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Association of Nonalcoholic Fatty Liver Disease With Lower Brain Volume in Healthy Middle-aged Adults in the Framingham Study
Open accessAbstract
Importance: Nonalcoholic fatty liver disease (NAFLD) is a common condition that is most often asymptomatic. It is associated with metabolic syndrome, incident diabetes, carotid atherosclerosis, and endothelial dysfunction, conditions that in turn are strongly linked with brain damage and cognitive impairment. However, it is not known whether NAFLD is associated with structural brain measures in humans. Objective: To assess the association between prevalent NAFLD and brain magnetic resonance imaging (MRI) measures. Design, Setting, and Participants: The cross-sectional association between NAFLD and brain MRI measures was assessed from November 6, 2002, to March 16, 2011, in 766 individuals from the Offspring cohort of the Framingham Study. Participants were included if they did not have excessive alcohol intake and were free of stroke and dementia. Data analysis was conducted from December 30, 2015, to June 15, 2016. Exposures: Nonalcoholic fatty liver disease was assessed by multidetector computed tomographic scans of the abdomen. Main Outcomes and Measures: Linear or logistic regression models were used to evaluate the cross-sectional association between NAFLD and brain MRI measures, adjusting for age, sex, alcohol consumption, visceral adipose tissue, body mass index, menopausal status, systolic blood pressure, hypertension, current smoking, high-density lipoprotein and low-density lipoprotein cholesterol levels, lipid treatment, type 2 diabetes, cardiovascular disease, physical activity, insulin resistance, C-reactive protein levels, and plasma homocysteine values. Brain MRI measures included total cerebral brain volume, hippocampal and white matter hyperintensity volumes, and presence or absence of covert brain infarcts. Results: Of the 766 individuals in the study sample (410 women and 356 men; mean [SD] age at the time of brain MRI, 67 [9] years), 137 (17.9%) had NAFLD. Nonalcoholic fatty liver disease was significantly associated with smaller total cerebral brain volume even after adjustment for all the covariates included in the study (β [SE], -0.26 [0.11]; P = .02). Differences in total cerebral brain volume between those with and without NAFLD corresponded to 4.2 years of brain aging in the general sample and to 7.3 years in individuals younger than 60 years of age. No statistically significant associations were observed between NAFLD and hippocampal or white matter hyperintensity volumes or covert brain infarcts. Conclusions and Relevance: Nonalcoholic fatty liver disease is associated with a smaller total cerebral brain volume, independent of visceral adipose tissue and cardiometabolic risk factors, pointing to a possible link between hepatic steatosis and brain aging.
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“Liver biopsies from older adults revealed that the degree of liver ageing is related to the severity of nonalcoholic fatty liver disease (NAFLD),220 which increases the brain age by approximately 4.2 years.221”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [221]
