Association of Neurocognitive and Physical Function With Gait Speed in Midlife

Key Points Question Is gait speed measured at age 45 years associated with accelerated biological aging, neurocognitive function, and cognitive decline? Findings In this 5-decade cohort study of 904 participants in New Zealand, physical and biological indicators of accelerated aging, including compromised brain integrity (eg, reduced brain volume and cortical thickness), were associated with slow gait measured at age 45 years. Lifelong compromised brain health—including poor neurocognitive functioning as early as age 3 years and childhood-to-adulthood decline in cognitive functioning—was associated with slower gait at midlife. Meaning Gait speed at midlife may be a summary index of lifelong aging with possible origins in childhood central nervous system deficits.


eMethods 1. Age 45 Assessment
Leg length and body composition (age 45) Leg length was measured in cm from the top of iliac crest to the ground.
Body composition, including total body fat and lean mass, was measured by dual-energy X-ray absorptiometry (DXA) after removing any jewelry and metal objects. Scans were conducted using the automatic total body scan mode (GE Lunar Prodigy; Madison, WI, USA; 16.0 enCore software version with CoreScan™). Fat mass index was calculated as total body fat in kg divided by height in m 2 . Lean mass index was calculated as total lean mass in kg divided by height in m 2 . The scanner was calibrated daily with bone phantoms for quality assurance. The coefficients of variation (CVs) for repeat in vivo scans in adults for BMC (g) and area (g/cm 2 ), respectively, were: 1.8% for total fat mass and 1.0% for bone-free lean tissue mass.

Physical function (age 45)
Functional capacity at age 45 was assessed by self-reported physical limitations (RAND 36-Item Health Survey 1.0) and by several brief exercises that index the ability to perform everyday activities: handgrip strength, one-legged balance, visual-motor coordination, chair-stand test, and 2-min step test.

Physical limitations (RAND SF36)
Physical limitations were measured with the 10-item RAND 36-Item Health Survey 1.0 physical functioning scale. 1 Participant responses ("limited a lot", "limited a little", "not limited at all") assessed their difficulty with completing various activities, e.g., climbing several flights of stairs, walking more than 1 km, participating in strenuous sports, etc. Scores were reversed to reflect physical limitations so that a high score indicates more limitations.

Handgrip strength
Handgrip strength was measured for the dominant hand (elbow held at 90°, upper arm held tight against the trunk) as the maximum value achieved across three trials using a Jamar digital dynamometer. 2,3 One-legged balance Balance was measured using the Unipedal Stance Test as the maximum time achieved across three trials of the test with eyes closed. [4][5][6]

Visual-motor coordination
Visual-motor coordination was measured as the time to completion of the Grooved Pegboard Test with the non-dominant hand. 7 Scores for the Grooved Pegboard test were reversed so that higher values corresponded to better performance.

Chair-stand test
Chair rises were measured as the number of stands a participant completed in 30 seconds from a seated position. 8,9 2-min step test The 2-min step test was measured as the number of times a participant lifted their right knee to mid-thigh height (measured as the height half-way between the knee cap and the iliac crest) in 2 minutes at a self-directed pace. 9,10 Pace of Aging (age 45) Pace of Aging was measured for each Dunedin participant with repeated assessments of a panel of 19 biomarkers taken at ages 26, 32, 38, and 45 years; a method previously described. 11 The 19 biomarkers were: body mass index, waist-hip ratio, glycated hemoglobin (HbA1C), leptin, blood pressure (mean arterial pressure), cardiorespiratory fitness (VO2Max), forced expiratory volume in one second (FEV1), FEV1 to forced vital capacity ratio (FEV1/FVC), total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, apolipoprotein B100/A1 ratio, lipoprotein(a), creatinine clearance, urea nitrogen, C-reactive protein, white blood cell count, gum health, and cariesaffected tooth surfaces. Measures were taken in counterbalanced order across participants with the exception of blood, which was drawn at the same time of day for all participants at all four ages and dental examinations which were conducted in the late afternoon at all four ages. Women who were pregnant at the time of a given assessment were excluded from that wave of data collection. The measurement of each biomarker is described below. Change over time in each biomarker was modeled with mixed-effects growth models, and these rates of change were combined into a single index scaled (within sex) in years of physiological change occurring per one chronological year, as per the method previously described. 11 Participants ranged in their Pace of Aging from near 0 years of physiological change per chronological year to nearly 3 years of physiological change per chronological year.

