’Original article

Cognitive assessment of patients with nonalcoholic

fatty liver disease
Asuman Celikbileka,*, Mehmet Celikbilekb,* and Gurbet Bozkurtc

Objective The aim of this study was to investigate cognitive performance for the first time in participants with nonalcoholic fatty
liver disease (NAFLD) using the Montreal Cognitive Assessment (MoCA).
Participants and methods In total, 70 participants with NAFLD and 73 age-matched and sex-matched healthy participants
were enrolled in this prospective cross-sectional study. The diagnosis of NAFLD was made on the basis of abdominal
ultrasonography findings. Anthropometric indices were calculated, and routine laboratory analyses were carried out for each
participant. All participants provided sociodemographic data and completed the Beck Depression Inventory-II. Cognitive
functions were evaluated using the Turkish version of the MoCA, with a cut-off score for mild cognitive impairment of less than 21
points.
Results The MoCA scores were significantly lower in participants with NAFLD than in the healthy group (P < 0.05). In addition,
more NAFLD participants than healthy participants presented with deficits in the visuospatial (P < 0.05) and executive function
domains (P < 0.05). In the multivariate model, education level [2.79 (1.12–6.96); P < 0.05] and area of residence [5.68
(2.24–14.38); P < 0.001] were associated independently with cognitive dysfunction in both the NAFLD and the healthy groups.
The MoCA scores were correlated negatively with fibrosis 4 scores in NAFLD participants (r = − 0.359; P < 0.05). However,
hepatosteatosis grade and the presence of metabolic syndrome were not correlated with MoCA scores in the NAFLD group
(P > 0.05).
Conclusion Our results show that NAFLD patients may have early or subtle cognitive dysfunction, including in the visuospatial
and executive function domains, as indexed by scores on the MoCA test. Further targeted psychometric testing will be required
to confirm the presence of cognitive impairment in this population. Eur J Gastroenterol Hepatol 00:000–000
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Introduction hyperglycemia and/or hypertension, may influence both

Metabolic syndrome (MetS) refers to a cluster of condi-
tions, including obesity, hypertension, dyslipidemia, and
insulin resistance. There is general agreement that the
prevalence of MetS is increasing, primarily because of
lifestyle factors and the well-documented increase in obe-
sity levels [1]. Cumulative evidence from different
population-based studies suggests that MetS and its com-
ponents have a negative effect on cognition [2–5]. In
numerous recent studies, obesity, diabetes, and/or hyper-
tension were associated with cognitive impairment, ran-
ging from mild cognitive changes to dementia [6–8].
However, the underlying mechanism linking MetS and its
components to cognitive impairment is not fully under-
stood. One possibility is that microcirculatory changes,
mainly because of metabolic imbalances manifested in
European Journal of Gastroenterology & Hepatology 2018, 00:000–000
Keywords: cognitive dysfunction, executive functioning, Montreal Cognitive
Assessment, nonalcoholic fatty liver disease, visuospatial domain
Departments of aNeurology, bGastroenterology and cPsychology, Bozok
University, School of Medicine, Yozgat, Turkey
Correspondence to Asuman Celikbilek, MD, Department of Neurology, School of
Medicine, Bozok University, Yozgat 66200, Turkey
Tel: + 90 505 653 2615; fax: + 90 354 217 1072;
e-mail: asunebioglu@yahoo.com
*Asuman Celikbilek and Mehmet Celikbilek both contributed equally to the writing
of this article.
Received 23 February 2018 Accepted 10 March 2018
the structure and the function of small blood vessels,
potentially causing alterations in cerebral blood flow and,
by extension, disruption of blood–brain barrier integrity
and function [9,10]. Certain cytokines, such as interleukin
1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α), were
associated with cognitive decline in previous studies [11].
In particular, TNF-α and IL-6 are known to be present in
specific brain areas, including the hypothalamus and the
hippocampus, and are both involved in neurogenesis,
synaptic transmission, and plasticity [11]. Higher levels of
these cytokines might contribute toward the development
of neuronal dysfunction and death, as well as memory
impairments [11,12]. Another factor in cognitive decline
may be the neurotrophin, brain-derived neurotrophic fac-
tor, which is produced by hypothalamic neuronal cells and
regulates food intake and body weight in experimental
animals and humans [13]. Brain-derived neurotrophic
factor, which is mainly present in the hippocampus and the
cortex (both of which are critically involved in cognition),
plays a crucial role in the neuroplasticity involved in
learning and memory, especially hippocampal-dependent
learning, as confirmed by animal studies [14,15].
MetS and its components are highly prevalent in par-
ticipants with nonalcoholic fatty liver disease (NAFLD),
which is now considered a precursor to MetS [16].
NAFLD is a chronic liver disease that affects approxi-
mately one-third of the world’s population and 30% of the
US population [17]. NAFLD is mainly induced by the

