Age-related differences in hippocampal subfield volumes across the human lifespan: A meta-analysis.

The human hippocampus (Hc) is critical for memory function across the lifespan. It is comprised of cytoarchitectonically distinct subfields: dentate gyrus (DG), cornu ammonis sectors (CA) 1-4, and subiculum, each of which may be differentially susceptible to neurodevelopmental and neurodegenerative mechanisms. Identifying age-related differences in Hc subfield volumes can provide insights into neural mechanisms of memory function across the lifespan. Limited evidence suggests that DG and CA3 volumes differ across development while other regions remain relatively stable, and studies of adulthood implicate a downward trend in all subfield volumes with prominent age effects on CA1. Due to differences in methods and limited sampling for any single study, the magnitude of age effects on Hc subfield volumes and their probable lifespan trajectories remain unclear. Here, we conducted a meta-analysis on cross-sectional studies (n = 48,278 participants, ages = 4-94 years) to examine the association between age and Hc subfield volumes in development (n = 11 studies), adulthood (n = 30 studies), and a combined lifespan sample (n = 41 studies) while adjusting estimates for sample sizes. In development, age was positively associated with DG and CA3-4 volumes, whereas in adulthood a negative association was observed with all subfield volumes. Notably, the observed age effects were not different across subfield volumes within each age group. All subfield volumes showed a nonlinear age pattern across the lifespan with DG and CA3-4 volumes showing a more distinct age trajectory as compared to the other subfields. Lastly, among all the study-level variables, only female percentage of the study sample moderated the age effect on CA1 volume: a higher female-to-male ratio in the study sample was linked to the greater negative association between age and CA1 volume. These results document that Hc subfield volumes differ as a function of age offering broader implications for constructing theoretical models of lifespan memory development.

Development and validation of a quality control procedure for automatic segmentation of hippocampal subfields.

Automatic segmentation methods for in vivo magnetic resonance imaging are increasing in popularity because of their high efficiency and reproducibility. However, automatic methods can be perfectly reliable and consistently wrong, and the validity of automatic segmentation methods cannot be taken for granted. Quality control (QC) by trained and reliable human raters is necessary to ensure the validity of automatic measurements. Yet QC practices for applied neuroimaging research are underdeveloped. We report a detailed QC and correction procedure to accompany our validated atlas for hippocampal subfield segmentation. We document a two-step QC procedure for identifying segmentation errors, along with a taxonomy of errors and an error severity rating scale. This detailed procedure has high between-rater reliability for error identification and manual correction. The latter introduces at maximum 3% error variance in volume measurement. All procedures were cross-validated on an independent sample collected at a second site with different imaging parameters. The analysis of error frequency revealed no evidence of bias. An independent rater with a third sample replicated procedures with high within-rater reliability for error identification and correction. We provide recommendations for implementing the described method along with hypothesis testing strategies. In sum, we present a detailed QC procedure that is optimized for efficiency while prioritizing measurement validity and suits any automatic atlas.

Lost Dynamics and the Dynamics of Loss: Longitudinal Compression of Brain Signal Variability is Coupled with Declines in Functional Integration and Cognitive Performance.

Reduced moment-to-moment blood oxygen level-dependent (BOLD) signal variability has been consistently linked to advanced age and poorer cognitive performance, showing potential as a functional marker of brain aging. To date, however, this promise has rested exclusively on cross-sectional comparisons. In a sample of 74 healthy adults, we provide the first longitudinal evidence linking individual differences in BOLD variability, age, and performance across multiple cognitive domains over an average period of 2.5 years. As expected, those expressing greater loss of BOLD variability also exhibited greater decline in cognition. The fronto-striato-thalamic system emerged as a core neural substrate for these change-change associations. Preservation of signal variability within regions of the fronto-striato-thalamic system also cohered with preservation of functional integration across regions of this system, suggesting that longitudinal maintenance of "local" dynamics may require across-region communication. We therefore propose this neural system as a primary target in future longitudinal studies on the neural substrates of cognitive aging. Given that longitudinal change-change associations between brain and cognition are notoriously difficult to detect, the presence of such an association within a relatively short follow-up period bolsters the promise of brain signal variability as a viable, experimentally sensitive probe for studying individual differences in human cognitive aging.

Microstructure of Human Corpus Callosum across the Lifespan: Regional Variations in Axon Caliber, Density, and Myelin Content.

