Parkinson's disease CA2-CA3 hippocampal atrophy is accompanied by increased cholinergic innervation in patients with normal cognition but not in patients with mild cognitive impairment.

Although brain cholinergic denervation has been largely associated with cognitive decline in patients with Parkinson's disease (PD), new evidence suggests that cholinergic upregulation occurs in the hippocampus of PD patients without cognitive deficits. The specific hippocampal sectors and potential mechanisms of this cholinergic compensatory process have been further studied here, using MRI volumetry and morphometry coupled with molecular imaging using the PET radiotracer [18F]-Fluoroethoxybenzovesamicol ([18F]-FEOBV). Following a thorough screening procedure, 18 participants were selected and evenly distributed in three groups, including cognitively normal PD patients (PD-CN), PD patients with mild cognitive impairment (PD-MCI), and healthy volunteers (HV). Participants underwent a detailed neuropsychological assessment, structural MRI, and PET imaging with [18F]-FEOBV. Basal forebrain Ch1-Ch2 volumes were measured using stereotaxic mapping. Hippocampal subfields were automatically defined using the MAGeT-Brain segmentation algorithm. Cholinergic innervation density was quantified using [18F]-FEOBV uptake. Compared with HV, both PD-CN and PD-MCI displayed significantly reduced volumes in CA2-CA3 bilaterally. We found no other hippocampal subfield nor Ch1-Ch2 volume differences between the three groups. PET imaging revealed higher [18F]-FEOBV uptake in CA2-CA3 of the PD-CN compared with HV or PD-MCI. A positive correlation was observed between cognitive performances and [18F]-FEOBV uptake in the right CA2-CA3 subfield. Reduced volume, together with increased [18F]-FEOBV uptake, were observed specifically in the CA2-CA3 hippocampal subfields. However, while the volume change was observed in both PD-CN and PD-MCI, increased [18F]-FEOBV uptake was present only in the PD-CN group. This suggests that a cholinergic compensatory process takes place in the atrophied CA2-CA3 hippocampal subfields and might underlie normal cognition in PD.

Memory Reactivation during Learning Simultaneously Promotes Dentate Gyrus/CA2,3 Pattern Differentiation and CA1 Memory Integration.

Events that overlap with previous experience may trigger reactivation of existing memories. However, such reactivation may have different representational consequences within the hippocampal circuit. Computational theories of hippocampal function suggest that dentate gyrus and CA2,3 (DG/CA2,3) are biased to differentiate highly similar memories, whereas CA1 may integrate related events by representing them with overlapping neural codes. Here, we tested whether the formation of differentiated or integrated representations in hippocampal subfields depends on the strength of memory reactivation during learning. Human participants of both sexes learned associations (AB pairs, either face-shape or scene-shape), and then underwent fMRI scanning while they encoded overlapping associations (BC shape-object pairs). Both before and after learning, participants were also scanned while viewing indirectly related elements of the overlapping memories (A and C images) in isolation. We used multivariate pattern analyses to measure reactivation of initial pair memories (A items) during overlapping pair (BC) learning, as well as learning-related representational change for indirectly related memory elements in hippocampal subfields. When prior memories were strongly reactivated during overlapping pair encoding, DG/CA2,3 and subiculum representations for indirectly related images (A and C) became less similar, consistent with pattern differentiation. Simultaneously, memory reactivation during new learning promoted integration in CA1, where representations for indirectly related memory elements became more similar after learning. Furthermore, memory reactivation and subiculum representation predicted faster and more accurate inference (AC) decisions. These data show that reactivation of related memories during new learning leads to dissociable coding strategies in hippocampal subfields, in line with computational theories.SIGNIFICANCE STATEMENT The flexibility of episodic memory allows us to remember both the details that differentiate similar events and the commonalities among them. Here, we tested how reactivation of past experience during new learning promotes formation of neural representations that might serve these two memory functions. We found that memory reactivation during learning promoted formation of differentiated representations for overlapping memories in the dentate gyrus/CA2,3 and subiculum subfields of the hippocampus, while simultaneously leading to the formation of integrated representations of related events in subfield CA1 Furthermore, memory reactivation and subiculum representation predicted success when inferring indirect relationships among events. These findings indicate that memory reactivation is an important learning signal that influences how overlapping events are represented within the hippocampal circuit.

