Introducción El hígado, vital y vulnerable, enfrenta múltiples enfermedades con diversas etiologías, y constituyen alrededor de la cuarta a quinta causa de muertes mundial, principalmente infecciones virales (hepatitis B y C), cirrosis (alcoholismo, hepatitis), hígado graso (alcohólico o no), cáncer y las enfermedades autoinmunes. La enfermedad del hígado graso no alcohólico (NAFLD, Non-alcoholic fatty liver disease, por sus siglas en inglés) se caracteriza por la acumulación de grasa en el hígado sin consumo significativo de alcohol. Puede variar desde hígado graso simple (NAFL, Non-alcoholic fatty liver, por sus siglas en inglés) hasta inflamación (NASH, Non-alcoholic steatohepatitis) y fibrosis, que puede llevar a cirrosis y cáncer hepático. Identificar riesgos temprano es crucial para prevenir complicaciones graves. NAFLD se ha convertido en una de las enfermedades hepáticas crónica más común [1]. La prevalencia mundial de la NAFLD es de alrededor del 25% [2]. El diagnóstico de la NAFLD implica identificar la acumulación de grasa en el hígado y evaluar el riesgo de progresión. Los niveles de transaminasas hepáticas, la ecografía y la elastografía transitoria son herramientas no invasivas útiles, pero la biopsia hepática sigue siendo la más precisa para diagnosticar la inflamación y la fibrosis en etapas avanzadas [3]. La NAFLD se asocia con el deterioro cognitivo leve (DCL), posiblemente independiente del síndrome metabólico, el cual a su vez ha sido vinculado con la disfunción cognitiva. Aunque se han realizado diferentes estudios, la metodología para detectar el DCL en pacientes con NAFLD aún no está claramente definida [4-9]. La inflamación desempeña un papel fundamental en la NAFLD y puede afectar negativamente al cerebro [10-12]. Estudios indican que, a mayor gravedad de la enfermedad hepática, mayor es el riesgo de deterioro cognitivo. La hiperamonemia, junto con la inflamación, contribuye al deterioro cognitivo en pacientes con NAFLD [13]. La microbiota intestinal desequilibrada también podría desempeñar un papel en el deterioro cognitivo [14-15]. Las comorbilidades metabólicas, como la diabetes y la obesidad, también aumentan el riesgo de deterioro cognitivo en pacientes con NAFLD [16-19]. Además, la NAFLD se ha asociado con una reducción en el volumen cerebral [20]. Se plantean hipótesis sobre el desarrollo de deterioro cognitivo leve en pacientes con NAFLD y su relación con cambios en la inflamación periférica y el sistema inmunitario. Los principales objetivos de esta tesis fueron evaluar las alteraciones neurológicas en pacientes con NAFLD, desarrollar una puntuación para clasificar a estos pacientes según la presencia de DCL y caracterizar los cambios en el sistema inmunológico e inflamación periférica relacionados con la aparición de DCL en pacientes con NAFLD. Desarrollo teórico En este estudio, se evaluaron a 73 pacientes con NAFLD y 64 controles mediante pruebas psicométricas que evaluaron diversas funciones neurológicas, incluyendo la batería PHES (Puntuación Psicométrica de Encefalopatía Hepática), d2, Stroop, SDMT Oral (Prueba de Modalidades de Dígitos y Símbolos), Digit Span, prueba número-letra y pruebas de coordinación bimanual y visual-motora [21-27]. Los pacientes con NAFLD mostraron deterioro en la atención, concentración mental, velocidad psicomotora, flexibilidad cognitiva, control mental inhibitorio y memoria de trabajo. Desarrollamos una nueva puntuación rápida y sensible basada en los parámetros