Association of CSF Biomarkers With Hippocampal-Dependent Memory in Preclinical Alzheimer Disease.

OBJECTIVE: To determine whether memory tasks with demonstrated sensitivity to hippocampal function can detect variance related to preclinical Alzheimer disease (AD) biomarkers, we examined associations between performance in 3 memory tasks and CSF ß-amyloid (Aß)42/Aß40 and phosopho-tau181 (p-tau181) in cognitively unimpaired older adults (CU). METHODS: CU enrolled in the Stanford Aging and Memory Study (n = 153; age 68.78 ± 5.81 years; 94 female) completed a lumbar puncture and memory assessments. CSF Aß42, Aß40, and p-tau181 were measured with the automated Lumipulse G system in a single-batch analysis. Episodic memory was assayed using a standardized delayed recall composite, paired associate (word-picture) cued recall, and a mnemonic discrimination task that involves discrimination between studied "target" objects, novel "foil" objects, and perceptually similar "lure" objects. Analyses examined cross-sectional relationships among memory performance, age, and CSF measures, controlling for sex and education. RESULTS: Age and lower Aß42/Aß40 were independently associated with elevated p-tau181. Age, Aß42/Aß40, and p-tau181 were each associated with (1) poorer associative memory and (2) diminished improvement in mnemonic discrimination performance across levels of decreased task difficulty (i.e., target-lure similarity). P-tau mediated the effect of Aß42/Aß40 on memory. Relationships between CSF proteins and delayed recall were similar but nonsignificant. CSF Aß42 was not significantly associated with p-tau181 or memory. CONCLUSIONS: Tests designed to tax hippocampal function are sensitive to subtle individual differences in memory among CU and correlate with early AD-associated biomarker changes in CSF. These tests may offer utility for identifying CU with preclinical AD pathology.

Hippocampal subfield volumetry from structural isotropic 1 mm3 MRI scans: A note of caution.

Spurred by availability of automatic segmentation software, in vivo MRI investigations of human hippocampal subfield volumes have proliferated in the recent years. However, a majority of these studies apply automatic segmentation to MRI scans with approximately 1 × 1 × 1 mm3 resolution, a resolution at which the internal structure of the hippocampus can rarely be visualized. Many of these studies have reported contradictory and often neurobiologically surprising results pertaining to the involvement of hippocampal subfields in normal brain function, aging, and disease. In this commentary, we first outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies, regardless of how images are segmented (i.e., manually or automatically). This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, we discuss the fact that automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images. For these reasons, we caution against using volumetric measurements of hippocampal subfields obtained from 1 × 1 × 1 mm3 images.

Hippocampal and cortical mechanisms at retrieval explain variability in episodic remembering in older adults.

Age-related episodic memory decline is characterized by striking heterogeneity across individuals. Hippocampal pattern completion is a fundamental process supporting episodic memory. Yet, the degree to which this mechanism is impaired with age, and contributes to variability in episodic memory, remains unclear. We combine univariate and multivariate analyses of fMRI data from a large cohort of cognitively normal older adults (N=100) to measure hippocampal activity and cortical reinstatement during retrieval of trial-unique associations. Trial-wise analyses revealed that (a) hippocampal activity scaled with reinstatement strength, (b) cortical reinstatement partially mediated the relationship between hippocampal activity and associative retrieval, (c) older age weakened cortical reinstatement and its relationship to memory behaviour. Moreover, individual differences in the strength of hippocampal activity and cortical reinstatement explained unique variance in performance across multiple assays of episodic memory. These results indicate that fMRI indices of hippocampal pattern completion explain within- and across-individual memory variability in older adults.

Progress update from the hippocampal subfields group.

INTRODUCTION: Heterogeneity of segmentation protocols for medial temporal lobe regions and hippocampal subfields on in vivo magnetic resonance imaging hinders the ability to integrate findings across studies. We aim to develop a harmonized protocol based on expert consensus and histological evidence. METHODS: Our international working group, funded by the EU Joint Programme-Neurodegenerative Disease Research (JPND), is working toward the production of a reliable, validated, harmonized protocol for segmentation of medial temporal lobe regions. The working group uses a novel postmortem data set and online consensus procedures to ensure validity and facilitate adoption. RESULTS: This progress report describes the initial results and milestones that we have achieved to date, including the development of a draft protocol and results from the initial reliability tests and consensus procedures. DISCUSSION: A harmonized protocol will enable the standardization of segmentation methods across laboratories interested in medial temporal lobe research worldwide.

Individual differences in associative memory among older adults explained by hippocampal subfield structure and function.

