Mnemonic Discrimination Task Research Articles

Amyloid-β deposition in basal frontotemporal cortex is associated with selective disruption of temporal mnemonic discrimination.

Cerebral amyloid-beta (Aβ) accumulation, a hallmark pathology of Alzheimer's disease (AD), precedes clinical impairment by two to three decades. However, it is unclear whether Aβ contributes to subtle memory deficits observed during the preclinical stage. The heterogenous emergence of Aβ deposition may selectively impact certain memory domains, which rely on distinct underlying neural circuits. In this context, we tested whether specific domains of mnemonic discrimination, a neural computation essential for episodic memory, exhibit specific deficits related to early Aβ deposition. We tested 108 cognitively unimpaired human older adults (66% female) who underwent 18F-florbetapir positron emission tomography (Aβ-PET), and a control group of 35 young adults, on a suite of mnemonic discrimination tasks taxing object, spatial, and temporal domains. We hypothesized that Aβ pathology would be selectively associated with temporal discrimination performance due to Aβ's propensity to accumulate in the basal frontotemporal cortex, which supports temporal processing. Consistent with this hypothesis, we found a dissociation in which generalized age-related deficits were found for object and spatial mnemonic discrimination, while Aβ-PET levels were selectively associated with deficits in temporal mnemonic discrimination. Further, we found that higher Aβ-PET levels in medial orbitofrontal and inferior temporal cortex, regions supporting temporal processing, were associated with greater temporal mnemonic discrimination deficits, pointing to the selective vulnerability of circuits related to temporal processing early in AD progression. These results suggest that Aβ accumulation within basal frontotemporal regions may disrupt temporal mnemonic discrimination in preclinical AD, and may serve as a sensitive behavioral biomarker of emerging AD progression.

Associations among attentional state, retrieval quality, and mnemonic discrimination

Memory specificity is shown when participants reject lures that are similar to studied objects. Lure rejections may reflect hippocampal pattern separation that encodes objects distinctively. However, lure features shared with studied objects may evoke pattern completion of varying quality. This was shown when self-reported attention during study promoted lure rejections and false alarms. We used an experimental and individual differences approach to examine the roles of attentive encoding and retrieval quality in lure classifications. An object-based mnemonic discrimination task included thought probes during study and subjective retrieval reports after recognition responses. On-task reports reflecting attentive encoding were associated with lure rejections and false alarms within-and between-subjects. Additionally, accurate lure and target classifications were more strongly associated with subjective recollection following on- than off-task reports. Collectively, these results suggest that attention during study was associated with recollection of criterial features that differentiated existing memories from perceptual inputs.

Emotional modulation of memorability in mnemonic discrimination

Although elements such as emotion may serve to enhance or impair memory for images, some images are consistently remembered or forgotten by most people, an intrinsic characteristic of images known as memorability. Memorability explains some of the variability in memory performance, however, the underlying mechanisms of memorability remain unclear. It is known that emotional valence can increase the memorability of an experience, but how these two elements interact is still unknown. Hippocampal pattern separation, a computation that orthogonalizes overlapping experiences as distinct from one another, may be a candidate mechanism underlying memorability. However, these two literatures have remained largely separate. To explore the interaction between image memorability and emotion on pattern separation, we examined performance on an emotional mnemonic discrimination task, a putative behavioral correlate of hippocampal pattern separation, by splitting stimuli into memorable and forgettable categories as determined by a convolutional neural network as well as by emotion, lure similarity, and time of testing (immediately and 24-hour delay). We measured target recognition, which is typically used to determine memorability scores, as well as lure discrimination, which taxes hippocampal pattern separation and has not yet been examined within a memorability framework. Here, we show that more memorable images were better remembered across both target recognition and lure discrimination measures. However, for target recognition, this was only true upon immediate testing, not after a 24-hour delay. For lure discrimination, we found that memorability interacts with lure similarity, but depends on the time of testing, where memorability primarily impacts high similarity lure discrimination when tested immediately but impacts low similarity lure discrimination after a 24-hour delay. Furthermore, only lure discrimination showed an interaction between emotion and memorability, in which forgettable neutral images showed better lure discrimination compared to more memorable images. These results suggest that careful consideration is required of what makes an image memorable and may depend on what aspects of the image are more memorable (e.g., gist vs. detail, emotional vs. neutral).

