Is there an association between non-alcoholic fatty liver ...

George et al. BMC Geriatrics (2022) 22:47 https://doi.org/10.1186/s12877-021-02721-w

RESEARCH

Is there an association between non-alcoholic fatty liver disease and cognitive function? A systematic reviewElena S. George*, Surbhi Sood, Robin M. Daly and Sze‑Yen Tan

Abstract

Background: Non‑alcoholic fatty liver disease (NAFLD) is represented as the most common liver disease worldwide. NAFLD is associated with metabolic risk factors underpinned by insulin resistance, inflammation and endothelial dysfunction, leading to extrahepatic changes in central nervous diseases such as cognitive impairment, Alzheimer’s disease and dementia. The aim of the review is to explore the association between NAFLD and cognitive function.

Methods: Using the PRISMA guidelines, a systematic electronic literature search was conducted in four databases: MEDLINE, PsychINFO, Embase and CINAHL from inception until March 2021. Neuropsychological tests utilised within each study were grouped into relevant cognitive domains including ‘general cognition’, ‘reasoning’, ‘mental speed, attention and psychomotor speed’, ‘memory and learning’, ‘language’, ‘visuospatial perception’ and ‘ideas, abstraction, figural creations and mental flexibility’.

Results: Eleven observational studies that involved 7978 participants with a mean age of 51 years were included. Those with NAFLD had poor cognitive performance in three cognitive domains, including ‘general cognition’, ‘mental speed, attention and psychomotor speed’, and ‘ideas, abstraction, figural creations and mental flexibility’.

Conclusion: The observed results from the 11 included studies showed that NAFLD was associated with lower cog‑nitive performance across several domains. However, studies conducted to date are limited to observational designs and are heterogeneous with varying diagnostic tools used to assess cognitive function.

Trial registration: PROSPERO Registration: CRD42 02016 1640.

Keywords: NAFLD, NAFLD, NASH, Cirrhosis, Cognition, Cognitive function, Cognitive impairment

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BackgroundNon-alcoholic fatty liver disease (NAFLD) is recog-nised as the most prevalent liver disease affecting approximately 30% of adults in Australia with simi-lar, high rates in the United States [1–4]. The burden of NAFLD continues to rise significantly in Australia with current estimates of 5.5 million cases in 2019, with expectations of seven million cases by 2030 [1, 5].

NAFLD is defined as a spectrum of diseases related to hepatic fat deposition, ranging from non-alcoholic fatty liver (NAFL) (simple steatosis) to non-alcoholic stea-tohepatitis (NASH), which can progress to increased fibrosis, cirrhosis and hepatocellular carcinoma [3, 6]. Progression from NAFLD to NASH is often described using the “two hit” hypothesis. The “first hit” consists of lipid accumulation of fatty acids, increasing susceptibil-ity of hepatocytes to secondary insults such as oxida-tive stress, insulin resistance and over production and release of pro-inflammatory cytokines. This can lead to the “second hit” which promotes steatohepatitis,

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*Correspondence: [email protected] of Exercise and Nutrition Sciences, Institute for Physical Activity and Nutrition (IPAN), Deakin University, Geelong, Victoria 3220, Australia

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of 19George et al. BMC Geriatrics (2022) 22:47

chronic inflammation and fibrosis [7]. NAFLD occurs in the absence of excessive alcohol consumption and is associated with a range of common chronic disease risk factors such as insulin resistance, hypertension, obesity and visceral fat accumulation, and dyslipidaemia [1, 6]. Such risk factors are known to be elucidated by inflam-mation and oxidative stress, which also play a role in extrahepatic diseases, including central nervous system diseases such as mild cognitive impairment, Alzhei-mer’s disease, and dementia [8–10].

The global number of individuals living with demen-tia is 50 million [11], with the prevalence of cogni-tive impairment and dementia rising and estimated to increase amongst older adults (60 years and above) to approximately 2 billion by 2050, accounting for 22% of the world’s population [12]. Cognitive function encom-passes multiple mental abilities and skills in reasoning, perception, memory, verbal and mathematical ability and problem solving [10, 13, 14]. Cognitive impair-ments have been associated with reduced ability to per-form complex tasks such as driving and work-related activities leading to impaired quality of life and in more serious cases, premature mortality [15]. Cardio-vascular disease (CVD), type 2 diabetes (T2DM) and metabolic syndrome (MetS) frequently co-exist with NAFLD and are also considered risk factors for cog-nitive decline [10] and dementia which are increased with ageing [16–18]. Individuals with NAFLD have high rates of metabolic syndrome components includ-ing dyslipidaemia, hypertension, abdominal obesity and insulin resistance, and there is also accumulating evi-dence that individuals with NAFLD have an increased risk of carotid atherosclerosis and carotid intima media thickness; all of which have been reported to contribute towards cognitive impairment [19, 20].

Previous cross-sectional and case-control studies have found that NAFLD is associated with poorer cog-nitive function across a number of cognitive domains as assessed using numerous common psychometric tests [21–23]. Studies in participants with NAFLD and hepatic encephalopathy have reported that they have lower brain volume [21], inflammation and hyperam-monemia [24], all of which are associated with cog-nitive impairment. Despite the known link between NAFLD and various cardiometabolic-related diseases and the underlying mechanisms which drive these chronic diseases as well as cognitive decline, to date there has been no published systematic review summa-rising the relationship between NAFLD and cognitive impairment. Thus, the aim of this review was to sys-tematically search the literature to explore the associa-tion between NAFLD and cognitive function.

MethodsAll methodology related to the analysis was specified prior to the literature search and detailed in a protocol registered with PROSPERO (CRD42020161640).

Search strategyThe review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [25], including independent execution of literature search and bias assessment, completed by author SS. MEDLINE, PsychINFO, Embase and CINAHL electronic databases were searched from inception until March 2021. The search terms were: (Cognit* or “Processing speed” or “mini mental state examination” or MMSE; Neuropsych* or Neurocog-nit* or Metacognit* or Recall or Memory or “Executive function” or “Verbal Fluency” or “Reaction time”) AND (“NAFLD” or “NASH” or “Cirrhosis” or “Non-alcoholic fatty liver” or “Nonalcoholic fatty liver” or “Non-alco-holic steatosis” or “Nonalcoholic steatosis”).

Eligibility criteriaStudies of all designs were included if they were in English language, conducted in humans, included adults aged 18 years and over with NAFLD or at risk of NAFLD (as deemed in each paper where NAFLD was an outcome) and assessed cognitive function in individ-uals with NAFLD. Studies were excluded if they were review articles, abstract only, or included participants with mental health and neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s Disease (PD) and PD-related disorders.

Selection processTitle and abstract screening was carried out by one researcher according to the predefined protocol, and duplicates and articles which did not meet the eligibil-ity criteria were excluded. Full text screening was con-ducted independently by two researchers (SS, SYT), and where there were any conflicts these were resolved by a third researcher (ESG). All articles included from the full-text screen were included in this systematic review. The search process is outlined in the PRISMA flowchart in Fig. 1.

