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Hippocampal pathology is central to Alzheimer's disease (AD) and other forms of dementia such as frontotemporal lobar degeneration (FTLD). Autopsy studies have shown that certain hippocampal subfields are more vulnerable than others to AD and FTLD pathology, in particular the subiculum and cornu ammonis 1 (CA1). We conducted shape analysis of hippocampi segmented from structural T1 MRI images on clinically diagnosed dementia patients and controls. The subjects included 19 AD and 35 FTLD patients [13 frontotemporal dementia (FTD), 13 semantic dementia (SD), and 9 progressive nonfluent aphasia (PNFA)] and 21 controls. Compared to controls, SD displayed severe atrophy of the whole left hippocampus. PNFA and FTD also displayed atrophy on the left side, restricted to the hippocampal head in FTD. Finally, AD displayed most atrophy in left hippocampal body with relative sparing of the hippocampal head. Consistent with neuropathological studies, most atrophic deformation was found in CA1 and subiculum areas in FTLD and AD. [ABSTRACT FROM AUTHOR]

In this study, we aimed to understand the contributions of hippocampal anteroposterior subregions (head, body, tail) and subfields (cornu ammonis 1-3 [CA1-3], dentate gyrus [DG], and subiculum [Sub]) and encoding strategies to the age-related verbal memory decline. Healthy participants were administered the California Verbal Learning Test-II to evaluate verbal memory performance and encoding strategies and underwent 4.7 T magnetic resonance imaging brain scan with subsequent hippocampal subregions and subfields manual segmentation. While total hippocampal volume was not associated with verbal memory performance, we found the volumes of the posterior hippocampus (body) and Sub showed significant effects on verbal memory performance. Additionally, the age-related volume decline in hippocampal body volume contributed to lower use of semantic clustering, resulting in lower verbal memory performance. The effect of Sub on verbal memory was statistically independent of encoding strategies. While total CA1-3 and DG volumes did not show direct or indirect effects on verbal memory, exploratory analyses with DG and CA1-3 volumes within the hippocampal body subregion suggested an indirect effect of age-related volumetric reduction on verbal memory performance through semantic clustering. As semantic clustering is sensitive to age-related hippocampal volumetric decline but not to the direct effect of age, further investigation of mechanisms supporting semantic clustering can have implications for early detection of cognitive impairments and decline., (© 2023 The Authors. Hippocampus published by Wiley Periodicals LLC.)

In the present study we investigated whether hippocampal subfield (cornu ammonis 1-3, dentate gyrus, and subiculum) and anteroposterior hippocampal subregion (head,body, and tail) volumes can predict episodic memory function using high-field high resolution structural magnetic resonance imaging (MRI). We recruited 126 healthy participants (18-85 years). MRI datasets were collected on a 4.7 T system. Participants were administered the Wechsler Memory Scale (WMS-IV) to evaluate episodic memory function. Structural equation modeling was used to test the relationship between studied variables. We found that the volume of the dentate gyrus subfield and posterior hippocampus (body) showed a significant direct effect on visuospatial memory performance; additionally, an indirect effect of age on visuospatial memory mediated through these hippocampal subfield/subregion was significant. Logical and verbal memory were not significantly associated with hippocampal subfield or subregion volumes., Competing Interests: Disclosure statement The authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The ability to recognize others' emotions is vital to everyday life. The goal of this study was to assess which emotions show age-related decline in recognition accuracy of facial emotional expressions across the entire adult lifespan and how this process is related to cognitive empathy (Theory of Mind [ToM]), alexithymia traits, and amygdala subnuclei volumes in a large cohort of healthy individuals. We recruited 140 healthy participants 18-85 years old. Facial affect processing was assessed with the Penn Emotion Recognition task (ER40) that contains images of the five basic emotions: Neutral, Happy, Sad, Angry, and Fearful. Structural magnetic resonance imaging (MRI) datasets were acquired on a 4.7T MRI system. Structural equation modeling was used to test the relationship between studied variables. We found that while both sexes demonstrated age-related reduction in recognition of happy emotions and preserved recognition of sadness, male participants showed age-related reduction in recognition of fear, while in female participants, age-related decline was linked to recognition of neutral and angry facial expressions. In both sexes, accurate recognition of sadness negatively correlated with alexithymia traits. On the other hand, better ToM capabilities in male participants were associated with improvement in recognition of positive and neutral emotions. Finally, none of the observed age-related reductions in emotional recognition were related to amygdala and its subnuclei volumes. In contrast, both global volume of amygdala and its cortical and centromedial subnuclei had significant direct effects on recognition of sad images., (© 2022 Wiley Periodicals LLC.)

