This study is based on a sub-cohort from the LifeLines Cohort Study. LifeLines is a multi-disciplinary prospective population-based cohort study examining in a unique three-generation design the health and health-related behaviors of 167,729 persons living in the North of The Netherlands. The present study includes a consecutive series of participants aged 18 years and older who visited the LifeLines study location in Groningen, the Netherlands between October 22nd and November 29th 2013. During this period all participants were invited to participate in an additional visit to complete an additional cognitive examination which consists of the RFFT and the CogState battery. This additional assessment took place approximately 2 weeks after the baseline visit by trained research assistants. A total of 509 participants participated in this additional examination.
The Lifelines Cohort Study employs a broad range of investigative procedures in assessing the biomedical, socio-demographic, behavioral, physical and psychological factors which contribute to the health and disease of the general population, with a special focus on multi-morbidity and complex genetics. Baseline assessment consisted of a physical examination, cognitive functioning assessment, drawing blood samples, collecting urine samples, and self-report questionnaires regarding demographics, health status, lifestyle and psychosocial aspects. LifeLines is a facility that is open for all researchers. Information on application and data access procedure is summarized on http://www.lifelines.net/. Details of the LifeLines study design are reported elsewhere [5, 23]. Briefly, the participant recruitment and baseline assessment started in 2006 and was finished in 2013 and was performed in 12 local research sites. The LifeLines adult study population is shown to be broadly representative for the general adult population of the north of the Netherlands . A three generation design and recruitment strategy was adopted to include participants [5, 23] Firstly, an index population aged 25–49 years was recruited via participating general practitioners (GPs), unless the participating GP considered the patient not eligible based on the following criteria: a) severe psychiatric or physical illness; b) limited life expectancy (<5 years); or c) insufficient knowledge of the Dutch language to complete a Dutch questionnaire. Subsequently, older and younger family members were invited by LifeLines to take part. In addition, adults could self-register to participate via the LifeLines website . The participants aged between 25 and 49 years and the percentage of women are overrepresented in the LifeLines Cohort Study compared to the general population . However, the mean age of the study population of the current study (mean: 53; SD: 14.6) is somewhat higher than the mean age of the study population of the LifeLines Cohort Study (mean: 45; SD: 13.1) and our study includes more males (50% versus 41) and higher educated participants (76% versus 69%). Although age distribution in the current study is not representative for the general population (i.e. there is an overrepresentation of participants aged 50 years and over) due to the recruitment strategy, for the current study it is also important to have sufficient variability in scores on cognitive functioning. All ages of 18 years and older are represented in the current study and although changes in cognitive performance can be observed in younger participants, higher variability in cognitive functioning is expected in older participants [6, 13]. Furthermore, a decline in cognitive functioning by age is also shown in higher educated participants . All participants gave informed consent before they received an invitation for the physical examination. The LifeLines Cohort Study is conducted according to the principles of the Declaration of Helsinki and approved by the medical ethical committee of the University Medical Center Groningen, The Netherlands.
The RFFT consists of five parts and each part consists of 35 identical five-dot patterns arranged in seven rows and five columns on a sheet of paper. However, the stimulus pattern differs between each of the five parts. In part 1, the five-dot pattern forms a regular pentagon. Parts 2 and 3 contain the same five-dot pattern as part 1 but includes various distractors (i.e. diamonds in part 2, and lines in part 3). In parts 4 and 5 there are no distracting elements, but the five-dot pattern is a variation of the pattern of part 1 . The task is to draw as many unique designs as possible within one minute by connecting the dots in different patterns. The test has been developed as a measure of nonverbal fluency and executive functioning, defined as the ability to utilize one or more strategies that maximize response production while at the same time avoiding or minimizing response repetition [7, 24]. Studies support the construct validity of the RFFT as a measure of initiation, planning and divergent reasoning. Performance on the RFFT is expressed as the total number of unique designs (the sum of all five parts, possible range: 0–175). The error ratio (i.e. the total number of perseverative errors (i.e. repetitions of designs are scored as perseverative errors) divided by the total number of unique designs ), is increasingly used as a measure of performance. The error ratio also reflects executive functioning, as it is an index for assessing the respondent’s ability to minimize repetition while maximizing unique productions. All participants completed the RFFT under supervision of a trained research nurse.
In the LifeLines Cohort Study, we used the CogState Brief Battery, designed to monitor cognitive change. Nonetheless, for the present study we added an executive functioning task (i.e. the Groton Maze Learning Test (GMLT)). Administration of the CogState battery was conducted on a personal computer. The total battery included the Groton Maze Learning Test (GMLT) with the delayed recall (GMLR) and the Brief Battery including four card tasks. The CogState subtasks are described in detail elsewhere [19, 25]. Briefly, instructions for each task were presented on the screen and participants were asked to carefully read these. A supervisor stayed present during the GMLT to help the participants understand the task during the practice session. During the CogState Brief Battery, no supervisor was present, although participants were informed that in case they needed assistance, a supervisor would be around to help them continue the task. The tests were administered in the following order:
Groton Maze Learning test (GMLT)
The GMLT is a hidden pathway maze learning task that measures executive function and spatial problem solving. This task consists of a 10 x 10 grid of tiles on a computer screen. To complete the maze, the participant must follow a hidden 28-step pathway from the start at the top left corner (indicated by a blue tile) to the finish at the bottom right of the grid (indicated by red circles). The subject is instructed to move one step from the start location and then to continue, one tile at a time, toward the end (bottom right). The participant moves by clicking a tile next to their current location using the computer mouse. After each move is made, the computer indicates whether this is correct by revealing a green checkmark, or incorrect by revealing a red cross. If a choice is incorrect (i.e. a red cross is revealed), the subject must go back to the last correct location and then make a different tile choice to advance toward the end. Once completed, participants are returned to the start location and repeat the task four more times, trying to remember the pathway they have just completed. The primary outcome measure was the total number of errors across five trails.