Theta mediated dynamics of human hippocampal-neocortical learning systems in memory formation and retrieval

Episodic memory arises as a function of dynamic interactions between the hippocampus and the neocortex, yet the mechanisms have remained elusive. Here, using human intracranial recordings during a mnemonic discrimination task, we report that 4-5 Hz (theta) power is differentially recruited during discrimination vs. overgeneralization, and its phase supports hippocampal-neocortical when memories are being formed and correctly retrieved. Interactions were largely bidirectional, with small but significant net directional biases; a hippocampus-to-neocortex bias during acquisition of new information that was subsequently correctly discriminated, and a neocortex-to-hippocampus bias during accurate discrimination of new stimuli from similar previously learned stimuli. The 4-5 Hz rhythm may facilitate the initial stages of information acquisition by neocortex during learning and the recall of stored information from cortex during retrieval. Future work should further probe these dynamics across different types of tasks and stimuli and computational models may need to be expanded accordingly to accommodate these findings.

Brain dynamics during mnemonic discrimination in preclinical and prodromal Alzheimer’s disease

AbstractBackgroundMnemonic discrimination of similar lures and targets is emerging as a promising marker of subtle memory decline in early Alzheimer’s disease (AD) due to its reliance on regions most affected by AD pathology. Tau pathology initially targets medial temporal lobe (MTL) regions in an anterior‐temporal (AT) brain network, which is preferentially involved in object processing, before it can be found in the posterior‐medial (PM) network associated with scene processing. Tests of object and scene mnemonic discrimination may therefore serve as behavioural indicators of the functional integrity of AT and PM regions, respectively. We investigated behavioural and neural changes in mnemonic discrimination across the AD spectrum.Method201 DELCODE cohort participants underwent fMRI scanning during an object‐scene mnemonic discrimination task at four time points from baseline to three‐year follow‐up. At baseline, participants were split by diagnostic group (cognitively unimpaired = CU, subjective cognitive decline = SCD, mild cognitive impairment = MCI, dementia of the Alzheimer’s type = DAT; Table 1). We identified brain regions showing lower activity to repeated targets but not similar lures, indicative of successful pattern separation of overlapping memory representations.ResultThese findings present cross‐sectional baseline data. Behavioural data showed a main effect of group but no group by category (objects, scenes) interaction. CUs and SCDs outperformed patients across domains and CUs scored higher than SCDs only in scene discrimination. Amyloid positive and negative CUs and SCDs did not differ in performance. Successful mnemonic discrimination engaged hippocampus, parahippocampal cortex, precuneus, angular gyrus, and inferior frontal regions for both objects and scenes. Correct object discrimination was additionally associated with amygdala and transentorhinal cortical activity. Reduced brain activation in regions of the anterior‐temporal and posterior‐medial network during successful object and scene mnemonic discrimination, respectively, was found in patient groups (MCI+DAT) compared to cognitively normal (CU+SCD) older adults.ConclusionOur findings lend further support to the utility of mnemonic discrimination as indicator of memory impairment in early AD. Object and scene tasks engage partially dissociable brain networks and individuals with cognitive impairment show reduced neural pattern separation effects. These findings lay the groundwork for future longitudinal analyses to track these changes based on clinical and biomarker status.

Microstructural integrity and structural connectivity of medial temporal lobe subregions is related to Alzheimer’s pathology