The prefrontal cortex (PFC) is a heterogenous structure that is highly susceptible to the effects of aging. Few studies have investigated age effects on the superficial white matter (WM) contained within the PFC using in-vivo magnetic resonance imaging (MRI). This study used diffusion tensor imaging (DTI) tractography to examine the effects of age, sex, and intracranial volume (ICV) on superficial WM within specific PFC subregions, and to model the relationships with age using higher order polynomial regression modelling. PFC WM of 140 healthy individuals, aged 18-85, was segmented into medial and lateral orbitofrontal, medial prefrontal, and dorsolateral prefrontal subregions. Differences due to age in microstructural parameters such as fractional anisotropy (FA), axial and radial diffusivities, and macrostructural measures of tract volumes, fiber counts, average fiber lengths, and average number of fibers per voxel were examined. We found that most prefrontal subregions demonstrated age effects, with decreases in FA, tract volume, and fiber counts, and increases in all diffusivity measures. Age relationships were mostly non-linear, with higher order regressions chosen in most cases. Declines in PFC FA began at the onset of adulthood while the greatest changes in diffusivity and volume did not occur until middle age. The effects of age were most prominent in medial tracts while the lateral orbitofrontal tracts were less affected. Significant effects of sex and ICV were also observed in certain parameters. The patterns mostly followed myelination order, with late-myelinating prefrontal subregions experiencing earlier and more pronounced age effects, further supporting the frontal theory of aging., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Recent findings have demonstrated that hippocampal subfields can be selectively affected in different disease states, which has led to efforts to segment the human hippocampus with in vivo magnetic resonance imaging (MRI). However, no studies have examined the histological accuracy of subfield segmentation protocols. The presence of MRI-visible anatomical landmarks with known correspondence to histology represents a fundamental prerequisite for in vivo hippocampal subfield segmentation. In the present study, we aimed to: 1) develop a novel method for hippocampal body segmentation, based on two MRI-visible anatomical landmarks (stratum lacunosum moleculare [SLM] & dentate gyrus [DG]), and assess its accuracy in comparison to the gold standard direct histological measurements; 2) quantify the accuracy of two published segmentation strategies in comparison to the histological gold standard; and 3) apply the novel method to ex vivo MRI and correlate the results with histology., Methods: Ultra-high resolution ex vivo MRI was performed on six whole cadaveric hippocampal specimens, which were then divided into 22 blocks and histologically processed. The hippocampal bodies were segmented into subfields based on histological criteria and subfield boundaries and areas were directly measured. A novel method was developed using mean percentage of the total SLM distance to define subfield boundaries. Boundary distances and subfield areas on histology were then determined using the novel method and compared to the gold standard histological measurements. The novel method was then used to determine ex vivo MRI measures of subfield boundaries and areas, which were compared to histological measurements., Results: For direct histological measurements, the mean percentages of total SLM distance were: Subiculum/CA1 = 9.7%, CA1/CA2 = 78.4%, CA2/CA3 = 97.5%. When applied to histology, the novel method provided accurate measures for CA1/CA2 (ICC = 0.93) and CA2/CA3 (ICC = 0.97) boundaries, but not for the Subiculum/CA1 (ICC = -0.04) boundary. Accuracy was poorer using previous techniques for CA1/CA2 (maximum ICC = 0.85) and CA2/CA3 (maximum ICC = 0.88), with the previously reported techniques also performing poorly in defining the Subiculum/CA1 boundary (maximum ICC = 0.00). Ex vivo MRI measurements using the novel method were linearly related to direct measurements of SLM length (r 2 = 0.58), CA1/CA2 boundary (r 2 = 0.39) and CA2/CA3 boundary (r 2 = 0.47), but not for Subiculum/CA1 boundary (r 2 = 0.01). Subfield areas measured with the novel method on histology and ex vivo MRI were linearly related to gold standard histological measures for CA1, CA2, and CA3/CA4/DG., Conclusions: In this initial proof of concept study, we used ex vivo MRI and histology of cadaveric hippocampi to develop a novel segmentation protocol for the hippocampal body. The novel method utilized two anatomical landmarks, SLM & DG, and provided accurate measurements of CA1, CA2, and CA3/CA4/DG subfields in comparison to the gold standard histological measurements. The relationships demonstrated between histology and ex vivo MRI supports the potential feasibility of applying this method to in vivo MRI studies., (Copyright © 2017. Published by Elsevier Inc.)

