MRI Asymmetry Index of Hippocampal Subfields Increases Through the Continuum From the Mild Cognitive Impairment to the Alzheimer's Disease

Abstract

Objective: It is well-known that the hippocampus presents significant asymmetry in Alzheimer's disease (AD) and that difference in volumes between left and right exists and varies with disease progression. However, few works investigated whether the asymmetry degree of subfields of hippocampus changes through the continuum from Mild Cognitive Impairment (MCI) to AD. Thus, aim of the present work was to evaluate the Asymmetry Index (AI) of hippocampal substructures as possible MRI biomarkers of Dementia. Moreover, we aimed to assess whether the subfields presented peculiar differences between left and right hemispheres. We also investigated the relationship between the asymmetry magnitude in hippocampal subfields and the decline of verbal memory as assessed by Rey's auditory verbal learning test (RAVLT). Methods: Four-hundred subjects were selected from ADNI, equally divided into healthy controls (HC), AD, stable MCI (sMCI), and progressive MCI (pMCI). The structural baseline T1s were processed with FreeSurfer 6.0 and volumes of whole hippocampus (WH) and 12 subfields were extracted. The AI was calculated as: (|Left-Right|/(Left+Right))^*100. ANCOVA was used for evaluating AI differences between diagnoses, while paired t-test was applied for assessing changes between left and right volumes, separately for each group. Partial correlation was performed for exploring relationship between RAVLT summary scores (Immediate, Learning, Forgetting, Percent Forgetting) and hippocampal substructures AI. The statistical threshold was Bonferroni corrected p < 0.05/13 = 0.0038. Results: We found a general trend of increased degree of asymmetry with increasing severity of diagnosis. Indeed, AD presented the higher magnitude of asymmetry compared with HC, sMCI and pMCI, in the WH (AI mean 5.13 ± 4.29 SD) and in each of its twelve subfields. Moreover, we found in AD a significant negative correlation (r = -0.33, p = 0.00065) between the AI of parasubiculum (mean 12.70 ± 9.59 SD) and the RAVLT Learning score (mean 1.70 ± 1.62 SD). Conclusions: Our findings showed that hippocampal subfields AI varies differently among the four groups HC, sMCI, pMCI, and AD. Moreover, we found-for the first time-that hippocampal substructures had different sub-patterns of lateralization compared with the whole hippocampus. Importantly, the severity in learning rate was correlated with pathological high degree of asymmetry in parasubiculum of AD patients.

Keywords: Alzheimer's disease; Mild Cognitive Impairment; asymmetry index; hippocampal subfields; hippocampus; neuroimaging.

Figure 1

Plot of the mean values per group of asymmetry index for each of the 12 hippocampal subfields and for the whole hippocampus, ordered by decreasing magnitude of asymmetry. HC, healthy control; MCI, Mild Cognitive Impairment; sMCI, stable MCI; pMCI, progressive MCI; AD, Alzheimer's disease.

Figure 2

Boxplots by diagnosis of the asymmetry mean values of the whole hippocampus and its 12 subfields. **Pairwise comparison survived at Bonferroni's correction (p < 0.0038). In the bottom right corner is an example of hippocampal subfields segmentation of a healthy control performed by Freesurfer 6.0.

Figure 3

Schematic representation of significant differences as evaluated by the paired t-test (Bonferroni's correction) between left and right volumes, normalized by ICV, of the whole hippocampus and its 12 subfields. A larger diameter of the circle indicated a larger volume in the respective hemisphere. Colors are taken from the original legend provided by Freesurfer 6.0 (in the bottom right corner). HC, healthy control; MCI, Mild Cognitive Impairment; sMCI, stable MCI; pMCI, progressive MCI; AD, Alzheimer's disease; L, left; R, right.

Figure 4

Scatterplots of asymmetry index of the parasubiculum and RAVLT Learning scores. (A) Linear regression performed separately for each diagnosis on raw data; (B) Linear regression and partial correlation performed on the residuals of AI of the parasubiculum and the residuals of the RAVLT Learning scores, obtained by partialling-out the effect of age, gender, years of education and intracranial volume. Correlation coefficient r = −0.33, p = 0.00065. HC, healthy control; MCI, Mild Cognitive Impairment; sMCI, stable MCI; pMCI, progressive MCI; AD, Alzheimer's disease; AI, asymmetry index.