Spatial correlation maps of the hippocampus with cerebrospinal fluid biomarkers and cognition in Alzheimer's disease: A longitudinal study

This study is an observational study that takes the existing longitudinal data from Alzheimer''s disease Neuroimaging Initiative to examine the spatial correlation map of hippocampal subfield atrophy with CSF biomarkers and cognitive decline in the course of AD. This study included 421 healthy controls (HC), 557 patients of stable mild cognitive impairment (s‐MCI), 304 Alzheimer''s Disease (AD) patients, and 241 subjects who converted to be AD from MCI (c‐MCI), and 6,525 MRI scans in a period from 2004 to 2019. Our findings revealed that all the hippocampal subfields showed their accelerated atrophy rate from cognitively normal aging to stable MCI and AD. The presubiculum, dentate gyrus, and fimbria showed greater atrophy beyond the whole hippocampus in the HC, s‐MCI, and AD groups and corresponded to a greater decline of memory and attention in the s‐MCI group. Moreover, the higher atrophy rates of the subiculum and CA2/3, CA4 were also associated with a greater decline in attention in the s‐MCI group. Interestingly, patients with c‐MCI showed that the presubiculum atrophy was associated with CSF tau levels and corresponded to the onset age of AD and a decline in attention in patients with c‐MCI. These spatial correlation findings of the hippocampus suggested that the hippocampal subfields may not be equally impacted by normal aging, MCI, and AD, and their atrophy was selectively associated with declines in specific cognitive domains. The presubiculum atrophy was highlighted as a surrogate marker for the AD prognosis along with tau pathology and attention decline.     

The relevance of hippocampal subfield integrity and clock drawing test performance for the diagnosis of Alzheimer’s disease and mild cognitive impairment

Objectives: The clock drawing test (CDT) is one of the worldwide most used screening tests for Alzheimer’s disease (AD). MRI studies have identified temporo-parietal regions being involved in CDT impairment. However, the contributions of specific hippocampal subfields and adjacent extrahippocampal structures to CDT performance in AD and mild cognitive impairment (MCI) have not been investigated so far. It is unclear whether morphological alterations or CDT score, or a combination of both, are able to predict AD.

Methods: 38 AD patients, 38?MCI individuals and 31 healthy controls underwent neuropsychological assessment and MRI at 3 Tesla. FreeSurfer 5.3 was used to perform hippocampal parcellation. We used a collection of statistical methods to better understand the relationship between CDT and hippocampal formation. We also tested the clinical feasibility of this relationship when predicting AD.

Results: Impaired CDT performance in AD was associated with widespread atrophy of the cornu ammonis, presubiculum, and subiculum, whereas MCI subjects showed CDT-related alterations of the CA4-dentate gyrus and subiculum. CDT correlates in AD and MCI showed regional and quantitative overlap. Importantly, CDT score was the best predictor of AD.

Conclusions: Our findings lend support for an involvement of different hippocampal subfields in impaired CDT performance in AD and MCI. CDT seems to be more efficient than subfield imaging for predicting AD.     

Hippocampal morphology and autobiographic memory in mild cognitive impairment and Alzheimer's disease

Autobiographical memory (AM) comprises memories of one's own past that are characterized by a sense of subjective time and autonoetic awareness. AM deficits are among the major complaints of patients with Alzheimer's disease (AD) even in early or preclinical stages. However, little is known on the association between cerebral alterations and AM in mild cognitive impairment (MCI) and AD. In the current study, patients with AD or MCI and healthy controls underwent high-resolution magnetic resonance imaging (MRI) and neuropsychological testing including semi-structured assessment of semantic and episodic AM of distinct lifetime periods. In MRI analysis, FSL-FIRST was used to automatically ascertain volume and shape of the hippocampal formation. Episodic, but not semantic AM loss was associated with morphological changes of the hippocampus, primarily involving the left hemisphere. According to shape analyses, these associations referred to regionally specific rather than global atrophy of the hippocampus. Our study demonstrates that loss of episodic AM early in the course of AD is associated with regionally confined hippocampal atrophy, thus supporting the multiple trace theory for the role of the hippocampus in episodic AM. Our findings are not only relevant for the understanding of memory function, but may also contribute to facilitating the early diagnosis of AD.     