Body mass index
Height was measured to the nearest millimeter using a portable stadiometer (Harpenden; Holtain, Ltd.). Weight was measured to the nearest 0.1 kg using calibrated scales. Individuals were weighed in light clothing. Body mass index (BMI) was calculated.

Waist-hip ratio
Waist girth was the perimeter at the level of the noticeable waist narrowing located between the costal border and the iliac crest. Hip girth was taken as the perimeter at the level of the greatest protuberance and at about the symphysion pubic level anteriorly. Measurements were repeated and the average used to calculate waist-hip ratio.

Glycated hemoglobin (HbA1C)
Whole blood glycated hemoglobin concentration (expressed as a percentage of total hemoglobin) was measured by ion exchange high performance liquid chromatography (Variant II: BioRad, Hercultes, Calif.), a method certified by the US National Glycohemoglobin Standardization Program (http://www.ngsp.org/).

Blood pressure (mean arterial pressure)
Systolic and diastolic blood pressure were assessed according to standard protocols with a Hawksley random-zero sphygmomanometer with a constant deflation valve. Mean arterial pressure (MAP) was calculated using the formula Diastolic Pressure+1/3(Systolic Pressure -Diastolic Pressure).

Cardiorespiratory fitness (VO2Max)
Cardiorespiratory fitness was assessed by measuring heart rate in response to a submaximal exercise test on a friction-braked cycle ergometer. Dependent on the extent to which heart rate increased during a 2-min 50 W warm-up, the workload was adjusted to elicit a steady heart-rate in the range 130-170 beats per minute. After a further 6-min constant power output stage, the maximum heart rate was recorded and used to calculate predicted maximum oxygen uptake adjusted for body weight in milliliters per minute per kilogram (VO2max) according to standard protocols. 12

Lung function (FEV1 and FEV1/FVC)
We calculated post-albuterol forced expiratory volume in one second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC; FEV1/FVC) using measurements from spirometry conducted with a Sensormedics body plethysmograph (Sensormedics Corporation, Yorba Linda, CA, USA).

Apolipoprotein B100/A1 ratio
Serum apolipoprotein A1 and apolipoprotein B100 (g/L) were measured by immunoturbidimetric assay on a Hitachi 917 analyzer (ages 26-32), a Modular P analyzer (age 38), and a Cobas c502 (age 45), and the ratio between the two was calculated.

High sensitivity Creactive protein (hsCRP)
Serum C-reactive protein (mg/L) was measured by high sensitivity immunoturbidimetric assay on a Hitachi 917 analyzer (age 32), a Modular P analyzer (age 38), and a Cobas c702 (age 45). Values were log-transformed for analysis.

Gum health (combined attachment loss)
Calibrated dentists examined periodontal health at three sites (mesiobuccal, buccal, and distolingual) per tooth. Gingival recession (the distance in millimeters from the cementoenamel junction to the gingival margin) and probing depth (the distance from the probe tip to the gingival margin) were recorded using a PCP-2 periodontal probe (Hu-Friedy; Chicago). The combined attachment loss for each site was computed by summing gingival recession and probing depth (third molars were not included) and then averaged across all periodontally examined teeth.

Caries-affected tooth surfaces
Teeth were examined for caries and restorations following the World Health Organization Oral Health Surveys methodology. 14,15 Four surfaces were considered for anterior teeth (canines and incisors): buccal, lingual, distal, and mesial; a fifth surface, occlusal, was considered for premolar and molar teeth. Tooth surfaces were classified as having untreated caries (DS) if a cavitated carious lesion was present, as filled (FS) if a dental restoration was present (including crowns), and missing due to caries (MS) if the participant indicated that a given tooth had been removed due to decay or failed dental restorative work. DS, MS, and FS counts were summed (ranging from 0 to 148 surfaces). Surfaces of teeth that were unerupted, lost due to trauma, extracted for reasons other than caries (impaction, orthodontic treatment, or periodontal disease), or could not be visualized by the examiner were excluded from calculations.

