Author, Year | Country | Study design; Length | Sample size | NAFLD mean age, sex (n females, n males) | Risk factors/co-morbidities | Cognitive tests | NAFLD diagnosis | Findingsb |
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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) |