Distinct Atrophy Pattern of Hippocampal Subfields in Patients with Progressive and Stable Mild Cognitive Impairment: A Longitudinal MRI Study.

BACKGROUND: Predicting the prognosis of mild cognitive impairment (MCI) has outstanding clinical value, and the hippocampal volume is a reliable imaging biomarker of AD diagnosis. OBJECTIVE: We aimed to longitudinally assess hippocampal sub-regional difference (volume and asymmetry) among progressive MCI (pMCI), stable MCI (sMCI) patients, and normal elderly. METHODS: We identified 29 pMCI, 52 sMCI, and 102 normal controls (NC) from the ADNI database. All participants underwent neuropsychological assessment and 3T MRI scans three times. The time interval between consecutive MRI sessions was about 1 year. Volumes of hippocampal subfield were measured by Freesurfer. Based on the analysis of variance, repeated measures analyses, and receiver operating characteristic curves, we compared cross-sectional and longitudinal alteration sub-regional volume and asymmetry index. RESULTS: Compared to NC, both MCI groups showed significant atrophy in all subfields. At baseline, pMCI have a smaller volume than sMCI in the bilateral subiculum, molecular layer (ML), the molecular and granule cell layers of the dentate gyrus, cornu ammonis 4, and right tail. Furthermore, repeated measures analyses revealed that pMCI patients showed a faster volume loss than sMCI in bilateral subiculum and ML. After controlling for age, gender, and education, most results remained unchanged. However, none of the hippocampal sub-regional volumes performed better than the whole hippocampus in ROC analyses, and no asymmetric difference between pMCI and sMCI was found. CONCLUSION: The faster volume loss in subiculum and ML suggest a higher risk of disease progression in MCI patients. The hippocampal asymmetry may have smaller value in predicting the MCI prognosis.

Automated Hippocampal Subfield Volumetric Analyses in Atypical Alzheimer's Disease.

BACKGROUND: Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are two of the most common variants of atypical Alzheimer's disease (AD). Both PCA and LPA are associated with relative sparing of hippocampus compared to neocortex, although hippocampal atrophy is observed. It is unclear whether regional patterns of hippocampal subfield involvement differ between PCA and LPA, and whether they differ from typical AD. OBJECTIVE: To assess volume of specific subfields of the hippocampus in PCA, LPA, and typical AD. METHODS: Fifty-nine patients with PCA and 77 patients with LPA were recruited and underwent T1-weighted MRI and Pittsburgh Compound B (PiB) PET at Mayo Clinic. Thirty-six probable AD patients and 100 controls were identified from the Alzheimer's Disease Neuroimaging Initiative. Hippocampal subfield volumes were calculated using Freesurfer, and volumes were compared between PCA, LPA, AD, and controls using Kruskal-Wallis and Dunn tests. RESULTS: The LPA and PCA groups both showed the most striking abnormalities in CA4, presubiculum, molecular layer of the hippocampus, molecular and granule cell layers of the dentate gyrus, and the hippocampal-amygdala transition area, although atrophy was left-sided in LPA. PCA showed smaller volume of right presubiculum compared to LPA, with trends for smaller volumes of right parasubiculum and fimbria. LPA showed a trend for smaller volumes of left CA1 compared to PCA. The AD group showed smaller volumes of the right subiculum, CA1, and presubiculum compared to LPA. CONCLUSION: Patterns of hippocampal subfield atrophy differ across the different syndromic variants of AD.

An Effect of Chronic Stress on Prospective Memory via Alteration of Resting-State Hippocampal Subregion Functional Connectivity.

