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.

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

“…Using hippocampus subfields can significantly decrease the rate of false positive findings in the prediction of future conversion from MCI to AD using manual [168] or automated [169] measurement. Sequences at 7 Tesla provide higher spatial resolution, new contrasts and access to even finer substructures of the hippocampus [170,171], but the clinical relevance of these measures needs to be explored in future studies [172].…”

APOE ε4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory

“…In prior work, we used high-resolution 7.0-tesla MRI to show that CA1-SRLM atrophy distinguished patients with mild AD dementia from age-matched controls 21 and correlated closely with memory performance. 22 Here, we investigated the effect of APOE e4 carrier status on hippocampal subfield and stratal size and memory dysfunction, with the central hypothesis that e4 would associate with greater CA1-SRLM atrophy and worse episodic memory performance.…”

“…The battery covered episodic memory, working memory, global intellectual function, language, visuospatial function, and executive function as previously described. 22 Episodic memory was assessed using the Hopkins Verbal Learning Test-Revised, 25 the Brief Visuospatial Memory Test-Revised, 26 and the Logical Memory subtest of the Wechsler Memory Scale, third edition. 27 From these 3 tests, we derived composite metrics of immediate free recall memory, delayed free recall memory, and delayed recognition memory as described previously.…”

“…27 From these 3 tests, we derived composite metrics of immediate free recall memory, delayed free recall memory, and delayed recognition memory as described previously. 22 APOE genotyping. Genomic DNA was extracted from frozen whole blood using the Gentra Puregene Blood Kit (Qiagen, Valencia, CA).…”

Seven-Tesla MRI and neuroimaging biomarkers for Alzheimer’s disease

“…44 The same group 2 years later was able to demonstrate that CA1 atrophy is linked to diminished recall performance. 43 Two subsequent studies in 2013 and 2014 further built on the knowledge base. The 2013 study was able to convincingly show a temporal connection between atrophy of the entorhinal cortex and CA1, two structures thought to be involved in the early stages of AD.…”