AbstractBackgroundThe earliest effects of Alzheimer’s disease pathology on medial temporal lobe (MTL) gray matter microstructure and white matter connectivity are still unknown. Here, we applied ultra‐high‐resolution diffusion MRI to characterize microstructural integrity and structural connectivity of the MTL, and tested associations with Alzheimer’s pathology and memory performance in cognitively normal older adults.Method83 participants (M = 71.7yrs, 66% female) received structural and ultra‐high‐resolution diffusion MRI (0.67×0.67×3mm). Subsamples received [18F]‐florbetapir (FBP) to measure Aß (n = 77; global summary SUVR), [18F]‐MK6240 to measure tau (n = 23; entorhinal SUVR), and performed an object mnemonic discrimination task (n = 74). Structural MRI was processed with ASHS to obtain MTL ROIs (Fig1). Diffusion MRI was processed with FSL DTIfit to calculate mean diffusivity (MD), an index of cellular integrity. Tractography was performed with DSI Studio. ROI‐to‐ROI streamlines were calculated (Fig3A) and used for structural connectivity graph analyses of the MTL network. Analyses controlled for age and sex, with scan interval and education in relevant models.ResultEntorhinal MK6240 SUVR was associated with increased MD in transentorhinal cortex (BA35; r = 0.72, p<0.001), entorhinal cortex (EC; r = 0.61, p = 0.004), and dentate gyrus (DG; r = 0.46, p = 0.04; Fig2A), while global FBP SUVR was associated with higher MD in EC (r = 0.25, p = 0.03). Worse mnemonic discrimination performance was associated with increased MD in DG (r = ‐0.29, p = 0.01), with trends in EC (r = ‐0.23, p = 0.06) and CA3 (r = ‐0.20, p = 0.09; Fig2B). The number of streamlines between EC and DG was not significantly associated with entorhinal MK6240 SUVR (r = ‐0.32, p = 0.17), FBP SUVR, or mnemonic discrimination (ps>0.37). Lower global efficiency of the MTL network was associated with increased entorhinal MK6240 SUVR (r = ‐0.50, p = 0.025) yet better mnemonic discrimination performance (r = ‐0.28, p = 0.02; Fig3B).ConclusionEntorhinal tau pathology and memory performance are closely related to microstructural integrity and structural connectivity of the MTL, suggesting tau‐related MTL neurodegeneration may drive early memory decline.

Microstructural integrity and structural connectivity of medial temporal lobe subregions is related to Alzheimer’s pathology

AbstractBackgroundThe earliest effects of Alzheimer’s disease pathology on medial temporal lobe (MTL) gray matter microstructure and white matter connectivity are still unknown. Here, we applied ultra‐high‐resolution diffusion MRI to characterize microstructural integrity and structural connectivity of the MTL, and tested associations with Alzheimer’s pathology and memory performance in cognitively normal older adults.Method83 participants (M = 71.7yrs, 66% female) received structural and ultra‐high‐resolution diffusion MRI (0.67×0.67×3mm). Subsamples received [18F]‐florbetapir (FBP) to measure Aβ (n = 77; global summary SUVR), [18F]‐MK6240 to measure tau (n = 23; entorhinal SUVR), and performed an object mnemonic discrimination task (n = 74). Structural MRI was processed with ASHS to obtain MTL ROIs (Fig1). Diffusion MRI was processed with FSL DTIfit to calculate mean diffusivity (MD), an index of cellular integrity. Tractography was performed with DSI Studio. ROI‐to‐ROI streamlines were calculated (Fig3A) and used for structural connectivity graph analyses of the MTL network. Analyses controlled for age and sex, with scan interval and education in relevant models.ResultEntorhinal MK6240 SUVR was associated with increased MD in transentorhinal cortex (BA35; r = 0.72, p<0.001), entorhinal cortex (EC; r = 0.61, p = 0.004), and dentate gyrus (DG; r = 0.46, p = 0.04; Fig2A), while global FBP SUVR was associated with higher MD in EC (r = 0.25, p = 0.03). Worse mnemonic discrimination performance was associated with increased MD in DG (r = ‐0.29, p = 0.01), with trends in EC (r = ‐0.23, p = 0.06) and CA3 (r = ‐0.20, p = 0.09; Fig2B). The number of streamlines between EC and DG was not significantly associated with entorhinal MK6240 SUVR (r = ‐0.32, p = 0.17), FBP SUVR, or mnemonic discrimination (ps>0.37). Lower global efficiency of the MTL network was associated with increased entorhinal MK6240 SUVR (r = ‐0.50, p = 0.025) yet better mnemonic discrimination performance (r = ