Table 1 Extraction table of included studies assessing the association between NAFLD and cognition^a

Weinstein et al. (2018) [27]

United States

Cross-sectional, population-based sampling survey; NHANES Survey data from 2011 to 2014

1102 participants

239 NAFLD participants

Mean NAFLD age: 68.6 years

NAFLD -

BMI 35.0 kg/m2

Obesity: 92.5%

Insulin resistance: 62.1%

HTN: 76.1%

High cholesterol: 82.2%

MetS: 58.5%

Control –

BMI 25.00 kg/m2

Obesity: 19.4%

Insulin resistance: 17.5%

HTN: 61.2%

High cholesterol: 74.2%

MetS: 11.1%

(1) The Word Learning subset - used to assess immediate and delayed learning ability

(2) The Animal Fluency Test - categorical verbal fluency

(3) The digit symbol substitution - involves processing speed, sustained and working memory

Fatty liver index score ≥ 60 Spanish.

(1) The Word Learning subset – Immediate verbal memory: NAFLD only (SD: 20.5 ± 0.4) vs the control group (SD: 20.0 ± 0.3)

Delayed verbal memory: NAFLD only group (SD: 6.6 ± 0.2) vs the control group (6.4 ± 0.1)

(2) AFT –

Verbal fluency: NAFLD only (18.6 ± 0.3) vs control group (18.3 ± 0.4)

(3) DSST –

Processing speed, sustained attention, working memory: NAFLD (55.9 ± 1.05) vs control group (53.6 ± 1.2)

Celikbilek et al. (2018) [22]

Turkey

Cross-sectional study

143 participants

70 NAFLD participants

Mean NAFLD age: 46.9 years, F (NAFLD): 41, M (NAFLD): 29

NAFLD –

T2DM: 30%

HTN: 20%

Hyperlipidaemia: 7.1%

MetS: 48.6%

Control –

T2DM: 4.1%

HTN: 2.7%

Hyperlipidaemia: 1.4%

MetS: 34.3%

(1) Montreal Cognitive Assessment Turkish version. (a) visuospatial abilities - clock-drawing task and three-dimensional cube-copying task, (b) Memory - delayed recall (c) Executive functioning - Trail Making B task, a phonemic fluency task, and a two-item verbal abstraction task, (d) Attention - a serial subtraction task and digits forward and backward tasks, (e) Language - three-item confrontation naming task, repetition of two syntactically complex sentences (f) orientation - orientation to time and place is also evaluated

Abdominal ultrasonography

(1) MoCA-TR - scores significantly lower in NAFLD group in comparison to control group (P < 0.001)

(a) Visuospatial abilities: P < 0.05

(b) Memory: P = 0.16

(c) Executive functioning: P < 0.05

(d) Attention: P = 0.56

(e) Language: P = 0.89

(f) Orientation: P = 0.29

Takahashi et al. (2017) [28]

Japan

Cross-sectional study

39 participants

24 NAFLD participants

Mean NAFLD age: 54 years

NAFLD –

T2DM: 41.6%

Dyslipidaemia: 58.3%

HTN: 29.2%

Control –

Not reported

(1) A verbal fluency task (VFT)

Asia-Pacific Working Party guidelines for the assessment and management of NAFLD.

Ultrasonography (in the absence of other causes of chronic liver disease e.g., hepatitis C antibody negative, hepatitis B surface antigen negative, and alcohol consumption < 20 g/day)

(1) VFT –

Number of words during VFT was significantly higher in controls compared to the NAFLD: p < 0.032

Number of words during VFT NAFLD: 12

Number of words during VFT controls: 14

Filipovic et al. (2018) [21]

Serbia

Case-control study

76 participants

40 NAFLD participants

Mean NAFLD age: 47.9 years,

M (NAFLD): 22,

F (NAFLD): 18

NAFLD –

T2DM: 30%

HTN: 80%

Obese: 50%

MetS: 85%

Control –

T2DM: 25%

HTN: 44%

Obese: 11%

MetS: 22%

(1) Montreal Cognitive Assessment test Serbian version.

(a) alternating connections, (b) vasoconstrictive abilities - draw a cube and a clock in 11:10 position of clock hands, (c) memory - numbers repeated in the same and reverse order, (d) attention - tap whenever you hear a letter A, serial subtraction of 7, starting with a hundred (e) sentence repeating and verbal fluency.

Abdominal ultrasonography, Sonographic evaluation (US) of hepatic steatosis

(1) MOCA-SR –

The cognitive status was lower in NAFLD compared to control:

OR 0.096, 95% CI 0.032–0.289, and p < 0.001

Elliott et al. (2013) [23]

UK (Europe)

Cohort, Prospective follow-up over 3 years

431 participants

224 NAFLD participant

Mean NAFLD age: 59 years, F (NAFLD): 101, M (NAFLD): 123

Not reported

(1) Cognitive Failures Questionnaire (CFQ) - measures memory, attention, concentration, forgetfulness, word finding abilities and confusion.

Liver Serum Biochemistry - ALT, ALP, ALB, Bilirubin.

(1) CFQ –

Cognitive symptoms CFQ associated with worse functional ability in NAFLD compared to controls: r = 0.4, p < 0.0001

Weinstein et al. (2019) [29]

United States

Population-based, multi-generational study (The Framingham Heart Study) Cross-sectional study

1287 participants

378 NAFLD participants

Mean NAFLD age: 61.1 years, F (NAFLD): 157, M (NAFLD): 221

NAFLD –

BMI: 31.0

T2DM: 20.5%

HTN (stage 1): 59.3%

Controls –

BMI: 26.8

T2DM: 6.9%

HTN (stage 1): 38.2%

(1) The Wechsler Memory Scale - verbal and visual memory

(2) Time to complete trail-making B minute time to complete trail-making A test (TrB-TrA) - executive function

(3) The similarities test (SIM) - abstract reasoning skills

(4) Hooper visual organization test (HVOT) - visual perception.

Multi-detector CT with 8-slice, A calibration phantom (Image Analysis, Lexington, KY) with a water equivalent compound - three areas from the liver and one from an external phantom were measured (NAFLD was defined as having a liver/phantom ratio ≤ 0.33).

(1) The Wechsler Memory Scale -

p = 0.610

(2) TrB-TrA – p = 0.418

(3) SIM – p = 0.746

(4) HVOT – p = 0.528

No significant association of NAFLD with cognitive measures identified.

Participants with NAFLD with advanced fibrosis was associated with poorer performance on the TrB-TrA (P = 0.028) and SIM test (P = 0.009)

Tarter et al. (1984) [30]

United States

Case-control study

40 participants

30 NAFLD participants

Mean NAFLD age: 40.9 years

Not reported

(1) Peabody picture intelligence test – verbal intelligence.

(2) Raven’s progressive matrices - nonverbal intelligence.

(3) Digit span forward.

(4) Digit span backward.

(5) Weschler Memory Scale): (a) Logical memory (b) Figural memory, (c) Paired associates, (d) Suprasan.

(6) Perceptual-Motor: (a) Finger tapping, (b) Purdue Pegboard, (c) Stary tracing, (d) Symbol digit modalities.

(7) Spatial: (a) Block design, (b) Tactual performance, (c) Trail making.

(8) Language: (a) Fluency, (b) Confrontation naming, (c) Responsive naming

(9) The Token Test -comprehensive capacity

Hepatic diagnosis - clinical, biochemical, serological confirmed by liver biopsy

(1) Peabody picture intelligence test – no difference

(2) Raven’s progressive matrices – no difference

(3) Digit span forward – no difference

(4) Digit span backward – no difference

(5) Weschler Memory Scale) – no difference

(6) Perceptual-Motor –

(a) Finger tapping: no difference

(b) Purdue Pegboard: p < 0.01

(c) Stary tracing: no difference

(d) Symbol digit modalities: p < 0.01

(7) Spatial –

(a) Block design: p < 0.06

(b) Tactual performance: p < 0.05

(c) Trail making: p < 0.05

(8) Language –

(a) Fluency: no difference

(b) Confrontation naming: no difference

(c) Responsive naming: no difference

(9) The Token Test – no difference

Tarter et al. (1987) [31]

United States

Case-control study

46 participants

23 NAFLD participants

Mean NAFLD age: 37.2 years, M (NAFLD): 11, F (NAFLD): 12

Not reported

(1) Digit Span Test - immediate memory

(2) Supraspan Learning Test - the number of trials required accurately to repeat a string of digits that is one digit longer than the digits forward score. (3) Benton Visual Retention Test (BVRT) - short term visual

(4) Rey-Osterreith Complex Figure Test - incidental learning ability

(5) Brown-Peterson Test - measures the rate of decay of information from short-term memory.

