Hippocampal CA1 apical neuropil atrophy and memory performance in Alzheimer's disease
Highlights
► 7 T microstructural MRI reveals hippocampal subfields and stratal layers in vivo. ► CA1 apical neuropil atrophy correlated with memory deficits in Alzheimer's disease. ► This correlation was stronger in the left hemisphere. ► Entorhinal cortex and CA1 stratum pyramidale thicknesses also correlated with memory. ► CA1 apical neuropil atrophy may be useful as a biomarker to track memory loss in 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.
Section snippets
Subjects
Patients with mild AD were recruited from the Stanford Center for Memory Disorders. Each subject provided written, informed consent in accordance with a protocol approved by the Stanford Institutional Review Board. Inclusion criteria included a diagnosis of probable AD (amnestic presentation) according to the National Institute on Aging-Alzheimer's Association criteria (McKhann et al., 2011), a Clinical Dementia Rating (CDR) score of 0.5 or 1 (Morris, 1993), and sufficient English language
Validation of semi-automated stratal width measurements
We measured CA1-SP and CA1-SRLM widths using both manual and semi-automated techniques (see Methods). The values correlated significantly (for CA1-SP, r = 0.74, p < 0.001; for CA1-SRLM, r = 0.75, p < 0.001). Unless otherwise stated, semi-automated measurements were used below.
Relationship of medial temporal microstructure with memory performance
We tested whether medial temporal microstructural metrics correlated with immediate recall, delayed recall, or delayed recognition memory (Fig. 3 and Table 2). For immediate recall, there was no significant relationship with any
Discussion
Our findings support the hypothesis that CA1-SRLM thickness correlates with delayed recall memory performance among patients with mild AD. We additionally found that the thicknesses of CA1-SP and ERC similarly correlated with delayed recall. These data establish that in addition to a role in discriminating patients with AD from healthy controls (Kerchner et al., 2010), hippocampal microstructural metrics also track the severity of a core neuropsychological feature of the disease.
Acknowledgments
We thank Christina Wyss-Coray, RN, Jeffrey Bernstein, BA, and Jennie Lambert-Lynch, BA, for patient recruitment and study logistics, as well as Mohammad-Mehdi Khalighi, PhD for work on 7 T MRI sequence development. This work was supported by grants from the Alzheimer's Association to GAK (NIRG-11-205493) and from the NIH to BKR (P41 RR09784).
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