Correlating hippocampal and amygdala volumes with neuropathological burden in Down syndrome and Alzheimer's disease and related neurodegenerative pathologies using 7T postmortem MRI

Abstract

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), is common in elderly brains and often seen in conjunction with Alzheimer's disease neuropathologic change (ADNC). LATE-NC typically begins in the amygdala and spreads to the hippocampus and neocortex. Whether it contributes to hippocampal and amygdala atrophy in Down syndrome (DS) remains unexplored. We analyzed amygdala and hippocampal volumes and neuropathological burden in 12 DS cases and 54 non-DS cases with AD and related neurodegenerative pathologies (ADRNP) using 7 Tesla (7T) postmortem ex vivo MRI. Postmortem and antemortem hippocampal volumes were significantly correlated in a subset of 17 cases with available antemortem MRI scans. DS cases had smaller hippocampal and amygdala volumes than ADRNP cases; these correlated with more severe Braak stage but not with Thal phase. LATE-NC and hippocampal sclerosis (HS) were uncommon in DS cases. In ADRNP cases, lower hippocampal volumes associated with dementia duration, advanced Thal phase, Braak NFT stage, C score, LATE-NC stage, HS and arteriolosclerosis severity; reduced amygdala volumes correlated with severe LATE-NC stage, HS, and arteriolosclerosis severity, but not with Thal phase or Braak NFT stage. Lewy body pathology did not affect hippocampal or amygdala volume in either cohort. Thus, hippocampal volumes in ADRNP were influenced by both ADNC and LATE-NC, and amygdala volumes were primarily influenced by LATE-NC. In DS, hippocampal and amygdala volumes were primarily influenced by tau pathology.

Keywords: Alzheimer disease; Down syndrome; amygdala; hippocampus; postmortem imaging.

Figure 1.

Postmortem-antemortem volume correlation. (A) Postmortem hippocampal and amygdala volumes obtained through manual segmentations are compared to a subset of cases with antemortem volumes derived from FreeSurfer. The representative segmentation was from an ADRNP case with intermediate ADNC and limbic LB pathologies; the antemortem-postmortem MRI scans were 44 months apart. (B) A significant correlation is observed between postmortem and antemortem hippocampal volumes (P = .0066). (C) In contrast, the correlation between postmortem and antemortem amygdala volumes does not reach statistical significance (P = .1182). (D) The difference in hippocampal volumes between postmortem and antemortem measurements is significantly correlated with the MRI scan interval (P = .0095). (E) However, the correlation between the amygdala volume difference and scan interval is not statistically significant (P = .0968).

Figure 2.

DS and ADRNP postmortem volume comparison. (A) Individuals with DS display a significantly lower hippocampal volume than those with ADRNP (P = .0004). (B) Similarly, the amygdala volume is significantly lower in the DS group (P = .0002). All volumes are normalized to fresh brain weight and adjusted for age, sex, and ApoE4 carriership.

Figure 3.

DS and ADRNP postmortem volume-clinical correlation. (A) In DS, while no significant correlation between DSMSE and hippocampal volume is observed (P = .2233), (B) a trend towards significance is noted in the amygdala (P = .0723). (C) In ADRNP, hippocampal volume shows an inverse correlation with dementia duration (P = .0174), (D) but no correlation is detected in the amygdala (P = .2086). (E) Last MMSE scores do not exhibit correlation with either hippocampal (P = .5826) or (F) amygdala volume in ADRNP (P = .7548). All volumes are normalized to fresh brain weight and adjusted for age, sex, and ApoE4 carriership.

Figure 4.

DS postmortem volume-neuropathology correlation in the hippocampus. (A) No correlation is observed between hippocampal volume and Thal phase (P = .9325). (B) The hippocampal volume is significantly correlated with Braak NFT stage (P = .0051) whereas (C) no correlation is detected with the C score (P = .1032). (D-F) No significant differences are detected in hippocampal volume between cases with and without LATE-NC (P = .2838), HS (P = .2221), or LB (P = .5262). (G, H) No correlation of hippocampal volume is observed with CAA (P = .4694) or arteriolosclerosis (P = .4300). None of the DS autopsy cases exhibit atherosclerosis. All volumes are normalized to fresh brain weight and adjusted for age, sex, and ApoE4 carriership.

Figure 5.

DS postmortem volume-neuropathology correlation in the amygdala. (A) No correlation is observed between amygdala volume and Thal phase (P = .9921). (B) The amygdala volume is significantly correlated with Braak NFT stage (P = .0127) and (C) a trend towards significance is detected with the C score (P = .0682). (D-F) No significant differences are detected in amygdala volume between cases with and without LATE-NC (P = .1610), HS (P = .3913), or LB (P = .9124). (G, H) No correlation of amygdala volume is observed with CAA (P = .2263) or arteriolosclerosis (P = .4357). None of the DS autopsy cases exhibit atherosclerosis. All volumes are normalized to fresh brain weight and adjusted for age, sex, and ApoE4 carriership.

Figure 6.

ADRNP postmortem volume-neuropathology correlation in the hippocampus. (A-D) Hippocampal volume shows significant correlations with Thal phase (P = .0117), Braak NFT stage (P = .0376), C score (P = .0008), and LATE-NC stage (P = .0013). (E) Hippocampal volume is significantly different between cases with and without HS (P = .0001). (F, G, I) No significant correlations are observed with LB stage (P = .9707), CAA (P = .1678), or atherosclerosis (P = .2749). (H) However, the hippocampal volume correlates with arteriolosclerosis severity (P = .0274). All volumes are normalized to fresh brain weight and adjusted for age, sex, and ApoE4 carriership.

Figure 7.

ADRNP postmortem volume-neuropathology correlation in the amygdala. (A-C) No correlation of amygdala volume is observed with Thal phase (P = .2454), Braak NFT stage (P = .9749), or C score (P = .8934). (D) The amygdala volume is corelated with LATE-NC stage (P = .0175). (E) Amygdala volume is significantly different between cases with and without HS (P = .0139). (F, G) No significant correlations are observed with LB stage (P = .3945) or CAA (P = .1984). (H) Amygdala volume correlates with arteriolosclerosis severity (P = .0205). (I) A trend towards significance is detected with atherosclerosis (P = .0899). All volumes are normalized to fresh brain weight and adjusted for age, sex, and ApoE4 4carriership.

Figure 8.

ADRNP postmortem volume stepwise regression. (A) C score and LATE-NC stage are the predictors accounting for 27.1% of the variance in hippocampal volume. (B) LATE-NC stage and arteriolosclerosis severity are the predictors accounting for 15.9% of the variance in amygdala volume. All volumes are normalized to fresh brain weight and adjusted for age, sex, and ApoE4 carriership.