The alteration of hippocampal function by chronic stress impairs higher order cognitive functions such as prospective memory (PM). However, how chronic stress affects hippocampal subregions related to PM remains largely unknown. In this study, the altered functional network of hippocampal subregions related to PM in chronic stress was explored. College students (N = 21) completed PM tasks and resting-state functional magnetic resonance imaging scans one month prior to (baseline) and during the final examination week (chronic stress). Hippocampal subregions' seed-based functional connectivity (FC) and PM were compared between baseline and chronic stress. PM performance declined in chronic stress. The FC of the cornu ammonis 2, 3 and dentate gyrus (CA23DG) with the bilateral caudate and precuneus was increased in chronic stress, while the FC of the subicular complex (SUBC) with the left middle frontal gyrus, the left inferior parietal gyrus and the right supramarginal gyrus was decreased. There was a negative correlation between PM performance and the FC of hippocampal subregions. We found chronic stress impairs PM by decreasing the FC of SUBC and increasing the FC of CA23DG. These findings suggest functional changes in hippocampal subregion networks as a mechanism underlying the impairment of PM in chronic stress.

Atrophy of hippocampal subfield CA2/3 in healthy elderly men is related to educational attainment.

A higher education level is a protective factor against cognitive decline in elders; however, the underlying neural mechanisms remain unclear. Modulated by both aging and education, the hippocampus is a starting point for understanding the long-lasting effect of education on the aging of human brain. Because the hippocampus possesses functionally heterogeneous subfields and exhibits sex differences, we examined hippocampal subfields in men and women separately. We performed both cross-sectional (n = 143) and longitudinal (n = 51) analyses on healthy participants aged 65-75 years, who underwent structural magnetic resonance imaging. Volumes of the hippocampi and their subfields were estimated by automated segmentation. We found significantly positive correlations between educational attainment and the volume of hippocampal CA2/3 in men but not in women. The longitudinal analysis focusing on this region validated the above results by showing that a higher education level attenuated the progression of atrophy during a 15-month follow-up period in the CA2/3 region in men. These findings suggest that, in men, education plays a role in the aging of specific hippocampal subfields.

Hippocampal subfield CA2+3 exhibits accelerated aging in Alcohol Use Disorder: A preliminary study.

The profile of brain structural dysmorphology of individuals with Alcohol Use Disorders (AUD) involves disruption of the limbic system. In vivo imaging studies report hippocampal volume loss in AUD relative to controls, but only recently has it been possible to articulate different regions of this complex structure. Volumetric analysis of hippocampal regions rather than total hippocampal volume may augment differentiation of disease processes. For example, damage to hippocampal subfield cornu ammonis 1 (CA1) is often reported in Alzheimer's disease (AD), whereas deficits in CA4/dentate gyrus are described in response to stress and trauma. Two previous studies explored the effects of chronic alcohol use on hippocampal subfields: one reported smaller volume of the CA2+3 in alcohol-dependent subjects relative to controls, associated with years of alcohol consumption; the other, smaller volumes of presubiculum, subiculum, and fimbria in alcohol-dependent relative to control men. The current study, conducted in 24 adults with DSM5-diagnosed AUD (7 women, 53.7 ±â€¯8.8) and 20 controls (7 women, 54.1 ±â€¯9.3), is the first to use FreeSurfer 6.0, which provides state-of-the art hippocampal parcellation, to explore the sensitivity of hippocampal sufields to alcoholism. T1- and T2- images were collected on a GE MR750 system with a 32-channel Nova head coil. FreeSurfer 6.0 hippocampal subfield analysis produced 12 subfields: parasubiculum; presubiculum; subiculum; CA1; CA2+3; CA4; GC-ML-DG (Granule Cell (GC) and Molecular Layer (ML) of the Dentate Gyrus (DG)); molecular layer; hippocampus-amygdala-transition-area (HATA); fimbria; hippocampal tail; hippocampal fissure; and whole volume for left and right hippocampi. A comprehensive battery of neuropsychological tests comprising attention, memory and learning, visuospatial abilities, and executive functions was administered. Multiple regression analyses of raw volumetric data for each subfields by group, age, sex, hemisphere, and supratentorial volume (svol) showed significant effects of svol (p < .04) on nearly all structures (excluding tail and fissure). Volumes corrected for svol showed effects of age (fimbria, fissure) and group (subiculum, CA1, CA4, GC-ML-DG, HATA, fimbria); CA2+3 showed a diagnosis-by-age interaction indicating older AUD individuals had a smaller volume than would be expected for their age. There were no selective relations between hippocampal subfields and performance on neuropsychological tests, likely due to lack of statistical power. The current results concur with the previous study identifying CA2+3 as sensitive to alcoholism, extend them by identifying an alcoholism-age interaction, and suggest an imaging phenotype distinguishing AUD from AD and stress/trauma.