Data extraction and groupingData was extracted from 11 studies by one researcher and then re-checked by a second researcher. Data extraction included the following: author, year pub-lished, study design, length, population characteristics, presence of co-morbidities, the measurement meth-ods for cognitive function and NAFLD, associations


between NAFLD and cognitive function, and any other relevant outcomes (e.g. body fat, visceral fat, CVD risk factors). These findings are shown in Table 1. Due to the wide range of cognitive tests available and identified across the 11 studies, the cognitive tests were grouped into the following seven categories (general cogni-tion, reasoning, mental speed and attention, memory and learning, language, visuospatial perception, ideas, abstraction, figural creations and mental flexibility) as

described by Goodwill et al. [26]. Grouping was carried out by two researchers.

Quality assessment and risk of biasThe quality of the included papers and risk of bias was assessed independently using The Academy of Nutrition and Dietetics Evidence Analysis Library Quality Criteria Checklist (Table 2) [34]. This checklist consists of an eval-uation of studies’ relevance (four questions) and validity

Fig. 1 PRISMA


Tabl

e 1

Extr

actio

n ta

ble

of in

clud

ed s

tudi

es a

sses

sing

the

asso

ciat

ion

betw

een

NA

FLD

and

cog

nitio

na

Aut

hor,

Year

Coun

try

Stud

y de

sign

; Le

ngth

Sam

ple

size

NA

FLD

mea

n ag

e,

sex

(n fe

mal

es, n

m

ales

)

Risk

fact

ors/

co-m

orbi

ditie

sCo

gniti

ve te

sts

NA

FLD

dia

gnos

isFi

ndin

gsb

Wei

nste

in e

t al.

(201

8) [2

7]U

nite

d St

ates

Cro

ss‑s

ectio

nal,

popu

latio

n‑ba

sed

sam

plin

g su

rvey

; N

HA

NES

Sur

vey

data

fro

m 2

011

to 2

014

1102

par

ticip

ants

239

NA

FLD

par

tici‑

pant

s

Mea

n N

AFL

D a

ge:

68.6

year

sN

AFL

D ‑

BMI 3

5.0

kg/m

2O

besi

ty: 9

2.5%

Insu

lin re

sist

ance

: 62

.1%

HTN

: 76.

1%H

igh

chol

este

rol:

82.2

%M

etS:

58.

5%Co

ntro

l –BM

I 25.

00 kg

/m2

Obe

sity

: 19.

4%In

sulin

resi

stan

ce:

17.5

%H

TN: 6

1.2%

Hig

h ch

oles

tero

l: 74

.2%

Met

S: 1

1.1%

(1) T

he W

ord

Lear

n-in

g su

bset

‑ us

ed

to a

sses

s im

med

iate

an

d de

laye

d le

arni

ng

abili

ty(2

) The

Ani

mal

Flu

-en

cy T

est -

cat

egor

i‑ca

l ver

bal fl

uenc

y(3

) The

dig

it sy

m-

bol s

ubst

itutio

n - i

nvol

ves

proc

essi

ng

spee

d, s

usta

ined

and

w

orki

ng m

emor

y

Fatt

y liv

er in

dex

scor

e ≥

60

Span

ish.

(1) T

he W

ord

Lear

n-in

g su

bset

– Im

med

i‑at

e ve

rbal

mem

ory:

N

AFL

D o

nly

(SD

: 20

.5 ±

0.4

) vs

the

cont

rol g

roup

(SD

: 20

.0 ±

0.3

)D

elay

ed v

erba

l m

emor

y: N

AFL

D o

nly

grou

p (S

D: 6

.6 ±

0.2

) vs

the

cont

rol g

roup

(6

.4 ±

0.1

)(2

) AFT

–Ve

rbal

flue

ncy:

NA

FLD

on

ly (1

8.6 ±

0.3

) vs

con

trol

gro

up

(18.

3 ±

0.4

)(3

) DSS

T –

Proc

essi

ng s

peed

, su

stai

ned

atte

ntio

n,

wor

king

mem

ory:

N

AFL

D (5

5.9 ±

1.0

5)

vs c

ontr

ol g

roup

(5

3.6 ±

1.2

)


Tabl

e 1

(con

tinue

d)

Aut

hor,

Year

Coun

try

Stud

y de

sign

; Le

ngth

Sam

ple

size

NA

FLD

mea

n ag

e,

sex

(n fe

mal

es, n

m

ales

)

Risk

fact

ors/

co-m

orbi

ditie

sCo

gniti

ve te

sts

NA

FLD

dia

gnos

isFi

ndin

gsb

Celik

bile

k et

al.

(201

8) [2

2]Tu

rkey

Cro

ss‑s

ectio

nal

stud

y14

3 pa

rtic

ipan

ts70

NA

FLD

par

tici‑

pant

s

Mea

n N

AFL

D a

ge:

46.9

year

s, F

(NA

FLD

): 41

, M (N

AFL

D):

29

NA

FLD

–T2

DM

: 30%

HTN

: 20%

Hyp

erlip

idae

mia

: 7.

1%M

etS:

48.

6%Co

ntro

l –T2

DM

: 4.1

%H

TN: 2

.7%

Hyp

erlip

idae

mia

: 1.

4%M

etS:

34.

3%

(1) M

ontr

eal C

ogni

-tiv

e A

sses

smen

t Tu

rkish

ver

sion.

(a)

visu

ospa

tial a

bilit

ies

‑ clo

ck‑d

raw

ing

task

an

d th

ree‑

dim

en‑

sion

al c

ube‑

copy

ing

task

, (b)

Mem

ory

‑ del

ayed

reca

ll (c

) Ex

ecut

ive

func

tion‑

ing

‑ Tra

il M

akin

g B

task

, a p

hone

mic

flu

ency

task

, and

a

two‑

item

ver

bal

abst

ract

ion

task

, (d)

A

tten

tion

‑ a s

eria

l su

btra

ctio

n ta

sk a

nd

digi

ts fo

rwar

d an

d ba

ckw

ard

task

s, (e

) La

ngua

ge ‑

thre

e‑ite

m c

onfro

ntat

ion

nam

ing

task

, rep

eti‑

tion

of tw

o sy

ntac

ti‑ca

lly c

ompl

ex s

en‑

tenc

es (f

) orie

ntat

ion

‑ orie

ntat

ion

to ti

me

and

plac

e is

als

o ev

alua

ted

Abd

omin

al u

ltra‑

sono

grap

hy(1

) MoC

A-T

R - s

core

s si

gnifi

cant

ly lo

wer

in

NA

FLD

gro

up in

co

mpa

rison

to c

ontr

ol

grou

p (P

< 0

.001

)(a

) Vis

uosp

atia

l abi

li‑tie

s: P

< 0

.05

(b) M

emor

y: P

= 0

.16

(c) E

xecu

tive

func

tion‑

ing:

P <

0.0

5(d

) Att

entio

n: P

= 0

.56

(e) L

angu

age:

P =

0.8

9(f

) Orie

ntat

ion:

P =

0.2

9

Taka

hash

i et a

l. (2

017)

[28]

Japa

nC

ross

‑sec

tiona

l st

udy

39 p

artic

ipan

ts24

NA

FLD

par

tici‑

pant

s

Mea

n N

AFL

D a

ge:

54 ye

ars

NA

FLD

–T2

DM

: 41.

6%D

yslip

idae

mia

: 58

.3%

HTN

: 29.