Older adults experience impairments in episodic memory, ranging from mild to clinically significant. Given the critical role of the medial temporal lobe (MTL) in episodic memory, age-related changes in MTL structure and function may partially account for individual differences in memory. Using ultra-high-field 7T structural MRI and high-resolution 3T functional MRI (hr-fMRI), we evaluated MTL subfield thickness and function in older adults representing a spectrum of cognitive health. Participants performed an associative memory task during hr-fMRI in which they encoded and later retrieved face-name pairs. Motivated by prior research, we hypothesized that differences in performance would be explained by the following: (i) entorhinal cortex (ERC) and CA1 apical neuropil layer [CA1-stratum radiatum lacunosum moleculare (SRLM)] thickness, and (ii) activity in ERC and the dentate gyrus (DG)/CA3 region. Regression analyses revealed that this combination of factors significantly accounted for variability in memory performance. Among these metrics, CA1-SRLM thickness was positively associated with memory, whereas DG/CA3 retrieval activity was negatively associated with memory. Furthermore, including structural and functional metrics in the same model better accounted for performance than did single-modality models. These results advance the understanding of how independent but converging influences of both MTL subfield structure and function contribute to age-related memory impairment, complementing findings in the rodent and human postmortem literatures.

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. © 2016 Wiley Periodicals, Inc.

Prospective representation of navigational goals in the human hippocampus.

Mental representation of the future is a fundamental component of goal-directed behavior. Computational and animal models highlight prospective spatial coding in the hippocampus, mediated by interactions with the prefrontal cortex, as a putative mechanism for simulating future events. Using whole-brain high-resolution functional magnetic resonance imaging and multi-voxel pattern classification, we tested whether the human hippocampus and interrelated cortical structures support prospective representation of navigational goals. Results demonstrated that hippocampal activity patterns code for future goals to which participants subsequently navigate, as well as for intervening locations along the route, consistent with trajectory-specific simulation. The strength of hippocampal goal representations covaried with goal-related coding in the prefrontal, medial temporal, and medial parietal cortex. Collectively, these data indicate that a hippocampal-cortical network supports prospective simulation of navigational events during goal-directed planning.

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.

Age-related differences in memory after attending to distinctiveness or similarity during learning.

Episodic memory is vulnerable to age-related change, with older adults demonstrating both impairments in retrieving contextual details and susceptibility to interference among similar events. Such impairments may be due in part to an age-related decline in the ability to encode distinct memory representations. Recent research has examined how manipulating stimulus properties to emphasize distinctiveness can reduce age-related deficits in memory. However, few studies have addressed whether learning strategies that differentially encourage distinctiveness processing attenuate age-related differences in episodic memory. In the present study, participants engaged in two incidental encoding tasks emphasizing either distinctiveness or similarity processing. Results demonstrated higher rates of recollection for stimuli studied under the distinctiveness task than the similarity task in younger but not older adults. These findings suggest a declining capacity for distinctiveness processing to benefit memory in older adults, and raise the possibility that strategies that enhance gist-based encoding may attenuate age-related memory deficits.

Top-down modulation of hippocampal encoding activity as measured by high-resolution functional MRI.

Memory formation is known to be critically dependent upon the medial temporal lobe (MTL). Despite this well-characterized role, it remains unclear whether and how MTL encoding processes are affected by top-down goal states. Here, we examined the manner in which task demands at encoding affect MTL activity and its relation to subsequent memory performance. Participants were scanned using high-resolution neuroimaging of the MTL while engaging in two incidental encoding tasks: one that directed participants' attention to stimulus distinctiveness, and the other requiring evaluation of similarities across stimuli. We hypothesized that attending to distinctiveness would lead to the formation of more detailed memories and would more effectively engage the hippocampal circuit than attending to similarity. In line with our hypotheses, higher rates of subsequent recollection were observed for stimuli studied under the Distinctiveness than Similarity task. Critically, within the hippocampus, CA1 and the subiculum demonstrated an interaction between memory performance and task such that a significant subsequent memory effect was found only when task goals required attention to stimulus distinctiveness. To this end, robust engagement of the hippocampal circuit may underlie the observed behavioral benefits of attending to distinctiveness. Taken together, these findings advance understanding of the effects of top-down intentional information on successful memory formation across subregions of the MTL.

Global similarity and pattern separation in the human medial temporal lobe predict subsequent memory.