Regional vulnerability of hippocampal subfields and memory deficits in Parkinson's disease

Neuropathological studies show the hippocampus is affected in Parkinson's disease (PD), with the second subfield of the cornu armonis (CA2) being the most involved. Our aims were to assess in vivo volumes of different hippocampal subfields in patients with PD with and without visual hallucinations using MRI and test their association with verbal learning and long‐term recall. A total of 18 nondemented PD patients, 18 nondemented PD patients with visual hallucinations and 18 neurologically unimpaired elderly controls matched by age and gender were enrolled in this study. We assessed the volumes of seven hippocampal subfields on MRI, including the cornu armonis (CA) sectors, subiculum, presubiculum, and the dentate gyrus (DG) using a novel technique that enables automated volumetry. The CA2‐3 and CA4‐DG subfields were significantly smaller in both groups of patients, while the subiculum was only reduced in PD patients with visual hallucinations, compared to controls. Significant correlations were found between learning performance and CA2‐3 as well as CA4‐DG volumes in the whole patient sample. These data show there is regional atrophy of specific hippocampal subfields in PD, which is more severe and further extends to the subiculum in patients with visual hallucinations. Our findings indicate that learning deficits are associated with volume loss in subfields that act as input regions in the hippocampal circuit, suggesting that degeneration in these regions could be responsible for cognitive dysfunction in PD. © 2013 Wiley Periodicals, Inc.     

Contributions of the hippocampal subfields and entorhinal cortex to disambiguation during working memory

The hippocampus and medial temporal lobes (MTL) support the successful formation of new memories without succumbing to interference from related, older memories. Computational models and animal findings have implicated the dentate gyrus (DG), CA3, CA1, and entorhinal cortex (EC) in the disambiguation and encoding of well‐established, episodic events that share common elements. However, it is unknown if these hippocampal subfields and MTL (entorhinal, perirhinal, parahippocampal) cortices also contribute during working memory when overlapping stimuli that share related features are rapidly encoded and subsequently maintained over a brief temporal delay. We hypothesized that activity in CA3/DG hippocampal subfields would be greater for the rapid encoding of stimuli with overlapping features than for the rapid encoding of stimuli with distinct features. In addition, we predicted that CA1 and EC, regions that are associated with creating long‐term episodic representations, would show greater sustained activity across both encoding and delay periods for representations of stimuli with overlapping features than for those with distinct features. We used high‐resolution fMRI during a delayed matching‐to‐sample (DMS) task using face pairs that either shared (overlapping condition, OL) or did not share (non‐overlapping condition, NOL) common elements. We contrasted the OL condition with the NOL condition separately at sample (encoding) and during a brief delay (maintenance). At sample, we observed activity localized to CA3/DG, the subiculum, and CA1. At delay, we observed activity localized to the subiculum and CA1 and activity within the entorhinal, perirhinal, and parahippocampal cortices. Our findings are consistent with our hypotheses and suggest that CA3/DG, CA1 and the subiculum support the disambiguation and encoding of overlapping representations while CA1, subiculum and entorhinal cortex maintain these overlapping representations during working memory. © 2013 Wiley Periodicals, Inc.     

Projections from the periamygdaloid cortex to the amygdaloid complex, the hippocampal formation, and the parahippocampal region: a PHA-L study in the rat