2%Co

ntro

l –N

ot re

port

ed

(1) A

ver

bal fl

uenc

y ta

sk (V

FT)

Asi

a‑Pa

cific

Wor

king

Pa

rty

guid

elin

es fo

r th

e as

sess

men

t and

m

anag

emen

t of

NA

FLD

.U

ltras

onog

raph

y (in

th

e ab

senc

e of

oth

er

caus

es o

f chr

onic

liv

er d

isea

se e

.g.,

hepa

titis

C a

ntib

ody

nega

tive,

hep

atiti

s B

surf

ace

antig

en

nega

tive,

and

alc

o‑ho

l con

sum

ptio

n <

20

g/da

y)

(1) V

FT –

Num

ber o

f wor

ds

durin

g VF

T w

as

sign

ifica

ntly

hig

her i

n co

ntro

ls c

ompa

red

to

the

NA

FLD

: p <

0.0

32N

umbe

r of w

ords

dur

-in

g VF

T N

AFLD

: 12

Num

ber o

f wor

ds d

ur-

ing

VFT

cont

rols:

14


Tabl

e 1

(con

tinue

d)

Aut

hor,

Year

Coun

try

Stud

y de

sign

; Le

ngth

Sam

ple

size

NA

FLD

mea

n ag

e,

sex

(n fe

mal

es, n

m

ales

)

Risk

fact

ors/

co-m

orbi

ditie

sCo

gniti

ve te

sts

NA

FLD

dia

gnos

isFi

ndin

gsb

Filip

ovic

et a

l. (2

018)

[2

1]Se

rbia

Case

‑con

trol

stu

dy76

par

ticip

ants

40 N

AFL

D p

artic

i‑pa

nts

Mea

n N

AFL

D a

ge:

47.9

year

s,M

(NA

FLD

): 22

,F

(NA

FLD

): 18

NA

FLD

–T2

DM

: 30%

HTN

: 80%

Obe

se: 5

0%M

etS:

85%

Cont

rol –

T2D

M: 2

5%H

TN: 4

4%O

bese

: 11%

Met

S: 2

2%

(1) M

ontr

eal C

ogni

-tiv

e A

sses

smen

t te

st S

erbi

an v

ersio

n.(a

) alte

rnat

ing

con‑

nect

ions

, (b)

vas

o‑co

nstr

ictiv

e ab

ilitie

s ‑ d

raw

a c

ube

and

a cl

ock

in 1

1:10

pos

i‑tio

n of

clo

ck h

ands

, (c

) mem

ory

‑ num

‑be

rs re

peat

ed in

the

sam

e an

d re

vers

e or

der,

(d) a

tten

tion

‑ tap

whe

neve

r you

he

ar a

lett

er A

, ser

ial

subt

ract

ion

of 7

, st

artin

g w

ith a

hun

‑dr

ed (e

) sen

tenc

e re

peat

ing

and

verb

al

fluen

cy.

Abd

omin

al

ultr

ason

ogra

phy,

So

nogr

aphi

c ev

alu‑

atio

n (U

S) o

f hep

atic

st

eato

sis

(1) M

OCA

-SR

–Th

e co

gniti

ve s

tatu

s w

as lo

wer

in N

AFL

D

com

pare

d to

con

trol

:O

R 0.

096,

95%

CI

0.03

2–0.

289,

and

p

< 0

.001

Ellio

tt e

t al.

(201

3)

[23]

UK

(Eur

ope)

Coho

rt, P

rosp

ec‑

tive

follo

w‑u

p ov

er

3 ye

ars

431

part

icip

ants

224

NA

FLD

par

tici‑

pant

Mea

n N

AFL

D a

ge:

59 ye

ars,

F (N

AFL

D):

101,

M (N

AFL

D):

123

Not

repo

rted

(1) C

ogni

tive

Fail-

ures

Que

stio

nnai

re

(CFQ

) - m

easu

res

mem

ory,

att

en‑

tion,

con

cent

ratio

n,

forg

etfu

lnes

s, w

ord

findi

ng a

bilit

ies

and

conf

usio

n.

Live

r Ser

um B

io‑

chem

istr

y ‑ A

LT, A

LP,

ALB

, Bili

rubi

n.

(1) C

FQ –

Cogn

itive

sym

ptom

s C

FQ a

ssoc

iate

d w

ith

wor

se fu

nctio

nal

abili

ty in

NA

FLD

co

mpa

red

to c

ontr

ols:

r = 0

.4, p

< 0

.000

1


Tabl

e 1

(con

tinue

d)

Aut

hor,

Year

Coun

try

Stud

y de

sign

; Le

ngth

Sam

ple

size

NA

FLD

mea

n ag

e,

sex

(n fe

mal

es, n

m

ales

)

Risk

fact

ors/

co-m

orbi

ditie

sCo

gniti

ve te

sts

NA

FLD

dia

gnos

isFi

ndin

gsb

Wei

nste

in e

t al.

(201

9) [2

9]U

nite

d St

ates

Popu

latio

n‑ba

sed,

m

ulti‑

gene

ratio

nal

stud

y (T

he F

ram

ing‑

ham

Hea

rt S

tudy

) C

ross

‑sec

tiona

l st

udy

1287

par

ticip

ants

378

NA

FLD

par

tici‑

pant

s

Mea

n N

AFL

D a

ge:

61.1

year

s, F

(NA

FLD

): 15

7, M

(NA

FLD

): 22

1

NA

FLD

–BM

I: 31

.0T2

DM

: 20.

5%H

TN (s

tage

1):

59.3

%Co

ntro

ls –

BMI:

26.8

T2D

M: 6

.9%

HTN

(sta

ge 1

): 38

.2%

(1) T

he W

echs

ler

Mem

ory

Scal

e ‑

verb

al a

nd v

isua

l m

emor

y(2

) Tim

e to

com

-pl

ete

trai

l-mak

ing

B m

inut

e tim

e to

co

mpl

ete

trai

l-m

akin

g A

test

(T

rB-T

rA) -

exe

cutiv

e fu

nctio

n(3

) The

sim

ilari

ties

test

(SIM

) - a

bstr

act

reas

onin

g sk

ills

(4) H

oope

r vis

ual

orga

niza

tion

test

(H

VOT)

- vi

sual

pe

rcep

tion.

Mul

ti‑de

tect

or

CT

with

8‑s

lice,

A

calib

ratio

n ph

anto

m

(Imag

e A

naly

sis,

Lexi

ngto

n, K

Y) w

ith

a w

ater

equ

ival

ent

com

poun

d ‑ t

hree

ar

eas

from

the

liver

an

d on

e fro

m a

n ex

tern

al p

hant

om

wer

e m

easu

red

(NA

FLD

was

de

fined

as

havi

ng

a liv

er/p

hant

om

ratio

≤ 0

.33)

.

(1) T

he W

echs

ler

Mem

ory

Scal

e -

p =

0.6

10(2

) TrB

-TrA

–

p =

0.4

18(3

) SIM

– p

= 0

.746

(4) H

VOT

– p =

0.5

28N

o sig

nific

ant a

sso-

ciat

ion

of N

AFLD

with

co

gniti

ve m

easu

res

iden

tified

.Pa

rtic

ipan

ts w

ith

NA

FLD

with

adv

ance

d fib

rosi

s w

as a

ssoc

iate

d w

ith p

oore

r per

for‑

man

ce o

n th

e Tr

B‑Tr

A

(P =

0.0

28) a

nd S

IM

test

(P =

0.0

09)


Tabl

e 1

(con

tinue

d)

Aut

hor,

Year

Coun

try

Stud

y de

sign

; Le

ngth

Sam

ple

size

NA

FLD

mea

n ag

e,

sex

(n fe

mal

es, n

m

ales

)

Risk

fact

ors/

co-m

orbi

ditie

sCo

gniti

ve te

sts

NA

FLD

dia

gnos

isFi

ndin

gsb

Tart

er e

t al.

