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. 2017 Sep 20;9:306.
doi: 10.3389/fnagi.2017.00306. eCollection 2017.

Atrophy of the Posterior Subiculum Is Associated With Memory Impairment, Tau- And Aβ Pathology in Non-demented Individuals

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Free PMC article

Atrophy of the Posterior Subiculum Is Associated With Memory Impairment, Tau- And Aβ Pathology in Non-demented Individuals

Olof Lindberg et al. Front Aging Neurosci. .
Free PMC article

Abstract

Alzheimer's disease (AD) is associated with atrophy of the cornu ammonis (CA) 1 and the subiculum subfield of the hippocampus (HC), and with deficits in episodic memory and spatial orientation. These deficits are mainly associated with the functionality of the posterior HC. We therefore hypothesized that key AD pathologies, i.e., β-amyloid and tau pathology would be particularly associated with the volume of the posterior subiculum in non-demented individuals. In our study we included 302 cognitively normal elderly participants (CN), 183 patients with subjective cognitive decline (SCD) and 171 patients with amnestic mild cognitive impairment (MCI), all of whom underwent 3T magnetic resonance images (MRI). The subicular subfield was segmented using Freesurfer 5.3 and divided into 10 volumetric segments moving from the most posterior (segment 1) to the most anterior part along the axis of the hippocampal head and body (segment 10). Cerebrospinal fluid (CSF) Aβ42 and phosphorylated tau (P-tau) were quantified using ELISA and were used as biomarkers for β-amyloid and tau pathology, respectively. In the total sample, tau-pathology and Aβ-pathology and (measured by elevated P-tau and low Aβ42 levels in CSF) and mild memory dysfunction were mostly associated with the volume changes of the posterior subiculum. Both SCD and MCI patients with elevated P-tau or low Aβ42 levels displayed predominantly posterior subicular atrophy in comparisons to control subjects with normal CSF biomarker levels. Finally, there was no main effect of Aβ42 or P-tau when comparing SCD with abnormal P-tau or Aβ42 with SCD with normal levels of these CSF-biomarkers. However, in the left subiculum there was a significant interaction revealing atrophy in the left posterior but not the anterior subiculum in participants with low Aβ42 levels. The same pattern was observed on the contralateral side in participants with elevated P-tau levels. In conclusion, AD pathologies and mild memory dysfunction are mainly associated with atrophy of the posterior parts of the subicular subfields of the HC in non-demented individuals. In light of these findings we suggest that segmentation of the HC subfields may benefit from considering the volume of the different anterior-posterior subsections of each subfield.

Keywords: beta amyloid; hippocampus subfield; mild cognitive impairment; preclinical AD; subjective cognitive decline.

Figures

Figure 1
Figure 1
The presubiculum subfield in Freesurfer (FS) 5.3. The Panels (A, sagittal, B, coronal) displays the presubicular (denoted subiculum in this study) subfield (yellow color) segmented in FS 5.3. Images 1–3 display the hippocampal body, images 4–6 the hippocampal head. The subfield ends in the most posterior part of the hippocampal body (displayed as the most posterior blue line in sagittal view and in the most anterior slice of the hippocampal head displayed by the most anterior blue line in sagittal view). Short red lines illustrate the position of the coronal slices. At coronal view image (1) is only the medial yellow label part of the presubicular subfield. The lateral part is the hippocampal tail. Panel (C) displays the parcellation of presubiculum into 10 volumetric segments in one individual.
Figure 2
Figure 2
Differences in subicular volume between cases with normal and low cerebrospinal fluid (CSF) Aβ42 levels. The figure denotes differences in subicular volume segment in participants with low (red line) and normal (blue line) levels of Aβ42 in all participants. The x-axis denotes volume segment from posterior (segment 1) to anterior (segment 10). The y-axis denotes the volume of segment normalized as z-scores. (A) left side, (B) right side. Analysis is controlled for gender, intracranial volume and age. Vertical bars denote 95% confidence interval.
Figure 3
Figure 3
Correlations between subicular volume and CSF-P-tau levels. The figure denotes the correlation coefficients between the subicular volume segments and CSF P-tau in the whole group (A, left, B, right). Y-axis denotes the correlation coefficients. Dots denote volume segment moving from posterior (left) to anterior (right).
Figure 4
Figure 4
Differences between participants that forgot 0–1. 2–3. 4–5 and 6–10 items in the bilateral anterior and posterior 50% of the subiculum. The summarized volume of left+right 50% of posterior (blue line) and anterior (red line). X-axis denotes number of forgotten items. The y-axis denotes the volume of the anterior and the posterior 50% of the subiculum. (A) All participants, (B) participants with no cognitive decline on neuropsychological test (subjective cognitive decline (SCD)+cognitively normal (CN)). The model is further including gender as factor and age and intracranial volume (ICV) as covariates.
Figure 5
Figure 5
SCD with low Aβ42 or elevated P-tau CSF levels compared with controls with normal Aβ42 or P-tau levels. The figure denotes differences in subicular volume segment in SCD with abnormal (red line) and CN with normal (blue line) CSF biomarkers. (A,B) Display the volume segment in left (A) and right (B) subiculum in CN without and SCD participants with low CSF Aβ42. (C,D) Display the volume segment in left (C) and right (D) subiculum in CN without and SCD participants with elevated CSF P-tau. The x-axis denotes volume segment from posterior (segment 1) to anterior (segment 10). The y-axis denotes the volume of segment normalized as z-scores. The analysis is controlled for gender, intracranial volume and age. Vertical bars denote 95% confidence interval.
Figure 6
Figure 6
Mild cognitive impairment (MCI) with low Aβ42 or elevated P-tau levels CSF compared with controls with normal Aβ42 or P-tau levels. The figure denotes differences in subicular volume segment in MCI with abnormal (red line) and CN with normal (blue line) CSF biomarkers. (A,B) display the volume segment in left (A) and right (B) subiculum in CN without and MCI participants with low CSF Aβ42. (C,D) display the volume segment in left (C) and right (D) subiculum in CN without and MCI with elevated CSF P-tau. The x-axis denotes volume segment from posterior (segment 1) to anterior (segment 10). The y-axis denotes the volume of segment normalized as z-scores. Analysis is controlled for gender, intracranial volume and age. Vertical bars denote 95% confidence interval.
Figure 7
Figure 7
SCD with normal vs. SCD with low CSF Aβ42 or elevated P-tau. The figure denotes the interaction between high vs. low levels of CSF Aβ42 and the anterior vs. posterior 50% of the left subicular subfield (A), and the interaction between high vs. low P-tau levels and the anterior vs. posterior 50% of the right subicular subfield (B). Blue line, normal CSF levels, red line, abnormal CSF levels. Vertical bars denote 95% confidence interval.

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