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2 European Journal of Gastroenterology & Hepatology
consumption of a high-fat diet and can range from simple
steatosis (fatty liver) or steatohepatitis (fatty liver with cell
injury and inflammation) to hepatic fibrosis or cirrhosis
[18]. In recent years, liver dysfunction has been shown to
affect cognitive abilities negatively [19]. Animal studies
have shown that a high-fructose diet impairs hippocampal-
dependent memory in rats [20,21]. This finding is impor-
tant because the hippocampus is integral to many types of
learning and memory [22], and a high-fructose diet, by
increases in triglycerides, impairs memory by causing
hippocampal insulin resistance [20,21,23]. In a recent
experimental study, Ghareeb et al. [24] reported that
NAFLD induced disturbances in neurotransmitter activ-
ities, accompanied by oxidative stress and metabolic dis-
orders, thereby serving as a risk factor for brain
dysfunction and brain tissue damage in NAFLD rats. More
recently, Kim et al. [25] showed that NAFLD-related
chronic inflammation outside of the brain can induce a
secondary increase in neuroinflammation and neurode-
generation in mice, in turn leading to neuronal death in
cortical and hippocampal areas in the absence of any
genetic predisposition. Moreover, removal of mice from a
high-fat diet regimen during acute NAFLD reversed liver
pathology and decreased signs of neuroinflammatory and
neurodegenerative changes [25]. However, clinical data on
cognitive functioning in NAFLD are limited. A study by
Elliott et al. [26] examined the cognitive symptoms of
NAFLD by a cognitive failure questionnaire, which
included items pertaining to memory, attention, con-
centration, forgetfulness, word-finding ability, and confu-
sion in 224 participants with biopsy-proven NAFLD. They
observed that increased cognitive difficulties were asso-
ciated independently with functional difficulties in the
NAFLD group compared with a healthy control group. In
addition, a recent cross-sectional study by Seo et al. [27]
examined the association between NAFLD and cognitive
impairment using computer-based tests of attention and
reaction times. Their study included 4472 middle-aged
adults drawn from the Third National Health and
Nutritional Examination Survey of Korea [27]. They
concluded that NAFLD was associated independently with
reduced cognitive performance, independent of cardio-
vascular disease and its risk factors. In the present study,
we hypothesized that NAFLD, which is closely related to
MetS, may also show a relationship with cognitive
impairment. Although we did not study the candidate
biomarkers of the biological mechanisms underlying this
association, we speculate that impaired vasculature
because of metabolic dysfunction, with a coincident
proinflammatory state, may induce neuroinflammatory
cytokines, thereby promoting neuronal damage in brain
regions critical to cognition. To date, the Mini–Mental
State Examination (MMSE) has been used most commonly
to index cognitive impairment in metabolic disorders [28].
However, the Montreal Cognitive Assessment (MoCA),
which is more sensitive and specific for mild cognitive
impairment (MCI) [29], was used in some studies to
demonstrate cognitive impairment in MetS, diabetes, and
chronic atrial fibrillation [30–32]. However, no previous
study has applied the MoCA to an NAFLD cohort.
Therefore, in this study, we investigated cognitive perfor-
mance in participants with NAFLD using the MoCA.
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Month 2018 • Volume 00 • Number 00
Participants and methods
Study population
A total of 70 consecutive participants with NAFLD,
recruited from a Gastroenterology Outpatient Clinic, and
73 age-matched and sex-matched healthy participants
from the outpatient clinics and hospital staff, ranging from
18 to 70 years old, were enrolled in this prospective cross-
sectional study. The study was carried out at Bozok
University Medical Faculty Hospital in the Yozgat region
(a rural area of Turkey) between September 2013 and
September 2014. Participants with malignancies, chronic
renal, hepatic, or cardiovascular disease, thyroid disease, a
history of dementia, psychiatric and/or central nervous
system disorders (such as traumatic brain injury, multiple
sclerosis, etc.), pregnancy, or morbid obesity, and those
who were current smokers or used drugs known to cause
fatty liver, or who had vitamin B12 or folate deficiency
and/or memory problems in daily life, were excluded from
the study. Participants with a history of alcohol con-
sumption, bile duct dilatation, hepatic mass, hepatitis,
viral or autoimmune liver disease, liver cirrhosis, or
hepatic surgery were also excluded.
Data collection
Comprehensive sociodemographic and clinical data were
collected, including demographic characteristics (age and
sex), comorbid conditions (diabetes mellitus, hypertension,
and/or hyperlipidemia), marital status (single, married, or
divorced), education level (illiterate, primary school, sec-
ondary school, high school, or university), and area of
residence (village, town, or city). All participants com-
pleted the Beck Depression Inventory-II; those with a score
of 14 or higher were excluded from the study [33].
Systolic blood pressure and diastolic blood pressure
were obtained from two independent measurements. Waist
circumference was measured for each participant and BMI
was calculated as weight in kilograms divided by height in
meters squared [34]. MetS was diagnosed according to the
National Cholesterol Education Program Adult Treatment
Panel III criteria [35].
Using standard laboratory methods, venous blood
samples were obtained from the antecubital vein after an
overnight fast for the measurement of fasting glucose,
creatinine, renal and liver function, complete blood count,
and lipid profile. The study protocol was approved by the
local research ethics committee of Bozok University.
Written informed consent was obtained from all
participants.
Nonalcoholic fatty liver disease assessment
NAFLD was diagnosed by abdominal ultrasonography
(US), which is a widely accessible imaging technique with
high diagnostic accuracy and reliability with respect to
fatty liver [36]. All US examinations were performed by
the same experienced radiologist, who was blinded to the
research design, using a commercially available US scanner
(Alpha 6; Japan Medical Systems, Tokyo, Japan) equipped
with a 2.0–5.0 MHz convex probe. The diagnosis of
NAFLD was made on the basis of increased echogenicity
on US that was compatible with fatty infiltration of the
liver with or without elevated alanine transaminase (ALT)
 Cognitive assessment of NAFLD Celikbilek et al. www.eurojgh.com 3