(198

4)

[30]

Uni

ted

Stat

esCa

se‑c

ontr

ol s

tudy

40 p

artic

ipan

ts30

NA

FLD

par

tici‑

pant

s

Mea

n N

AFL

D a

ge:

40.9

year

sN

ot re

port

ed(1

) Pea

body

pic

ture

in

telli

genc

e te

st –

ve

rbal

inte

llige

nce.

(2) R

aven

’s pr

ogre

s-si

ve m

atri

ces

‑ non

‑ve

rbal

inte

llige

nce.

(3) D

igit

span

fo

rwar

d.(4

) Dig

it sp

an

back

war

d.(5

) Wes

chle

r M

emor

y Sc

ale)

: (a)

Lo

gica

l mem

ory

(b)

Figu

ral m

emor

y, (c

) Pa

ired

asso

ciat

es, (

d)

Supr

asan

.(6

) Per

cept

ual-

Mot

or: (

a) F

inge

r ta

ppin

g, (b

) Pur

due

Pegb

oard

, (c)

Sta

ry

trac

ing,

(d) S

ymbo

l di

git m

odal

ities

.(7

) Spa

tial:

(a) B

lock

de

sign

, (b)

Tac

tual

pe

rfor

man

ce, (

c) T

rail

mak

ing.

(8) L

angu

age:

(a)

Flue

ncy,

(b) C

onfro

n‑ta

tion

nam

ing,

(c)

Resp

onsi

ve n

amin

g(9

) The

Tok

en T

est

‑com

preh

ensi

ve

capa

city

Hep

atic

dia

gnos

is

‑ clin

ical

, bio

‑ch

emic

al, s

erol

ogic

al

confi

rmed

by

liver

bi

opsy

(1) P

eabo

dy p

ictu

re

inte

llige

nce

test

– n

o di

ffere

nce

(2) R

aven

’s pr

ogre

s-si

ve m

atri

ces

– no

di

ffere

nce

(3) D

igit

span

for-

war

d –

no d

iffer

ence

(4) D

igit

span

bac

k-w

ard

– no

diff

eren

ce(5

) Wes

chle

r Mem

ory

Scal

e) –

no

diffe

renc

e(6

) Per

cept

ual-M

otor

– (a

) Fin

ger t

appi

ng: n

o di

ffere

nce

(b) P

urdu

e Pe

gboa

rd:

p <

0.0

1(c

) Sta

ry tr

acin

g: n

o di

ffere

nce

(d) S

ymbo

l dig

it m

odal

ities

: p <

0.0

1(7

) Spa

tial –

(a) B

lock

des

ign:

p

< 0

.06

(b) T

actu

al p

erfo

r‑m

ance

: p <

0.0

5(c

) Tra

il m

akin

g:

p <

0.0

5(8

) Lan

guag

e –

(a) F

luen

cy: n

o di

ffer‑

ence

(b) C

onfro

ntat

ion

nam

ing:

no

diffe

renc

e(c

) Res

pons

ive

nam

‑in

g: n

o di

ffere

nce

(9) T

he T

oken

Tes

t –

no d

iffer

ence


Tabl

e 1

(con

tinue

d)

Aut

hor,

Year

Coun

try

Stud

y de

sign

; Le

ngth

Sam

ple

size

NA

FLD

mea

n ag

e,

sex

(n fe

mal

es, n

m

ales

)

Risk

fact

ors/

co-m

orbi

ditie

sCo

gniti

ve te

sts

NA

FLD

dia

gnos

isFi

ndin

gsb

Tart

er e

t al.

(198

7)

[31]

Uni

ted

Stat

esCa

se‑c

ontr

ol s

tudy

46 p

artic

ipan

ts23

NA

FLD

par

tici‑

pant

s

Mea

n N

AFL

D

age:

37.

2 ye

ars,

M (N

AFL

D):

11, F

(N

AFL

D):

12

Not

repo

rted

(1) D

igit

Span

Tes

t ‑

imm

edia

te m

emor

y(2

) Sup

rasp

an

Lear

ning

Tes

t - th

e nu

mbe

r of t

rials

re

quire

d ac

cura

tely

to

repe

at a

str

ing

of d

igits

that

is o

ne

digi

t lon

ger t

han

the

digi

ts fo

rwar

d sc

ore.

(3

) Ben

ton

Visu

al

Rete

ntio

n Te

st

(BVR

T) ‑

shor

t ter

m

visu

al(4

) Rey

-Ost

erre

ith

Com

plex

Fig

ure

Test

‑ in

cide

ntal

le

arni

ng a

bilit

y(5

) Bro

wn-

Pete

rson

Te

st ‑

mea

sure

s th

e ra

te o

f dec

ay o

f in

form

atio

n fro

m

shor

t‑te

rm m

emor

y.

Sero

logi

cal t

ests

, cl

inic

al h

isto

ry a

nd

phys

ical

exa

min

a‑tio

ns, a

nd w

as

confi

rmed

by

a pe

rcut

aneo

us li

ver

biop

sy.

(1) D

igit

Span

Tes

t –

no d

iffer

ence

(2) S

upra

span

Lea

rn-

ing

Test

– p

< 0

.05

(3) B

VRT

– p

< 0

.000

1(4

) Rey

-Ost

erre

ith

Com

plex

Fig

ure

Test

–

no d

iffer

ence

(5) B

row

n-Pe

ters

on

Test

– n

o di

ffere

nce

Seo

et a

l. (2

016)

[32]

Uni

ted

Stat

esC

ross

‑sec

tiona

l st

udy

(NH

AN

ES II

I ‑

surv

ey)

4472

par

ticip

ants

874

NA

FLD

par

tici‑

pant

Mea

n N

AFL

D a

ge:

40.9

year

sN

AFL

D –

T2D

M: 1

3.6%

HTN

: 36.

3%H

yper

chol

este

rola

e‑m

ia: 3

0.4%

Stro

ke: 1

.5%

Cont

rols

–T2

DM

: 5.2

%H

TN: 1

7.5%

Hyp

erch

oles

tero

‑le

stel

emia

: 22.

2%St

roke

: 0.5

%

(1) T

he S

impl

e Re

actio

n Ti

me

Test

(S

RTT)

- m

easu

res

resp

onse

tim

e,

visu

al‑m

otor

spe

ed(2

) The

Sym

bol

Dig

it Su

bstit

u-tio

n Te

st (S

DST

) - a

sses

ses

visu

al

atte

ntio

n an

d co

d‑in

g ab

ility

(3) T

he S

eria

l D

igit

Lear

ning

Te

st (S

DLT

) - te

st

lear

ning

, rec

all,

and

conc

entr

atio

n.

Gal

lbla

dder

exa

mi‑

natio

n by

ultr

asou

nd

with

a T

oshi

ba

SSA

‑90A

mac

hine

w

ith a

3.7

5 an

d 5.

0 M

Hz

tran

sduc

er.

Live

r enz

ymes

(ALT

, A

ST) w

ere

assa

yed

with

Hita

chi 7

37

auto

mat

ed m

ulti‑

chan

nel c

hem

istr

y an

alys

er. N

AFL

D w

as

defin

ed a

s m

oder

‑at

e/se

vere

ste

atos

is

as d

eter

‑ min

ed b

y ul

tras

ound

.