It's All in the Details: Relations Between Young Children's Developing Pattern Separation Abilities and Hippocampal Subfield Volumes.

The ability to keep similar experiences separate in memory is critical for forming unique and lasting memories, as many events share overlapping features (e.g., birthday parties, holidays). Research on memory in young children suggests their memories often lack high-resolution details, i.e., show impoverished pattern separation (PS). Recently developed assessments of PS suitable for children allow us to relate the formation of distinct, detailed memories for the development of the hippocampus, a neural structure critical for this ability in adults. The hippocampus displays a protracted developmental profile and underlies the ability to form detailed memories. This study examined age-related differences in hippocampal subfield volumes in 4- to 8-year-old children and relations with performance on a mnemonic similarity task (MST) designed to index memory specificity. Results revealed age-moderated associations between MST performance and cornu ammonis 2-4/dentate gyrus subfields. Specifically, age-related differences in the ability to form detailed memories tracked with normative patterns of volume increases followed by reductions over this age range. That is, greater volume correlated with better performance in younger children, whereas smaller volume correlated with better performance in older children. These findings support the hypothesis that developmental differences in hippocampal circuitry contribute to age-related improvements in detailed memory formation during this period.

Cerebral Corpora amylacea are dense membranous labyrinths containing structurally preserved cell organelles.

Corpora amylacea are cell-derived structures that appear physiologically in the aged human brain. While their histological identification is straightforward, their ultrastructural composition and microenvironment at the nanoscale have remained unclear so far, as has their relevance to aging and certain disease states that involve the sequestration of toxic cellular metabolites. Here, we apply correlative serial block-face scanning electron microscopy and transmission electron tomography to gain three-dimensional insight into the ultrastructure and surrounding microenvironment of cerebral Corpora amylacea in the human brainstem and hippocampal region. We find that cerebral Corpora amylacea are composed of dense labyrinth-like sheets of lipid membranes, contain vesicles as well as morphologically preserved mitochondria, and are in close proximity to blood vessels and the glymphatic system, primarily within the cytoplasm of perivascular glial cells. Our results clarify the nature of cerebral Corpora amylacea and provide first hints on how they may arise and develop in the aging brain.

Microstructural Integrity of Hippocampal Subregions Is Impaired after Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) affects a large number of individuals and diffusion tensor imaging can be used to investigate microstructural integrity of brain tissue after mTBI. However, results have varied considerably between studies and gray matter (GM) integrity has been largely neglected in these investigations. Given impaired working memory processing after mTBI and its possible association with Alzheimer's disease, we investigated hippocampal integrity and parcellated this structure into five subregions: subiculum, cornu ammonis (CA) 1, CA 2/3, CA 4/dentate gyrus, and stratum radiatum/lacunosum-moleculare. We also employed shape analysis of bilateral hippocampi to explore whether morphological changes had occurred due to the traumatic injury and conducted neuropsychological memory tests. The sample comprised 15 subjects with mTBI (18-55 years, nine female) and 13 age- and sex-matched healthy control subjects (19-57 years, nine female). Voxelwise analyses showed significantly increased mean diffusivity in patients, compared with controls, in the right hippocampus and three of its five subregions (family-wise error corrected p < 0.05). Additionally, results from probabilistic tractography indicated impaired CA 1 connectivity after mTBI (Benjamini-Hochberg false discovery rate [FDR] corrected p < 0.05). Shape of bilateral hippocampi did not significantly differ between groups (Benjamini-Hochberg FDR corrected p > 0.05). Subjects with mTBI reported more symptoms and performed worse in a non-standard verbal working memory task. Based on these preliminary findings, we were able to demonstrate altered diffusivity of hippocampal subregions following mTBI, indicating impaired GM microstructural integrity. These differences highlight the potential of diffusion imaging for investigation of subtle yet relevant changes in GM microstructure not detected otherwise following mTBI.

