Modeling grey matter atrophy as a function of time, aging or cognitive decline show different anatomical patterns in Alzheimer's disease

Abstract

Background: Grey matter (GM) atrophy in Alzheimer's disease (AD) is most commonly modeled as a function of time. However, this approach does not take into account inter-individual differences in initial disease severity or changes due to aging. Here, we modeled GM atrophy within individuals across the AD clinical spectrum as a function of time, aging and MMSE, as a proxy for disease severity, and investigated how these models influence estimates of GM atrophy.

Methods: We selected 523 individuals from ADNI (100 preclinical AD, 288 prodromal AD, 135 AD dementia) with abnormal baseline amyloid PET/CSF and ≥1 year of MRI follow-up. We calculated total and 90 regional GM volumes for 2281 MRI scans (median [IQR]; 4 [3-5] scans per individual over 2 [1.6-4] years) and used linear mixed models to investigate atrophy as a function of time, aging and decline on MMSE. Analyses included clinical stage as interaction with the predictor and were corrected for baseline age, sex, education, field strength and total intracranial volume. We repeated analyses for a sample of participants with normal amyloid (n = 387) to assess whether associations were specific for amyloid pathology.

Results: Using time or aging as predictors, amyloid abnormal participants annually declined -1.29 ± 0.08 points and - 0.28 ± 0.03 points respectively on the MMSE and -12.23 ± 0.47 cm³ and -8.87 ± 0.34 respectively in total GM volume (p < .001). For the time and age models atrophy was widespread and preclinical and prodromal AD showed similar atrophy patterns. Comparing prodromal AD to AD dementia, AD dementia showed faster atrophy mostly in temporal lobes as modeled with time, while prodromal AD showed faster atrophy in mostly frontoparietal areas as modeled with age (p_FDR < 0.05). Modeling change in GM volume as a function of decline on MMSE, slopes were less steep compared to those based on time and aging (-4.1 ± 0.25 cm³ per MMSE point decline; p < .001) and showed steeper atrophy for prodromal AD compared to preclinical AD in the right inferior temporal gyrus (p < .05) and compared to AD dementia mostly in temporal areas (p_FDR < 0.05). Associations with time, aging and MMSE remained when accounting for these effects in the other models, suggesting that all measures explain part of the variance in GM atrophy. Repeating analyses in amyloid normal individuals, effects for time and aging showed similar widespread anatomical patterns, while associations with MMSE were largely reduced.

Conclusion: Effects of time, aging and MMSE all explained variance in GM atrophy slopes within individuals. Associations with MMSE were weaker than those for time or age, but specific for amyloid pathology. This suggests that at least some of the atrophy observed in time or age models may not be specific to AD.

Keywords: Aging; Alzheimer's disease; Amyloid; Atrophy; Cognition; Longitudinal.

Fig. 1

Hypothesized difference between taking time, age versus MMSE as a measure for disease progression. For the time model, we included follow-up time (in years) as the predictor, a random intercept for subjects and subject-specific random slopes for follow-up time. For the age model, we included age as the predictor, a random intercept for subjects and subject-specific random slopes for age. For the MMSE model, we included MMSE as a predictor, a random intercept for subjects and subject-specific random slopes for MMSE. We additionally included an interaction effect with baseline clinical stage (i.e., CN, MCI, dementia) to estimate cross-sectional and longitudinal differences between the different clinical stages. Models were corrected for age at baseline (time and MMSE model), sex, education and field strength.

Fig. 2

Predicted changes in grey matter volumes and cognitive functioning (a) as a function of follow-up time, (b) as a function of aging and (c) as a function of MMSE for the baseline clinical stages in individuals with abnormal amyloid markers. Predicted values are based on raw values and were estimated with linear mixed models. The models included the terms age (for the time and MMSE models), sex, education, field strength and total intracranial volume (for grey matter volumes), and time, age or MMSE as predictor, and the interaction term predictor × diagnosis. Regression lines are based on cross-sectional (intercepts) and longitudinal (slopes) estimates of the respective model and are based on estimated marginal means for the clinical stages. Vertical line in (b) indicates mean age at baseline for the total sample. GM, grey matter.

Fig. 3

Surface plots of longitudinal associations of local grey matter volumes with (a) follow-up time, (b) aging and (c) decline in MMSE over time for the total groups and per baseline clinical stage. The color bar indicates the effect sizes as t ratios based on local GM volumes standardized to the mean values of cognitively normal individuals with normal amyloid at baseline (for descriptive data see Inline Supplementary Table 7) and were obtained with linear mixed models. Analyses were adjusted for age (for time and MMSE models), sex, education, field strength and total intracranial volume. Note that t ratios indicate the strength of the effect and do not correspond to betas. For associations in the total group and baseline clinical stages, negative values indicate steeper grey matter atrophy with increasing time or age and positive values indicate steeper grey matter atrophy with worsening MMSE. For comparison of clinical stages, negative values indicate steeper atrophy rates for e.g. prodromal AD as compared to preclinical AD and positive values indicate less steep atrophy rates for e.g. prodromal AD as compared to preclinical AD. Subcortical structures are plotted in ventricular areas as approximation. The model for the association with MMSE for the total group did not converge for the left supramarginal gyrus. L, left hemisphere; R, right hemisphere; ^⁎p_uncorrected < 0.05.

Fig. 4

Surface plots of longitudinal associations of local grey matter volumes with (a) follow-up time, (b) aging and (c) decline in MMSE over time for the total groups and per baseline clinical stage in individuals with normal amyloid. The color bar indicates the effect sizes as t ratios based on local GM volumes standardized to the mean values of cognitively normal individuals with normal amyloid at baseline (for descriptive data see Inline Supplementary Table 7) and were obtained with linear mixed models. Analyses were adjusted for age (for time and MMSE models), sex, education, field strength and total intracranial volume. Note that t ratios indicate the strength of the effect and do not correspond to betas. For associations in the total group and baseline clinical stages, negative values indicate steeper grey matter atrophy with increasing time or age and positive values indicate steeper grey matter atrophy with worsening MMSE. For comparison of clinical stages, negative values indicate steeper atrophy rates for e.g. prodromal AD as compared to preclinical AD and positive values indicate less steep atrophy rates for e.g. prodromal AD as compared to preclinical AD. Subcortical structures are plotted in ventricular areas as approximation. L, left hemisphere; R, right hemisphere; ^⁎p_uncorrected < 0.05.