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Gorelick, P. B., Scuteri, A., Black, S. E., DeCarli, C., Greenberg, S. M., Iadecola, C., Launer, L. J., Laurent, S., Lopez, O. L., Nyenhuis, D., et al. (2011) · Stroke · doi:10.1161/str.0b013e3182299496 · Cited by 3,811
Self-citationVernon, G. C., Baranova, A. V., & Younossi, Z. M. (2011) · Alimentary Pharmacology & Therapeutics · doi:10.1111/j.1365-2036.2011.04724.x · Cited by 3,116
Fox, C. S., Massaro, J. M., Hoffmann, U., Pou, K. M., Maurovich-Horvat, P., Liu, C.-Y., Vasan, R. S., Murabito, J. M., Meigs, J. B., Cupples, L. A., et al. (2007) · Circulation · doi:10.1161/circulationaha.106.675355 · Cited by 2,882
Self-citationVilar-Gomez, E., Martinez-Perez, Y., Calzadilla-Bertot, L., Torres-Gonzalez, A., Gra-Oramas, B., Gonzalez-Fabian, L., Friedman, S. L., Diago, M., & Romero-Gomez, M. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.04.005 · Cited by 2,492
Williams, C. D., Stengel, J. Z., Asike, M., Torres, D. M., Shaw, J. C., Contreras, M., Landt, C. L., & Harrison, S. A. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.09.038 · Cited by 2,182
Risk of Cardiovascular Disease in Patients with Nonalcoholic Fatty Liver Disease
Targher, G., Day, C. P., & Bonora, E. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0912063 · Cited by 1,907
Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis
Anstee, Q. M., Targher, G., & Day, C. P. (2013) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2013.41 · Cited by 1,747
Loomba, R. S., & Sanyal, A. J. (2013) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2013.171 · Cited by 1,732
The framingham offspring study. Design and preliminary data
Feinleib, M., Kannel, W. B., Garrison, R. J., McNamara, P. M., & Castelli, W. P. (1975) · Preventive Medicine · doi:10.1016/0091-7435(75)90037-7 · Cited by 926
Pou, K. M., Massaro, J. M., Hoffmann, U., Vasan, R. S., Maurovich‐Horvat, P., Larson, M. G., Keaney, J. F., Meigs, J. B., Lipinska, I., Kathiresan, S., et al. (2007) · Circulation · doi:10.1161/circulationaha.107.710509 · Cited by 915
Self-citationMitchell, G. F., van Buchem, M. A., Sigurdsson, S. O., Gotal, J. D., Jónsdóttir, M. K., Kjartansson, Ó., García, M., Aspelund, T., Harris, T. B., Gudnason, V. G., et al. (2011) · Brain · doi:10.1093/brain/awr253 · Cited by 891
Some health benefits of physical activity. The Framingham Study
Kannel, W. B. (1979) · Archives of Internal Medicine · doi:10.1001/archinte.139.8.857 · Cited by 783
Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline
Debette, S., Seshadri, S., Beiser, A., Au, R., Himali, J. J., Palumbo, C., Wolf, P. A., & DeCarli, C. (2011) · Neurology · doi:10.1212/wnl.0b013e318227b227 · Cited by 772
Self-citationNonalcoholic fatty liver disease: A precursor of the metabolic syndrome
Lonardo, A., Ballestri, S., Marchesini, G., Angulo, P., & Loria, P. (2014) · Digestive and Liver Disease · doi:10.1016/j.dld.2014.09.020 · Cited by 692
DeCarli, C., Massaro, J., Harvey, D., Hald, J., Tullberg, M., Au, R., Beiser, A., D’Agostino, R., & Wolf, P. A. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.05.004 · Cited by 680
Self-citationFrancque, S., van der Graaff, D., & Kwanten, W. J. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.04.005 · Cited by 591