Facial Aging (age 45)
Facial Aging was based on ratings by an independent panel of 8 raters of each participant's facial photograph. Facial Aging was based on two measurements of perceived age. First, Age Range was assessed by an independent panel of 4 raters, who were presented with standardized (non-smiling) facial photographs of participants and were kept blind to their actual age. Raters used a Likert scale to categorize each participant into a 5-year age range (i.e., from 20-24 years old up to 70+ years old) (interrater reliability = .77). Scores for each participant were averaged across all raters. Second, Relative Age was assessed by a different panel of 4 raters, who were told that all photos were of people aged 45 years old. Raters then used a 7-item Likert scale to assign a "relative age" to each participant (1="young looking", 7="old looking") (interrater reliability = .79). Image Processing. Structural MRI data were analyzed using the Human Connectome Project (HCP) minimal preprocessing pipeline as extensively detailed elsewhere. 16 Briefly, T1-weighted and FLAIR images were processed through the PreFreeSurfer, FreeSurfer, and PostFreeSurfer pipelines. T1-weighted and FLAIR images were corrected for readout distortion using the gradient echo field map, coregistered, brain-extracted, and aligned together in the native T1 space using boundary-based registration. 17 Images were then processed with a custom FreeSurfer recon-all pipeline that is optimized for structural MRI with higher resolution than 1 mm isotropic. Finally, recon-all output were converted into CIFTI format and registered to common 32k_FS_LR mesh using MSM-sulc. 18 Outputs of the minimal preprocessing pipeline were visually checked for accurate surface generation by examining each participant's myelin map, pial surface, and white matter boundaries.
For brain volume, cortical thickness, and surface area data, participants were excluded if they failed visual inspection of surface generation, had major incidental findings, or were missing T2-weighted or field map scans, yielding 861 datasets for analyses.

Total brain volume
Total brain volume was extracted from the FreeSurfer "aseg" parcellation.

Cortical thickness and surface area
For each participant the mean cortical thickness and surface area were then extracted from each of the 360 cortical areas in the HCP-MPP1.0 parcellation. 19

White matter hyperintensities
To identify and extract the total volume of white matter hyperintensities (WMHs), T1-weighted and FLAIR images for each participant were processed with the UBO Detector, a cluster-based, fully-automated pipeline with high reliability in our data (test-retest ICC = 0.87) and out of sample performance. 20 The resulting WMH probability maps were thresholded at 0.7, which is the suggested standard. WMH volume is measured in Montreal Neurological Institute (MNI) space, thus removing the influence of differences in brain volume on WMH volume. Because of the potential for bias and false positives due to the thresholds and masks applied in UBO, the resulting WMH maps for each participant were manually checked by two independent raters to ensure that false detections did not substantially contribute to estimates of WMH volume. Visual inspections were done blind to the participants' cognitive status. Due to the tendency of automated algorithms to mislabel regions surrounding the septum as WMHs, these regions were manually masked out, to further ensure the most accurate grading possible. For WMH data, participants were excluded if they had missing FLAIR scans, Multiple Sclerosis, or inaccurate white matter labelling or low-quality MRI data, yielding 852 datasets for analyses. In all analyses, WMH volume was logtransformed.

Trail-Making Test
The Trail Making Test 22 (for adults) is a non-verbal test of executive functioning and consists of two separate tests. Part A has been suggested to be a measure of visual search and motor speed skills. Part B is additionally a measure of task-switching, mental flexibility, and related higher order cognitive skills. Participants were given standard instructions and a demonstration of both Parts A and B of the test.

Animal Naming Test
The Animal Naming Test 23 is a test of memory and verbal fluency. Participants were asked to name as many animals as they can think of, as quickly as possible in 60 seconds. The total score was the number of animals, excluding errors of intrusion or perseveration. Credit can be given for all animals, including birds, fish, reptiles, insects, humans, extinct animals, etc., for general category terms (e.g., dog) and for specific instances (e.g., terriers) when both are given. Only one item is credited if the same animal at different developmental stages (e.g., sheep, lamb) is named.