más afectados en los pacientes con NAFLD, revelando que el 30% (21 de 73) de los pacientes con NAFLD presentan DCL. Utilizando la nueva puntuación desarrollada, 30% de los pacientes con NAFLD presentan deterioro cognitivo leve, con alteraciones en la atención, concentración, memoria de trabajo y coordinación motora. La inflamación desempeña un papel crucial en la aparición y progresión del deterioro cognitivo leve en NAFLD y sus alteraciones neurológicas asociadas. Se analizó la caracterización y activación de poblaciones de leucocitos y subpoblaciones de CD4+ mediante citometría de flujo. También se analizaron las citocinas liberadas de cultivos de células CD4+ y la expresión de ARN de factores de transcripción y receptores en células mononucleares de sangre periférica. Los pacientes con NAFLD presentan un aumento en el número de monocitos proinflamatorios en sangre y un ambiente proinflamatorio en plasma que condicionan la activación y el tipo de diferenciación de los linfocitos. El aumento de los niveles plasmáticos de CCL2 y de la expresión de su receptor CCR2 en los pacientes con DCL podrían promover la infiltración de monocitos en el SNC y desencadenar la neuroinflamación [28]. Además, los pacientes con DCL presentan un aumento en el estado de activación de varias subpoblaciones de linfocitos T, como indican el aumento del marcador CD69 y de citocinas proinflamatorias plasmáticas. La aparición de DCL en pacientes con NAFLD se asoció con un aumento en la activación de los subtipos linfocitos T CD4+, principalmente del subtipo Th17, niveles plasmáticos elevados de citocinas proinflamatorias y antiinflamatorias como IL-17A, IL-23, IL-21, IL-22, IL-6, INF-γ e IL-13. Se encontró una expresión constitutiva de IL-17 en cultivos de células CD4+ de pacientes con DCL, lo que refleja la activación de Th17. El aumento de los niveles plasmáticos de IL-17, podría causar la ruptura de la barrera hematoencefálica, favoreciendo la entrada en el SNC de las células inmunes periféricas, incluidas las células Th17, induciendo la neuroinflamación [29]. La mayor concentración de la citocina antinflamatoria IL-13 en pacientes con DCL son predictivos de DCL y podrían reflejar una respuesta reguladora y compensatoria para contrarrestar la inflamación y el daño neuronal asociados con el deterioro cognitivo en la NAFLD [30]. . Conclusiones Este estudio de tesis ha identificado algunas alteraciones específicas del sistema inmunológico e inflamación asociadas a la aparición de las alteraciones neurológicas en pacientes con DCL y NAFLD, lo que podría ser la base para mejorar y restaurar las funciones cognitivas y la calidad de vida en estos pacientes. Bibliografía 1. Serfaty, L., & Lemoine, M. (2008). Definition and natural history of metabolic steatosis: clinical aspects of NAFLD, NASH and cirrhosis. Diabetes & metabolism, 34(6 Pt 2), 634–637. https://doi.org/10.1016/S1262-3636(08)74597-X 2. Younossi, Z. M., Koenig, A. B., Abdelatif, D., Fazel, Y., Henry, L., & Wymer, M. (2016). Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology (Baltimore, Md.), 64(1), 73–84. https://doi.org/10.1002/hep.28431 3. Maurice, J., & Manousou, P. (2018). Non-alcoholic fatty liver disease. Clinical medicine (London, England), 18(3), 245–250. https://doi.org/10.7861/clinmedicine.18-3-245 4. Colognesi, M., Gabbia, D., & De Martin, S. (2020). Depression and Cognitive Impairment-Extrahepatic Manifestations of NAFLD and NASH. Biomedicines, 8(7), 229. https://doi.org/10.3390/biomedicines8070229 5. Seo, S. W., Gottesman, R. F., Clark, J. M., Hernaez, R., Chang, Y., Kim, C., Ha, K. H., Guallar, E., & Lazo, M. (2016). Nonalcoholic fatty liver disease is associated with cognitive function in adults. Neurology, 86(12), 1136–1142. https://doi.org/10.1212/WNL.0000000000002498 6. Weinstein, G., Davis-Plourde, K., Himali, J. J., Zelber-Sagi, S., Beiser, A. S., & Seshadri, S. (2019). Non-alcoholic fatty liver disease, liver fibrosis score and cognitive function in middle-aged adults: The Framingham Study. Liver international: official journal of the International Association for the Study of the Liver, 39(9), 1713–1721. https://doi.org/10.1111/liv.14161 7. Celikbilek, A., Celikbilek, M., & Bozkurt, G. (2018). Cognitive assessment of patients with nonalcoholic fatty liver disease. European journal of gastroenterology & hepatology, 30(8), 944–950. https://doi.org/10.1097/MEG.0000000000001131 8. Tuttolomondo, A., Petta, S., Casuccio, A., Maida, C., Corte, V. D., Daidone, M., Di Raimondo, D., Pecoraro, R., Fonte, R., Cirrincione, A., Zafonte, R., Cabibi, D., Cammà, C., Di Marco, V., Licata, A., Magliozzo, F., Marchesini, G., Merlino, G., Craxì, A., & Pinto, A. (2018). Reactive hyperemia index (RHI) and cognitive performance indexes are associated with histologic markers of liver disease in subjects with non-alcoholic fatty liver disease (NAFLD): a case control study. Cardiovascular diabetology, 17(1), 28. https://doi.org/10.1186/s12933-018-0670-7 9. Kjærgaard, K., Mikkelsen, A. C. D., Wernberg, C. W., Grønkjær, L. L., Eriksen, P. L., Damholdt, M. F., Mookerjee, R. P., Vilstrup, H., Lauridsen, M. M., & Thomsen, K. L. (2021). Cognitive Dysfunction in Non-Alcoholic Fatty Liver Disease-Current Knowledge, Mechanisms and Perspectives. Journal of clinical medicine, 10(4), 673. https://doi.org/10.3390/jcm10040673 10. Miller, A. A., & Spencer, S. J. (2014). Obesity and neuroinflammation: a pathway to cognitive impairment. Brain, behavior, and immunity, 42, 10–21. https://doi.org/10.1016/j.bbi.2014.04.001 11. Viscogliosi, G., Andreozzi, P., Chiriac, I. M., Cipriani, E., Servello, A., Marigliano, B., Ettorre, E., & Marigliano, V. (2013). Depressive symptoms in older people with metabolic syndrome: is there a relationship with inflammation? International journal of geriatric psychiatry, 28(3), 242–247. https://doi.org/10.1002/gps.3817 12. Balzano, T., Forteza, J., Molina, P., Giner, J., Monzó, A., Sancho-Jiménez, J., Urios, A., Montoliu, C., & Felipo, V. (2018). The Cerebellum of Patients with Steatohepatitis Shows Lymphocyte Infiltration, Microglial Activation and Loss of Purkinje and Granular Neurons. Scientific reports, 8(1), 3004. https://doi.org/10.1038/s41598-018-21399-6 13. Felipo, V., Urios, A., Montesinos, E., Molina, I., Garcia-Torres, M. L., Civera, M., Olmo, J. A., Ortega, J., Martinez-Valls, J., Serra, M. A., Cassinello, N., Wassel, A., Jordá, E., & Montoliu, C. (2012b). Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy. Metabolic brain disease, 27(1), 51–58. https://doi.org/10.1007/s11011-011-9269-3 14. Higarza, S. G., Arboleya, S., Gueimonde, M., Gómez-Lázaro, E., Arias, J. L., & Arias, N. (2019). Neurobehavioral dysfunction in non-alcoholic steatohepatitis is associated with hyperammonemia, gut dysbiosis, and metabolic and functional brain regional deficits. PloS one, 14(9), e0223019. https://doi.org/10.1371/journal.pone.0223019 15. Mohammed, S. K., Magdy, Y. M., El-Waseef, D. A., Nabih, E. S., Hamouda, M. A., & El-Kharashi, O. A. (2020). Modulation