The periamygdaloid cortex, an amygdaloid region that processes olfactory information, projects to the hippocampal formation and parahippocampal region. To elucidate the topographic details of these projections, pathways were anterogradely traced using Phaseolus vulgaris leukoagglutinin (PHA-L) in 14 rats. First, we investigated the intradivisional, interdivisional, and intra-amygdaloid connections of various subfields [periamygdaloid subfield (PAC), medial subfield (PACm), sulcal subfield (PACs)] of the periamygdaloid cortex. Thereafter, we focused on projections to the hippocampal formation (dentate gyrus, hippocampus proper, subiculum) and to the parahippocampal region (presubiculum, parasubiculum, entorhinal, and perirhinal and postrhinal cortices). The PACm had the heaviest intradivisional projections and it also originated light interdivisional projections to other periamygdaloid subfields. Projections from the other subfields converged in the PACs. All subfields provided substantial intra-amygdaloid projections to the medial and posterior cortical nuclei. In addition, the PAC subfield projected to the ventrolateral and medial divisions of the lateral nucleus. The heaviest periamygdalohippocampal projections originated in the PACm and PACs, which projected moderately to the temporal end of the stratum lacunosum moleculare of the CA1 subfield and to the molecular layer of the ventral subiculum. The PACm also projected moderately to the temporal CA3 subfield. The heaviest projections to the entorhinal cortex originated in the PACs and terminated in the amygdalo-entorhinal, ventral intermediate, and medial subfields. Area 35 of the perirhinal cortex was lightly innervated by the PAC subfield. Thus, these connections might allow for olfactory information entering the amygdala to become associated with signals from other sensory modalities that enter the amygdala via other nuclei. Further, the periamygdalohippocampal pathways might form one route by which the amygdala modulates memory formation and retrieval in the medial temporal lobe memory system. These pathways can also facilitate the spread of seizure activity from the amygdala to the hippocampal and parahippocampal regions in temporal lobe epilepsy.     

Longitudinal trajectory of Amyloid‐related hippocampal subfield atrophy in nondemented elderly

Hippocampal atrophy and abnormal β‐Amyloid (Aβ) deposition are established markers of Alzheimer's disease (AD). Nonetheless, longitudinal trajectory of Aβ‐associated hippocampal subfield atrophy prior to dementia remains unclear. We hypothesized that elevated Aβ correlated with longitudinal subfield atrophy selectively in no cognitive impairment (NCI), spreading to other subfields in mild cognitive impairment (MCI). We analyzed data from two independent longitudinal cohorts of nondemented elderly, including global PET‐Aβ in AD‐vulnerable cortical regions and longitudinal subfield volumes quantified with a novel auto‐segmentation method (FreeSurfer v.6.0). Moreover, we investigated associations of Aβ‐related progressive subfield atrophy with memory decline. Across both datasets, we found a converging pattern that higher Aβ correlated with faster CA1 volume decline in NCI. This pattern spread to other hippocampal subfields in MCI group, correlating with memory decline. Our results for the first time suggest a longitudinal focal‐to‐widespread trajectory of Aβ‐associated hippocampal subfield atrophy over disease progression in nondemented elderly.     

Three-dimensional surface mapping of hippocampal atrophy progression from MCI to AD and over normal aging as assessed using voxel-based morphometry

The hippocampus is the brain structure of highest and earliest structural alteration in Alzheimer's disease (AD). New developments in neuroimaging methods recently made it possible to assess the respective involvement of the different hippocampal subfields by mapping atrophy on a 3D hippocampal surface view. In this longitudinal study on patients with mild cognitive impairment (MCI), we used such an approach to map the profile of hippocampal atrophy and its progression over an 18-month follow-up period in rapid converters to AD and "non-converters" compared to age-matched controls. For the sake of comparison, we also assessed the profile of hippocampal atrophy associated with AD and with increasing age in a healthy control population ranging from young adult to elderly. We found major involvement of the lateral part of the superior hippocampus mainly corresponding to the CA1 subfield in MCI and AD while increasing age was mainly associated with subiculum atrophy in the healthy population. Moreover, the CA1 subfield also showed highest atrophy rates during follow-up, in both rapid converters and "non-converters" although increased effects were observed in the former group. This study emphasizes the differences between normal aging and AD processes leading to hippocampal atrophy, pointing to a specific AD-related CA1 involvement while subiculum atrophy would represent a normal aging process. Our findings also suggest that the degree of hippocampal atrophy, more than its spatial localization, predicts rapid conversion to AD in patients with MCI.     