levels [37]. Hepatosteatosis was graded on US as mild, size calculations for the primary analysis are given as
moderate, or severe as described previously [38]. Of the Cohen’s d or φ coefficient. We used Pearson’s correlations
participants with NAFLD, 24 (34.3%) had mild, 41 to examine the relationships between MoCA scores and the
(58.6%) had moderate, and five (7.1%) had severe hepa- markers of NAFLD severity, such as FIB4 and hepatostea-
tosteatosis. The fibrosis 4 (FIB4) index (on the basis of age, tosis grade, and the presence of MetS in participants with
aspartate transaminase and ALT levels, and platelet count) NAFLD. Risk factors postulated to be linked to poorer
is used to evaluate hepatic fibrosis. The FIB4 score was cognition were included in a univariate analysis. Differences
calculated as follows: [age (years) × aspartate transaminase were considered statistically significant at a P value of less
(IU/l)]/[platelet count (109/l) × ALT (IU/l)]1/2 [39]. than 0.05 in univariate logistic regression analysis and
backward stepwise elimination was performed using the
Cognitive function assessment Wald statistic at the P value of less than 0.05 level to
determine independent predictors of cognitive performance.
One neuropsychologist, blinded to group identity, used the
Covariates of diabetes mellitus, hypertension, hyperlipi-
MoCA to evaluate cognitive functions. Six domains of
demia, and MetS were coded as dichotomous variables
cognition were assessed: visuospatial abilities, memory,
(yes/no). Marital status was divided into two categories:
executive functioning, attention, language, and orienta-
single or divorced (group 1) and married (group 2).
tion. In the MoCA, visuospatial abilities are evaluated by a
Education level was also divided into two categories: less
clock-drawing task (three points) and a three-dimensional
than 8 years of education (group 1) and more than
cube-copying task (one point). The memory assessment
8 years of education (group 2). Area of residence was
involves delayed recall (∼5 min) of five nouns subsequent
classified as village or town (group 1) and city (group 2).
to two learning trials (five points). Executive functioning is
For each factor, odds ratios were calculated with 95%
assessed using an alternation task adapted from the Trail
confidence intervals. Analyses were carried out using the
Making B task (one point), a phonemic fluency task (one
SPSS software (version 15.0; SPSS Inc., Chicago, Illinois,
point), and a two-item verbal abstraction task (two
USA). Statistical significance was set at a P value of less
points). Attention is evaluated using a sustained attention
than 0.05.
task (target detection indicated by tapping; one point), a
serial subtraction task (three points), and digits forward
and backward tasks (one point each). Language is assessed Results
using a three-item confrontation naming task featuring
The demographic and laboratory data of the healthy and
low-familiarity animals (lion, camel, rhinoceros; three
NAFLD groups are summarized in Table 1. No significant
points), repetition of two syntactically complex sentences
differences were found between the two groups in age or
(two points), and the aforementioned fluency task.
sex (P > 0.05), and no significant associations were
Orientation to time and place is also evaluated (six points).
observed in BMI, waist circumference, systolic blood
Total scores range from 0 to 30, with a score less than 26
pressure, and diastolic blood pressure between these
indicating MCI in the original version of the MoCA [29].
groups (P > 0.05). However, fasting glucose (P < 0.05),
However, we used the Turkish version of the MoCA
liver enzyme (P < 0.001), and triglyceride levels (P < 0.05)
(MoCA-TR), which has a cut-off score for MCI of less
were significantly higher, whereas total bilirubin (P < 0.05)
than 21 points [40]. The MoCA-TR features certain cul-
and high-density lipoprotein cholesterol (P < 0.001) levels
tural and linguistic changes from the original version, and
were significantly lower in participants with NAFLD
shows high sensitivity and specificity for detecting MCI in
compared with those in the healthy group (Table 1).
patients who perform normally on the MMSE-TR. Total
Comorbidities, such as diabetes mellitus and hypertension,
scores on the MoCA-TR range from 0 to 30, with higher
were also significantly more prevalent in participants with
scores indicating better cognition and scores below 21
NAFLD than in the healthy group, but the incidence of
indicating cognitive dysfunction [40,41]. The highest
hyperlipidemia and the presence of MetS were similar
possible scores on the cognitive domains of visuospatial
between the groups (P > 0.05). The two groups were also
abilities, memory, executive functioning, attention, lan-
similar with respect to marital status, education level, and
guage, and orientation are 4, 5, 4, 6, 5, and 6, respectively.
area of residence (P > 0.05; Table 1). Table 2 shows that
Participants scoring below a certain threshold (< 4 points
the total MoCA scores were normally distributed and were
for visuospatial abilities, <5 points for memory, <4 points
significantly lower in the NAFLD group than in the heal-
for executive functioning, <6 points for attention, <5
thy group (P < 0.001; Fig. 1). We observed deficits in each
points for language, and <6 points for orientation) in any
cognitive domain for some participants. Furthermore,
of these domains are classified as having deficits, which
compared with the controls, a greater number of NAFLD
may indicate cognitive dysfunction.
participants presented with deficits in the visuospatial
(P < 0.05) and executive functioning (P < 0.05) domains
Statistical analysis
(Table 2).
A Shapiro–Wilks test, histograms, and q-q plots were used In the multivariate model, education level [2.79
to test the normality of the data, and Levene’s test was (1.12–6.96); P < 0.05] and area of residence [5.68
used to assess homogeneity of variance. Independent- (2.24–14.38); P < 0.001] were associated independently
sample t-tests and Mann–Whitney U tests were used to with cognitive dysfunction in both groups (odds ratios,
compare group differences in continuous variables, and 95% confidence intervals; Table 3). Dysfunction was more
χ2 tests were used to assess differences in categorical vari- likely in those reporting lower education levels (including
ables. Values are expressed as frequencies and percentages, primary or secondary school education) and in those living
mean and SD, or medians and interquartile ranges. Effect in a rural area (village or town).