Causes and Metabolic Consequences of Fatty Liver
Stefan, N., Kantartzis, K., & Häring, H. (2008) · Endocrine Reviews · doi:10.1210/er.2008-0009 · Cited by 536
Debette, S., Beiser, A., DeCarli, C., Au, R., Himali, J. J., Kelly-Hayes, M., Romero, J. R., Kase, C. S., Wolf, P. A., & Seshadri, S. (2010) · Stroke · doi:10.1161/strokeaha.109.570044 · Cited by 508
Self-citationThe role of hepatokines in metabolism
Stefan, N., & Häring, H.-U. (2013) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2012.258 · Cited by 500
Brain atrophy rates predict subsequent clinical conversion in normal elderly and amnestic MCI
Jack, C. R., Shiung, M. M., Weigand, S. D., O’Brien, P. C., Gunter, J. L., Boeve, B. F., Knopman, D. S., Smith, G. E., Ivnik, R. J., Tangalos, E. G., et al. (2005) · Neurology · doi:10.1212/01.wnl.0000180958.22678.91 · Cited by 492
Stroke Risk Profile Predicts White Matter Hyperintensity Volume: The Framingham Study
Jeerakathil, T., Wolf, P. A., Beiser, A., Massaro, J., Seshadri, S., D’Agostino, R. B., & DeCarli, C. (2004) · Stroke · doi:10.1161/01.str.0000135226.53499.85 · Cited by 479
Self-citationSpeliotes, E. K., Massaro, J. M., Hoffmann, U., Vasan, R. S., Meigs, J. B., Sahani, D. V., Hirschhorn, J. N., O’Donnell, C. J., & Fox, C. S. (2010) · Hepatology · doi:10.1002/hep.23593 · Cited by 431
Self-citationSookoian, S. C., & Pirola, C. J. (2008) · Journal of Hepatology · doi:10.1016/j.jhep.2008.06.012 · Cited by 407
Molecular pathways in non-alcoholic fatty liver disease
Auguet, T., Berlanga, A., Guiu‐Jurado, E., & Porras, J. A. (2014) · Clinical and Experimental Gastroenterology · doi:10.2147/ceg.s62831 · Cited by 395
Kim, D.-G., Krenz, A., Toussaint, L. E., Maurer, K. J., Robinson, S.-A., Yan, A., Torres, L., & Bynoe, M. S. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0467-5 · Cited by 330
Prevalence and Correlates of Silent Cerebral Infarcts in the Framingham Offspring Study
Das, R. R., Seshadri, S., Beiser, A. S., Kelly-Hayes, M., Au, R., Himali, J. J., Kase, C. S., Benjamin, E. J., Polak, J. F., O'Donnell, C. J., et al. (2008) · Stroke · doi:10.1161/strokeaha.108.516575 · Cited by 324
Self-citationWu, S., Wu, F., Ding, Y., Hou, J., Bi, J., & Zhang, Z. (2016) · Scientific Reports · doi:10.1038/srep33386 · Cited by 318
Plasma Fetuin-A Levels and the Risk of Myocardial Infarction and Ischemic Stroke
Weikert, C., Stefan, N., Schulze, M. B., Pischon, T., Berger, K., Joost, H., Häring, H., Boeing, H., & Fritsche, A. (2008) · Circulation · doi:10.1161/circulationaha.108.814418 · Cited by 315
Nutrition and physical activity in NAFLD: An overview of the epidemiological evidence
Zelber‐Sagi, S. (2011) · World Journal of Gastroenterology · doi:10.3748/wjg.v17.i29.3377 · Cited by 307
Self-citationStructural Imaging Measures of Brain Aging
Lockhart, S. N., & DeCarli, C. S. (2014) · Neuropsychology Review · doi:10.1007/s11065-014-9268-3 · Cited by 301
Self-citationInflammatory biomarkers are associated with total brain volume
Jefferson, A. L., Massaro, J. M., Wolf, P. A., Seshadri, S. S., Au, R., Vasan, R. S., Larson, M. G., Meigs, J. B., Keaney, J. F., Lipinska, I., et al. (2007) · Neurology · doi:10.1212/01.wnl.0000257815.20548.df · Cited by 277
Self-citationNonalcoholic fatty liver disease and aging: epidemiology to management.