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., (© 2016 Wiley Periodicals, Inc.)

One of the most replicated findings has been that hippocampus volume is decreased in patients with major depressive disorder (MDD). Recent volumetric magnetic resonance imaging (MRI) studies suggest that localized differences in hippocampal volume may be more prominent than global differences. Preclinical and post-mortem studies in MDD indicated that different subfields of the hippocampus may respond differently to stress and may also have differential levels of plasticity in response to antidepressant treatment. Advances in high-field MRI allowed researchers to visualize and measure hippocampal subfield volumes in MDD patients in vivo. The results of these studies provide the first in vivo evidence that hippocampal volume reductions in MDD are specific to the cornu ammonis and dentate gyrus hippocampal subfields, findings that appear, on the surface, consistent with preclinical evidence for localized mechanisms of hippocampal neuroplasticity. In this review we discuss how recent advances in neuroimaging allow researchers to further understand hippocampal neuroplasticity in MDD and how it is related to antidepressant treatment, memory function, and disease progression., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Objective: An increasing number of human in vivo magnetic resonance imaging (MRI) studies have focused on examining the structure and function of the subfields of the hippocampal formation (the dentate gyrus, CA fields 1-3, and the subiculum) and subregions of the parahippocampal gyrus (entorhinal, perirhinal, and parahippocampal cortices). The ability to interpret the results of such studies and to relate them to each other would be improved if a common standard existed for labeling hippocampal subfields and parahippocampal subregions. Currently, research groups label different subsets of structures and use different rules, landmarks, and cues to define their anatomical extents. This paper characterizes, both qualitatively and quantitatively, the variability in the existing manual segmentation protocols for labeling hippocampal and parahippocampal substructures in MRI, with the goal of guiding subsequent work on developing a harmonized substructure segmentation protocol., Method: MRI scans of a single healthy adult human subject were acquired both at 3 T and 7 T. Representatives from 21 research groups applied their respective manual segmentation protocols to the MRI modalities of their choice. The resulting set of 21 segmentations was analyzed in a common anatomical space to quantify similarity and identify areas of agreement., Results: The differences between the 21 protocols include the region within which segmentation is performed, the set of anatomical labels used, and the extents of specific anatomical labels. The greatest overall disagreement among the protocols is at the CA1/subiculum boundary, and disagreement across all structures is greatest in the anterior portion of the hippocampal formation relative to the body and tail., Conclusions: The combined examination of the 21 protocols in the same dataset suggests possible strategies towards developing a harmonized subfield segmentation protocol and facilitates comparison between published studies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: This study aimed to have international experts converge on a harmonized definition of whole hippocampus boundaries and segmentation procedures, to define standard operating procedures for magnetic resonance (MR)-based manual hippocampal segmentation., Methods: The panel received a questionnaire regarding whole hippocampus boundaries and segmentation procedures. Quantitative information was supplied to allow evidence-based answers. A recursive and anonymous Delphi procedure was used to achieve convergence. Significance of agreement among panelists was assessed by exact probability on Fisher's and binomial tests., Results: Agreement was significant on the inclusion of alveus/fimbria (P = .021), whole hippocampal tail (P = .013), medial border of the body according to visible morphology (P = .0006), and on this combined set of features (P = .001). This definition captures 100% of hippocampal tissue, 100% of Alzheimer's disease-related atrophy, and demonstrated good reliability on preliminary intrarater (0.98) and inter-rater (0.94) estimates., Discussion: Consensus was achieved among international experts with respect to hippocampal segmentation using MR resulting in a harmonized segmentation protocol., (Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance., Methods: Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web-platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T., Results: The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001)., Conclusions: The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms., (Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: Depression is very common in Parkinson's disease (PD). The neuropathological basis for this remains unclear; however, dysfunction in prefrontal and limbic regions may play a role., Methods: We examined non-demented PD patients with and without depression and healthy controls (n = 6 per group) for differences in limbic structures and connections between these structures and the prefrontal cortex. Depressed individuals were selected from a representative sample of 33 PD patients using scores from the 15 question geriatric depression scale (GDS). Magnetic resonance diffusion tensor imaging (DTI) tractography was used to examine the structural integrity of the uncinate fasciculus (UF), a white matter tract that projects from the hippocampus, amygdala and temporal pole to the orbitofrontal cortex, and the corpus callosum. Integrity of the UF and corpus callosum was established through measures of mean diffusivity (MD), fractional anisotropy (FA) and tract length. A volumetric analysis of the hippocampal head, body and tail, as well as the amygdala was performed to determine whether volume differences in these structures in PD relate to depression., Results: The depressed PD group showed smaller amygdala volumes compared to healthy controls, but the groups did not differ on any other measure., Conclusions: The present study found intact limbic connectivity but suggests that amygdala atrophy may be present in Parkinson's disease with depression. Further work is needed to replicate these findings., (Copyright © 2012. Published by Elsevier Ltd.)

