Hippocampal CA1 apical neuropil atrophy and memory performance in Alzheimer's disease

Abstract

Memory loss is often the first and most prominent symptom of Alzheimer's disease (AD), coinciding with the spread of neurofibrillary pathology from the entorhinal cortex (ERC) to the hippocampus. The apical dendrites of hippocampal CA1 pyramidal neurons, in the stratum radiatum/stratum lacunosum-moleculare (SRLM), are among the earliest targets of this pathology, and atrophy of the CA1-SRLM is apparent in postmortem tissue from patients with mild AD. We previously demonstrated that CA1-SRLM thinning is also apparent in vivo, using ultra-high field 7-Tesla (7 T) MRI to obtain high-resolution hippocampal microstructural imaging. Here, we hypothesized that CA1-SRLM thickness would correlate with episodic memory performance among patients with mild AD. We scanned nine patients, using an oblique coronal T2-weighted sequence through the hippocampal body with an in-plane resolution of 220 μm, allowing direct visual identification of subfields — dentate gyrus (DG)/CA3, CA2, CA1, and ERC — and hippocampal strata — SRLM and stratum pyramidale (SP). We present a novel semi-automated method of measuring stratal width that correlated well with manual measurements. We performed multi-domain neuropsychological evaluations that included three tests of episodic memory, yielding composite scores for immediate recall, delayed recall, and delayed recognition memory. Strong correlations occurred between delayed recall performance and the widths of CA1-SRLM (r² = 0.69; p = 0.005), CA1-SP (r² = 0.5; p = 0.034), and ERC (r² = 0.62; p = 0.012). The correlation between CA1-SRLM width and delayed recall lateralized to the left hemisphere. DG/CA3 size did not correlate significantly with any aspect of memory performance. These findings highlight a role for 7 T hippocampal microstructural imaging in revealing focal structural pathology that correlates with the central cognitive feature of AD.

Introduction

Episodic memory dysfunction is the earliest and most profound symptom in most cases of Alzheimer's disease (AD). The hippocampus plays a key role in the consolidation of new episodic memories (Milner, 2005), and neuropathological alterations of this structure (Braak et al., 2006) probably account for early symptoms of the disease.

Hippocampal degeneration in early AD is not uniform. After inundation of the entorhinal cortex (ERC) by neurofibrillary tangle pathology, the synapse-rich CA1 stratum radiatum and stratum lacunosum-moleculare (SRLM) is the next area to become affected (Braak and Braak, 1997, Braak et al., 2006, Thal et al., 2000). The appearance of aggregates of the microtubule-associated protein tau in CA1-SRLM precedes the loss of CA1 pyramidal neurons themselves, and coincides with the earliest cognitive symptoms (Braak and Braak, 1997, Thal et al., 2000). At autopsy, profound synaptic loss and atrophy appears in this area (Braak and Braak, 1997, Mizutani and Kasahara, 1997, Qin et al., 2004, Scheff et al., 2007, Thal et al., 2000).

Confirming the predictions of this postmortem literature, CA1-SRLM atrophy distinguished patients with mild AD from age-matched normal controls (Kerchner et al., 2010). This prior study took advantage of the ability of ultra-high field 7-Tesla (7 T) magnetic resonance imaging (MRI) to reveal distinct hippocampal subfield and stratal boundaries, including a separation between CA1-SRLM and the adjacent cell body layer, the stratum pyramidale (CA1-SP) (Kerchner, 2011, Kerchner et al., 2010). Using lower field imaging techniques not designed to discriminate between hippocampal strata, other labs have observed general volume loss in CA1 or adjacent subiculum in conjunction with normal aging (La Joie et al., 2010), Mild Cognitive Impairment (MCI) (Apostolova et al., 2006a, Mueller et al., 2010, Yassa et al., 2010), and AD (Apostolova et al., 2006a, Mueller et al., 2007, Mueller et al., 2010). One group has shown that CA1 atrophy predicts future cognitive decline among healthy subjects (Apostolova et al., 2010b) or patients with MCI (Apostolova et al., 2006b). In our prior study, CA1-SP thickness did not differ between subjects with mild AD or normal cognition (Kerchner et al., 2010), suggesting that CA1-SRLM atrophy could conceivably be driving the findings of other groups. Only one group found atrophy in the dentate gyrus (DG) and CA3 to be greater than in CA1 among patients with MCI (Yassa et al., 2010).

There is likely a connection between early episodic memory dysfunction and early CA1 neurofibrillary pathology in AD. Indeed, others have reported correlations between overall CA1 size and delayed memory performance (Apostolova et al., 2010a, Atienza et al., 2011, Mueller et al., 2011a), and other work suggests a specific role for CA1 in the recollection of recently learned cues (Eldridge et al., 2005). Given the special vulnerability of the CA1 apical neuropil to early AD, we hypothesized that CA1-SRLM thickness should correlate with delayed recall performance among patients. Using a new T2-weighted 7 T MRI sequence for microstructural imaging of the medial temporal lobe, together with a novel method of stratal width determination, we endeavored to test this hypothesis in patients with mild AD.