OBJECTIVE An increasing number of human in vivo magnetic resonance imaging (MRI) studies have focused on examining the structure and function of the subfields of the hippocampal formation (the dentate gyrus, CA fields 1–3, and the subiculum) and subregions of the parahippocampal gyrus (entorhinal, perirhinal, and parahippocampal cortices). The ability to interpret the results of such studies and to relate them to each other would be improved if a common standard existed for labeling hippocampal subfields and parahippocampal subregions. Currently, research groups label different subsets of structures and use different rules, landmarks, and cues to define their anatomical extents. This paper characterizes, both qualitatively and quantitatively, the variability in the existing manual segmentation protocols for labeling hippocampal and parahippocampal substructures in MRI, with the goal of guiding subsequent work on developing a harmonized substructure segmentation protocol. METHOD MRI scans of a single healthy adult human subject were acquired both at 3 Tesla and 7 Tesla. Representatives from 21 research groups applied their respective manual segmentation protocols to the MRI modalities of their choice. The resulting set of 21 segmentations was analyzed in a common anatomical space to quantify similarity and identify areas of agreement. RESULTS The differences between the 21 protocols include the region within which segmentation is performed, the set of anatomical labels used, and the extents of specific anatomical labels. The greatest overall disagreement among the protocols is at the CA1/subiculum boundary, and disagreement across all structures is greatest in the anterior portion of the hippocampal formation relative to the body and tail. CONCLUSIONS The combined examination of the 21 protocols in the same dataset suggests possible strategies towards developing a harmonized subfield segmentation protocol and facilitates comparison between published studies.

The advent of high-resolution magnetic resonance imaging (MRI) has enabled in vivo research in a variety of populations and diseases on the structure and function of hippocampal subfields and subdivisions of the parahippocampal gyrus. Due to the many extant and highly discrepant segmentation protocols, comparing results across studies is difficult. To overcome this barrier, the Hippocampal Subfields Group was formed as an international collaboration with the aim of developing a harmonized protocol for manual segmentation of hippocampal and parahippocampal subregions on high-resolution MRI. In this commentary we discuss the goals for this protocol and the associated key challenges involved in its development. These include differences among existing anatomical reference materials, striking the right balance between reliability of measurements and anatomical validity, and the development of a versatile protocol that can be adopted for the study of populations varying in age and health. The commentary outlines these key challenges, as well as the proposed solution of each, with concrete examples from our working plan. Finally, with two examples, we illustrate how the harmonized protocol, once completed, is expected to impact the field by producing measurements that are quantitatively comparable across labs and by facilitating the synthesis of findings across different studies.