Detection task (DET)
The DET is a simple reaction time task that measures psychomotor functioning and speed of processing. In this task, the participant must attend to the center of the screen and follow the rule “Has the card turned face up? Subjects were instructed to press the “Yes” key as soon as the card turned face up. The task ended after 35 correct trials had been recorded. The primary outcome measure was reaction time (in milliseconds), which was normalized using log10 transformation.
Identification task (IDN)
The IDN is a choice reaction task that measures visual attention. In this task, the participant must attend to the card in the center of the screen and response to the question: “Is the card red”? Participants were required to press the “Yes” key if it is and the “No” key if it is not. This task continued until 30 correct responses have been recorded. Reaction time (in milliseconds and log10 transformed) was the primary outcome measure.
One Back task (OBK)
The OBK is a measure of attention and working memory. In this task, the participant must to attend to the card in the center of the screen and respond to the question “Is this card the same as that on the immediately previous trial”? If the answer was yes, participants were instructed to press the “Yes” key, and the “No” key if the answer was no. The task ends after 30 correct trials. The primary outcome measure was the proportion of correct answers, which was normalized using arcsine transformation.
One Card Learning task (OCL)
The OCL is a visual learning and memory task. In this task, the participant must attend to the card in the center of the screen and respond to the question “have you seen this card before in this task”? If the answer was yes, participants were instructed to press the “Yes” key, and the “No” key if the answer was no. The task ends after 42 trials. The primary outcome measure was the proportion of correct answers, normalized using arcsine transformation.
Groton Maze learning task – delayed recall (GMLR)
The GMLR is a measure of visual learning and memory. In this task, the 10 x 10 grid of tiles is shown again on the computer screen and participants are asked to reproduce the same hidden path as was identified in the GMLT. The participant completes this delayed recall trial once. The primary outcome measure was the total number of errors.
After the CogState battery, participants were administered a short questionnaire evaluating the CogState. Questions concerned whether participants had experience using a computer mouse (1 = never; 2 = rarely; 3 = occasionally; 4 = regularly; 5 = often), whether (physical) impairments limited them to perform the tasks (1 = yes; 2 = no), and whether participants experienced the CogState as stressful (1 = not at all stressful; 2 = a little stressful; 3 = reasonably stressful; 4 = fairly stressful; 5 = very stressful) or tiresome (1 = not at all tiresome; 2 = a little tiresome; 3 = reasonably tiresome; 4 = fairly tiresome; 5 = very tiresome).
The following participants characteristics were collected: age, gender, educational level (categorized as low (≤12 years), or high (>12 years) according to the International Standard Classification of Education (ISCED) ), nationality (i.e. based on the father’s and mother’s country of birth according to the definition of Statistics Netherlands ), marital status (being in a relationship or not), smoking status (never smoker, past smoker, or current smoker), alcohol use (no alcohol use, moderate alcohol use, or problematic alcohol use), physical activity (complying with the Dutch norm of at least half an hour of moderately intensive exercise at least 5 days a week, yes or no ), and the number of neurological (i.e. stroke, multiple sclerosis, epilepsy; range 0 to 3) or cardiovascular disorders (i.e. myocardial infarction, arrhythmia, heart failure, high blood pressure; range 0 to 4), diabetes (yes or no), or depression (yes or no (i.e. major or minor depression according to the Mini International Neuropsychiatric Interview (MINI) ).
Sample characteristics are described by displaying percentages for categorical variables, the mean (SD) for normally distributed continuous variables and the median (IQR) for not normally distributed continuous variables.
Spearman rank correlation coefficients were calculated to compare the RFFT scores (i.e. total number of unique designs and error ratio) to the scores on the six CogState subtasks. Positive correlations are interpreted as small (r ≤ 0.29), medium (r = 0.30 to r = 0.49), or large (r ≥ 0.50) . For negative correlations the same guidelines are applied for interpretation, but in opposite directions. As both cognitive scores are influenced by age, education level, and gender [6, 9, 31], we controlled for these covariates. Partial correlation could not be performed since not all assumptions were met. Therefore, we conducted subgroup analyses for: a) age (young: 18–49 years versus middle-age: 50–64 years versus older adults: ≥65 years); b) education (low versus high); and c) gender. Sensitivity analyses were performed to investigate whether having little experience using a computer mouse, being limited by (physical) impairments, or reporting one of the following conditions: problematic alcohol use, having (had) a neurological disorder (stroke, multiple sclerosis, or epilepsy), or depression, would alter the results and our conclusions, by excluding those participants from the analyses. IBM SPSS statistics software version 22 was used for the statistical analysis. Significance levels were set at p < 0.05 and all tests were two-tailed.