Intense debate surrounds the role of medial temporal lobe (MTL) structures in recognition memory. Using high-resolution fMRI and analyses of pattern similarity in humans, we examined the encoding computations subserved by MTL subregions. Specifically, we tested the theory that MTL cortex supports memory by encoding overlapping representations, whereas hippocampus supports memory by encoding pattern-separated representations. Consistent with this view, the relationship between encoding pattern similarity and subsequent memory dissociated MTL cortex and hippocampus: later memory was predicted by greater across-item pattern similarity in perirhinal cortex and in parahippocampal cortex, but greater pattern distinctiveness in hippocampus. Additionally, by comparing neural patterns elicited by individual stimuli regardless of subsequent memory, we found that perirhinal cortex and parahippocampal cortex exhibited differential content sensitivity for multiple stimulus categories, whereas hippocampus failed to demonstrate content sensitivity. These data provide novel evidence that complementary MTL encoding computations subserve declarative memory.

Imaging the human medial temporal lobe with high-resolution fMRI.

High-resolution functional MRI (hr-fMRI) affords unique leverage on the functional properties of human medial temporal lobe (MTL) substructures. We review initial hr-fMRI efforts to delineate (1) encoding and retrieval processes within the hippocampal circuit, (2) hippocampal subfield contributions to pattern separation and pattern completion, and (3) the representational capabilities of distinct MTL subregions. Extant data reveal functional heterogeneity within human MTL and highlight the promise of hr-fMRI for bridging human, animal, and computational approaches to understanding MTL function.

Neural activity in the hippocampus and perirhinal cortex during encoding is associated with the durability of episodic memory.

Studies examining medial temporal lobe (MTL) involvement in memory formation typically assess memory performance after a single, short delay. Thus, the relationship between MTL encoding activity and memory durability over time remains poorly characterized. To explore this relationship, we scanned participants using high-resolution functional imaging of the MTL as they encoded object pairs; using the remember/know paradigm, we then assessed memory performance for studied items both 10 min and 1 week later. Encoding trials were classified as either subsequently recollected across both delays, transiently recollected (i.e., recollected at 10 min but not after 1 week), consistently familiar, or consistently forgotten. Activity in perirhinal cortex (PRC) and a hippocampal subfield comprising the dentate gyrus and CA fields 2 and 3 reflected successful encoding only when items were recollected consistently across both delays. Furthermore, in PRC, encoding activity for items that later were consistently recollected was significantly greater than that for transiently recollected and consistently familiar items. Parahippocampal cortex, in contrast, showed a subsequent memory effect during encoding of items that were recollected after 10 min, regardless of whether they also were recollected after 1 week. These data suggest that MTL subfields contribute uniquely to the formation of memories that endure over time, and highlight a role for PRC in supporting subsequent durable episodic recollection.

The neural correlates of recollection: hippocampal activation declines as episodic memory fades.

Memories for certain events tend to linger in rich, vivid detail, and retrieval of these memories includes a sense of re-experiencing the details of the event. Most events, however, are not retained in any detailed way for more than a few days. According to one theory, the hippocampus plays a specific role in supporting episodic retrieval, that is, the re-experiencing of an event as part of one's personal past. This theory predicts that as episodic memories fade over time and are reduced to feelings of familiarity, activity in the hippocampus should no longer be associated with retrieval. We used high-resolution functional imaging to explore neural activity in medial temporal lobe subregions while participants performed a recognition task at both a short (10-min) and long (1-week) study-test delay. For each recognized item, subjects made "Remember/Know" judgments, allowing us to distinguish between items that were consistently episodic across the two tests and items that were initially episodic, but later became merely familiar. Our results demonstrate that activity in the subiculum is specifically associated with episodic recollection. Overall, recollected items were associated with higher activity in the subiculum than other items. For transiently recollected items, there was a decrease in subicular activity across the 1-week delay as memory faded from recollection to familiarity, whereas consistently recollected items were associated with enhanced subicular activity at both delays. These results provide evidence of a link between subicular activation and recollective experience.

Nonlinearities in rapid event-related fMRI explained by stimulus scaling.

Because of well-known nonlinearities in fMRI, responses measured with rapid event-related designs are smaller than responses measured with spaced designs. Surprisingly, no study to date has tested whether rapid designs also change the pattern of responses across different stimulus conditions. Here we report the results of such a test. We measured cortical responses to a flickering checkerboard at different contrasts using rapid and spaced event-related fMRI. The relative magnitude of responses across contrast conditions differed between rapid and spaced designs. Modeling the effect of the rapid design as a scaling of stimulus strength provided a good account of the data. The data were less well fit by a model that scaled the strength of responses. A similar stimulus scaling model has explained effects of neural adaptation, which suggests that adaptation may account for the observed difference between rapid and spaced designs. In a second experiment, we changed the stimulus in ways known to reduce neural adaptation and found much smaller differences between the two designs. Stimulus scaling provides a simple way to account for nonlinearities in event-related fMRI and relate data from rapid designs to data gathered using slower presentation rates.