(1) S

RTT

– B =

7.8

27,

95%

CI 0

.975

to 1

4.67

9(2

) SD

ST –

B =

0.1

10,

95%

CI 0

.004

to 0

.216

(3) S

DLT

– B

= 0

.880

, 95

% C

I 0.3

17 to

1.4

43Pa

rtic

ipan

ts w

ith

NAF

LD h

ad lo

wer

pe

rfor

man

ces o

n SR

TT,

SDST

and

SD

LT


Tabl

e 1

(con

tinue

d)

Aut

hor,

Year

Coun

try

Stud

y de

sign

; Le

ngth

Sam

ple

size

NA

FLD

mea

n ag

e,

sex

(n fe

mal

es, n

m

ales

)

Risk

fact

ors/

co-m

orbi

ditie

sCo

gniti

ve te

sts

NA

FLD

dia

gnos

isFi

ndin

gsb

Felip

o et

al.

(201

2)

[24]

Spai

n (E

urop

e)Ca

se c

ontr

ol s

tudy

179

part

icip

ants

29 N

AFL

D p

artic

i‑pa

nt

Mea

n N

AFL

D a

ge:

45 ye

ars,

F (N

AFL

D):

24, M

(NA

FLD

): 5

Not

repo

rted

(1) T

he D

igit

Sym

bol t

est (

DST

) –

men

tal s

peed

(2) T

he N

umbe

r Co

nnec

tion

Test

A

(NCT

-A) –

men

tal

spee

d(3

) The

Num

ber

Conn

ectio

n Te

st B

(N

CT-B

) – m

enta

l sp

eed

(4) T

he S

eria

l Dot

-tin

g Te

st –

men

tal

spee

d(5

) The

line

trac

ing

test

(LTT

) – v

isuo

s‑pa

tial

Live

r bio

psy

obta

ined

dur

ing

hist

olog

ical

stu

dy.

(1) D

ST –

no

dif‑

fere

nce

in N

AFL

D,

cirr

hosi

s or

NA

SH(2

) NCT

-A –

no

dif‑

fere

nce

in N

AFL

D,

impa

ired

in p

atie

nts

with

NA

SH a

nd c

ir‑rh

osis

(P <

0.0

01)

(3) N

CT-B

– n

o di

f‑fe

renc

e in

NA

FLD

, im

paire

d in

NA

SH a

nd

cirr

hosi

s (P

< 0

.001

)(4

) The

Ser

ial

Dot

ting

Test

– n

o di

ffere

nce

in N

AFL

D,

impa

ired

in c

irrho

sis

(P <

0.0

01) a

nd N

ASH

(P

< 0

.01)

(5) L

TT –

no

diffe

renc

e in

NA

FLD

, im

paire

d in

NA

SH a

nd c

irrho

sis

(P <

0.0

01)

Tutt

olom

ondo

et a

l. (2

018)

[33]

Italy

(Eur

ope)

Case

con

trol

stu

dy16

3 pa

rtic

ipan

ts80

NA

FLD

par

tici‑

pant

s

Mea

n N

AFL

D a

ge:

53.7

year

sN

AFL

D –

BMI:

28.7

HTN

: 35.

0%T2

DM

: 38.

8%D

yslip

idae

mia

: 18

.8%

Prev

ious

CVD

: 3.7

5%Co

ntro

ls –

BMI:

25.3

HTN

: 15.

7%T2

DM

: 8.4

%D

yslip

idae

mia

: 16

.9%

Prev

ious

CVD

: 0

(1) M

ini-m

enta

l st

ate

exam

inat

ion

(MM

SE)

Incr

ease

d se

rum

le

vels

of A

LT fo

r at

leas

t 6 m

onth

s an

d al

coho

l con

sum

p‑tio

n of

< 2

0 g/

day

in

the

prev

ious

yea

r. Li

ver u

ltras

ound

fin

ding

of s

teat

osis

an

d a

liver

stiff

ness

va

lue

> 6

kPa.

Liv

er

biop

sy fo

r NA

FLD

. H

epat

ic s

teat

osis

w

as d

efine

d by

de

tect

ion

of B

right

Li

ver E

cho

patt

ern.

(1) M

MSE

–N

AFL

D h

ad a

low

er

mea

n M

MSE

sco

re

whe

n co

mpa

red

to

cont

rols

(26.

9 ±

1.6

vs.

28.0

± 1

.36;

p =

0.0

05)

a Abb

revi

atio

ns: A

FT a

nim

al fl

uenc

y te

st, A

LT a

lani

ne a

min

otra

nsfe

rase

, ALP

alk

alin

e ph

osph

atas

e, A

ST a

spar

tate

am

inot

rans

fera

se, B

MI b

ody

mas

s in

dex,

BVR

T Be

nton

vis

ual r

eten

tion

test

, CFQ

Cog

nitiv

e Fa

ilure

s Q

uest

ionn

aire

, DSS

T Th

e di

git s

ymbo

l sub

stitu

tion

test

, DST

dig

it sy

mbo

l tes

t, H

VOT

hoop

er v

isua

l org

anis

atio

n te

st, H

TN h

yper

tens

ion,

LTT

line

trac

ing

test

, MoC

A-TR

Mon

trea

l cog

nitiv

e as

sess

men

t Tur

kish

ver

sion

, M

oCA-

SR M

ontr

eal c

ogni

tive

asse

ssm

ent S

erbi

an v

ersi

on, M

CI m

ild c

ogni

tive

impa

irmen

t, M

etS

met

abol

ic s

yndr

ome,

NAF

LD n

on-a

lcoh

olic

fatt

y liv

er d

isea

se, N

ASH

non

-alc

ohol

ic s

teat

osis

, NCT

A nu

mbe

r con

nect

ion

test

A,

NCT

B nu

mbe

r con

nect

ion

test

B, S

IM s

imila

ritie

s te

st, S

RRT

sim

ple

reac

tion

time

test

, SD

ST s

ymbo

l dig

it su

bstit

utio

n te

st, S

DT

seria

l dot

ting

test

, SD

LT s

eria

l dig

it le

arni

ng te

st, V

FT v

erba

l flue

ncy

task

b Sig

nific

ant e

ffect

(p <

0.0

5); n

o eff

ect (

p >

0.05

); CI

con

fiden

ce in

terv

al, O

R od

ds ra

tio, R

R re

lativ

e ris

k


Tabl

e 2

Crit

ical

app

rais

al o

f the

11

stud

ies

with

the

use

of Q

ualit

y C

riter

ia C

heck

lista

Celik

bile

k,

2018

[22]

Ellio

tt, 2

013

[23]

Felip

o, 2

012

[24]

Filip

ovic

, 20

18 [2

1]Se

o, 2

016

[32]

Taka

hash

i, 20

17 [2

8]Ta

rter

, 198

4 [3

0]Ta

rter

, 198

7 [3

1]Tu

ttol

omon

do,

2018

[33]

Wei

nste

in,

2018

[27]

Wei

nste

in,

2019

[29]

Rele

vanc

e Q

uest

ions

1.

Wou

ld

impl

emen

ting

the

stud

ied

inte

rven

tion

or p

roce

dure

(if

foun

d su

c‑ce

ssfu

l) re

sult

in im

prov

ed

outc

omes

for

the

patie

nts/

clie

nts/

popu

‑la

tion

grou

p?