Bertolotti, M. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i39.14185 · Cited by 270
Visceral fat is associated with lower brain volume in healthy middle‐aged adults
Debette, S., Beiser, A., Hoffmann, U., DeCarli, C. S., O’Donnell, C. J., Massaro, J. M., Au, R., Himali, J. J., Wolf, P. A., Fox, C. S., et al. (2010) · Annals of Neurology · doi:10.1002/ana.22062 · Cited by 262
Self-citationNon-alcoholic fatty liver disease and risk of cardiovascular disease
Lonardo, A., Sookoian, S. C., Pirola, C. J., & Targher, G. (2015) · Metabolism · doi:10.1016/j.metabol.2015.09.017 · Cited by 236
Sugar-sweetened beverage, diet soda, and fatty liver disease in the Framingham Heart Study cohorts
Ma, J., Fox, C. S., Jacques, P. F., Speliotes, E. K., Hoffmann, U., Smith, C. E., Saltzman, E. J., & McKeown, N. M. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.03.032 · Cited by 224
Self-citationHepatic steatosis and cardiovascular disease outcomes: An analysis of the Framingham Heart Study
Mellinger, J. L., Pencina, K. M., Massaro, J. M., Hoffmann, U., Seshadri, S. S., Fox, C. S., O’Donnell, C. J., & Speliotes, E. K. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.02.045 · Cited by 218
Self-citationSung, K., Jeong, W. S., Wild, S. H., & Byrne, C. D. (2012) · Diabetes Care · doi:10.2337/dc11-1853 · Cited by 217
Nonalcoholic fatty liver disease is associated with cognitive function in adults
Seo, S. W., Gottesman, R. F., Clark, J. M., Hernáez, R., Chang, Y., Kim, C., Ha, K. H., Güallar, E., & Lazo, M. (2016) · Neurology · doi:10.1212/wnl.0000000000002498 · Cited by 192
Abdominal Obesity and Fatty Liver
Jakobsen, M. U., Berentzen, T. L., Sørensen, T. I. A., & Overvad, K. (2007) · Epidemiologic Reviews · doi:10.1093/epirev/mxm002 · Cited by 185
Association of Plasma Total Homocysteine Levels With Subclinical Brain Injury
Seshadri, S. S., Wolf, P. A., Beiser, A., Selhub, J., Au, R., Jacques, P. F., Yoshita, M., Rosenberg, I. H., D’Agostino, R. B., & DeCarli, C. S. (2008) · Archives of Neurology · doi:10.1001/archneur.65.5.642 · Cited by 176
Self-citationYamazaki, H., Tsuboya, T., Tsuji, K., Dohke, M., & Maguchi, H. (2015) · Diabetes Care · doi:10.2337/dc15-0140 · Cited by 171
Does the brain shrink as the waist expands?
Willette, A. A., & Kapogiannis, D. (2015) · Ageing Research Reviews · doi:10.1016/j.arr.2014.03.007 · Cited by 162
Fukuda, T., Hamaguchi, M., Kojima, T., Hashimoto, Y., Ohbora, A., Kato, T., Nakamura, N., & Fukui, M. (2015) · Liver International · doi:10.1111/liv.12912 · Cited by 157
Tan, Z. S., Beiser, A., Fox, C. S., Au, R., Himali, J. J., Debette, S., DeCarli, C. S., Vasan, R. S., Wolf, P. A., & Seshadri, S. S. (2011) · Diabetes Care · doi:10.2337/dc11-0308 · Cited by 135
Self-citationInterrelationship between Fatty Liver and Insulin Resistance in the Development of Type 2 Diabetes
Sung, K., & Kim, S. H. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-2190 · Cited by 132
Should we continue to use BMI as a cardiovascular risk factor?