of hippocampal TLR4/BDNF signal pathway using probiotics is a step closer towards treating cognitive impairment in NASH model. Physiology & behavior, 214, 112762. https://doi.org/10.1016/j.physbeh.2019.112762 16. Ng, T. P., Feng, L., Nyunt, M. S., Feng, L., Gao, Q., Lim, M. L., Collinson, S. L., Chong, M. S., Lim, W. S., Lee, T. S., Yap, P., & Yap, K. B. (2016). Metabolic Syndrome and the Risk of Mild Cognitive Impairment and Progression to Dementia: Follow-up of the Singapore Longitudinal Ageing Study Cohort. JAMA neurology, 73(4), 456–463. https://doi.org/10.1001/jamaneurol.2015.4899 17. Atti, A. R., Valente, S., Iodice, A., Caramella, I., Ferrari, B., Albert, U., Mandelli, L., & De Ronchi, D. (2019). Metabolic Syndrome, Mild Cognitive Impairment, and Dementia: A Meta-Analysis of Longitudinal Studies. The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry, 27(6), 625–637. https://doi.org/10.1016/j.jagp.2019.01.214 18. Cheng, G., Huang, C., Deng, H., & Wang, H. (2012). Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Internal medicine journal, 42(5), 484–491. https://doi.org/10.1111/j.1445-5994.2012.02758.x 19. Pedditzi, E., Peters, R., & Beckett, N. (2016). The risk of overweight/obesity in mid-life and late life for the development of dementia: a systematic review and meta-analysis of longitudinal studies. Age and ageing, 45(1), 14–21. https://doi.org/10.1093/ageing/afv151 20. Weinstein, G., Zelber-Sagi, S., Preis, S. R., Beiser, A. S., DeCarli, C., Speliotes, E. K., Satizabal, C. L., Vasan, R. S., & Seshadri, S. (2018). Association of Nonalcoholic Fatty Liver Disease With Lower Brain Volume in Healthy Middle-aged Adults in the Framingham Study. JAMA neurology, 75(1), 97–104. https://doi.org/10.1001/jamaneurol.2017.3229 21. Weissenborn, K., Ennen, J. C., Schomerus, H., Rückert, N., & Hecker, H. (2001). Neuropsychological characterization of hepatic encephalopathy. Journal of hepatology, 34(5), 768–773. https://doi.org/10.1016/s0168-8278(01)00026-5 22. Bates, M. E., & Lemay, E. P., Jr (2004). The d2 Test of attention: construct validity and extensions in scoring techniques. Journal of the International Neuropsychological Society: JINS, 10(3), 392–400. https://doi.org/10.1017/S135561770410307X 23. Glaser, M. O., & Glaser, W. R. (1982). Time course analysis of the Stroop phenomenon. Journal of experimental psychology. Human perception and performance, 8(6), 875–894. https://doi.org/10.1037//0096-1523.8.6.875 24. Wechsler, D. (1955) Manual for the Wechsler adult intelligence scale. Psychological Corporation, New York. 25. Egeland J. (2015). Measuring Working Memory With Digit Span and the Letter-Number Sequencing Subtests From the WAIS-IV: Too Low Manipulation Load and Risk for Underestimating Modality Effects. Applied neuropsychology. Adult, 22(6), 445–451. https://doi.org/10.1080/23279095.2014.992069 26. Yela, M. & López Ladrón, L. Un test de coordinación visuo-motora. Revista de Psicología General y Aplicada 10, 409–421 (1995). 27. Yela, M. Un test de rapidez motora. Revista de Psicología General y Aplicada 10, 137–148 (1955). 28. Galimberti, D., Fenoglio, C., Lovati, C., Venturelli, E., Guidi, I., Corrà, B., Scalabrini, D., Clerici, F., Mariani, C., Bresolin, N., & Scarpini, E. (2006). Serum MCP-1 levels are increased in mild cognitive impairment and mild Alzheimer's disease. Neurobiology of aging, 27(12), 1763–1768. https://doi.org/10.1016/j.neurobiolaging.2005.10.007. 29. Cipollini, V., Anrather, J., Orzi, F., & Iadecola, C. (2019). Th17 and Cognitive Impairment: Possible Mechanisms of Action. Frontiers in neuroanatomy, 13, 95. https://doi.org/10.3389/fnana.2019.00095 30. Miossec, P., & van den Berg, W. (1997). Th1/Th2 cytokine balance in arthritis. Arthritis and rheumatism, 40(12), 2105–2115. https://doi.org/10.1002/art.1780401203