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

2.

Did

the

auth

ors

stud

y an

out

com

e (d

epen

dent

va

riabl

e) o

r to

pic

that

th

e pa

tient

s/cl

ient

s/po

pu‑

latio

n gr

oup

wou

ld c

are

abou

t?

YY

YY

YY

YY

YY

Y

3.

Is th

e fo

cus

of th

e in

terv

entio

n or

pro

cedu

re

(inde

pend

ent

varia

ble)

or

topi

c of

stu

dy

a co

mm

on

issu

e of

con

‑ce

rn to

die

tet‑

ics

prac

tice?

YY

YY

YY

YY

YY

Y

4.

Is th

e in

terv

entio

n or

pro

cedu

re

feas

ible

?

YY

YY

YY

YY

YY

Y

Valid

ity

Que

stio

ns

1. W

as th

e re

sear

ch q

ues‑

tion

clea

rly

stat

ed?

YY

YY

YY

YY

YY

Y


Tabl

e 2

(con

tinue

d)

Celik

bile

k,

2018

[22]

Ellio

tt, 2

013

[23]

Felip

o, 2

012

[24]

Filip

ovic

, 20

18 [2

1]Se

o, 2

016

[32]

Taka

hash

i, 20

17 [2

8]Ta

rter

, 198

4 [3

0]Ta

rter

, 198

7 [3

1]Tu

ttol

omon

do,

2018

[33]

Wei

nste

in,

2018

[27]

Wei

nste

in,

2019

[29]

2.

Was

the

sele

ctio

n of

st

udy

sub‑

ject

s/pa

tient

s fre

e fro

m b

ias?

YY

YY

YY

NN

YY

Y

3.

Wer

e st

udy

grou

ps

com

para

ble

or

was

an

appr

o‑pr

iate

refe

r‑en

ce s

tand

ard

used

?

YN

Unc

lear

YY

YN

YY

YY

4.

Wer

e m

etho

ds

of h

andl

ing

loss

es fr

om

the

orig

inal

sa

mpl

e (w

ithdr

awal

s)

desc

ribed

?

YN

NA

YN

NN

NN

AN

AY

5.

Was

bl

indi

ng u

sed

to p

reve

nt

intr

oduc

tion

of b

ias?

YY

YY

YY

Unc

lear

YY

YY

6.

Was

the

inte

rven

tion/

trea

tmen

t re

gim

en/

expo

sure

fac‑

tor,

proc

edur

e,

proc

ess

or

prod

uct

of in

tere

st,

and

any

com

paris

on(s

) de

scrib

ed in

de

tail?

Wer

e in

terv

en‑

ing

fact

ors

desc

ribed

?

YY

YY

YY

YY

YY

Y


Tabl

e 2

(con

tinue

d)

Celik

bile

k,

2018

[22]

Ellio

tt, 2

013

[23]

Felip

o, 2

012

[24]

Filip

ovic

, 20

18 [2

1]Se

o, 2

016

[32]

Taka

hash

i, 20

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(ten questions). Based on these criteria, the researcher assigned each article a quality rating of positive, neutral or negative (+, Ø, −).

Data analysisQualitative analyses were carried out and results were presented narratively. For the qualitative analysis, differ-ence in measures between NAFLD and control groups or pre- and post- in prospective studies and change between groups where appropriate, were reported, depending on the analysis reported for individual studies. Data were considered statistically significant if the reported p-value was < 0.05. Due to the heterogeneity of interventions, and measured outcomes, a meta-analysis was not possible.

ResultsStudy selectionThe literature search process is shown in Fig. 1. The search strategy resulted in 1893 articles, of which 1229 remained after duplicates were removed. From this, 1135 articles were deemed ineligible as a result of title and abstract screening. Ninety-four studies were eligible for full-text screening and 84 were excluded for the following reasons: non-NAFLD population (n = 36), abstract only (n = 29), no cognitive outcome(s) (n = 15), duplicates (n = 2), and not available online (n = 2). One additional study was added through manual search of references (n = 1); there were no clinical trials found and thus, 11 observational studies were included in this systematic review.

Study characteristicsThe data extracted from the included 11 studies are presented in Table 1. All studies were of observational design; five were case-control [21, 24, 30, 31, 33], five were cross-sectional [22, 27–29, 32], and one was a cohort study [23]. The articles were published between 1984 and 2019. The studies were conducted in the United States, Turkey, Japan, Serbia, United Kingdom, Italy and Spain, and included a total of 7978 participants aged between 37 and 70 years (mean 51 years). The risk of bias assessment for each study is reported in Table 2. Nine articles received a positive quality rating [21–24, 27–30, 32], and two articles received a neutral quality rating [31, 33]; indicating majority of the studies posed a low risk of bias. While the risk of bias tool applied does not assess publication bias there appears to be a combination of positive and negative results in the included studies. The cognitive abilities and associated neuropsychological tests measured in each study are summarised in Table 3.

Cognitive abilitiesGeneral cognitionFour studies including two case-control [21, 33], one cross-sectional [22] and one cohort study [23] inves-tigated the associations between general cognitive performance and NAFLD using multiple neuropsycho-logical tests. All four studies reported that individuals with NAFLD had significantly lower general cognitive function, measured with the Serbian [21] and the Turk-ish [22] MOCA (n = 76 and n = 213 respectively), MMSE (n = 163) [33], and the cognitive symptoms questionnaire (CFQ) (n = 431) [23].

ReasoningOne case-control study conducted in the US including 40 adults with a mean age of 41 years utilised the Raven’s Progressive Matrices to evaluate reasoning and found no significant difference between those with or without NAFLD [30].

Mental speed, attention and psychomotor speedFive studies including three cross-sectional [22, 27, 32] and two case-control studies [24, 30] reported on the mental speed, attention and psychomotor speed. Over-all, three studies indicated poorer performance in this cognitive domain in those with NAFLD [27, 30, 32], with one additional study indicating only those with the more progressed state of the disease, NASH, having poorer cognitive outcomes [24]. Two of these studies were cross-sectional studies conducted in the US and included 1102 and 4472 participants with mean ages of 69 and 41 years, respectively [27, 32]. Only one of the five included stud-ies in this domain indicated that NAFLD or NASH was not associated with cognitive performance. One study reported that individuals with NASH had evidence of cognitive decline [22, 24]. Collectively, it appears that mental speed, attention and psychomotor speed in the majority (three out of five studies) was negatively influ-enced in individuals with NAFLD.

Memory and learningFive studies including three case-control [22, 30, 31] and two cross-sectional studies [29, 32] utilised multiple neu-ropsychological tests to report on the memory and learn-ing domain. Two observational studies (one case-control and a cross-sectional study) reported lower memory and learning test scores (Supraspan Learning test and Ben-ton Visual Retention test and Serial Digit Learning test) in adults with NAFLD [31, 32]. Conversely, another three studies that used the Wechsler Memory Scale [27, 32] or the Delayed Recall Memory test (MoCA-TR) [22] did not observe significant difference in logical and figural


memory among those with NAFLD. Collectively, the limited data available assessing memory and learning in those with NAFLD is conflicting and inconclusive.