Franzosi, M. G. (2006) · The Lancet · doi:10.1016/s0140-6736(06)69222-2 · Cited by 124
Yamada, T., Fukatsu, M., Suzuki, S., Wada, T., Yoshida, T., & Joh, T. (2009) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2009.05998.x · Cited by 116
Nonalcoholic Fatty Liver Disease and Vascular Function
Long, M. T., Wang, N., Larson, M. G., Mitchell, G. F., Palmisano, J. N., Vasan, R. S., Hoffmann, U., Speliotes, E. K., Vita, J. A., Benjamin, E. J., et al. (2015) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.114.305200 · Cited by 90
Self-citationZelber‐Sagi, S., Lotan, R., Shibolet, O., Webb, M., Buch, A., Nitzan, D., Halpern, Z., Santo, E., & Oren, R. (2013) · Liver International · doi:10.1111/liv.12200 · Cited by 88
Self-citationDoycheva, I., Watt, K. D. S., Rifai, G., Mrad, R. A., López, R., Zein, N. N., Carey, W. D., & Alkhouri, N. (2017) · Digestive Diseases and Sciences · doi:10.1007/s10620-017-4492-3 · Cited by 85
Abdominal obesity and lower gray matter volume: a Mendelian randomization study
Debette, S., Wolf, C., Lambert, J., Crivello, F., Soumaré, A., Zhu, Y., Schilling, S., Dufouil, C., Mazoyer, B. M., Amouyel, P., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.07.022 · Cited by 82
Brain Imaging and Cognitive Predictors of Stroke and Alzheimer Disease in the Framingham Heart Study
Weinstein, G., Beiser, A., DeCarli, C. S., Au, R., Wolf, P. A., & Seshadri, S. S. (2013) · Stroke · doi:10.1161/strokeaha.113.000947 · Cited by 56
Self-citationGhareeb, D. A., Hafez, H. S., Hussien, H. M., & Kabapy, N. F. (2011) · Metabolic Brain Disease · doi:10.1007/s11011-011-9261-y · Cited by 52
Harnois, D. M. (2011) · Yearbook of Gastroenterology · doi:10.1016/j.ygas.2011.07.031 · Cited by 43
Takahashi, A., Kono, S., Wada, A., Oshima, S., Abe, K., Imaizumi, H., Fujita, M., Hayashi, M., Okai, K., Miura, I., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0174169 · Cited by 36
Liver disease as a risk factor for cognitive decline and dementia: An Under-recognized issue #
Yilmaz, Y. N., & Ozdogan, O. C. (2008) · Hepatology · doi:10.1002/hep.22752 · Cited by 32
SAPMAZ, F. P., Uzman, M., Başyığıt, S., Özkan, S., Yavuz, B., Yeniova, A. Ö., Kefeli, A., Asiltürk, Z., & Nazlıgül, Y. (2016) · Medicine · doi:10.1097/md.0000000000003280 · Cited by 31
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Roizen, M. F. (2011) · Yearbook of Anesthesiology and Pain Management · doi:10.1016/j.yane.2011.01.012 · Cited by 5
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Newton, J. L. (2008) · Hepatology · doi:10.1002/hep.22784 · Cited by 3
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Metadata
- Authors
- Weinstein, G., Zelber-Sagi, S., Preis, S. R., Beiser, A. S., DeCarli, C., Speliotes, E. K., Satizabal, C. L., Vasan, R. S., & Seshadri, S.
- Affiliations
- University of Haifa (IL)
- School of Public Health, University of Haifa, Haifa, Israel
- Boston University (US)
- University of California, Davis (US)
- Broad Institute (US)
- The Framingham Study, Framingham, Massachusetts
- Corresponding author
- Weinstein, Galit
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2018-01-01
- Volume
- 75
- Issue
- 1
- Pages
- 97
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC5833484
- OpenAlex
- W2770554136
- Cited by
- 186
- References
- 59
- Citations by year
- 2026: 19 · 2025: 28 · 2024: 35 · 2023: 30 · 2022: 24 · 2021: 19 · 2020: 17 · 2019: 12 · 2018: 2
- FWCI
- 6.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Neurology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P30AG010129)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107904, R01DK106621)
- National Institute of Neurological Disorders and Stroke (R01NS017950)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Keywords
- non-alcoholic fatty liver disease, brain volume, hippocampal hyperintensity, white matter hyperintensities, brain aging, middle-aged adults, metabolic syndrome, cognitive impairment, Framingham Offspring cohort, brain MRI, cardiovascular risk factors, insulin resistance, homocysteine
- MeSH terms
- Abdomen, Aged, Alcohol Drinking, Brain, C-Reactive Protein, Carotid Artery Diseases, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Humans, Insulin Resistance, Magnetic Resonance Imaging, Male, Middle Aged, Risk Factors, Cohort Studies, Tomography Scanners, X-Ray Computed, Prevalence, Logistic Models, Metabolic Syndrome, Non-alcoholic Fatty Liver Disease
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