Introduction The liver, vital and vulnerable, faces multiple diseases with diverse etiologies, constituting around the fourth to fifth leading cause of global deaths, mainly viral infections (hepatitis B and C), cirrhosis (alcoholism, hepatitis), non-alcoholic fatty liver disease (NAFLD), liver cancer, and autoimmune diseases. Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of fat in the liver without significant alcohol consumption. It can range from simple fatty liver (NAFL) to inflammation (non-alcoholic steatohepatitis or NASH) and fibrosis, which can progress to cirrhosis and liver cancer. Early identification of risks is crucial for preventing serious complications. NAFLD has become one of the most common chronic liver diseases [1], with a global prevalence of around 25% [2]. The diagnosis of NAFLD involves identifying fat accumulation in the liver and assessing the risk of progression. Hepatic transaminase levels, ultrasound, and transient elastography are useful non-invasive tools, but liver biopsy remains the most accurate for diagnosing inflammation and fibrosis in advanced stages [3]. NAFLD is associated with mild cognitive impairment (MCI), possibly independent of metabolic syndrome, which, in turn, has been linked to cognitive dysfunction. Despite various studies, the methodology for detecting MCI in NAFLD patients is not clearly defined [4-9]. Inflammation plays a crucial role in NAFLD and can negatively impact the brain [10-12]. Studies indicate that the greater the severity of liver disease, the higher the risk of cognitive impairment. Hyperammonemia, along with inflammation, contributes to cognitive impairment in NAFLD patients [13]. Imbalanced intestinal microbiota could also play a role in cognitive impairment [14-15]. Metabolic comorbidities, such as diabetes and obesity, also increase the risk of cognitive impairment in NAFLD patients [16-19]. Additionally, NAFLD has been associated with a reduction in brain volume [20]. Hypotheses are proposed regarding the development of mild cognitive impairment in NAFLD patients and its relationship with changes in peripheral inflammation and the immune system. The main objectives of this thesis were to evaluate neurological alterations in NAFLD patients, develop a score to classify these patients based on the presence of MCI, and characterize changes in the immune system and peripheral inflammation related to the onset of MCI in NAFLD patients. Theoretical Development In this study, 73 NAFLD patients and 64 controls were evaluated using psychometric tests assessing various neurological functions, including the PHES battery (Psychometric Hepatic Encephalopathy Score), d2, Stroop, SDMT Oral (Symbol Digit Modalities Test), Digit Span, number-letter test, and bimanual and visual-motor coordination tests [21-27]. NAFLD patients showed impairment in attention, mental concentration, psychomotor speed, cognitive flexibility, inhibitory mental control, and working memory. We developed a new, quick, and sensitive score based on the most affected parameters in NAFLD patients, revealing that 30% (21 out of 73) of NAFLD