LanguageTwo studies including one cross-sectional [28] and one case-control [30] examined the effects of NAFLD on the language domain of cognitive performance. One cross-sectional study in Japan (n = 39) reported significantly lower scores in the Verbal Fluency Task (VFL) among individuals with NAFLD [28]. On the other hand, another study in the US (n = 40) did not find significant group differences using the VFT, the Confrontation Naming task, and the Peabody Picture Intelligence test and Token test [30]. However, this latter study used a Crohn’s Dis-ease control group. It is also difficult to compare the findings between studies due to the different cognitive function tests used. Overall, the number of studies and participants included in this cognitive domain is limited, include small sample sizes, and the findings are conflict-ing and thus inconclusive.

Visuospatial perceptionFive studies including two cross-sectional [22, 29] and three case-control studies [21, 24, 30] reported on the visuospatial perception cognitive domain. Three of the five studies found poorer visuospatial perception scores, measured with MOCA [21, 22] or Tactual Performance task [30], in individuals with NAFLD. Conversely, no sig-nificant group differences were found in three studies for visuospatial perception as assessed using the Hooper Visual Organisation test [29], Block Design task [30] and Line Tracing test were used [24]. Together, these observa-tions indicate that NAFLD may be associated with lower visuospatial perception and cognitive impairment.

Ideas, abstraction, figural creations and mental flexibilityFour studies including three cross-sectional [22, 27, 29] and one case-control [30] observed differences in the Ideas, Abstraction, Figural creations and Mental flex-ibility domain. Three studies (one case-control and two cross-sectional) reported significantly higher scores in the Trail Making task, indicating cognitive impairment, in individuals with NAFLD [22, 29, 30]. Another cross-sectional study that used the Animal Fluency test also observed cognitive decline (lower scores) in those with NAFLD [27]. Individuals with NAFLD also had poorer abstract reasoning skills in two studies, as measured by the Phenomic Fluency, Two-item Verbal Abstraction and Similarities test [22, 29]. In total, all available studies consistently reported that NAFLD was associated with poorer ideas, abstraction, figural creations and mental flexibility.

DiscussionThis systematic review, which is the first to examine the association between NAFLD and cognitive function, included 11 observational studies with 7978 participants across five countries. Based on the current literature available, the findings indicate that NAFLD is likely asso-ciated with poorer cognitive function across a number of domains. Specifically, three out of seven domains assessed in this review indicated there was evidence of poor cognitive performance in participants with NAFLD, including ‘general cognition’, ‘mental speed, attention and psychomotor speed’, and ‘ideas, abstraction, figural creations and mental flexibility’. The remaining cogni-tive domains (reasoning, memory and learning, language, visuospatial perception) produced conflicting and thus inconclusive findings potentially due to the limited num-ber of studies and heterogenous designs and methodolo-gies (e.g. study populations and cognitive tests).

The findings from this review indicating that NAFLD, the ‘hepatic manifestation’ of the metabolic syndrome, was associated with cognitive decline is in line with other literature indicating that metabolic syndrome and its components are strongly implicated in cognitive decline [35]. The reason why only three of the seven cog-nitive domains explored in this review were more likely to be impacted by NAFLD may relate to differences in the characteristics of the studies included. As all studies included the assessment of multiple cognitive domains, it is unlikely results showing cognitive decline with NAFLD were due to study design or sample size in the respective studies. Studies that investigate cognitive decline typi-cally focus on older adults as this is when cognition is most sensitive to change [36, 37]. What was noted how-ever was that only one of the 11 studies in this review included older adults with a mean age above 65 years and the overall mean age of participants in this review was middle aged [27]. Therefore, there was heterogeneity in the timing and rate of cognitive decline in different cog-nitive measures based on age and this may explain the mixed findings in terms of the link with only three of the seven cognitive domains assessed in this review. There are known disparate effects on cognition with numerous cognitive domains exhibiting decline such as memory and fluid cognition, while others are preserved with age such as language or vocabulary [38]. Declines in ‘general cognition’, ‘mental speed, attention and psychomotor speed’, and ‘ideas, abstraction, figural creations and men-tal flexibility’ may be explained by the fact that cognitive tasks requiring verbal fluency, processing or transform-ing information to make a decision, working memory and executive functioning are particularly sensitive to changes with age [35]. This decline is worsened with age, but the fact that this review demonstrated a decline in


Table 3 Cognitive abilities and neuropsychological tests used in assessment in included studiesa

Cognitive abilities Neuropsychological testsb Cognitive impairment seen in NAFLD

No difference seen in NAFLD

Study

General Cognition Montreal Cognitive Assessment test Serbian version + Filipovic et al. 2018 [21]

Montreal Cognitive Assessment Turkish version + Celikbilek et al. 2018 [22]

Mini Mental State Examination + Tuttolomondo et al. 2018 [33]

Cognitive Failures Questionnaire + Elliott et al. 2013 [23]

Reasoning Raven’s Progressive Matrices – Tarter et al. 1984 [30]

Mental speed, Atten-tion and Psychomotor speed

Digit Symbol Substitution Test + Weinstein et al. 2018 [27]

MoCA‑TR Attention: Sustained attention task – Celikbilek et al. 2018 [22]

MoCA‑TR Attention: A serial subtraction task – Celikbilek et al. 2018 [22]

MoCA‑TR Attention: Digits forward and backward tasks

– Celikbilek et al. 2018 [22]

Digit span forward – Tarter et al. 1984 [30]

Digit span backward – Tarter et al. 1984 [30]

Mental control – Tarter et al. 1984 [30]

Purdue Pegboard + Tarter et al. 1984 [30]

Stary Tracing – Tarter et al. 1984 [30]

Symbol Digit Substitution Test + Seo et al. 2016 [32]

The Simple Reaction Time Test + Seo et al. 2016 [32]

Symbol Digit Modalities Test + Tarter et al. 1984 [30]

The number connection test A – Felipo et al. 2012 [24]

The number connection test B – Felipo et al. 2012 [24]

The Serial Dotting Test – Felipo et al. 2012 [24]

Memory and learning The Wechsler Memory Scale (verbal and visual) – Weinstein et al. 2019 [29]

Logical memory – Tarter et al. 1984 [30]

Figural memory – Tarter et al. 1984 [30]

Paired associates – Tarter et al. 1984 [30]

Supraspan ‑ Weschler Memory Scale – Tarter et al. 1984 [30]

Supraspan Learning Test + Tarter et al. 1987 [31]

Digit Span Test – Tarter et al. 1987 [31]

Benton Visual Retention Test + Tarter et al. 1987 [31]

Rey‑Osterreith Complex Figure Test – Tarter et al. 1987 [31]

Brown‑Peterson Test – Tarter et al. 1987 [31]

The Serial Digit Learning Test + Seo et al. 2016 [32]

Language Fluency – Tarter et al. 1984 [30]

Confrontation Naming – Tarter et al. 1984 [30]

Responsive Naming – Tarter et al. 1984 [30]

Peabody Picture Intelligence Test – Tarter et al. 1984 [30]

A Verbal Fluency Task + Takahashi et al. 2017 [28]

The Token Test – Tarter et al. 1984 [30]

Visuospatial perception MoCA‑TR Visuospatial abilities: Clock drawing + Celikbilek et al. 2018 [22]

MoCA‑SR visuoconstructive: Draw a cube and a clock in 11:10 position of clock hands

+ Filipovic et al. 2018 [21]

MoCA‑TR Visuospatial abilities: Three‑dimensional cube‑copying task

+ Celikbilek et al. 2018 [22]

Hooper Visual Organization Test – Weinstein et al. 2019 [29]

Block Design – Tarter et al. 1984 [30]

Tactual Performance + Tarter et al. 1984 [30]

The Line Tracing Test – Felipo et al. 2012 [24]


cognition which was more pronounced in NAFLD in individuals aged 37-61 years suggests that this condition may contribute to early onset cognitive decline particu-larly in certain domains.