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4 European Journal of Gastroenterology & Hepatology Month 2018 • Volume 00 • Number 00

Table 1. Demographic and laboratory data of the healthy and nonalcoholic fatty liver disease groups
Variables Healthy (n = 73) NAFLD (n = 70) P Effect size
Sociodemographic variables
Age (years) 43.9 ± 9.3 46.9 ± 10.1 0.067 − 0.30
Female sex 49 (67.1) 41 (58.6) 0.290 0.08
BMI (kg/m2) 34.93 (30.83–36.84) 35.02 (30.1–37.7) 0.682 − 0.07
WC (cm) 105 (96–112) 103 (95–110) 0.165 0.27
SBP (mmHg) 130 (120–140) 130 (120–140) 0.815 − 0.07
DBP (mmHg) 80 (80–90) 80 (80–90) 0.468 − 0.21
Marital status
Single 4 (5.5) 2 (2.8) 0.741 0.03
Married 69 (94.5) 67 (95.7)
Divorced 0 (0) 1 (1.4)
Education level
Illiterate 0 (0) 5 (7.1) 0.726 0.03
Primary school 38 (52.1) 38 (54.3)
Secondary school 13 (17.8) 4 (5.7)
High school 12 (16.4) 14 (20)
University 10 (13.7) 9 (12.9)
Area of residence
Village 6 (8.2) 6 (8.6) 0.219 0.10
Town 20 (27.4) 26 (37.1)
City 47 (64.4) 38 (54.3)
Laboratory markers
Fasting glucose (mg/dl) 92.1 ± 8.2 95.6 ± 12.7 0.046 − 0.34
Creatinine (mg/dl) 0.79 (0.71–0.87) 0.80 ± 0.70–0.89 0.629 −0
WBC (103/mm3) 7.82 (7.07–8.82) 7.81 (6.76–9.34) 0.787 − 0.17
Hemoglobin (mg/dl) 13.4 (12.6–15.1) 14.3 (12.9–15.3) 0.073 0.12
Platelet (103/mm3) 243 (212.5–275) 244.5 (200–295.7) 0.958 − 0.02
AST (IU/l) 17 (14–21.5) 22.5 (17–31.2) < 0.001 − 0.76
ALT (IU/l) 15 (12–23) 25.5 (17–39.5) < 0.001 − 0.91
GGT (IU/l) 17 (12–23.5) 32 (19.7–50) < 0.001 − 0.82
ALP (IU/l) 62.1 ± 17.5 73.4 ± 18.4 < 0.001 − 0.63
Total bilirubin (mg/dl) 0.90 (0.60–1) 0.70 (0.50–0.92) 0.030 0.32
Direct bilirubin (mg/dl) 0.30 (0.20–0.40) 0.30 (0.21–0.40) 0.215 − 0.06
TC (mg/dl) 189 (169.5–213.5) 191.5 (161–216.2) 0.480 0.14
TG (mg/dl) 108 (86.5–166.5) 158.5 (125–210.7) 0.001 − 0.42
HDL-C (mg/dl) 47 (38.5–53) 40 (35–45) < 0.001 0.39
LDL-C (mg/dl) 120.2 (104.9–135.3) 126.6 (94.2–141.4) 0.937 − 0.02
Comorbidities
DM 3 (4.1) 21 (30) < 0.001 0.35
HT 2 (2.7) 14 (20) 0.001 0.27
HL 1 (1.4) 5 (7.1) 0.085 0.14
MetS 25 (34.25) 34 (48.57) 0.082 0.14

Values are expressed as n (%), mean ± SD or median (25th–75th percentiles).

Effect size calculations were given as Cohen’s d or φ coefficient.
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DBP, diastolic blood pressure; DM, diabetes mellitus; GGT, γ-glutamyl-
transferase; HDL-C, high-density lipoprotein cholesterol; HL, hyperlipidemia; HT, hypertension; LDL-C, low-density lipoprotein cholesterol; MetS, metabolic syndrome;
NAFLD, nonalcoholic fatty liver disease; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride; WBC, white blood cells; WC, waist circumference.
Bold values indicate statistically significant (P < 0.05).

