Andrew R. Bender

Quantitative comparison of 21 protocols for labeling hippocampal subfields and parahippocampal subregions in in vivo MRI: Towards a harmonized segmentation protocol

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 T and 7 T. 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.

Associative Deficit in Recognition Memory in a Lifespan Sample of Healthy Adults

Advanced age is associated with decrements in episodic memory, which are more pronounced in memory for associations than for individual items. The associative deficit hypothesis (ADH) states that age differences in recognition memory reflect difficulty in binding components of a memory episode and retrieving bound units. To date, ADH has received support only in studies of extreme age groups, and the influence of sex, education, and health on age-related associative deficit is unknown. We address those issues using a verbal paired-associate yes-no recognition paradigm on a lifespan sample of 278 healthy, well-educated adults. In accord with the ADH, greater age was associated with lower hit and greater false alarm rates and more liberal response bias on associative recognition tests. Women outperformed men on recognition of items and associations, but among normotensive participants, women outperformed men only on memory for associations and not on item recognition. Thus, although supporting ADH in a large lifespan sample of healthy adults, the findings indicate that the effect may be partially driven by an age-related increase in liberal bias in recognition of associations. Sex differences and health factors may modify the associative deficit regardless of age.

Age differences in hippocampal subfield volumes from childhood to late adulthood

The hippocampus is composed of distinct subfields: the four cornu ammonis areas (CA1‐CA4), dentate gyrus (DG), and subiculum. The few in vivo studies of human hippocampal subfields suggest that the extent of age differences in volume varies across subfields during healthy childhood development and aging. However, the associations between age and subfield volumes across the entire lifespan are unknown. Here, we used a high‐resolution imaging technique and manually measured hippocampal subfield and entorhinal cortex volumes in a healthy lifespan sample (N = 202), ages 8–82 yrs. The magnitude of age differences in volume varied among the regions. Combined CA1‐2 volume evidenced a negative linear association with age. In contrast, the associations between age and volumes of CA3‐DG and the entorhinal cortex were negative in mid‐childhood and attenuated in later adulthood. Volume of the subiculum was unrelated to age. The different magnitudes and patterns of age differences in subfield volumes may reflect dynamic microstructural factors and have implications for cognitive functions across the lifespan.

Vascular Risk Moderates Associations between Hippocampal Subfield Volumes and Memory

Advanced age and vascular risk negatively affect episodic memory. The hippocampus (HC) is a complex structure, and little is known about the roles of different HC regions in age-related memory declines. Using data from an ongoing longitudinal study, we investigated whether memory functions are related to volumes of specific HC subregions (CA1-2, CA3-4/dentate gyrus, and subiculum). Furthermore, we inquired if arterial hypertension, a common age-related vascular risk factor, modifies age-related differences in HC regional volumes, concurrent memory performance, and improvement in memory over multiple administrations. Healthy adults (n = 49, 52–82 years old) completed associative recognition and free recall tasks. In grouped path models, covariance structures differed between hypertensive and normotensive participants. Whereas larger CA3-4/dentate gyrus volumes predicted greater improvement in associative memory over repeated tests regardless of vascular risk, CA1-2 volumes were associated with improvement in noun recall only in hypertensive participants. Only among hypertensive participants, CA1-2 volumes negatively related to age and CA3-4/dentate gyrus and CA1-2 volumes were associated with performance at the last measurement occasion. These findings suggest that relatively small regions of the HC may play a role in age-related memory declines and that vascular risk factors associated with advanced age may modify that relationship.

Age-related differences in memory and executive functions in healthy APOE ɛ4 carriers: The contribution of individual differences in prefrontal volumes and systolic blood pressure

Advanced age and vascular risk are associated with declines in the volumes of multiple brain regions, especially the prefrontal cortex, and the hippocampus. Older adults, even unencumbered by declining health, perform less well than their younger counterparts in multiple cognitive domains, such as episodic memory, executive functions, and speed of perceptual processing. Presence of a known genetic risk factor for cognitive decline and vascular disease, the ɛ4 allele of the apolipoprotein E (APOE) gene, accounts for some share of those declines; however, the extent of the joint contribution of genetic and physiological vascular risk factors on the aging brain and cognition is unclear. In a sample of healthy adults (age 19-77), we examined the effects of a vascular risk indicator (systolic blood pressure, SBP) and volumes of hippocampus (HC), lateral prefrontal cortex (lPFC), and prefrontal white matter (pFWM) on processing speed, working memory (WM), and recognition memory. Using path analyses, we modeled indirect effects of age, SBP, and brain volumes on processing speed, WM, and memory and compared the patterns of structural relations among those variables in APOE ɛ4 carriers and ɛ3 homozygotes. Among ɛ4 carriers, age differences in WM were explained by increase in SBP, reduced FWM volume, and slower processing. In contrast, lPFC and FWM volumes, but not BP, explained a share of age differences in WM among ɛ3 homozygotes. Thus, even in healthy older carriers of the APOE ɛ4 allele, clinically unremarkable increase in vascular risk may be associated with reduced frontal volumes and impaired cognitive functions.

A harmonized segmentation protocol for hippocampal and parahippocampal subregions : why do we need one and what are the key goals?

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. Because of 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.