Wechsler Memory Scale -Mental Control
The Wechsler Memory Scale (WMS-III) 24 test of Mental Control is a test of attention and tracking. It requires reciting the months of the year in backwards order, starting with December. Responses were scored according to the instructions in the WMS-III manual. Scores ranged from 1 (poor performance) to 5 (good performance) and reflect both accuracy and speed.

Rey Auditory Verbal Learning Test
This is a test of verbal learning and memory administered at 45 years. 7 The test involves a five-trial presentation of a 15-word list and a one-time presentation of an interference list. Four trials of the 15-word list were administered due to time constraints. Words are recalled immediately after each trial and later after a 25-30 minute delay. Total Recall is the total number of words (0-60) recalled over four trials (the sum of words recalled across trials 1-4). Delayed Recall is the total number of words (0-15) recalled after a 25-30 minute delay.

Childhood Brain Health (age 3)
Brain Health was assessed with a summary factor score indexing the child's early neurocognitive status based on information from the child examination and behavior ratings. At age 3 years, each child participated in a 45-minute examination that included assessment by a pediatric neurologist and standardized tests of intelligence, receptive language, and motor skills. Afterwards the examiners (having no prior knowledge of the child) rated each child's emotional and behavioral regulation. The summary score was created with confirmatory factor analysis of these five indicators of Brain Health assessed at age 3: neurological abnormalities, lack of control, receptive language, Peabody Picture Vocabulary Test, and motor development 25 . The model fit the data well, χ2 (N = 1,035, df = 5) = 6.459, p = .2641, CFI = .999, TLI = .997, RMSEA = 0.17. Factor scores were output and standardized to a mean = 0 and SD = 1.

Neurological abnormalities
At age 3 years, each child was examined by a pediatric neurologist for neurological signs, including assessment of motility, passive movements, reflexes, facial musculature, strabismus, nystagmus, foot posture, and gait, based on procedures described by Touwen and Prechtl (1970). 26

Peabody Picture Vocabulary test
Intelligence was assessed at age 3 years with the Peabody Picture Vocabulary Test. 27

Receptive language
Receptive language was assessed at age 3 years with Reynell Developmental Language Scales. 28

Lack of control
At age 3 years, each child participated in a testing session involving cognitive and motor tasks. The children were tested by examiners who had no knowledge of their behavioral history. Following the testing, each examiner rated the child's lack of control in the testing session, yielding a behavioral style factor, labeled Lack of Control, 30 which characterized children who were labile, had low frustration tolerance, lacked reserve, were resistant, restless, impulsive, required attention, and lacked persistence in reaching goals.

Wechsler Intelligence Scale for Children-Revised
The Wechsler Intelligence Scale for Children-Revised (WISC-R) 31 was administered to the participants at ages 7, 9, and 11 years, yielding the IQ. Scores were averaged across the three assessments. The tests were individually administered at each assessment according to standard protocol. Examiners were blind to the children's performance on previous administrations of the WISC-R.

Childhood socioeconomic status
The socioeconomic statuses of cohort members' childhood families were measured using a 6-point Elley-Irving socioeconomic index for New Zealand 32 that assessed parents' occupational statuses, defined based on average income and educational levels derived from the New Zealand Census. The highest occupational status of either parent was averaged across the childhood assessments at ages 3, 5, 7, 9, 11, 13, and 15 years.

eMethods 3. Attrition Analysis
We conducted an attrition analysis using childhood neurocognitive functioning (the Wechsler Intelligence Scale for Children-Revised; WISC-R) and socioeconomic status (SES) to determine whether participants in the Phase 45 data collection were representative of the original cohort.
No significant differences in WISC-R were found between the full cohort, those still alive, those seen at Phase 45, or those with gait data at Phase 45. Those who were deceased by the Phase 45 data collection had significantly lower scores on the WISC-R than those who were still alive (t=2.09, P=.04).