Table 2. Overall Montreal Cognitive Assessment scores and number of

the healthy participants and nonalcoholic fatty liver disease participants
showing point deficits within each cognitive domain
Variables Healthy (n = 73) NAFLD (n = 70) P
MoCA scores a
21.08 ± 3.93 18.17 ± 5.20 < 0.001
Frequency of cognitive 32 (43.8) 49 (70) 0.002
dysfunctionb
MoCA itemsc
Visuospatial 37 (50.7) 53 (75.7) 0.002
Memory 67 (91.8) 68 (97.1) 0.163
Executive 49 (67.1) 58 (82.9) 0.030
Attention 60 (82.2) 60 (85.7) 0.567
Language 62 (84.9) 60 (85.7) 0.895
Orientation 25 (34.2) 30 (42.9) 0.290

Values are expressed as n (%) or mean ± SD.

MoCA, Montreal Cognitive Assessment; NAFLD, nonalcoholic fatty liver disease.
a
The lower MoCA score represents the poorer cognitive performance (over 30
points).
b
Cognitive functions were evaluated using the Turkish version of the MoCA, with a
cut-off score for mild cognitive impairment of less than 21 points.
c
The numerical data indicate the number of the affected individuals showing point Fig. 1. Total Montreal Cognitive Assessment (MoCA) scores in healthy
deficits within each MoCA item. participants and nonalcoholic fatty liver disease (NAFLD) participants.
Bold values indicate statistically significant (P < 0.05).

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 Cognitive assessment of NAFLD Celikbilek et al. www.eurojgh.com 5