patients have MCI. Using the newly developed score, 30% of NAFLD patients exhibit mild cognitive impairment, with impairments in attention, concentration, working memory, and motor coordination. Inflammation plays a crucial role in the onset and progression of mild cognitive impairment in NAFLD and its associated neurological alterations. The characterization and activation of leukocyte populations and CD4+ subpopulations were analyzed through flow cytometry. Cytokines released from CD4+ cell cultures and the expression of RNA transcription factors and receptors in peripheral blood mononuclear cells were also analyzed. NAFLD patients showed an increase in the number of proinflammatory monocytes in the blood and a proinflammatory environment in plasma that conditions the activation and differentiation of lymphocytes. Increased plasma levels of CCL2 and the expression of its receptor CCR2 in MCI patients could promote the infiltration of monocytes into the CNS and trigger neuroinflammation [28]. Furthermore, MCI patients exhibited increased activation status in various T lymphocyte subpopulations, as indicated by increased CD69 marker and proinflammatory plasma cytokines. The onset of MCI in NAFLD patients was associated with increased activation of CD4+ T lymphocyte subtypes, mainly the Th17 subtype, elevated plasma levels of proinflammatory and anti-inflammatory cytokines such as IL-17A, IL-23, IL-21, IL-22, IL-6, INF-γ, and IL-13. Constitutive expression of IL-17 was found in CD4+ cell cultures of MCI patients, reflecting Th17 activation. Elevated plasma levels of IL-17 could cause disruption of the blood-brain barrier, facilitating the entry of peripheral immune cells, including Th17 cells, into the CNS, inducing neuroinflammation [29]. The higher concentration of the anti-inflammatory cytokine IL-13 in MCI patients is predictive of MCI and could reflect a regulatory and compensatory response to counteract inflammation and neuronal damage associated with cognitive impairment in NAFLD [30]. Conclusions This thesis study has identified specific immune system and inflammation alterations associated with the onset of neurological abnormalities in MCI and NAFLD patients, laying the foundation for improving and restoring cognitive functions and quality of life in these patients. Bibliografía 1. Serfaty, L., & Lemoine, M. (2008). Definition and natural history of metabolic steatosis: clinical aspects of NAFLD, NASH and cirrhosis. Diabetes & metabolism, 34(6 Pt 2), 634–637. https://doi.org/10.1016/S1262-3636(08)74597-X 2. Younossi, Z. M., Koenig, A. B., Abdelatif, D., Fazel, Y., Henry, L., & Wymer, M. (2016). Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology (Baltimore, Md.), 64(1), 73–84. https://doi.org/10.1002/hep.28431 3. Maurice, J., & Manousou, P. (2018). Non-alcoholic fatty liver disease. Clinical medicine (London, England), 18(3), 245–250. https://doi.org/10.7861/clinmedicine.18-3-245 4. Colognesi, M., Gabbia, D., & De Martin, S. (2020). Depression and Cognitive Impairment-Extrahepatic Manifestations of NAFLD and NASH. Biomedicines, 8(7), 229. https://doi.org/10.3390/biomedicines8070229 5. Seo, S. W., Gottesman, R. F., Clark, J. M., Hernaez, R., Chang, Y., Kim, C., Ha, K. H., Guallar, E., & Lazo, M. (2016). Nonalcoholic fatty liver disease is associated with cognitive function in adults. Neurology, 86(12), 1136–1142. https://doi.org/10.1212/WNL.0000000000002498 6. Weinstein, G., Davis-Plourde, K., Himali, J. J., Zelber-Sagi, S., Beiser, A. S., & Seshadri, S. (2019). Non-alcoholic