Hippocampal subfields and limbic white matter jointly predict learning rate in older adults

First published online: 04 December 2019Age-related memory impairments have been linked to differences in structural brain parameters, including cerebral white matter (WM) microstructure and hippocampal (HC) volume, but their combined influences are rarely investigated. In a population-based sample of 337 older participants aged 61-82 years (Mage = 69.66, SDage = 3.92 years), we modeled the independent and joint effects of limbic WM microstructure and HC subfield volumes on verbal learning. Participants completed a verbal learning task of recall over five repeated trials and underwent magnetic resonance imaging (MRI), including structural and diffusion scans. We segmented three HC subregions on high-resolution MRI data and sampled mean fractional anisotropy (FA) from bilateral limbic WM tracts identified via deterministic fiber tractography. Using structural equation modeling, we evaluated the associations between learning rate and latent factors representing FA sampled from limbic WM tracts, and HC subfield volumes, and their latent interaction. Results showed limbic WM and the interaction of HC and WM-but not HC volume alone-predicted verbal learning rates. Model decomposition revealed HC volume is only positively associated with learning rate in individuals with higher WM anisotropy. We conclude that the structural characteristics of limbic WM regions and HC volume jointly contribute to verbal learning in older adults

Recognition Memory Dysfunction Relates to Hippocampal Subfield Volume: A Study of Cognitively Normal and Mildly Impaired Older Adults.

ObjectivesThe current study examined recognition memory dysfunction and its neuroanatomical substrates in cognitively normal older adults and those diagnosed with mild cognitive impairment (MCI).MethodsParticipants completed the Mnemonic Similarity Task, which provides simultaneous measures of recognition memory and mnemonic discrimination. They also underwent structural neuroimaging to assess volume of medial temporal cortex and hippocampal subfields.ResultsAs expected, individuals diagnosed with MCI had significantly worse recognition memory performance and reduced volume across medial temporal cortex and hippocampal subfields relative to cognitively normal older adults. After controlling for diagnostic group differences, however, recognition memory was significantly related to whole hippocampus volume, and to volume of the dentate gyrus/CA3 subfield in particular. Recognition memory was also related to mnemonic discrimination, a fundamental component of episodic memory that has previously been linked to dentate gyrus/CA3 structure and function.DiscussionResults reveal that hippocampal subfield volume is sensitive to individual differences in recognition memory in older adults independent of clinical diagnosis. This supports the notion that episodic memory declines along a continuum within this age group, not just between diagnostic groups

Hippocampal subfield volumes and pre-clinical Alzheimer's disease in 408 cognitively normal adults born in 1946

BACKGROUND: The human hippocampus comprises a number of interconnected histologically and functionally distinct subfields, which may be differentially influenced by cerebral pathology. Automated techniques are now available that estimate hippocampal subfield volumes using in vivo structural MRI data. To date, research investigating the influence of cerebral β-amyloid deposition-one of the earliest hypothesised changes in the pathophysiological continuum of Alzheimer's disease-on hippocampal subfield volumes in cognitively normal older individuals, has been limited. METHODS: Using cross-sectional data from 408 cognitively normal individuals born in mainland Britain (age range at time of assessment = 69.2-71.9 years) who underwent cognitive assessment, 18F-Florbetapir PET and structural MRI on the same 3 Tesla PET/MR unit (spatial resolution 1.1 x 1.1 x 1.1. mm), we investigated the influences of β-amyloid status, age at scan, and global white matter hyperintensity volume on: CA1, CA2/3, CA4, dentate gyrus, presubiculum and subiculum volumes, adjusting for sex and total intracranial volume. RESULTS: Compared to β-amyloid negative participants (n = 334), β-amyloid positive participants (n = 74) had lower volume of the presubiculum (3.4% smaller, p = 0.012). Despite an age range at scanning of just 2.7 years, older age at time of scanning was associated with lower CA1 (p = 0.007), CA4 (p = 0.004), dentate gyrus (p = 0.002), and subiculum (p = 0.035) volumes. There was no evidence that white matter hyperintensity volume was associated with any subfield volumes. CONCLUSION: These data provide evidence of differential associations in cognitively normal older adults between hippocampal subfield volumes and β-amyloid deposition and, increasing age at time of scan. The relatively selective effect of lower presubiculum volume in the β-amyloid positive group potentially suggest that the presubiculum may be an area of early and relatively specific volume loss in the pathophysiological continuum of Alzheimer's disease. Future work using higher resolution imaging will be key to exploring these findings further

