Dorothee Schoemaker

Quantitative comparison of 21 protocols for labeling hippocampal subfields and parahippocampal subregions in in vivo MRI: Towards a harmonized segmentation protocol

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.

A harmonized segmentation protocol for hippocampal and parahippocampal subregions : why do we need one and what are the key goals?

The advent of high‐resolution magnetic resonance imaging (MRI) has enabled in vivo research in a variety of populations and diseases on the structure and function of hippocampal subfields and subdivisions of the parahippocampal gyrus. Because of the many extant and highly discrepant segmentation protocols, comparing results across studies is difficult. To overcome this barrier, the Hippocampal Subfields Group was formed as an international collaboration with the aim of developing a harmonized protocol for manual segmentation of hippocampal and parahippocampal subregions on high‐resolution MRI. In this commentary we discuss the goals for this protocol and the associated key challenges involved in its development. These include differences among existing anatomical reference materials, striking the right balance between reliability of measurements and anatomical validity, and the development of a versatile protocol that can be adopted for the study of populations varying in age and health. The commentary outlines these key challenges, as well as the proposed solution of each, with concrete examples from our working plan. Finally, with two examples, we illustrate how the harmonized protocol, once completed, is expected to impact the field by producing measurements that are quantitatively comparable across labs and by facilitating the synthesis of findings across different studies.

Recollection and familiarity in aging individuals with mild cognitive impairment and Alzheimer's disease: a literature review.

Memory impairment is a central cognitive symptom in mild cognitive impairment (MCI) and Alzheimer Disease (AD). Recognition tasks are often used to characterize and define the nature of memory deficits. Dual-process theories posit that familiarity and recollection are independently involved in the recognition of previously encountered material and both contribute to successful recognition. Recent evidence indicates that there is a double dissociation in the neuronal substrates of those two processes. More precisely, it has been suggested that perirhinal and entorhinal areas are selectively involved in familiarity-based recognition, while the hippocampus is associated with recollection. Interestingly, these regions are among the first to be targeted by neurofibrillary tangles, one of AD’s neuropathological hallmarks. Impairment in recognition performance can occur in the very early stages of AD, such as MCI. To define the nature of recognition impairment in these clinical populations, we reviewed the current literature on familiarity and recollection performance in individuals with MCI and AD. Together with clinical features, methodological factors are taken into consideration in the interpretation of findings.

White Matter Abnormalities and Structural Hippocampal Disconnections in Amnestic Mild Cognitive Impairment and Alzheimer’s Disease

The purpose of this project was to evaluate white matter degeneration and its impact on hippocampal structural connectivity in patients with amnestic mild cognitive impairment, non-amnestic mild cognitive impairment and Alzheimer’s disease. We estimated white matter fractional anisotropy, mean diffusivity and hippocampal structural connectivity in two independent cohorts. The ADNI cohort included 108 subjects [25 cognitively normal, 21 amnestic mild cognitive impairment, 47 non-amnestic mild cognitive impairment and 15 Alzheimer’s disease]. A second cohort included 34 subjects [15 cognitively normal and 19 amnestic mild cognitive impairment] recruited in Montreal. All subjects underwent clinical and neuropsychological assessment in addition to diffusion and T1 MRI. Individual fractional anisotropy and mean diffusivity maps were generated using FSL-DTIfit. In addition, hippocampal structural connectivity maps expressing the probability of connectivity between the hippocampus and cortex were generated using a pipeline based on FSL-probtrackX. Voxel-based group comparison statistics of fractional anisotropy, mean diffusivity and hippocampal structural connectivity were estimated using Tract-Based Spatial Statistics. The proportion of abnormal to total white matter volume was estimated using the total volume of the white matter skeleton. We found that in both cohorts, amnestic mild cognitive impairment patients had 27-29% white matter volume showing higher mean diffusivity but no significant fractional anisotropy abnormalities. No fractional anisotropy or mean diffusivity differences were observed between non-amnestic mild cognitive impairment patients and cognitively normal subjects. Alzheimer’s disease patients had 66.3% of normalized white matter volume with increased mean diffusivity and 54.3% of the white matter had reduced fractional anisotropy. Reduced structural connectivity was found in the hippocampal connections to temporal, inferior parietal, posterior cingulate and frontal regions only in the Alzheimer’s group. The severity of white matter degeneration appears to be higher in advanced clinical stages, supporting the construct that these abnormalities are part of the pathophysiological processes of Alzheimer’s disease.

Resting state executive control network adaptations in amnestic mild cognitive impairment.

Executive dysfunction is frequently associated with episodic memory decline in amnestic mild cognitive impairment (aMCI) patients. Resting state executive control network (RS-ECN) represents a novel approach to interrogate the integrity of brain areas underlying executive dysfunction. The present study aims to investigate RS-ECN in aMCI and examine a possible link between changes in brain functional connectivity and declines in executive function. aMCI individuals (n = 13) and healthy subjects (n = 16) underwent cognitive assessment including executive function and high field functional magnetic resonance imaging. Individual RS-ECN maps were estimated using a seed-based cross-correlation method. Between groups RS-ECN functional connectivity comparison was assessed using voxel-wise statistic parametric mapping. aMCI individuals had reduced RS-ECN connectivity in the anterior cingulate cortex (ACC) and dorsal lateral prefrontal cortex (DLPFC), bilaterally. In contrast, aMCI showed increased connectivity in ventral lateral and anterior prefrontal cortex, bilaterally. Connectivity strength was associated with executive function in the ACC (r = 0.6213, p = 0.023) and right DLPFC (r = 0.6454, p = 0.017). Coexistence between connectivity declines and recruitment of brain regions outside the RS-ECN as reported here fits a brain reserve conceptual framework in which brain networks undergo remodeling in aMCI individuals.

