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

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.

Contribution of mixed pathology to medial temporal lobe atrophy in Alzheimer's disease

“…The topography of this progression is similar to the progression of brain atrophy, supporting a direct relationship between tau pathology and atrophy. Indeed, a number of studies have associated volumetric magnetic resonance imaging (MRI) with either pathological, 10–12 cerebrospinal fluid (CSF), 13–15 or positron emission tomography (PET) 16–18 measures of NFT burden.…”

Cell-Type-Specific Changes in Intrinsic Excitability in the Subiculum following Learning and Exposure to Novel Environmental Contexts

“…The subiculum mediates various aspects of behavior including spatial and declarative memory, contextual fear memory, memory retrieval, discrimination of complex scenes, temporal control of behavior, and motivated behavior (Gabrieli et al, 1997; Maren, 1999; O'Mara et al, 2009; Hodgetts et al, 2017; Roy et al, 2017; Cembrowski et al, 2018). In humans, it is involved in both normal cognitive function and in diseases characterized by impaired cognition including schizophrenia and Alzheimer’s disease (Carlesimo et al, 2015; Haukvik et al, 2015; Lindberg et al, 2017; Zammit et al, 2017). The subiculum is organized in both proximal-distal and dorsal-ventral directions, with heterogenous inputs and outputs, cell types, cytoarchitecture, contributions to behavior, and gene and protein expression along each axis (O'Mara, 2005; O'Mara et al, 2009; Kim and Spruston, 2012; Honda and Ishizuka, 2015; Ishihara and Fukuda, 2016; Tang et al, 2016; Roy et al, 2017; Cembrowski et al, 2018).…”

Cognitive mapping style relates to posterior–anterior hippocampal volume ratio

“…As spatial disorientation is an early and common symptom of AD, the relationship between navigational strategy and the detection of pathological aging patterns needs to be explored in future work (Coughlan, Laczó, Hort, Minihane, & Hornberger, ). Recent research has found that atrophy of the pHPC in cases of MCI and AD is associated with tau‐pathology, Aβ‐pathology and declines in verbal and spatial memory (Lindberg et al, ; Llado et al, ), whereas nonpathological aging has generally been associated with mid‐ or anterior, but not posterior, volume reductions (Malykhin, Huang, Hrybouski, & Olsen, ; Rajah, Kromas, Han, & Pruessner, ; Ta et al, ). Thus, changes to pHPC/aHPC volume ratios could potentially serve as indicators of MCI or AD vulnerability, and accompany changes in spatial memory and navigation strategy.…”