fatty liver disease, liver fibrosis score and cognitive function in middle-aged adults: The Framingham Study. Liver international: official journal of the International Association for the Study of the Liver, 39(9), 1713–1721. https://doi.org/10.1111/liv.14161 7. Celikbilek, A., Celikbilek, M., & Bozkurt, G. (2018). Cognitive assessment of patients with nonalcoholic fatty liver disease. European journal of gastroenterology & hepatology, 30(8), 944–950. https://doi.org/10.1097/MEG.0000000000001131 8. Tuttolomondo, A., Petta, S., Casuccio, A., Maida, C., Corte, V. D., Daidone, M., Di Raimondo, D., Pecoraro, R., Fonte, R., Cirrincione, A., Zafonte, R., Cabibi, D., Cammà, C., Di Marco, V., Licata, A., Magliozzo, F., Marchesini, G., Merlino, G., Craxì, A., & Pinto, A. (2018). Reactive hyperemia index (RHI) and cognitive performance indexes are associated with histologic markers of liver disease in subjects with non-alcoholic fatty liver disease (NAFLD): a case control study. Cardiovascular diabetology, 17(1), 28. https://doi.org/10.1186/s12933-018-0670-7 9. Kjærgaard, K., Mikkelsen, A. C. D., Wernberg, C. W., Grønkjær, L. L., Eriksen, P. L., Damholdt, M. F., Mookerjee, R. P., Vilstrup, H., Lauridsen, M. M., & Thomsen, K. L. (2021). Cognitive Dysfunction in Non-Alcoholic Fatty Liver Disease-Current Knowledge, Mechanisms and Perspectives. Journal of clinical medicine, 10(4), 673. https://doi.org/10.3390/jcm10040673 10. Miller, A. A., & Spencer, S. J. (2014). Obesity and neuroinflammation: a pathway to cognitive impairment. Brain, behavior, and immunity, 42, 10–21. https://doi.org/10.1016/j.bbi.2014.04.001 11. Viscogliosi, G., Andreozzi, P., Chiriac, I. M., Cipriani, E., Servello, A., Marigliano, B., Ettorre, E., & Marigliano, V. (2013). Depressive symptoms in older people with metabolic syndrome: is there a relationship with inflammation? International journal of geriatric psychiatry, 28(3), 242–247. https://doi.org/10.1002/gps.3817 12. Balzano, T., Forteza, J., Molina, P., Giner, J., Monzó, A., Sancho-Jiménez, J., Urios, A., Montoliu, C., & Felipo, V. (2018). The Cerebellum of Patients with Steatohepatitis Shows Lymphocyte Infiltration, Microglial Activation and Loss of Purkinje and Granular Neurons. Scientific reports, 8(1), 3004. https://doi.org/10.1038/s41598-018-21399-6 13. Felipo, V., Urios, A., Montesinos, E., Molina, I., Garcia-Torres, M. L., Civera, M., Olmo, J. A., Ortega, J., Martinez-Valls, J., Serra, M. A., Cassinello, N., Wassel, A., Jordá, E., & Montoliu, C. (2012b). Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy. Metabolic brain disease, 27(1), 51–58. https://doi.org/10.1007/s11011-011-9269-3 14. Higarza, S. G., Arboleya, S., Gueimonde, M., Gómez-Lázaro, E., Arias, J. L., & Arias, N. (2019). Neurobehavioral dysfunction in non-alcoholic steatohepatitis is associated with hyperammonemia, gut dysbiosis, and metabolic and functional brain regional deficits. PloS one, 14(9), e0223019. https://doi.org/10.1371/journal.pone.0223019 15. Mohammed, S. K., Magdy, Y. M., El-Waseef, D. A., Nabih, E. S., Hamouda, M. A., & El-Kharashi, O. A. (2020). Modulation of hippocampal TLR4/BDNF signal pathway using probiotics is a step closer towards treating cognitive impairment in NASH model. Physiology & behavior, 214, 112762. https://doi.org/10.1016/j.physbeh.2019.112762 16. Ng, T. P., Feng, L., Nyunt, M. S., Feng, L., Gao, Q., Lim, M. L., Collinson, S. L., Chong, M. S., Lim, W. S., Lee, T. S., Yap, P., & Yap, K. B. (2016). Metabolic