Organizational connectivity among the CA1, subiculum,presubiculum, and entorhinal cortex in the rabbit

The laminar and topographical organization of connections between the hippocampal formation and parahippocampal regions was investigated in the rabbit following in vivo injection of cholera toxin B subunit as a retro‐ and antero‐grade tracer and biotinylated dextran amine as an anterograde tracer. We confirmed several connectional features different from those of the rat, that is, the rabbit presubiculum received abundant afferents from CA1 and had many reciprocal connections with the entorhinal cortex. On the other hand, we identified many similarities with the rat: both the CA1 and subicular afferents that originated from the entorhinal cortex were abundant; moreover, the presubiculum received many inputs from the subiculum and sent massive projections to the entorhinal cortex. By plotting retrograde and anterograde labels in two‐dimensional unfolded maps of the entire hippocampal and parahippocampal regions, we found that each group of entorhinal cells that project to CA1, subiculum, and presubiculum, and also the termination of the presubiculo‐entorhinal projection, was distributed in band‐like zones in layers II–III, extending across the medial and lateral entorhinal cortex. Our results suggest that the rabbit has a basic connectivity that is common with that of the rat, and also has additional hippocampal–presubicular and entorhino–presubicular connections that may reflect functional evolution in learning and memory.     

Hippocampal atrophy patterns in mild cognitive impairment and Alzheimer's disease

Background:

Histopathological studies and animal models suggest that hippocampal subfields may be differently affected by aging, Alzheimer's disease (AD), and other diseases. High‐resolution images at 4 Tesla depict details of the internal structure of the hippocampus allowing for in vivo volumetry of different subfields. The aims of this study were as follows: (1) to determine patterns of volume loss in hippocampal subfields in normal aging, AD, and amnestic mild cognitive impairment (MCI). (2) To determine if measurements of hippocampal subfields provide advantages over total hippocampal volume for differentiation between groups.

Methods:

Ninety‐one subjects (53 controls (mean age: 69.3 ± 7.3), 20 MCI (mean age: 73.6 ± 7.1), and 18 AD (mean age: 69.1 ± 9.5) were studied with a high‐resolution T2 weighted imaging sequence aimed at the hippocampus. Entorhinal cortex (ERC), subiculum, CA1, CA1‐CA2 transition zone (CA1‐2), CA3 & dentate gyrus (CA3&DG) were manually marked in the anterior third of the hippocampal body. Hippocampal volume was obtained from the Freesurfer and manually edited.

Results:

Compared to controls, AD had smaller volumes of ERC, subiculum, CA1, CA1‐2, and total hippocampal volumes. MCI had smaller CA1‐2 volumes. Discriminant analysis and power analysis showed that CA1‐2 was superior to total hippocampal volume for distinction between controls and MCI.

Conclusion:

The patterns of subfield atrophy in AD and MCI were consistent with patterns of neuronal cell loss/reduced synaptic density described by histopathology. These preliminary findings suggest that hippocampal subfield volumetry might be a better measure for diagnosis of early AD and for detection of other disease effects than measurement of total hippocampus. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.

     

Episodic and semantic memory in mild cognitive impairment

Little is known about episodic and semantic memory in the early predementia stage of Alzheimer's disease (AD), which is referred to as mild cognitive impairment (MCI). To explore person knowledge, item recognition and spatial associative memory, we designed the Face Place Test (FPT). A total of 75 subjects participated: 22 patients with early AD, 24 with MCI and 29 matched controls. As predicted, AD patients showed significant deficits in person naming, item recognition and recall of spatial location (placing). Surprisingly, subjects with MCI were also impaired on all components. There was no significant difference between AD and MCI except on the placing component. Analysis of the relationship between semantic (naming) and episodic (recognition and placing) components of the FPT revealed a significant association between the two episodic tasks, but not between episodic and semantic performance. Patients with MCI show deficits of episodic and semantic memory. The extent of impairment suggests dysfunction beyond the medial temporal lobe. The FPT might form the basis of a sensitive early indicator of AD.     