Normal aging and Alzheimer's disease : hippocampal and episodic memory differences

Alzheimer’s Disease (AD) and normal aging (NA) are characterized by structural brain changes as well as cognitive changes that appear over the lifespan. The hippocampus is an area susceptible to early atrophy in both AD and NA; however the differential causes of atrophy are not entirely clear. Hippocampal volume loss in AD is attributed to neuronal death due to underlying pathology. AD often is diagnosed years after the onset of pathology and subsequent atrophy. NA is a continuation of cognitive decline that does not become dementia. Episodic memory (EM) is processed within the hippocampus and is one of the first systems to show deficits in conjunction with both patterns of aging. This review focuses on hippocampal volume loss and EM decline in NA and AD.Communication Sciences and Disorder

Hippocampal maturity promotes memory distinctiveness in childhood and adolescence

Adaptive learning systems need to meet two complementary and partially conflicting goals: detecting regularities in the world versus remembering specific events. The hippocampus (HC) keeps a fine balance between computations that extract commonalities of incoming information (i.e., pattern completion) and computations that enable encoding of highly similar events into unique representations (i.e., pattern separation). Histological evidence from young rhesus monkeys suggests that HC development is characterized by the differential development of intrahippocampal subfields and associated networks. However, due to challenges in the in vivo investigation of such developmental organization, the ontogenetic timing of HC subfield maturation remains controversial. Delineating its course is important, as it directly influences the fine balance between pattern separation and pattern completion operations and, thus, developmental changes in learning and memory. Here, we relate in vivo, high-resolution structural magnetic resonance imaging data of HC subfields to behavioral memory performance in children aged 6–14 y and in young adults. We identify a multivariate profile of age-related differences in intrahippocampal structures and show that HC maturity as captured by this pattern is associated with age differences in the differential encoding of unique memory representations

The impact of aging on subregions of the hippocampal complex in healthy adults

The hippocampal complex, an anatomical composite of several subregions, is known to decrease in size with increasing age. However, studies investigating which subregions are particularly prone to age-related tissue loss revealed conflicting findings. Possible reasons for such inconsistencies may reflect differences between studies in terms of the cohorts examined or techniques applied to define and measure hippocampal subregions. In the present study, we enhanced conventional MR-based information with microscopically defined cytoarchitectonic probabilities to investigate aging effects on the hippocampal complex in a carefully selected sample of 96 healthy subjects (48 males/48 females) aged 18-69 years. We observed significant negative correlations between age and volumes of the cornu ammonis, fascia dentata, subiculum, and hippocampal-amygdaloid transition area, but not the entorhinal cortex. The estimated age-related annual atrophy rates were most pronounced in the left and right subiculum with -0.23% and -0.22%, respectively. These findings suggest age-related atrophy of the hippocampal complex overall, but with differential effects in its subregions. If confirmed in future studies, such region-specific information may prove useful for the assessment of diseases and disorders known to modulate age-related hippocampal volume loss.NC is funded by Australian Research Council Future fellowship number 120100227. EL is funded by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under award number R01HD081720 and further supported by the Cousins Center for Psychoneuroimmunology at the University of California, Los Angeles (UCLA)

Effect of cardiorespiratory exercise intervention on the volume of dentate gyrus and CA3 subfields of the hippocampus