Previous diffusion tensor imaging (DTI) studies confirmed the vulnerability of frontal callosal fibers to normal aging. The present study extended this examination systematically to other prefrontal white matter regions. Structural magnetic resonance imaging and DTI datasets were acquired from 69 healthy subjects aged 22-84 years. The prefrontal white matter was parcellated into several anatomical sub-regions: medial and lateral orbitofrontal white matter, dorsolateral prefrontal white matter, and medial prefrontal white matter, using reliable DTI-tractography protocols. Tract-specific characteristics were calculated using Matlab. Regression models were used to determine the relationship between age and structural integrity of white matter tracts. The results of our study demonstrate regional age-related changes in the prefrontal white matter tracts of the human brain. This study was cross-sectional and therefore additional longitudinal studies are needed to confirm our findings., (© Springer-Verlag 2011)

We examined age-related changes in the cerebral white matter. Structural magnetic resonance images (MRIs) and diffusion tensor images (DTIs) were acquired from 69 healthy subjects aged 22-84 years. Quantitative DTI tractography was performed for nine different white matter tracts to determine tract volume, fractional anisotropy (FA), mean diffusivity (MD), axial, and radial diffusivities. We used automated and manual segmentation to determine volumes of gray matter (GM), white mater (WM), cerebrospinal fluid (CSF), and intracranial space. The results showed significant effects of aging on WM, GM, CSF volumes, and selective effects of aging on structural integrity of different white matter tracts. WM of the prefrontal region was the most vulnerable to aging, while temporal lobe connections, cingulum, and parieto-occipital commissural connections showed relative preservation with age. This study was cross-sectional, and therefore, additional longitudinal studies are needed to confirm our findings., (Copyright 2010 Elsevier Inc. All rights reserved.)

Diffusion tensor imaging (DTI) provides the opportunity to study white matter tracts in vivo. The goal was to estimate the reliability of DTI tractography for the analysis of limbic and paralimbic white matter. Normative data from 24 healthy subjects and reliability data from four healthy and four depressed subjects were acquired at 1.5 Tesla, using twice-refocused spin-echo, echoplanar DTI and Fluid-Attenuated Inversion Recovery (FLAIR) DTI sequences. Fiber tracking was performed using the Fiber Assignment by Continuous Tracking algorithm. Fractional Anisotropy (FA), trace Apparent Diffusion Coefficient and tract volumes were calculated. The inter-rater (and intra-rater) intraclass correlation coefficients for FA values were as follows: rostral cingulum 0.89 (0.87), dorsal cingulum 0.85 (0.90), parahippocampal cingulum 0.85 (0.95), uncinate fasciculus 0.85 (0.87), medial prefrontal white matter 0.97 (0.99), ventromedial prefrontal white matter 0.92 (0.93), crus of fornix 0.80 (0.81). The reported DTI protocol provides a reliable method to analyze limbic and paralimbic white matter tracts relevant to psychiatric disorders.

