7T amygdala and hippocampus subfields in volumetry-based associations with memory: A 3-year follow-up study of early Alzheimer's disease

Abstract

Introduction: The hippocampus is the most prominent single region of interest (ROI) for the diagnosis and prediction of Alzheimer's disease (AD). However, its suitability in the earliest stages of cognitive decline, i.e., subjective cognitive decline (SCD), remains uncertain which warrants the pursuit of alternative or complementary regions. The amygdala might be a promising candidate, given its implication in memory as well as other psychiatric disorders, e.g. depression and anxiety, which are prevalent in SCD. In this 7 tesla (T) magnetic resonance imaging (MRI) study, we aimed to compare the contribution of volumetric measurements of the hippocampus, the amygdala, and their respective subfields, for early diagnosis and prediction in an AD-related study population.

Methods: Participants from a longitudinal study were grouped into SCD (n = 29), mild cognitive impairment (MCI, n = 23), AD (n = 22) and healthy control (HC, n = 31). All participants underwent 7T MRI at baseline and extensive neuropsychological testing at up to three visits (baseline n = 105, 1-year n = 78, 3-year n = 39). Analysis of covariance (ANCOVA) was used to assess group differences of baseline volumes of the amygdala and the hippocampus and their subfields. Linear mixed models were used to estimate the effects of baseline volumes on yearly changes of a z-scaled memory score. All models were adjusted to age, sex and education.

Results: Compared to the HC group, individuals with SCD showed smaller amygdala ROI volumes (range across subfields -11% to -1%), but not hippocampus ROI volumes (-2% to 1%) except for the hippocampus-amygdala-transition-area (-7%). However, cross-sectional associations between baseline memory and volumes were smaller for amygdala ROIs (std. ß [95% CI] ranging between 0.16 [0.08; 0.25] and 0.46 [0.31; 0.60]) than hippocampus ROIs (between 0.32 [0.19; 0.44] and 0.53 [0.40; 0.67]). Further, the association of baseline volumes with yearly memory change in the HC and SCD groups was similarly weak for amygdala ROIs and hippocampus ROIs. In the MCI group, volumes of amygdala ROIs were associated with a relevant yearly memory decline [95% CI] ranging between -0.12 [-0.24; 0.00] and -0.26 [-0.42; -0.09] for individuals with 20% smaller volumes than the HC group. However, effects were stronger for hippocampus ROIs with a corresponding yearly memory decline ranging between -0.21 [-0.35; -0.07] and -0.31 [-0.50; -0.13].

Conclusion: Volumes of amygdala ROIs, as determined by 7T MRI, might contribute to objectively and non-invasively identify patients with SCD, and thus aid early diagnosis and treatment of individuals at risk to develop dementia due to AD, however associations with other psychiatric disorders should be evaluated in further studies. The amygdala's value in the prediction of longitudinal memory changes in the SCD group remains questionable. Primarily in patients with MCI, memory decline over 3 years appears to be more strongly associated with volumes of hippocampus ROIs than amygdala ROIs.

Keywords: 7T MRI; Alzheimer’s disease; Amygdala; Hippocampus; Memory; SCD.

Fig. 1

Estimated mean group differences [95 %CI] of ROI volumes in percent (%). Values were estimated adjusting for the covariates age, sex and education in ANCOVA models which corrected for multiple group comparison (Tukey). Percentages are highlighted in red for a relative smaller and blue for relative bigger volume when compared to the HC group. Abbreviations: AAA = anterior amygdaloid area, AD = Alzheimer’s disease, CATA = corticoamygdaloid transition area, CA = cornu ammonis region, GC-ML-DG = granule cell and molecular layer of the dentate gyrus, HATA = hippocampus-amygdala-transition-area, HC = healthy control, MCI = mild cognitive impairment, SCD = subjective cognitive decline. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Change of memory performance during three years. Memory was assessed by a z-scaled memory composite score for 105 participants at baseline, and when available at one (n = 78) and three years (n = 39) after baseline. The thin lines link individual memory performances at each available visit. The linear fits are presented with 95% CI (shaded areas) estimated by a linear mixed model adjusted for age, sex and education. Abbreviations: AD = Alzheimer’s disease, CI = confidence interval, HC = healthy control, MCI = mild cognitive impairment, SCD = subjective cognitive decline.

Fig. 3

Total (model 1) and group-wise (model 2) estimated yearly change of z-scaled memory performance depending on the baseline volume of the ROIs. Adjusted marginal effect estimates [95 %CI] were calculated for specific values to ease interpretation: baseline mean volume of the HC group, −10% and −20% volume. Number of participants (n part.) in the models ranged between 101 and 104. Number of baseline and follow-up observations (n obs.) ranged between 216 and 219. Estimates for the AD group are not shown due to the high number of missing values not at random (MNAR) for follow-up memory assessment. Linear mixed models included age, sex and education as covariates. Abbreviations: AAA = anterior amygdaloidarea, AD = Alzheimer’s disease, CA = cornu ammonis, CATA = corticoamygdaloid transition area, CI = confidence interval, GC-ML-DG = granule cell and molecular layer of the dentate gyrus, HATA = hippocampus-amygdala-transition-area, HC = healthy control, MCI = mild cognitive impairment, obs. = observations, part. = participants, ROI = region of interest, SCD = subjective cognitive decline.