Intrinsic connectivity of hippocampal subfields in normal elderly and mild cognitive impairment patients

Hippocampal connectivity has been widely described but connectivity specificities of hippocampal subfields and their changes in early AD are poorly known. The aim of this study was to highlight hippocampal subfield networks in healthy elderly (HE) and their changes in amnestic patients with mild cognitive impairment (aMCI). Thirty‐six HE and 27 aMCI patients underwent resting‐state functional MRI scans. Specific intrinsic connectivity of bilateral CA1, SUB (subiculum), and CA2/3/4/DG was identified in HE (using seeds derived from manually delineation on high‐resolution scans) and compared between HE and aMCI. Compared to the other subfields, CA1 was more strongly connected to the amygdala and occipital regions, CA2/3/4/DG to the left anterior cingulate cortex, temporal, and occipital regions, and SUB to the angular, precuneus, putamen, posterior cingulate, and frontal regions. aMCI patients showed reduced connectivity within the SUB network (with frontal and posterior cingulate regions). Our study highlighted for the first time three specific and distinct hippocampal subfield functional networks in HE, and their alterations in aMCI. These findings are important to understand AD specificities in both cognitive deficits and lesion topography, given the role of functional connectivity in these processes. Hum Brain Mapp 38:4922–4932, 2017. © 2017 Wiley Periodicals, Inc.     

Projections from the posterior cortical nucleus of the amygdala to the hippocampal formation and parahippocampal region in rat

The posterior cortical nucleus of the amygdala is involved in the processing of pheromonal information and presumably participates in ingestive, defensive, and reproductive behaviors as a part of the vomeronasal amygdala. Recent studies suggest that the posterior cortical nucleus might also modulate memory processing via its connections to the medial temporal lobe memory system. To investigate the projections from the posterior cortical nucleus to the hippocampal formation and the parahippocampal region, as well as the intra-amygdaloid connectivity in detail, we injected the anterograde tracer phaseolus vulgaris-leucoagglutinin into different rostrocaudal levels of the posterior cortical nucleus. Within the hippocampal formation, the stratum lacunosum-moleculare of the temporal CA1 subfield and the adjacent molecular layer of the proximal temporal subiculum received a moderate projection. Within the parahippocampal region, the ventral intermediate, dorsal intermediate, and medial subfields of the entorhinal cortex received light to moderate projections. Most of the labeled terminals were in layers I, II, and III. In the ventral intermediate subfield, layers V and VI were also moderately innervated. Layers I and II of the parasubiculum received a light projection. There were no projections to the presubiculum or to the perirhinal and postrhinal cortices. The heaviest intranuclear projection was directed to the deep part of layer I and to layer II of the posterior cortical nucleus. There were moderate-to-heavy intra-amygdaloid projections terminating in the bed nucleus of the accessory olfactory tract, the central division of the medial nucleus, and the sulcal division of the periamygdaloid cortex. Our data suggest that via these topographically organized projections, pheromonal information processed within the posterior cortical nucleus can influence memory formation in the hippocampal and parahippocampal areas. Also, these pathways provide routes through which seizure activity can spread from the epileptic amygdala to the surrounding region of the temporal lobe.     

Stereological estimation of neuron number and plaque load in the hippocampal region of a transgenic rat model of Alzheimer's disease

The main hallmarks of Alzheimer's disease (AD) are senile plaques, neurofibrillary tangles and neuronal death. The McGill‐R‐Thy1‐APP rat is one of the few transgenic rat models of AD that displays progressive amyloid pathology. This study aimed to further characterise this rat model, focusing on the pathological changes in the hippocampal formation and the parahippocampal region. These structures, that are important for episodic memory and spatial navigation, are affected in the early stages of the disease. This study used unbiased stereology to investigate possible neuronal loss in the CA1, subiculum and entorhinal cortex of 18‐month‐old homozygous McGill‐R‐Thy1‐APP rats, and also quantified the plaque load in all the areas of the hippocampal formation and parahippocampal region from 9 to 18 months old. A significant reduction of neurons at 18 months was only seen in the subiculum. The first plaque pathology was seen at 9 months in the subiculum. Although the quantified plaque load was variable between animals, the pattern of spatiotemporal progression was similar for all animals. The spread of plaque pathology mainly affected anatomically connected regions. Overall, the plaque pathology observed in the transgenic rats was similar to the early phases of amyloid beta (Aβ)‐deposition described in human patients. The findings here thus indicate that the McGill‐R‐Thy1‐APP rat could be a good model of the Aβ pathology in AD, but less so with respect to neuron loss.     