The myeloarchitecture of the corpus callosum (CC) is characterized as a mosaic of distinct differences in fiber density of small- and large-diameter axons along the anterior-posterior axis; however, regional and age differences across the lifespan are not fully understood. Using multiecho T2 magnetic resonance imaging combined with multi-T2 fitting, the myelin water fraction (MWF) and geometric-mean of the intra-/extracellular water T2 (geomT2IEW) in 395 individuals (7-85 years; 41% males) were examined. The approach was validated where regional patterns along the CC closely resembled the histology; MWF matched mean axon diameter and geomT2IEW mirrored the density of large-caliber axons. Across the lifespan, MWF exhibited a quadratic association with age in all 10 CC regions with evidence of a positive linear MWF-age relationship among younger participants and minimal age differences in the remainder of the lifespan. Regarding geomT2IEW, a significant linear age × region interaction reflected positive linear age dependence mostly prominent in the regions with the highest density of small-caliber fibers-genu and splenium. In all, these two indicators characterize distinct attributes that are consistent with histology, which is a first. In addition, these results conform to rapid developmental progression of CC myelination leveling in middle age as well as age-related degradation of axon sheaths in older adults.

Hippocampal subfield volumetry from structural isotropic 1 mm3 MRI scans: A note of caution.

Spurred by availability of automatic segmentation software, in vivo MRI investigations of human hippocampal subfield volumes have proliferated in the recent years. However, a majority of these studies apply automatic segmentation to MRI scans with approximately 1 × 1 × 1 mm3 resolution, a resolution at which the internal structure of the hippocampus can rarely be visualized. Many of these studies have reported contradictory and often neurobiologically surprising results pertaining to the involvement of hippocampal subfields in normal brain function, aging, and disease. In this commentary, we first outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies, regardless of how images are segmented (i.e., manually or automatically). This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, we discuss the fact that automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images. For these reasons, we caution against using volumetric measurements of hippocampal subfields obtained from 1 × 1 × 1 mm3 images.

Fluid intelligence and gross structural properties of the cerebral cortex in middle-aged and older adults: A multi-occasion longitudinal study.

According to Parieto-Frontal Integration Theory (P-FIT, Jung and Haier, 2007), individual differences in a circumscribed set of brain regions account for variations in general intelligence (g). The components of g, fluid (Gf) and crystallized (Gc) reasoning, exhibit distinct trajectories of age-related change. Because the brain also ages differentially, we hypothesized that age-related cognitive and neural changes would be coupled. In a sample of healthy middle-aged and older adults, we examined changes in Gf (operationalized by Cattell Culture Fair Test) and Gc (indexed by two vocabulary tests) as well as in structural properties of 19 brain regions. We fitted linear mixed models to the data collected on 73 healthy adults who participated in baseline assessment, with 43 returning for at least one follow-up, and 16 of them contributing four repeated assessments over seven years. We observed age differences as well as longitudinal decline in Gf, contrasted to a lack of age differences and stability in Gc. Cortical thickness and cortical volume exhibited significant age differences and longitudinal declines, which were accelerated in P-FIT regions. Gf (but not Gc) was associated with cortical thickness, but no such relationship was found for cortical volume. Uniformity of cognitive change (lack of reliable individual differences) precluded examination of the coupling between cognitive and brain changes. Cortical shrinkage was greater in high-Gc individuals, whereas in participants with higher Gf cortical volume slower volume shrinkage was observed.

Optimization and validation of automated hippocampal subfield segmentation across the lifespan.

Automated segmentation of hippocampal (HC) subfields from magnetic resonance imaging (MRI) is gaining popularity, but automated procedures that afford high speed and reproducibility have yet to be extensively validated against the standard, manual morphometry. We evaluated the concurrent validity of an automated method for hippocampal subfields segmentation (automated segmentation of hippocampal subfields, ASHS; Yushkevich et al., ) using a customized atlas of the HC body, with manual morphometry as a standard. We built a series of customized atlases comprising the entorhinal cortex (ERC) and subfields of the HC body from manually segmented images, and evaluated the correspondence of automated segmentations with manual morphometry. In samples with age ranges of 6-24 and 62-79 years, 20 participants each, we obtained validity coefficients (intraclass correlations, ICC) and spatial overlap measures (dice similarity coefficient) that varied substantially across subfields. Anterior and posterior HC body evidenced the greatest discrepancies between automated and manual segmentations. Adding anterior and posterior slices for atlas creation and truncating automated output to the ranges manually defined by multiple neuroanatomical landmarks substantially improved the validity of automated segmentation, yielding ICC above 0.90 for all subfields and alleviating systematic bias. We cross-validated the developed atlas on an independent sample of 30 healthy adults (age 31-84) and obtained good to excellent agreement: ICC (2) = 0.70-0.92. Thus, with described customization steps implemented by experts trained in MRI neuroanatomy, ASHS shows excellent concurrent validity, and can become a promising method for studying age-related changes in HC subfield volumes.

