Patterns of longitudinal cortical atrophy over 3 years in empirically derived MCI subtypes

Abstract

Objective: We previously identified 4 empirically derived mild cognitive impairment (MCI) subtypes via cluster analysis within the Alzheimer's Disease Neuroimaging Initiative (ADNI) and demonstrated high correspondence between patterns of cortical thinning at baseline and each cognitive subtype. We aimed to determine whether our MCI subtypes demonstrate unique longitudinal atrophy patterns.

Methods: ADNI participants (295 with MCI and 134 cognitively normal [CN]) underwent annual structural MRI and neuropsychological assessments. General linear modeling compared vertex-wise differences in cortical atrophy rates between each MCI subtype and the CN group. Linear mixed models examined trajectories of cortical atrophy over 3 years within lobar regions of interest.

Results: Compared to the CN group, those with amnestic MCI (memory deficit) initially demonstrated greater atrophy rates within medial temporal lobe regions that became more widespread over time. Those with dysnomic/amnestic MCI (naming/memory deficits) showed greater atrophy rates largely localized to temporal lobe regions. The mixed MCI (impairment in all cognitive domains) group showed greater atrophy rates in widespread regions at all time points. The cluster-derived normal group, who had intact neuropsychological performance and normal cortical thickness at baseline despite their MCI diagnosis via conventional diagnostic criteria, continued to show normal cognition and minimal cortical atrophy over 3 years.

Conclusions: ADNI's purported amnestic MCI sample produced more refined cognitive subtypes with unique longitudinal cortical atrophy rates. These novel MCI subtypes reliably reflect underlying atrophy, reduce false-positive diagnostic errors, and improve prediction of clinical course. Such improvements have implications for the selection of participants for clinical trials and for providing more precise risk assessment for individuals diagnosed with MCI.

Figure 1. Neuropsychological performance of the cluster groups at each time point

Mean demographically corrected z scores at (A) baseline, (B) year 1, (C) year 2, and (D) year 3. Error bars denote SEM; horizontal dotted line indicates the typical cutoff for impairment (−1.5 SDs). AVLT = Rey Auditory Verbal Learning Test; BNT = Boston Naming Test; MCI = mild cognitive impairment; TMT = Trail Making Test.

Figure 2. Surface-based atrophy rate maps showing differences in cortical atrophy rates between each MCI subgroup and the CN group from baseline to each annual follow-up visit

Cyan/blue shades represent areas where the mild cognitive impairment (MCI) subgroup had greater atrophy relative to the cognitively normal (CN) group. Surface-based maps are false discovery rate (FDR) corrected and covary for age, age², sex, education, days from baseline (BL), and magnet strength. Number of CN participants at each time point: year (Y) 1, n = 134; Y2, n = 113; and Y3, n = 58.

Figure 3. Trajectories of cortical thickness by group in select composite regions of interest showing significant group × visit interactions

(A) Left medial temporal, (B) right medial temporal, (C) left lateral temporal, (D) right lateral temporal, (E) left frontal, and (F) right parietal; 0 = baseline; 1 = year 1; 2 = year 2; and 3 = year 3. Error bars represent 95% confidence intervals. MCI = mild cognitive impairment.