Hippocampal hyperactivation associated with cortical thinning in Alzheimer's disease signature regions in non-demented elderly adults

Alzheimer's disease (AD) is associated with functional and structural alterations in a distributed network of brain regions supporting memory and other cognitive domains. Functional abnormalities are present in mild cognitive impairment (MCI) with evidence of early hyperactivity in medial temporal lobe regions, followed by failure of hippocampal activation as dementia develops. Atrophy in a consistent set of cortical regions, the "cortical signature of AD," has been reported at the stage of dementia, MCI, and even in clinically normal (CN) older individuals predicted to develop AD. Despite multiple lines of evidence for each of these findings, the relationship between this structural marker of AD-related neurodegeneration and this functional marker of the integrity of the episodic memory system has not yet been elucidated. We investigated this relationship in 34 nondemented older humans (CN, N = 18; MCI, N = 16). Consistent with previous studies, we found evidence of hippocampal hyperactivation in MCI compared with CN. Additionally, within this MCI group, increased hippocampal activation correlated with cortical thinning in AD-signature regions. Even within the CN group, increased hippocampal activity was negatively correlated with cortical thinning in a subset of regions, including the superior parietal lobule (r = -0.66; p < 0.01). These findings, across a continuum of nondemented and mildly impaired older adults, support the hypothesis that paradoxically increased hippocampal activity may be an early indicator of AD-related neurodegeneration in a distributed network.     

Automated measurement of hippocampal subfields in PTSD: Evidence for smaller dentate gyrus volume

Smaller hippocampal volume has been consistently observed as a biomarker of posttraumatic stress disorder (PTSD). However, less is known about individual volumes of the subfields composing the hippocampus such as the dentate gyrus and cornu ammonis (CA) fields 1–4 in PTSD. The aim of the present study was to examine the hypothesis that volume of the dentate gyrus, a region putatively involved in distinctive encoding of similar events, is smaller in individuals with PTSD versus trauma-exposed controls. Ninety-seven recent war veterans underwent structural imaging on a 3T scanner and were assessed for PTSD using the Clinician-Administered PTSD Scale. The hippocampal subfield automated segmentation program available through FreeSurfer was used to segment the CA4/dentate gyrus, CA1, CA2/3, presubiculum, and subiculum of the hippocampus. Results showed that CA4/dentate gyrus subfield volume was significantly smaller in veterans with PTSD and scaled inversely with PTSD symptom severity. These results support the view that dentate gyrus abnormalities are associated with symptoms of PTSD, although additional evidence is necessary to determine whether these abnormalities underlie fear generalization and other memory alterations in PTSD.     

Hippocampal volume reduction and autobiographical memory deficits in chronic schizophrenia

Although autobiographical memory (AM) deficits and hippocampal changes are frequently found in schizophrenia, their actual association remained yet to be established. AM performance and hippocampal volume were examined in 33 older, chronic schizophrenic patients and 21 healthy volunteers matched for age, gender and education. Psychopathological symptoms and additional neuropsychological parameters were assessed by using appropriate rating scales; magnetic resonance imaging (MRI) 3-T data were analyzed via an automated region-of-interest procedure. When compared with the control subjects, patients showed significantly decreased left anterior and posterior hippocampal volumes. Episodic but not semantic AM performance was significantly lower in the patients than in the healthy controls. Both episodic and semantic AM deficits were significantly correlated with volume of the left hippocampus in the patient group. In contrast, deficits in verbal memory, working memory and remote semantic memory observed in the patients did not relate to hippocampal volume. Our findings indicate that AM deficits in chronic schizophrenia are associated with hippocampal volume reductions and underline the importance of this pathology in schizophrenia.     