Table 3. Univariate and multiple logistic regression analyses to identify on computer-based cognitive tests. In line with these
the predictors of cognitive dysfunction in the healthy participants and results, we found that NAFLD participants had sig-
nonalcoholic fatty liver disease participants nificantly lower MoCA scores (in a range indicating cog-
Univariate Multiple nitive dysfunction) than the healthy group. Accordingly,
the incidence of cognitive dysfunction was higher in the
Variables OR (95%CI) P OR (95%CI) P
NAFLD group. We also found that the presence of
Age 1.06 (1.02–1.09) 0.004 – – NAFLD was a risk factor for cognitive dysfunction in
Sex 0.54 (0.27–1.08) 0.081 – –
Alkaline 1.02 (1.00–1.04) 0.024 – – univariate analysis. Despite the lack of a similar associa-
phosphatase tion in a multivariate model (possibly because of the small
Triglyceride 1.01 (1.00–1.01) 0.017 – – sample size), we speculate that the relationship between
DM 2.09 (0.81–5.40) 0.129 – –
HT 6.27 (1.37–28.72) 0.018 – –
NAFLD and cognitive dysfunction observed in the uni-
MetS 2.21 (1.10–4.42) 0.025 – – variate analysis was not coincidental. Nonetheless, we
Marital status 0.98 (0.21–4.54) 0.978 – – could not determine whether NAFLD and cognitive dys-
Education level 4.12 (1.95–8.73) < 0.001 2.79 (1.12–6.96) 0.028
Area of residence 4.71 (2.22–9.99) < 0.001 5.68 (2.24–14.38) < 0.001
function are conditions on the same spectrum. In contrast
Presence of 2.99 (1.50–5.96) 0.002 – – to previous studies, we evaluated cognitive functioning
NAFLD using the MoCA because it is more sensitive and specific to
MCI [29]. The participants in our study were not screened
Cognitive functions were evaluated using the Turkish version of the MoCA, with a
cut-off score for mild cognitive impairment of less than 21 points. a priori for cognitive deficits and thus would likely have
95%CI, 95% confidence intervals; DM, diabetes mellitus; HT, hypertension; MetS, ‘normal’ scores on the MMSE, which represents the
metabolic syndrome; NAFLD, nonalcoholic fatty liver disease; OR, odds ratio. instrument most widely used by frontline physicians. In
Bold values indicate statistically significant (P < 0.05).
fact, as a screening instrument, the MoCA is preferable
because it encompasses a broader range of cognitive
In the correlation analysis, the MoCA score was cor- domains, including abstract thought and executive func-
related negatively with age (r = − 0.450; P < 0.001) and the tioning, and enables a more rapid assessment [29]. The
FIB4 score in NAFLD participants (r = − 0.359; P < 0.05), MoCA can be administered in 10 min, fits on one page,
but no correlations were observed with either hepatos- and is therefore appropriate for use in the context of the
teatosis grade or the presence of MetS (P > 0.05). generally limited assessment window available in the
clinical setting.
Discussion We observed cognitive deficits mainly in the executive
functioning and visuospatial domains on the MoCA in our
Three main findings emerged from this study. First, MoCA NAFLD participants. Executive functioning, which is
scores were significantly lower, including in the visuospa- associated with the frontal lobe (especially the prefrontal
tial and executive functioning domains, in the participants area and the orbitofrontal cortex), encompasses planning,