Pathways to Brain Aging and Their Modifiers: Free-Radical-Induced Energetic and Neural Decline in Senescence (FRIENDS) Model - A Mini-Review.

In this mini-review, we survey the extant literature on brain aging, with the emphasis on longitudinal studies of neuroanatomy, including regional brain volumes and white matter microstructure. We assess the impact of vascular, metabolic, and inflammatory risk factors on the trajectories of change in regional brain volumes and white matter properties, as well as the relationships between neuroanatomical and physiological changes and their influence on cognitive performance. We examine these findings in the context of current biological theories of aging and propose the means of integrating noninvasive measures - spectroscopic indices of brain energy metabolism and regional iron deposits - as valuable proxies for elucidating the basic neurobiology of human brain aging. In a brief summary of the recent findings pertaining to age-related changes in the brain structure and their impact on cognition, we discuss the role of vascular, metabolic, and inflammatory risk factors in shaping the trajectories of change. Drawing on the extant biological theories of aging and mindful of the brain's role as a disproportionately voracious energy consumer in mammals, we emphasize the importance of the fundamental bioenergetic mechanisms as drivers of age-related changes in brain structure and function. We sketch out a model that builds on the conceptualization of aging as an expression of cumulative cellular damage inflicted by reactive oxygen species and ensuing declines in energy metabolism. We outline the ways and means of adapting this model, Free-Radical-Induced Energetic and Neural Decline in Senescence (FRIENDS), to human aging and testing it within the constraints of noninvasive neuroimaging.

A virtual water maze revisited: Two-year changes in navigation performance and their neural correlates in healthy adults.

Age-related declines in spatial navigation are associated with deficits in procedural and episodic memory and deterioration of their neural substrates. For the lack of longitudinal evidence, the pace and magnitude of these declines and their neural mediators remain unclear. Here we examined virtual navigation in healthy adults (N=213, age 18-77 years) tested twice, two years apart, with complementary indices of navigation performance (path length and complexity) measured over six learning trials at each occasion. Slopes of skill acquisition curves and longitudinal change therein were estimated in structural equation modeling, together with change in regional brain volumes and iron content (R2* relaxometry). Although performance on the first trial did not differ between occasions separated by two years, the slope of path length improvement over trials was shallower and end-of-session performance worse at follow-up. Advanced age, higher pulse pressure, smaller cerebellar and caudate volumes, and greater caudate iron content were associated with longer search paths, i.e. poorer navigation performance. In contrast, path complexity diminished faster over trials at follow-up, albeit less so in older adults. Improvement in path complexity after two years was predicted by lower baseline hippocampal iron content and larger parahippocampal volume. Thus, navigation path length behaves as an index of perceptual-motor skill that is vulnerable to age-related decline, whereas path complexity may reflect cognitive mapping in episodic memory that improves with repeated testing, although not enough to overcome age-related deficits.

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. © 2016 Wiley Periodicals, Inc.

Test-retest reliability and concurrent validity of in vivo myelin content indices: Myelin water fraction and calibrated T1 w/T2 w image ratio.

In an age-heterogeneous sample of healthy adults, we examined test-retest reliability (with and without participant repositioning) of two popular MRI methods of estimating myelin content: modeling the short spin-spin (T2 ) relaxation component of multi-echo imaging data and computing the ratio of T1 -weighted and T2 -weighted images (T1 w/T2 w). Taking the myelin water fraction (MWF) index of myelin content derived from the multi-component T2 relaxation data as a standard, we evaluate the concurrent and differential validity of T1 w/T2 w ratio images. The results revealed high reliability of MWF and T1 w/T2 w ratio. However, we found significant correlations of low to moderate magnitude between MWF and the T1 w/T2 w ratio in only two of six examined regions of the cerebral white matter. Notably, significant correlations of the same or greater magnitude were observed for T1 w/T2 w ratio and the intermediate T2 relaxation time constant, which is believed to reflect differences in the mobility of water between the intracellular and extracellular compartments. We conclude that although both methods are highly reliable and thus well-suited for longitudinal studies, T1 w/T2 w ratio has low criterion validity and may be not an optimal index of subcortical myelin content. Hum Brain Mapp 38:1780-1790, 2017. © 2017 Wiley Periodicals, Inc.