Alzheimer’s disease (AD) is widely accepted as being linked with abnormal atrophy of the hippocampus. In the nonhuman-focused literature, the hippocampus has been identified as one of the prominent regions of interest with mechanisms of adult neurogenesis from aerobic exercise. Several human studies over the past decade have shown the effect of exercise that improves cardiorespiratory fitness on the size and function of the hippocampus in participants. However, the size of hippocampal subfields, especially the dentate gyrus (DG), has not been examined in humans even though various animal studies have identified the DG subfield as the primary region of adult neurogenesis induced by aerobic exercise. The point of this investigation, therefore, was to investigate the effect of an exercise intervention on the size of the DG subfield and the related subfield of cornu ammonis (CA) 3. The hypothesis was that an endurance training intervention, designed to improve cardiorespiratory fitness, would increase the volume of the DG and CA3 subfields of the hippocampus more than a resistance training intervention, designed to increase strength, flexibility, and balance, and that improvement in cardiorespiratory fitness would positively correlate with the change in volumes of these subfields. For this investigation, 32 participants (young adults from age 20 to 33 with sedentary lifestyles) were selected from a data set collected for an ongoing study by the Brain Plasticity and Neuroimaging (BPN) Laboratory at Boston University School of Medicine (Boston, MA, USA). The fitness data and T1-weighted and T2-weighted structural magnetic resonance imaging (MRI) data were used in the analysis. FreeSurfer v6.0 software was used to extract volumetric data of the hippocampal subfields using a hippocampal subfield segmentation algorithm. Analysis of variance (ANOVA) with repeated measures and linear regression were used to analyze the statistical significance of the results. The change in volumes for the whole hippocampus, DG, and CA3 did not show any statistically significant differences after endurance training compared with after resistance training. The effect of exercise on the volume of the CA3 subfield appeared to be asymmetrical from left to right, with heavier impact on the left CA3 than on the right CA3. There was no statistically significant correlation between the change in cardiorespiratory fitness and the change in volume of any of the regions analyzed. However, the left whole hippocampus showed a slight trend (p = 0.078; R = 0.317) of weak positive correlation between its volume change and the cardiorespiratory fitness change of the participants. This result was consistent with the previous human literature. Although statistically not significant, most data showed that the endurance training group saw more preservation or increase in volume. This result is encouraging and should be explored further to validate the efficacy of cardiorespiratory exercise as a possible prevention mechanism against AD for young adults later in life

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.,2015b) 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

Hippocampal subfield volumes and pre-clinical Alzheimer's disease in 408 cognitively normal adults born in 1946.

BACKGROUND: The human hippocampus comprises a number of interconnected histologically and functionally distinct subfields, which may be differentially influenced by cerebral pathology. Automated techniques are now available that estimate hippocampal subfield volumes using in vivo structural MRI data. To date, research investigating the influence of cerebral β-amyloid deposition-one of the earliest hypothesised changes in the pathophysiological continuum of Alzheimer's disease-on hippocampal subfield volumes in cognitively normal older individuals, has been limited. METHODS: Using cross-sectional data from 408 cognitively normal individuals born in mainland Britain (age range at time of assessment = 69.2-71.9 years) who underwent cognitive assessment, 18F-Florbetapir PET and structural MRI on the same 3 Tesla PET/MR unit (spatial resolution 1.1 x 1.1 x 1.1. mm), we investigated the influences of β-amyloid status, age at scan, and global white matter hyperintensity volume on: CA1, CA2/3, CA4, dentate gyrus, presubiculum and subiculum volumes, adjusting for sex and total intracranial volume. RESULTS: Compared to β-amyloid negative participants (n = 334), β-amyloid positive participants (n = 74) had lower volume of the presubiculum (3.4% smaller, p = 0.012). Despite an age range at scanning of just 2.7 years, older age at time of scanning was associated with lower CA1 (p = 0.007), CA4 (p = 0.004), dentate gyrus (p = 0.002), and subiculum (p = 0.035) volumes. There was no evidence that white matter hyperintensity volume was associated with any subfield volumes. CONCLUSION: These data provide evidence of differential associations in cognitively normal older adults between hippocampal subfield volumes and β-amyloid deposition and, increasing age at time of scan. The relatively selective effect of lower presubiculum volume in the β-amyloid positive group potentially suggest that the presubiculum may be an area of early and relatively specific volume loss in the pathophysiological continuum of Alzheimer's disease. Future work using higher resolution imaging will be key to exploring these findings further