Reliability of structural brain change in cognitively healthy adult samples

Abstract

In neuroimaging research, tracking individuals over time is key to understanding the interplay between brain changes and genetic, environmental, or cognitive factors across the lifespan. Yet, the extent to which we can estimate the individual trajectories of brain change over time with precision remains uncertain. In this study, we estimated the reliability of structural brain change in cognitively healthy adults from multiple samples and assessed the influence of follow-up time and number of observations. Estimates of cross-sectional measurement error and brain change variance were obtained using the longitudinal FreeSurfer processing stream. Our findings showed, on average, modest longitudinal reliability with two years of follow-up. Increasing the follow-up time was associated with a substantial increase in longitudinal reliability while the impact of increasing the number of observations was comparatively minor. On average, 2-year follow-up studies require ≈2.7 and ≈4.0 times more individuals than designs with follow-ups of 4 and 6 years to achieve comparable statistical power. Subcortical volume exhibited higher longitudinal reliability compared to cortical area, thickness, and volume. The reliability estimates were comparable to those estimated from empirical data. The reliability estimates were affected by both the cohort's age where younger adults had lower reliability of change, and the preprocessing pipeline where the FreeSurfer's longitudinal stream was notably superior than the cross-sectional. Suboptimal reliability inflated sample size requirements and compromised the ability to distinguish individual trajectories of brain aging. This study underscores the importance of long-term follow-ups and the need to consider reliability in longitudinal neuroimaging research.

Keywords: Longitudinal; aging; observations; reliability; structural MRI; study duration; validity.

Figure 1. Schematic representation of time and follow-up effects on reliability.

Hypothetical scenario illustrating a participant scanned twice at each time point, represented by the green and red lines. Measurement error causes deviations in the estimated slopes from the true trajectory (black line), which represents actual change over time. In the main plots, points represent observed cross-sectional measurements, lines estimated longitudinal (linear) trajectories, and density plots represent the distribution of possible values for a given cross-sectional observation. The boxes show the observed yearly brain change. a) Effects of follow-up time: Extending the follow-up time from 2 years to 4 years reduces the impact of cross-sectional measurement error on yearly change estimates. b) Effects of increasing the number of observations which leads to reductions of measurement error on yearly change estimates.

Figure 2. Longitudinal reliability of structural brain features.

a) Mean reliability (ICC) of structural brain change across features as a function of total follow-up time and number of equispaced observations. Error bars represent ±1 SD. b) Longitudinal reliability (ICC) for individual structural features, grouped by modality, shown for follow-up time of 4 years and 3 observations. Subcortical features are numbered as follows: 1. Lateral Ventricle, 2. Caudate, 3. Thalamus, 4. Pallidum, 5. Putamen, 6. Amygdala, 7. Hippocampus. Obs. = Number of observations.

Figure 3. Power analysis for detecting correlations with longitudinal brain change.

a) Mean required sample size across structural features (with power = 80%, p < .05) for detecting correlations with longitudinal brain change of small, medium, and large effect sizes (based on conventional guidelines) across different follow-up times and number of observations. Grey horizontal lines are the estimated effect sizes given reliability ICC = 1. Estimated sample size required to detect significant correlations (p < .05, 80% power) between b) the left hippocampus, c) left entorhinal thickness and phenotypes with real correlations ranging from r = 0.05 to 0.4, across different follow-up times and number of observations. For visualization purposes in b) and c), follow-up time is capped at 8 years and the number of observations shown is 3 and 7. r = Pearson’s Correlation. Obs. = Number of observations. Cth = Cortical thickness.

Figure 4.. Overlapping between observed estimates of change.

a) Mean Bhattacharyya coefficient (BC) across features, quantifying the degree of overlap between two samples as a function of follow-up time and number of observations. The distributions represent possible observed estimates of brain change for three individuals: a normal ager, a maintainer, and a decliner who show decline at an average rate, 1 SD slower, and 1 SD faster, respectively. Overlap in observed brain change distributions for the b) Left Hippocampus, and c) Left Entorhinal Thickness. For b) and c), distributions are shown for 3 and 7 observations and 2, 6, and 10 years of study duration.

Figure 5.. Misclassification based on external criteria.

Misclassification of individuals based on an external criterion, i.e., whether they exhibit no brain decline over the duration of the study. The density plots show the distribution of real trajectories of those subjects for whom we would observe no brain decline over time. Green and red fillings represent the proportion of real brain maintenance and real brain decliners, respectively. The text represents the proportion of participants showing no observed brain decline. Shown for the a) Left Hippocampus and b) Left Entorhinal Thickness. Distributions displayed at 3 and 7 observations and 2, 6, and 10 years of study duration.

Figure 6.. Longitudinal reliability and sample characteristics.

Effect of cohort’s age on longitudinal reliability. Older individuals exhibit higher reliability than younger individuals, due to greater variability in slope estimates. Longitudinal reliability as a function of follow-up time, age, and number of observations for the a) Left Hippocampus, and b) Left Entorhinal Thickness. Only distributions at 3 and 7 observations are shown.

Figure 7.. Longitudinal reliability using FreeSurfer cross-sectional stream.

Impact of preprocessing stream on longitudinal reliability. a) Mean reliability (ICC) of structural brain change across features as a function of total follow-up time and number of equispaced observations, estimated using the FreeSurfer cross-sectional stream. Mean differences in longitudinal reliability, by b) follow-up time and number of observations and c) modality, between data processed with the longitudinal versus cross-sectional FreeSurfer stream. Positive ΔICC indicates improved reliability estimates when using the longitudinal FreeSurfer Stream. Error bars represent ±1 SD. FS = FreeSurfer. Obs. = Observations.

Figure 8.. Longitudinal reliability estimated empirically.

Error variance of the slopes was estimated from a multi-cohort dataset rather than being analytically-derived from the GRR index. a) Mean reliability (ICC) of structural brain change across features as a function of total follow-up time and number of equispaced observations. Mean differences in longitudinal reliability by b) follow-up time and number of observations and c) modality, between the analytically-derived and the empirical estimations of reliability. Positive ΔICC indicates higher estimates for the analytical derivation of reliability. Error bars represent ±1 SD. Obs. = Observations.