Syndrome and the Risk of Mild Cognitive Impairment and Progression to Dementia: Follow-up of the Singapore Longitudinal Ageing Study Cohort. JAMA neurology, 73(4), 456–463. https://doi.org/10.1001/jamaneurol.2015.4899 17. Atti, A. R., Valente, S., Iodice, A., Caramella, I., Ferrari, B., Albert, U., Mandelli, L., & De Ronchi, D. (2019). Metabolic Syndrome, Mild Cognitive Impairment, and Dementia: A Meta-Analysis of Longitudinal Studies. The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry, 27(6), 625–637. https://doi.org/10.1016/j.jagp.2019.01.214 18. Cheng, G., Huang, C., Deng, H., & Wang, H. (2012). Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Internal medicine journal, 42(5), 484–491. https://doi.org/10.1111/j.1445-5994.2012.02758.x 19. Pedditzi, E., Peters, R., & Beckett, N. (2016). The risk of overweight/obesity in mid-life and late life for the development of dementia: a systematic review and meta-analysis of longitudinal studies. Age and ageing, 45(1), 14–21. https://doi.org/10.1093/ageing/afv151 20. Weinstein, G., Zelber-Sagi, S., Preis, S. R., Beiser, A. S., DeCarli, C., Speliotes, E. K., Satizabal, C. L., Vasan, R. S., & Seshadri, S. (2018). Association of Nonalcoholic Fatty Liver Disease With Lower Brain Volume in Healthy Middle-aged Adults in the Framingham Study. JAMA neurology, 75(1), 97–104. https://doi.org/10.1001/jamaneurol.2017.3229 21. Weissenborn, K., Ennen, J. C., Schomerus, H., Rückert, N., & Hecker, H. (2001). Neuropsychological characterization of hepatic encephalopathy. Journal of hepatology, 34(5), 768–773. https://doi.org/10.1016/s0168-8278(01)00026-5 22. Bates, M. E., & Lemay, E. P., Jr (2004). The d2 Test of attention: construct validity and extensions in scoring techniques. Journal of the International Neuropsychological Society: JINS, 10(3), 392–400. https://doi.org/10.1017/S135561770410307X 23. Glaser, M. O., & Glaser, W. R. (1982). Time course analysis of the Stroop phenomenon. Journal of experimental psychology. Human perception and performance, 8(6), 875–894. https://doi.org/10.1037//0096-1523.8.6.875 24. Wechsler, D. (1955) Manual for the Wechsler adult intelligence scale. Psychological Corporation, New York. 25. Egeland J. (2015). Measuring Working Memory With Digit Span and the Letter-Number Sequencing Subtests From the WAIS-IV: Too Low Manipulation Load and Risk for Underestimating Modality Effects. Applied neuropsychology. Adult, 22(6), 445–451. https://doi.org/10.1080/23279095.2014.992069 26. Yela, M. & López Ladrón, L. Un test de coordinación visuo-motora. Revista de Psicología General y Aplicada 10, 409–421 (1995). 27. Yela, M. Un test de rapidez motora. Revista de Psicología General y Aplicada 10, 137–148 (1955). 28. Galimberti, D., Fenoglio, C., Lovati, C., Venturelli, E., Guidi, I., Corrà, B., Scalabrini, D., Clerici, F., Mariani, C., Bresolin, N., & Scarpini, E. (2006). Serum MCP-1 levels are increased in mild cognitive impairment and mild Alzheimer's disease. Neurobiology of aging, 27(12), 1763–1768. https://doi.org/10.1016/j.neurobiolaging.2005.10.007. 29. Cipollini, V., Anrather, J., Orzi, F., & Iadecola, C. (2019). Th17 and Cognitive Impairment: Possible Mechanisms of Action. Frontiers in neuroanatomy, 13, 95. https://doi.org/10.3389/fnana.2019.00095 30. Miossec, P., & van den Berg, W. (1997). Th1/Th2 cytokine balance in arthritis. Arthritis and rheumatism, 40(12), 2105–2115. https://doi.org/10.1002/art.1780401203