Changes in Search Path Complexity and Length During Learning of a Virtual Water Maze: Age Differences and Differential Associations with Hippocampal Subfield Volumes.

Impairment of hippocampus-dependent cognitive processes has been proposed to underlie age-related deficits in navigation. Animal studies suggest a differential role of hippocampal subfields in various aspects of navigation, but that hypothesis has not been tested in humans. In this study, we examined the association between volume of hippocampal subfields and age differences in virtual spatial navigation. In a sample of 65 healthy adults (age 19-75 years), advanced age was associated with a slower rate of improvement operationalized as shortening of the search path over 25 learning trials on a virtual Morris water maze task. The deficits were partially explained by greater complexity of older adults' search paths. Larger subiculum and entorhinal cortex volumes were associated with a faster decrease in search path complexity, which in turn explained faster shortening of search distance. Larger Cornu Ammonis (CA)1-2 volume was associated with faster distance shortening, but not in path complexity reduction. Age differences in regional volumes collectively accounted for 23% of the age-related variance in navigation learning. Independent of subfield volumes, advanced age was associated with poorer performance across all trials, even after reaching the asymptote. Thus, subiculum and CA1-2 volumes were associated with speed of acquisition, but not magnitude of gains in virtual maze navigation.

Striatal iron content predicts its shrinkage and changes in verbal working memory after two years in healthy adults.

The accumulation of non-heme iron in the brain has been proposed as a harbinger of neural and cognitive decline in aging and neurodegenerative disease, but support for this proposal has been drawn from cross-sectional studies, which do not provide valid estimates of change. Here, we present longitudinal evidence of subcortical iron accumulation in healthy human adults (age 19-77 at baseline). We used R2* relaxometry to estimate regional iron content twice within a 2 year period, measured volumes of the striatum and the hippocampus by manual segmentation, and assessed cognitive performance by working memory tasks. Two-year change and individual differences in the change of regional volumes, regional iron content, and working memory were examined by latent change score models while taking into account the age at baseline and metabolic risk indicators. Over the examined period, volume reduction occurred in the caudate nucleus and hippocampus, but iron content increased only in the striatum, where it explained shrinkage. Higher iron content in the caudate nucleus at baseline predicted lesser improvement in working memory after repeat testing. Although advanced age and elevated metabolic syndrome risk were associated with greater iron content in the putamen at baseline, neither age nor metabolic risk influenced change in any variable. Thus, longitudinal evidence supports the notion that accumulation of subcortical iron is a risk factor for neural and cognitive decline in normal aging.

Accumulation of iron in the putamen predicts its shrinkage in healthy older adults: A multi-occasion longitudinal study.

Accumulation of non-heme iron is believed to play a major role in neurodegeneration of the basal ganglia. In healthy aging, however, the temporal relationship between change in brain iron content and age-related volume loss is unclear. Here, we present the first long-term longitudinal multi-occasion investigation of changes in iron content and volume in the neostriatum in a sample of healthy middle-aged and older adults (N=32; ages 49-83years at baseline). Iron content, estimated via R2* relaxometry, increased in the putamen, but not the caudate nucleus. In the former, the rate of accumulation was coupled with change in volume. Moreover, greater baseline iron content predicted faster shrinkage and smaller volumes seven years later. Older age partially accounted for individual differences in neostriatal iron content and volume, but vascular risk did not. Thus, brain iron content may be a promising biomarker of impending decline in normal aging.

Differential aging of cerebral white matter in middle-aged and older adults: A seven-year follow-up.

The few extant reports of longitudinal white matter (WM) changes in healthy aging, using diffusion tensor imaging (DTI), reveal substantial differences in change across brain regions and DTI indices. According to the "last-in-first-out" hypothesis of brain aging late-developing WM tracts may be particularly vulnerable to advanced age. To test this hypothesis we compared age-related changes in association, commissural and projection WM fiber regions using a skeletonized, region of interest DTI approach. Using linear mixed effect models, we evaluated the influences of age and vascular risk at baseline on seven-year changes in three indices of WM integrity and organization (axial diffusivity, AD, radial diffusivity, RD, and fractional anisotropy, FA) in healthy middle-aged and older adults (mean age=65.4, SD=9.0years). Association fibers showed the most pronounced declines over time. Advanced age was associated with greater longitudinal changes in RD and FA, independent of fiber type. Furthermore, older age was associated with longitudinal RD increases in late-developing, but not early-developing projection fibers. These findings demonstrate the increased vulnerability of later developing WM regions and support the "last-in-first-out" hypothesis of brain aging.