Automated Hippocampal Subfield Segmentation at 7T MRI.

BACKGROUND AND PURPOSE: High resolution 7T MRI is increasingly used to investigate hippocampal subfields in vivo, but most studies rely on manual segmentation which is labor intensive. We aimed to evaluate an automated technique to segment hippocampal subfields and the entorhinal cortex at 7T MRI. MATERIALS AND METHODS: The cornu ammonis (CA)1, CA2, CA3, dentate gyrus, subiculum, and entorhinal cortex were manually segmented, covering most of the long axis of the hippocampus on 0.70-mm(3) T2-weighted 7T images of 26 participants (59 ± 9 years, 46% men). The automated segmentation of hippocampal subfields approach was applied and evaluated by using leave-one-out cross-validation. RESULTS: Comparison of automated segmentations with corresponding manual segmentations yielded a Dice similarity coefficient of >0.75 for CA1, the dentate gyrus, subiculum, and entorhinal cortex and >0.54 for CA2 and CA3. Intraclass correlation coefficients were >0.74 for CA1, the dentate gyrus, and subiculum; and >0.43 for CA2, CA3, and the entorhinal cortex. Restricting the comparison of the entorhinal cortex segmentation to a smaller range along the anteroposterior axis improved both intraclass correlation coefficients (left: 0.71; right: 0.82) and Dice similarity coefficients (left: 0.78; right: 0.77). The accuracy of the automated segmentation versus a manual rater was lower, though only slightly for most subfields, than the intrarater reliability of an expert manual rater, but it was similar to or slightly higher than the accuracy of an expert-versus-manual rater with ∼170 hours of training for almost all subfields. CONCLUSIONS: This work demonstrates the feasibility of using a computational technique to automatically label hippocampal subfields and the entorhinal cortex at 7T MRI, with a high accuracy for most subfields that is competitive with the labor-intensive manual segmentation. The software and atlas are publicly available: http://www.nitrc.org/projects/ashs/.

Smaller Dentate Gyrus and CA2 and CA3 Volumes Are Associated with Kynurenine Metabolites in Collegiate Football Athletes.

An imbalance in kynurenine pathway metabolism is hypothesized to be associated with dysregulated glutamatergic neurotransmission, which has been proposed as a mechanism underlying the hippocampal volume loss observed in a variety of neurological disorders. Pre-clinical models suggest that the CA2-3 and dentate gyrus hippocampal subfields are particularly susceptible to excitotoxicity after experimental traumatic brain injury. We tested the hypothesis that smaller hippocampal volumes in collegiate football athletes with (n = 25) and without (n = 24) a concussion history would be most evident in the dentate gyrus and CA2-3 subfields relative to nonfootball healthy controls (n = 27). Further, we investigated whether the concentration of peripheral levels of kynurenine metabolites are altered in football athletes. Football athletes with and without a self-reported concussion history had smaller dentate gyrus (p < 0.05, p < 0.10) and CA2-3 volumes (p's < 0.05) relative to healthy controls. Football athletes with and without a concussion history had a trend toward lower (p < 0.10) and significantly lower (p < 0.05) kynurenine levels compared with healthy controls, while athletes with a concussion history had greater levels of quinolinic acid compared with athletes without a concussion history (p < 0.05). Finally, plasma levels of 3-hydroxykynurenine inversely correlated with bilateral hippocampal volumes in football athletes with a concussion history (p < 0.01), and left hippocampal volume was correlated with the ratio of kynurenic acid to quinolinic acid in football athletes without a concussion history (p < 0.05). Our results raise the possibility that abnormalities of the kynurenine metabolic pathway constitute a mechanism for hippocampal volume differences in the context of sports-related brain injury.