Regional brain shrinkage over two years: individual differences and effects of pro-inflammatory genetic polymorphisms.

We examined regional changes in brain volume in healthy adults (N=167, age 19-79years at baseline; N=90 at follow-up) over approximately two years. With latent change score models, we evaluated mean change and individual differences in rates of change in 10 anatomically-defined and manually-traced regions of interest (ROIs): lateral prefrontal cortex (LPFC), orbital frontal cortex (OF), prefrontal white matter (PFw), hippocampus (Hc), parahippocampal gyrus (PhG), caudate nucleus (Cd), putamen (Pt), insula (In), cerebellar hemispheres (CbH), and primary visual cortex (VC). Significant mean shrinkage was observed in the Hc, CbH, In, OF, and PhG, and individual differences in change were noted in all regions, except the OF. Pro-inflammatory genetic variants modified shrinkage in PhG and CbH. Carriers of two T alleles of interleukin-1β (IL-1β C-511T, rs16944) and a T allele of methylenetetrahydrofolate reductase (MTHFR C677T, rs1801133) polymorphisms showed increased PhG shrinkage. No effects of a pro-inflammatory polymorphism for C-reactive protein (CRP-286C>A>T, rs3091244) or apolipoprotein (APOE) ε4 allele were noted. These results replicate the pattern of brain shrinkage observed in previous studies, with a notable exception of the LPFC, thus casting doubt on the unique importance of prefrontal cortex in aging. Larger baseline volumes of CbH and In were associated with increased shrinkage, in conflict with the brain reserve hypothesis. Contrary to previous reports, we observed no significant linear effects of age and hypertension on regional brain shrinkage. Our findings warrant further investigation of the effects of neuroinflammation on structural brain change throughout the lifespan.

Normal-appearing cerebral white matter in healthy adults: mean change over 2 years and individual differences in change

Diffusion tensor imaging studies show age-related differences in cerebral white matter (WM). However, few have studied WM changes over time, and none evaluated individual differences in change across a wide age range. Here, we examined 2-year WM change in 96 healthy adults (baseline age, 19-78 years), individual differences in change, and the influence of vascular and metabolic risk thereon. Fractional anisotropy (FA), axial diffusivity, and radial diffusivity (RD) represented microstructural properties of normal-appearing WM within 13 regions. Cross-sectional analyses revealed age-related differences in all WM indices across the regions. In contrast, latent change score analyses showed longitudinal declines in axial diffusivity in association and projection fibers and increases in anterior commissural fibers. FA and RD evidenced a less consistent pattern of change. Metabolic risk mediated the effects of age on FA and RD change in corpus callosum body and dorsal cingulum. These findings underscore the importance of longitudinal studies in evaluating individual differences in change and the role of metabolic factors in shaping trajectories of brain aging.

Regional brain shrinkage and change in cognitive performance over two years : The bidirectional influences of the brain and cognitive reserve factors

We examined relationships between regional brain shrinkage and changes in cognitive performance, while taking into account the influence of chronological age, vascular risk, Apolipoprotein E variant and socioeconomic status. Regional brain volumes and cognitive performance were assessed in 167 healthy adults (age 19-79 at baseline), 90 of whom returned for the follow-up after two years. Brain volumes were measured in six regions of interest (ROIs): lateral prefrontal cortex (LPFC), prefrontal white matter (PFw), hippocampus (Hc), parahippocampal gyrus (PhG), cerebellar hemispheres (CbH), and primary visual cortex (VC), and cognitive performance was evaluated in three domains: episodic memory (EM), fluid intelligence (Gf), and vocabulary (V). Average volume loss was observed in Hc, PhG and CbH, but reliable individual differences were noted in all examined ROIs. Average positive change was observed in EM and V performance but not in Gf scores, yet only the last evidenced individual differences in change. We observed reciprocal influences among neuroanatomical and cognitive variables. Larger brain volumes at baseline predicted greater individual gains in Gf, but differences in LPFC volume change were in part explained by baseline level of cognitive performance. In one region (PFw), individual change in volume was coupled with change in Gf. Larger initial brain volumes did not predict slower shrinkage. The results underscore the complex role of brain maintenance and cognitive reserve in adult development.

Path Complexity in Virtual Water Maze Navigation: Differential Associations with Age, Sex, and Regional Brain Volume

Studies of human navigation in virtual maze environments have consistently linked advanced age with greater distance traveled between the start and the goal and longer duration of the search. Observations of search path geometry suggest that routes taken by older adults may be unnecessarily complex and that excessive path complexity may be an indicator of cognitive difficulties experienced by older navigators. In a sample of healthy adults, we quantify search path complexity in a virtual Morris water maze with a novel method based on fractal dimensionality. In a two-level hierarchical linear model, we estimated improvement in navigation performance across trials by a decline in route length, shortening of search time, and reduction in fractal dimensionality of the path. While replicating commonly reported age and sex differences in time and distance indices, a reduction in fractal dimension of the path accounted for improvement across trials, independent of age or sex. The volumes of brain regions associated with the establishment of cognitive maps (parahippocampal gyrus and hippocampus) were related to path dimensionality, but not to the total distance and time. Thus, fractal dimensionality of a navigational path may present a useful complementary method of quantifying performance in navigation.