Differential effect of age on posterior and anterior hippocampal functional connectivity.

Aging is associated with declines in cognitive performance and multiple changes in the brain, including reduced default mode functional connectivity (FC). However, conflicting results have been reported regarding age differences in FC between hippocampal and default mode regions. This discrepancy may stem from the variation in selection of hippocampal regions. We therefore examined the effect of age on resting state FC of anterior and posterior hippocampal regions in an adult life-span sample. Advanced age was associated with lower FC between the posterior hippocampus and three regions: the posterior cingulate cortex, medial prefrontal cortex, and lateral parietal cortex. In addition, age-related reductions of FC between the left and right posterior hippocampus, and bilaterally along the posterior to anterior hippocampal axis were noted. Age differences in medial prefrontal and inter-hemispheric FC significantly differed between anterior and posterior hippocampus. Older age was associated with lower performance in all cognitive domains, but we observed no associations between FC and cognitive performance after controlling for age. We observed a significant effect of gender and a linear effect of COMT val158met polymorphism on hippocampal FC. Females showed higher FC of anterior and posterior hippocampus and medial prefrontal cortex than males, and the dose of val allele was associated with lower posterior hippocampus - posterior cingulate FC, independent of age. Vascular and metabolic factors showed no significant effects on FC. These results suggest differential age-related reduction in the posterior hippocampal FC compared to the anterior hippocampus, and an age-independent effect of gender and COMT on hippocampal FC.

Adult age differences in subcortical myelin content are consistent with protracted myelination and unrelated to diffusion tensor imaging indices.

Post mortem studies suggest protracted myelination of subcortical white matter into the middle age followed by gradual decline in the late adulthood. To date, however, establishing the proposed inverted-U pattern of age-myelin association proved difficult, as the most common method of investigating white matter, diffusion tensor imaging (DTI), usually reveals only linear associations between DTI indices and age among healthy adults. Here we use a novel method of estimating Myelin Water Fraction (MWF) based on modeling the short spin-spin (T2) relaxation component from multi-echo T2 relaxation imaging data and assess subcortical myelin content within six white matter tracts in a sample of healthy adults (N=61, age 18-84 years). Myelin content evidenced a quadratic relationship with age, in accord with the pattern observed postmortem studies. In contrast, DTI-derived indices that are frequently cited as proxies for myelination, fractional anisotropy (FA) and radial diffusivity (RD), exhibited linear or null relationships with age. Furthermore, the magnitude of age differences in MWF varied across the white matter tracts. Myelin content estimated by MWF was unrelated to FA and correlated with RD only in the splenium. These findings are consistent with the notion that myelination continues throughout the young adulthood into the middle age. The results demonstrate that single-tensor DTI cannot serve as a source of specific proxies for myelination of white matter tracts.

White matter and memory in healthy adults: Coupled changes over two years.

Numerous cross-sectional studies have used diffusion tensor imaging (DTI) to link age-related differences in white matter (WM) anisotropy and concomitant decrements in cognitive ability. Due to a dearth of longitudinal evidence, the relationship between changes in diffusion properties of WM and cognitive performance remains unclear. Here we examine the relationship between two-year changes in WM organization and cognitive performance in healthy adults (N=96, age range at baseline=18-79 years). We used latent change score models (LCSM) to evaluate changes in age-sensitive cognitive abilities - fluid intelligence and associative memory. WM changes were assessed by fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) in WM regions that are considered part of established memory networks and exhibited individual differences in change. In modeling change, we postulated reciprocal paths between baseline measures and change factors, within and between WM and cognition domains, and accounted for individual differences in baseline age. Although baseline cross-sectional memory performance was positively associated with FA and negatively with RD, longitudinal effects told an altogether different story. Independent of age, longitudinal improvements in associative memory were significantly associated with linear reductions in FA and increases in RD. The present findings demonstrate the sensitivity of DTI-derived indices to changes in the brain and cognition and affirm the importance of longitudinal models for evaluating brain-cognition relations.

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.

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. © 2015 Wiley Periodicals, Inc.