There are numerous potential underlying mechanisms that may explain the possible early onset of cognitive decline with NAFLD. These include insulin resistance and progressive lipid deposition in the liver in NAFLD, comorbidities which are highly prevalent in middle aged populations and have been shown to increase periph-eral hyperinsulinemia, lipid peroxidation, and system-atic inflammatory damage to brain cells [38]. Obesity, T2DM and the MetS co-exist with NAFLD and are all driven by inflammation and oxidation, which contribute to impaired vascular function, and subsequently poorer cognitive function [39]. Furthermore, emerging evi-dence suggests that NAFLD poses an additional risk for dysbiosis by disrupting the gut brain axis and thus may also deteriorate cognition in individuals with this disease [40]. Liver diseases especially NAFLD and its more pro-gressed form, NASH, can lead to elevated ammonia lev-els (also known as hyperammonemia) [41, 42], and when combined with inflammation this can lead to cognitive impairment [24]. This is supported by the only study in this review that assessed NAFLD severity and demon-strated that participants with NASH showed significant cognitive impairment compared to those with only sim-ple steatosis (NAFLD) [24]. Therefore, NAFLD co-exist-ing with multiple co-morbidities (e.g. chronic diseases, hyperinsulinemia, systemic inflammation and extrahe-patic change to the central nervous system) and/or more progressed NAFLD, namely NASH, theoretically will

exacerbate cognitive impairment. In part support of this notion, there is evidence in middle-aged adults showing that cognitive decline is associated with the presence of other comorbidities such as adiposity [40]. The findings from this review shows some early evidence that this may be the case for NAFLD and cognition, although more research is needed to confirm this relationship.

This review contains several strengths including a com-prehensive and systematic search in multiple databases and achieving an overall positive Risk of Bias assessment score (Table 2). Furthermore, this review provides early evidence on the possible association between NAFLD and cognition across various domains. All of the studies included measured cognitive function using validated diagnostic criteria, including a variety of standardised neuropsychological tests such as MoCA, MMSE and CFQ. This review was also robust in that we pooled and discussed studies based on cognitive domains using a previously established method [26]. However, the review had several limitations such as the small number of stud-ies and participant numbers included and an absence of clinical trials to demonstrate causation. All studies were observational in design and predominantly case-control and cross-sectional. A further limitation was the hetero-geneous diagnostic tools, with unknown cross-compa-rability used to measure cognitive function, making the comparison of research findings difficult. This limitation has also been raised in previous reviews, where there is an urgent need for consensus on using standard cogni-tive assessments [44, 45]. In addition, due to the hetero-geneity of populations, with regard to co-morbidities and severity of NAFLD and tools to assess cognition amongst

Table 3 (continued)

Cognitive abilities Neuropsychological testsb Cognitive impairment seen in NAFLD

No difference seen in NAFLD

Study

Ideas, abstraction, figural creations and mental flexibility

The Animal Fluency Test + Weinstein et al. 2018 [27]

Trail Making + Tarter et al. 1984 [30]

MoCA‑TR Executive functioning abilities: Trail Making B task


MoCA‑TR Executive functioning abilities: Phonemic fluency task


MoCA‑TR Executive functioning abilities: Two‑item verbal abstraction task


Time to complete trail‑making B minus time to complete trail‑making A test

+ Weinstein et al. 2019 [29]

The Similarities Test + Weinstein et al. 2019 [29]a Abbreviations: MOCA-TR Montreal Cognitive Assessment Turkish, MOCA-SR Montreal Cognitive Assessment Serbian, NAFLD Non-alcoholic fatty liver disease, NASH Non-alcoholic steatohepatitis, MMSE Mini mental state examination, T2DM Type 2 diabetes mellitus, CFQ Cognitive failures questionnaire, VFT Verbal fluency taskb Plus (+) = impaired cognitive function observed in NAFLD for specific cognitive test. Negative (−) = no association or similar association observed in NAFLD for specific cognitive test


studies and the scarcity of literature reporting on the relationship between NAFLD and cognitive function, a meta-analysis could not be conducted. Finally, there is a known association between cognition and other chronic conditions such as diabetes and cardiovascular disease and therefore without well designed studies that can con-trol for these cardiometabolic conditions it is difficult to deduce what the role of NAFLD is specifically, outside of the cluster of metabolic conditions.

ConclusionIn conclusion, this review of 11 studies indicates that there is an association between NAFLD and lower cog-nitive performance. Particularly, that young and middle-aged adults with NAFLD had poorer cognitive function across several domains, including ‘general cognition’, ‘mental speed, attention and psychomotor speed’, and ‘ideas, abstraction, figural creations and mental flexibil-ity’. This suggests that NAFLD in mid-life may accelerate cognitive decline in certain domains, particularly those that aren’t preserved with older age. However, prospec-tive, adequately powered longitudinal studies that used valid and sensitive tools are needed to confirm the asso-ciation between NAFLD and cognition in the future. Future studies should also consider standard tools to enable comparison of results between studies, in order to promote a better understanding of the relationship between NAFLD and cognition, and as practical tools to identify those at risk of cognitive decline.

AbbreviationsALD: Alcoholic liver disease; AFT: Animal fluency test; ALT: Alanine aminotrans‑ferase; ALP: Alkaline phosphatase; AST: Aspartate aminotransferase; BMI: Body mass index; BVRT: Benton visual retention test; CFQ: Cognitive Failures Questionnaire; CVD: Cardiovascular disease; DSST: The digit symbol substitu‑tion test; DST: Digit symbol test; HVOT: Hooper visual organisation test; HTN: Hypertension; LTT: Line tracing test; MoCA‑TR: Montreal cognitive assessment Turkish version; MoCA‑SR: Montreal cognitive assessment Serbian version; MCI: Mild cognitive impairment; MetS: Metabolic syndrome; NAFLD: Non‑alcoholic fatty liver disease; NASH: Non‑alcoholic steatosis; NCTA : Number connection test A; NCTB: Number connection test B; PRISMA: Preferred reporting items for systematic reviews and meta‑analysis; SIM: Similarities test; SRRT : Simple reaction time test; SDST: Symbol digit substitution test; SDT: Serial dotting test; SDLT: Serial digit learning test; T2DM: Type 2 diabetes mellitus; VFT: Verbal fluency task.

AcknowledgementsWe would like to thank Annie Curtis for her help as a second reviewer for the full text screening of papers included in this systematic review.

Authors’ contributionsESG, RMD and SYT conceptualised and designed this review. ESG, SS and SYT conducted the systematic literature review and analyzed and interpreted the results. All authors read and approved the final manuscript.

FundingThe authors have no funding to declare.

Availability of data and materialsDetailed findings of the selection process of included and excluded articles are available upon request.

Declarations

Ethics approval and consent to participateNot applicable.

Consent for publicationNot applicable.

Competing interestsThe authors declare that they have no competing interests.

Received: 28 May 2021 Accepted: 14 December 2021

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