:66. doi:10.1186/1741-7015-10-66
McAndrews MP, Farcnik K, Carlen P et al (2005) Prevalence and significance of neurocognitive dysfunction in hepatitis C in the absence of correlated risk factors. Hepatology 41:801–808. doi:10.1002/hep.20635
Nygaard GO, Walhovd KB, Sowa P et al (2014) Cortical thickness and surface area relate to specific symptoms in early relapsing-remitting multiple sclerosis. Mult Scler. doi:10.1177/1352458514543811
Oster S, Christoffersen P, Gundersen HJ et al (1993) Cerebral atrophy in AIDS: a stereological study. Acta Neuropathol 85:617–622
Pakkenberg B, Gundersen HJ (1997) Neocortical neuron number in humans: effect of sex and age. J Comp Neurol 384:312–320
Pelvig DP, Pakkenberg H, Stark AK, Pakkenberg B (2008) Neocortical glial cell numbers in human brains. Neurobiol Aging 29:1754–1762. doi:10.1016/j.neurobiolaging.2007.04.013
Perry W, Hilsabeck RC, Hassanein TI (2008) Cognitive dysfunction in chronic hepatitis C: a review. Dig Dis Sci 53:307–321. doi:10.1007/s10620-007-9896-z
Piche T, Gelsi E, Schneider SM et al (2002) Fatigue is associated with high circulating leptin levels in chronic hepatitis C. Gut 51:434–439
Poynard T, Cacoub P, Ratziu V et al (2002) Fatigue in patients with chronic hepatitis C. J Viral Hepat 9:295–303
Radkowski M, Wilkinson J, Nowicki M et al (2002) Search for hepatitis C virus negative-strand RNA sequences and analysis of viral sequences in the central nervous system: evidence of replication. J Virol 76:600–608
Saunders JB, Aasland OG, Babor TF et al (1993) Development of the alcohol use disorders identification test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption--II. Addiction 88:791–804
Seaman K, Paterson BL, Vallis M et al (2009) Future directions for investigation of fatigue in chronic hepatitis C viral infection. Chronic Illness 5:115–128. doi:10.1177/1742395309104476
Sled JG, Zijdenbos AP, Evans AC (1998) A nonparametric method for automatic correction of intensity nonuniformity in MRI data. IEEE Trans Med Imaging 17:87–97. doi:10.1109/42.668698
Thompson PM, Dutton RA, Hayashi KM et al (2005) Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4 + T lymphocyte decline. Proc Natl Acad Sci U S A 102:15647–15652. doi:10.1073/pnas.0502548102
Treadway MT, Waskom ML, Dillon DG et al (2014) Illness progression, recent stress, and morphometry of Hippocampal subfields and medial prefrontal cortex in major depression. Biol Psychiatry. doi:10.1016/j.biopsych.2014.06.018
Tucker KA, Robertson KR, Lin W et al (2004) Neuroimaging in human immunodeficiency virus infection. J Neuroimmunol 157:153–162. doi:10.1016/j.jneuroim.2004.08.036
Vivithanaporn P, Maingat F, Lin LT et al (2010) Hepatitis C virus core protein induces neuroimmune activation and potentiates human immunodeficiency virus-1 neurotoxicity. PLoS One 5:e12856. doi:10.1371/journal.pone.0012856
Wang L, Goldstein FC, Veledar E et al (2009) Alterations in cortical thickness and white matter integrity in mild cognitive impairment measured by whole-brain cortical thickness mapping and diffusion tensor imaging. Am J Neuroradiol 30:893–899. doi:10.3174/ajnr.A1484
Wang X, Xie H, Cotton AS et al (2014) Early cortical thickness changes after mild traumatic brain injury following motor vehicle collision. J Neurotrauma. doi:10.1089/neu.2014.3492
Weissenborn K, Krause J, Bokemeyer M et al (2004) Hepatitis C virus infection affects the brain-evidence from psychometric studies and magnetic resonance spectroscopy. J Hepatol 41:845–851. doi:10.1016/j.jhep.2004.07.022
Wilkinson J, Radkowski M, Laskus T (2009) Hepatitis C virus neuroinvasion: identification of infected cells. J Virol 83:1312–1319. doi:10.1128/JVI.01890-08
Wilkinson J, Radkowski M, Eschbacher JM, Laskus T (2010) Activation of brain macrophages/microglia cells in hepatitis C infection. Gut 59:1394–1400. doi:10.1136/gut.2009.199356
Wing JK, Babor T, Brugha T et al (1990) SCAN. Schedules for clinical assessment in neuropsychiatry. Arch Gen Psychiatry 47:589–593
Wing JK, Ustun TB, Sartorius N (1998) Diagnosis and clinical measurement in psychiatry: a reference manual for SCAN. Cambridge University Press, Cambridge
Worsley KJ, Andermann M, Koulis T et al (1999) Detecting changes in nonisotropic images. Hum Brain Mapp 8:98–101
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The study was funded through unrestricted research grants from Roche, Puljen til Styrkelsen af Psykiatrisk Forskning i Region Midt, Region Midts Sundhedsvidenskabelige Forskningsfond, Læge Gerhard Linds Legat, Fonden til Lægevidenskabens Fremme, Marie og Børge Kroghs Fond, Fonden til Forskning i Sindslidelser. Funders exerted no influence upon study design, data collection and analyses, or decision to publish results.
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Simon Hjerrild, Signe Groth Renvillard, Leif Hovgaard Sørensen, Leif Østergaard, Simon Fristed Eskildsen, and Poul Videbech declare no conflicts of interest.
Peter Leutscher declares that he has received research grants and personal fees from Roche during the study.
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Hjerrild, S., Renvillard, S.G., Leutscher, P. et al. Reduced cerebral cortical thickness in Non-cirrhotic patients with hepatitis C. Metab Brain Dis 31, 311–319 (2016). https://doi.org/10.1007/s11011-015-9752-3
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DOI: https://doi.org/10.1007/s11011-015-9752-3