The hippocampus (HC) and amygdala (AG) decrease in volume with age and in Parkinson's disease (PD) with (PDD) and without dementia. We compared 44 PD to 44 age, sex and education-matched subjects without PD (non-PD) and 13 PDD subjects. T1-weighted MR images were used to manually segment the head, body and tail of the HC and the AG. HC volumes, corrected to intracranial volume, were smaller in PDD than non-PD (p=0.04), reflected predominantly by head atrophy. Right AG volumes were smaller in PD compared to non-PD (p=0.03). HC volumes in older (>70), but not younger, non-demented PD differed from non-PD (HC, p=0.02; head, p=0.03). Age correlated negatively with overall HC (r=-0.43, p=0.004) and head (r=-0.48, p=0.001) in PD, but not in non-PD. In PD, left HC head volumes correlated with recall, but not recognition scores on the CVLT-II (r=0.35, p=0.02) and BVMT-R (r=0.35, p=0.02); AG volumes correlated with CVLT-II recall (r=0.35, p=0.02). No correlations were found in non-PD (p>0.4). In conclusion, functionally meaningful age-associated hippocampal and amygdala atrophy occurs in PD.

A single-voxel proton NMR J-difference editing method for discriminating between the 1.31 ppm resonances of lactate (Lac) and threonine (Thr) in human brain in vivo at 3 T is reported. One double-band and two triple-band Gaussian 180 degrees RF pulses, all with a bandwidth of 15 Hz, were employed within an adiabatic-refocused double-echo localization sequence to induce the target signals of Lac and Thr and simultaneously acquire a creatine singlet in each subscan. The optimum echo time and the editing efficiency were obtained by numerical analysis of the filtering performance. The Lac and Thr signals were extracted, without lipid contamination, from three subspectra. Using the calculated yields, the concentrations of Lac and Thr in the human occipital cortex were estimated to be 0.47+/-0.07 and 0.56+/-0.06 mM (mean+/-SD, N=7), respectively, with reference to Cr at 8 mM., (Copyright (c) 2006 Wiley-Liss, Inc.)

A new single-voxel proton NMR spectrally-selective refocusing method for measuring glutamate (Glu) and glutamine (Gln) in the human brain in vivo at 3T is reported. Triple-resonance selective 180 degrees RF pulses with a bandwidth of 12 Hz were implemented within point-resolved spectroscopy (PRESS) for selective detection of Glu or Gln, and simultaneous acquisition of creatine singlets for use as a reference in phase correction. The carriers of the spectrally-selective 180 degrees pulses and the echo times (TEs) were optimized with both numerical and experimental analyses of the filtering performance, which enabled measurements of the target metabolites with negligible contamination from N-acetylaspartate and glutathione. The concentrations of Glu and Gln in the prefrontal cortex were estimated to be 9.7+/-0.5 and 3.0+/-0.7 mM (mean+/-SD, N=7), with reference to Cr at 8 mM., (Copyright (c) 2006 Wiley-Liss, Inc.)

A new proton NMR single-voxel spectral editing strategy for the rapid measurement of myo-inositol in human brain is proposed. The spectral editing detects the 4.06-ppm, weakly coupled resonance by means of selective J rewinding. An 84.6-ms-long quadruple-resonance selective 180 degrees radiofrequency pulse, implemented within an adiabatic-refocused localization sequence, induces an in-phase triplet at 4.06 ppm, while eliminating the contribution from creatine, phosphorylethanolamine, lactate, and serine in this spectral region. The myo-inositol concentration in human prefrontal cortex is estimated to be 5.7 +/- 0.9 mumol/g (mean +/- SD, n = 7), with reference to NAA at 10 micromol/g.