with NAFLD compared with those in the healthy group. purposeful organized behavior, abstract thought, response
Second, education level and area of residence were asso- inhibition, mental flexibility, working memory, and
ciated independently with cognitive dysfunction in a mul- self-control [42]. The MoCA measures these executive
tivariable model. Third, MoCA scores were correlated functions in triplicate: it includes an alternation task
negatively with age and FIB4 scores in participants adapted from the Trail Making B task, a phonemic fluency
with NAFLD. task, and a two-item verbal abstraction task. Lower scores
NAFLD is characterized by an accumulation of lipids in indicate greater impairment in executive functioning.
the hepatocytes, and infiltration of inflammatory immune Intact executive functions have been identified as crucial
cells into the liver parenchyma (leading to the secretion of for the management of chronic conditions [32]. Several
proinflammatory cytokines that potentially cause liver studies have shown that executive functioning is impaired
damage) [18]. Recent data suggest that proinflammatory in chronic metabolic conditions, probably because of
cytokines, such as IL-1, IL-6, and TNF, also serve specific chronic vascular pathology in the white matter circuits
functions in synaptic plasticity, learning, and cognitive that connect the subcortical nuclei to frontal cortical
processing [11]. If so, NAFLD – a highly inflammatory areas [32,42,43]. NAFLD, which is another inflammatory
condition – is likely to also promote similar damage in metabolic condition, may cause a similar disturbance in
neurons involved specifically in cognition. Experimental these connections, possibly limiting an individual’s ability
studies, and a limited number of clinical investigations, to recognize their own symptoms and make decisions on
have pointed to a link between NAFLD and poor cognitive the targeted behavior. Spitznagel et al. [19] examined
functioning. However, it is unclear whether liver damage postoperative cognitive functions using the WebNeuro
directly impacts cognition or serves as a trigger for sub- computerized cognitive test battery, which measures
sequent deleterious inflammation or metabolic dysfunc- executive function, attention, and memory, in individuals
tion. According to animal models, chronic inflammation in with or without liver fibrosis at the time of bariatric
association with NAFLD can induce a secondary neu- surgery. They found poorer cognitive performance post-
roinflammation, which is followed by neurodegeneration operatively on executive function and memory tasks in the
and neuronal death in specific brain regions in NAFLD bariatric patients with liver fibrosis, which represents
rats [24,25]. In a clinical study, Elliott et al. [26] reported an advanced form of NAFLD. They concluded that the
cognitive difficulties on a cognitive symptom questionnaire accumulation of connective tissue in the liver occurs in the
among NAFLD participants. Similarly, Seo et al. [27] context of metabolic dysfunction and inflammatory pro-
showed that, among Korean adults, NAFLD was asso- cesses and in turn may affect cognition [19]. However, our
ciated independently with reduced cognitive performance NAFLD participants showed deficits in the visuospatial