Development of hippocampal subfield volumes from 4 to 22 years

The hippocampus supports several important cognitive functions known to undergo substantial development during childhood and adolescence, for example, encoding and consolidation of vivid personal memories. However, diverging developmental effects on hippocampal volume have been observed across studies. It is possible that the inconsistent findings may attribute to varying developmental processes and functions related to different hippocampal subregions. Most studies to date have measured global hippocampal volume. We aimed to explore early hippocampal development both globally and regionally within subfields. Using cross‐sectional 1.5 T magnetic resonance imaging data from 244 healthy participants aged 4–22 years, we performed automated hippocampal segmentation of seven subfield volumes; cornu ammonis (CA) 1, CA2/3, CA4/dentate gyrus (DG), presubiculum, subiculum, fimbria, and hippocampal fissure. For validation purposes, seven subjects were scanned at both 1.5 and 3 T, and all subfields except fimbria showed strong correlations across field strengths. Effects of age, left and right hemisphere, sex and their interactions were explored. Nonparametric local smoothing models (smoothing spline) were used to depict age‐trajectories. Results suggested nonlinear age functions for most subfields where volume increases until 13–15 years, followed by little age‐related changes during adolescence. Further, the results showed greater right than left hippocampal volumes that seemed to be augmenting in older age. Sex differences were also found for subfields; CA2/3, CA4/DG, presubiculum, subiculum, and CA1, mainly driven by participants under 13 years. These results provide a detailed characterization of hippocampal subfield development from early childhood. Hum Brain Mapp 35:5646–5657, 2014. © 2014 Wiley Periodicals, Inc.     

Socioeconomic disadvantage and episodic memory ability in the ABCD sample: Contributions of hippocampal subregion and subfield volumes

Socioeconomic disadvantage is associated with volumetric differences in stress-sensitive neural structures, including the hippocampus, and deficits in episodic memory. Rodent studies provide evidence that memory deficits arise via stress-related structural differences in hippocampal subdivisions; however, human studies have only provided limited evidence to support this notion. We used a sample of 10,695 9–13-year-old participants from two timepoints of the Adolescent Brain and Cognitive Development (ABCD) Study to assess whether socioeconomic disadvantage relates to episodic memory performance through hippocampal volumes. We explored associations among socioeconomic disadvantage, measured via the Area Deprivation Index (ADI), concurrent subregion (anterior, posterior) and subfield volumes (CA1, CA3, CA4/DG, subiculum), and episodic memory, assessed via the NIH Toolbox Picture Sequence Memory Test at baseline and 2-year follow-up (Time 2). Results showed that higher baseline ADI related to smaller concurrent anterior, CA1, CA4/DG, and subiculum volumes and poorer Time 2 memory performance controlling for baseline memory. Moreover, anterior, CA1, and subiculum volumes mediated the longitudinal association between the ADI and memory. Results suggest that greater socioeconomic disadvantage relates to smaller hippocampal subregion and subfield volumes and less age-related improvement in memory. These findings shed light on the neural mechanisms linking socioeconomic disadvantage and cognitive ability in childhood.     

The effect of age and Alzheimer's disease on pyramidal neuron density in the individual fields of the hippocampal formation

Summary Pyramidal neuron density was determined at autopsy in the brains of 12 neurologically normal patients (age range 6–87 years) and 18 patients with histopathologically confirmed Alzheimer's disease (AD; age range 62–89 years). Paraffin wax sections were cut at the level of the central part of the cornu ammonis and stained with cresyl fast violet. Pyramidal neuron density was determined in the stratum pyramidale of the presubiculum, subiculum, prosubiculum and CA1–4. The width of the stratum pyramidale in these areas was also determined. There was no significant effect of age on pyramidal neuron density in any of the fields of the hippocampal formation. However, there was a significant decrease in pyramidal neuron density in the subiculum (44%), prosubiculum (28%) and CA1 (41%) of AD brains compared to controls. There was no significant effect of AD on pyramidal neuron density in the presubiculum, CA2 and CA3, but in CA4 it increased (23%) significantly. Pyramidal band width decreased significantly with age in the presubiculum but there was no effect of age on any other region of the hippocampal formation investigated. The width of the stratum pyramidale was significantly lower in the presubiculum (19%), subiculum (30%) and CA3 (17%) of AD compared with control brains. These data suggest that a reduction in pyramidal neuron density within the hippocampal formation does not occur in the absence of underlying pathology. In AD, pyramidal neuron loss predominantly occurs from that sector of the hippocampal formation which comprises the subiculum, prosubiculum and CA1.Supported in part by MRC intercalated awards to N. H. and S. L. I.