Serological tests, clinical history and physical examinations, and was confirmed by a percutaneous liver biopsy.

(1) Digit Span Test – no difference

(2) Supraspan Learning Test – p < 0.05

(3) BVRT – p < 0.0001

(4) Rey-Osterreith Complex Figure Test – no difference

(5) Brown-Peterson Test – no difference

Seo et al. (2016) [32]

United States

Cross-sectional study (NHANES III - survey)

4472 participants

874 NAFLD participant

Mean NAFLD age: 40.9 years

NAFLD –

T2DM: 13.6%

HTN: 36.3%

Hypercholesterolaemia: 30.4%

Stroke: 1.5%

Controls –

T2DM: 5.2%

HTN: 17.5%

Hypercholesterolestelemia: 22.2%

Stroke: 0.5%

(1) The Simple Reaction Time Test (SRTT) - measures response time, visual-motor speed

(2) The Symbol Digit Substitution Test (SDST) - assesses visual attention and coding ability

(3) The Serial Digit Learning Test (SDLT) - test learning, recall, and concentration.

Gallbladder examination by ultrasound with a Toshiba SSA-90A machine with a 3.75 and 5.0 MHz transducer. Liver enzymes (ALT, AST) were assayed with Hitachi 737 automated multichannel chemistry analyser. NAFLD was defined as moderate/severe steatosis as deter- mined by ultrasound.

(1) SRTT – B = 7.827, 95% CI 0.975 to 14.679

(2) SDST – B = 0.110, 95% CI 0.004 to 0.216

(3) SDLT – B = 0.880, 95% CI 0.317 to 1.443

Participants with NAFLD had lower performances on SRTT, SDST and SDLT

Felipo et al. (2012) [24]

Spain (Europe)

Case control study

179 participants

29 NAFLD participant

Mean NAFLD age: 45 years, F (NAFLD): 24, M (NAFLD): 5

Not reported

(1) The Digit Symbol test (DST) – mental speed

(2) The Number Connection Test A (NCT-A) – mental speed

(3) The Number Connection Test B (NCT-B) – mental speed

(4) The Serial Dotting Test – mental speed

(5) The line tracing test (LTT) – visuospatial

Liver biopsy obtained during histological study.

(1) DST – no difference in NAFLD, cirrhosis or NASH

(2) NCT-A – no difference in NAFLD, impaired in patients with NASH and cirrhosis (P < 0.001)

(3) NCT-B – no difference in NAFLD, impaired in NASH and cirrhosis (P < 0.001)

(4) The Serial Dotting Test – no difference in NAFLD, impaired in cirrhosis (P < 0.001) and NASH (P < 0.01)

(5) LTT – no difference in NAFLD, impaired in NASH and cirrhosis (P < 0.001)

Tuttolomondo et al. (2018) [33]

Italy (Europe)

Case control study

163 participants

80 NAFLD participants

Mean NAFLD age: 53.7 years

NAFLD –

BMI: 28.7

HTN: 35.0%

T2DM: 38.8%

Dyslipidaemia: 18.8%

Previous CVD: 3.75%

Controls –

BMI: 25.3

HTN: 15.7%

T2DM: 8.4%

Dyslipidaemia: 16.9%

Previous CVD: 0

(1) Mini-mental state examination (MMSE)

Increased serum levels of ALT for at least 6 months and alcohol consumption of < 20 g/day in the previous year. Liver ultrasound finding of steatosis and a liver stiffness value > 6 kPa. Liver biopsy for NAFLD. Hepatic steatosis was defined by detection of Bright Liver Echo pattern.

(1) MMSE –

NAFLD had a lower mean MMSE score when compared to controls (26.9 ± 1.6 vs. 28.0 ± 1.36; p = 0.005)