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6 European Journal of Gastroenterology & Hepatology
domain more frequently than the healthy group.
Visuospatial ability includes spatial memory, navigation,
and mental representation of three-dimensional space [44].
The MoCA measures this ability through a two-step test,
composed of a clock-drawing task and a three-dimensional
cube-copying task. Lower scores indicate greater impair-
ment in visuospatial ability. It is difficult to explain why
visuospatial abilities are impaired in metabolic disorders.
In previous reports, overweight adolescents showed poorer
performance in visuospatial organization [45] and mental
rotation tasks [46] compared with healthy-weight con-
trols. In their recent functional magnetic resonance ima-
ging study, García-García et al. [47] reported decreased
functional connectivity of the middle frontal gyrus and the
lateral occipital cortex with the overall brain network in
obese participants; these regions feature in several brain
circuits involved in the signaling of perceptual processes,
attention, and executive and motor functions. In a very
recent work, Tsai et al. [48] investigated behavioral and
cognitive electrophysiological functioning in 26 obese
children during the performance of a visuospatial attention
task. The obese children showed poorer behavioral per-
formance, with slower reaction times, lower accuracy
rates, and smaller potentials compared with the healthy
group. These two studies showed that obesity is associated
with impairment in the central processing of cognition
during executive functioning, with concomitant disen-
gagement of visuospatial attention [47,48]. This may
provide a clue as to why impairments were observed in
these domains on the MoCA in metabolic disorder
patients, but any such explanation for the impairments
observed in NAFLD is currently lacking. Future studies
should examine the multifaceted nature of these domains
by using instruments that are more precise than the
MoCA.
In the present study, the independent risk factors for
cognitive dysfunction were sociodemographic factors, such
as education level and area of residence. However, the
relatively small sample size did not allow us to assess the
effects of other independent parameters. Well-known fac-
tors that promote positive neuroplasticity, thereby
increasing cognitive reserve, include education, physical
activity, social interaction, intellectual pursuits, and cog-
nitive remediation [49]. Education may also have an
indirect effect on cognition by promoting healthful beha-
viors during aging. According to Borovok et al. [50],
spatial memory depends on the hippocampus, which is
probably relatively vulnerable to aging. In support of this,
MoCA scores in our study were correlated negatively with
age; poor performance on spatial tasks in particular was
noted with older age. Although our NAFLD participants
were slightly older than the healthy group, we did not
consider this to be a potential confounder because the
difference was not statistically significant. Factors that
promote negative neuroplasticity, and consequently
decreased cognitive reserve, include poor health, nutrition,
and sleep hygiene, as well as substance abuse, depression,
and anxiety [49]. Individuals with a lower socioeconomic
status and those who do not exercise frequently, receive
medical care, and eat healthier diets containing fresh fruit
and vegetables typically live in rural areas as found in our
study population, and this may explain why the average
MoCA score of our healthy participants was at the lower
Copyright r 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Month 2018 • Volume 00 • Number 00
limit of our cut-off score for MCI of less than 21 points.
Finally, the MoCA scores in our study were correlated
negatively with FIB4 scores. As the accumulation of con-
nective tissue often coincides with increased levels of
inflammatory cytokines [51], which have deleterious
effects on cognitive processing when present in large
quantities [11], it is not surprising that participants with
NAFLD and considerable liver damage can show poorer
cognitive functioning than those with milder forms of
NAFLD. However, we failed to find a correlation between
cognitive dysfunction and hepatosteatosis grade, which
might be attributable to an insufficient number of partici-
pants in the hepatosteatosis subgroups; larger cohorts may
be needed to draw any firm conclusion.
The present study had certain limitations. First, the
sample size was relatively small. Second, we used a cross-
sectional design and thus could not determine causality.
Third, we cannot exclude an influence on cognition from
residual confounding factors, such as nutritional, sleeping,
and physical exercise habits. Fourth, we did not confirm
fatty liver histologically because of the ethical concerns
associated with using an asymptomatic population for
research purposes. Fifth, there may have been a selection
bias because we included illiterate participants, although
we also carried out a supplementary analysis after
excluding those participants. Our results did not change
significantly in either MoCA scores or MoCA items
(visuospatial and executive). Yancar Demir et al. [52]
noted that the applicability of the MoCA did not differ
according to education level among a Turkish population,
with the exception of the language domain.
Conclusion
In conclusion, to the best of our knowledge, this is the first
study to use the MoCA for the initial screening of cognitive
performance in participants with NAFLD. Our data show
that NAFLD patients may have early or subtle cognitive
dysfunction, including in the visuospatial and executive
function domains, on the MoCA. We suggest that assess-
ments of NAFLD patients should also include a brief
cognitive screening test, such as the MoCA, to optimize
management, which could be valuable from a preventive
perspective.
Acknowledgements
Conflicts of interest
There are no conflicts of interest.
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