Selective familiarity deficits in otherwise cognitively intact aging individuals with genetic risk for Alzheimer's disease

Familiarity has been associated with integrity of the rhinal cortex. Thus, impairment in familiarity is expected in very early stages of Alzheimers disease (AD). The apolipoprotein E (APOE) ε4 allele is a major risk factor for AD. Here, we investigated the effect of the APOE ε4 status on familiarity in cognitively normal aging individuals.

Recollection and familiarity in aging individuals: Gaining insight into relationships with medial temporal lobe structural integrity

Dual‐process theories posit that two separate processes are involved in recognition, namely recollection and familiarity. Studies investigating the neuroanatomical substrates of these two processes have frequently revealed that, while recollection is functionally linked with the hippocampus, familiarity appears to be associated with perirhinal and/or entorhinal cortices integrity. Interestingly these regions are known to be sensitive to normal and neuropathological aging processes. The objective of this study was to examine the effects of aging on recollection and familiarity performance, as well as to investigate associations with the rate of false alarms. In older individuals, we further aimed to explore relationships between these recognition variables and structural integrity of the hippocampus and the entorhinal and perirhinal cortices. Younger (N = 56) and older (N = 59) adults were tested on a computerized recollection and familiarity task. In a separate session, older adults (N = 56) underwent a structural MRI. Hippocampal, entorhinal and perihinal cortices volumes were automatically segmented and then manually corrected to ensure validity of the volumetric assessment. Regional volumes were normalized for total intracranial volume. While the overall recognition performance did not significantly differ across groups, our results reveal a decrease in recollection, together with an increase in familiarity in older adults. The increase reliance on familiarity was significantly and positively associated with the rate of false alarms. In the older adult sample, significant positive associations were found between recollection estimates and normalized hippocampal volumes. The normalized total hippocampal volume accounted for 25% of the variance in recollection performance. No correlation was found between any recognition variables and perirhinal or entorhinal cortices volumes. Overall, our results suggest that the age‐related impairment in recollection is linked with reduced hippocampal structural integrity.

Response to editor to the comment by Bastin and Besson (2016) to our article entitled “Selective familiarity deficits in otherwise cognitively intact aging individuals with genetic risk for Alzheimer's disease”

Wewould like to thank Christine Bastin and Gabriel Besson for their thoughtful and pertinent comments regarding our recent article entitled “Selective familiarity deficits in otherwise cognitively intact aging individuals with genetic risk for Alzheimer’s disease” [1]. The authors correctly note that, for the analysis of our experiment, recollection was estimated from the proportion of correct recognition accompanied with correct source attribution, whereas familiarity was defined as the proportion of correct recognition in absence of accurate source attribution. Bastin and Besson argue that, defined as such, familiarity scores might be underestimated as both processes are known to co-occur. The authors clearly have a point here as this argument has been raised by dual-process theorists postulating that recollection and familiarity are independent processes. However, across dual-process models, the nature of the interplay and relationship between the two processes of recollection and familiarity remains a matter of debate [2]. For example, Gardiner and Parkin have suggested that recollection and familiarity might instead operate in a mutually exclusive manner [3]. In a different dual-process model proposed by Atkinson and Juola, recollection is believed to come into play only when familiarity fails to provide a clear recognition response [4]. Thus, the possibility that familiarity contributes to some extent to the recollection performance seems to be guided by theoretical considerations and conceptualizations of recollection and familiarity. Proponents of the independence assumption of recollection and familiarity have in the past introduced mathematical formulas to account for the potential co-occurrence of these two processes during the recollective experience. For example, researchers using the “Remember/Know” method sometimes divide the proportion of “Know” responses by the overall possibility of making a “Know” (K/(1 2 R)). This approach, also referred to as the Independence Remember/ Know procedure, aims to compensate for the fact that

Corrigendum to “Hippocampus and amygdala volumes from magnetic resonance images in children: Assessing accuracy of FreeSurfer and FSL against manual segmentation”[NeuroImage 129 (2016) 1–14]

Author(s): Schoemaker, Dorothee; Buss, Claudia; Head, Kevin; Sandman, Curt A; Davis, Elysia P; Chakravarty, M Mallar; Gauthier, Serge; Pruessner, Jens C

Familiarity deficits in cognitively normal aging individuals with APOE ε4: A follow-up investigation of medial temporal lobe structural correlates

The apolipoprotein E ε4 (APOE ε4) allele is a well‐documented risk factor for Alzheimers disease (AD). Accordingly, aging individuals carrying one or more ε4 alleles are at considerably greater risk of developing AD over time. In an effort to characterize early cognitive manifestations of AD, we previously outlined selective deficits in familiarity‐based recognition in otherwise asymptomatic carriers of the APOE ε4 allele (Schoemaker et al., 2016). In this follow‐up report, we aimed to explore the neural correlates of this selective cognitive impairment.