Objectives: Using high-resolution structural MRI, we endeavored to study the relationships among APOE e4, hippocampal subfield and stratal anatomy, and episodic memory.Methods: Using a cross-sectional design, we studied 11 patients with Alzheimer disease dementia, 14 patients with amnestic mild cognitive impairment, and 14 age-matched healthy controls with no group differences in APOE e4 carrier status. Each subject underwent ultra-high-field 7.0-tesla MRI targeted to the hippocampus and neuropsychological assessment.Results: We found a selective, dose-dependent association of APOE e4 with greater thinning of the CA1 apical neuropil, or stratum radiatum/stratum lacunosum-moleculare (CA1-SRLM), a hippocampal subregion known to exhibit early vulnerability to neurofibrillary pathology in Alzheimer disease. The relationship between the e4 allele and CA1-SRLM thinning persisted after controlling for dementia severity, and the size of other hippocampal subfields and the entorhinal cortex did not differ by APOE e4 carrier status. Carriers also exhibited worse episodic memory function but similar performance in other cognitive domains compared with noncarriers. In a statistical mediation analysis, we found support for the hypothesis that CA1-SRLM thinning may link the APOE e4 allele to its phenotypic effects on memory. Conclusions:The APOE e4 allele segregated dose-dependently and selectively with CA1-SRLM thinning and worse episodic memory performance in a pool of older subjects across a cognitive spectrum. These findings highlight a possible role for this gene in influencing a critical hippocampal subregion and an associated symptomatic manifestation. Neurology ® 2014;82:691-697 GLOSSARY AD 5 Alzheimer disease; aMCI 5 amnestic mild cognitive impairment; ANOVA 5 analysis of variance; CA1-SP 5 CA1 stratum pyramidale; CA1-SRLM 5 CA1 stratum radiatum/lacunosum-moleculare; CDR 5 Clinical Dementia Rating; DG/CA3 5 dentate gyrus and CA3; ERC 5 entorhinal cortex; MTL 5 medial temporal lobe; NIA-AA 5 National Institute on Aging-Alzheimer's Association; OC 5 older control.ApoE influences the metabolism of b-amyloid, the major peptide constituent of amyloid plaques in Alzheimer disease (AD).1 The ApoE4 isoform confers an increased risk of sporadic late-onset AD dementia. 2,3Carriers of the APOE e4 allele who have AD dementia or its clinical precursor, amnestic mild cognitive impairment (aMCI), exhibit greater hippocampal volume loss than noncarriers in some studies, 4-9 although this finding is controversial. [10][11][12] Perhaps these divergent findings arise from disproportionate effects of the e4 allele on individual hippocampal subfields that are not always evident in global volumetric analyses.Specific effects of the APOE e4 allele on hippocampal subfields are of interest. AD-related neuropathology itself is subfield-and even strata-selective, affecting the CA1 subfield, including specifically the stratum radiatum/stratum lacunosum-moleculare (CA1-SRLM), before affecting the remainder of the hippocampus. [13][14][15...

Older adults experience impairments in episodic memory, ranging from mild to clinically significant. Given the critical role of the medial temporal lobe (MTL) in episodic memory, age-related changes in MTL structure and function may partially account for individual differences in memory. Using ultra-high-field 7T structural MRI and high-resolution 3T functional MRI (hr-fMRI), we evaluated MTL subfield thickness and function in older adults representing a spectrum of cognitive health. Participants performed an associative memory task during hr-fMRI in which they encoded and later retrieved face-name pairs. Motivated by prior research, we hypothesized that differences in performance would be explained by the following: (i) entorhinal cortex (ERC) and CA1 apical neuropil layer [CA1-stratum radiatum lacunosum moleculare (SRLM)] thickness, and (ii) activity in ERC and the dentate gyrus (DG)/CA3 region. Regression analyses revealed that this combination of factors significantly accounted for variability in memory performance. Among these metrics, CA1-SRLM thickness was positively associated with memory, whereas DG/CA3 retrieval activity was negatively associated with memory. Furthermore, including structural and functional metrics in the same model better accounted for performance than did single-modality models. These results advance the understanding of how independent but converging influences of both MTL subfield structure and function contribute to age-related memory impairment, complementing findings in the rodent and human postmortem literatures.episodic memory | hippocampus | aging | mild cognitive impairment | Alzheimer's disease E pisodic memory, or the capacity to encode and subsequently retrieve memories for events, is known to be particularly vulnerable to age-related change (1-3). Older adults show varying degrees of episodic memory impairment, ranging from mild to clinically significant. One potential factor underlying such differences is variability in the structure and function of the medial temporal lobe (MTL).The MTL is essential for episodic memory (4-7), and research across species indicates that the MTL changes in both healthy aging and in age-related neurodegenerative disease (for reviews, see refs. 8 and 9). Critically, however, the MTL is not a unitary structure. Rather, it is composed of multiple regions with differing anatomy and connectivity (see, e.g., ref. 10), including subfields of the hippocampal formation [CA1, CA2, CA3, dentate gyrus (DG), and subiculum], and the entorhinal (ERC), perirhinal (PRC), and parahippocampal (PHC) cortices (Fig. 1A). Moreover, evidence in rodents and humans suggests that these subfields are differentially affected by age, as well as by age-related disease (8, 9, 11).Converging evidence in human studies of healthy aging using high-resolution magnetic resonance imaging (MRI) suggests disproportionate age-related atrophy in CA1 (12-15), although some studies point to selective atrophy of the subiculum or DG/CA3, while others suggest changes encompassing multip...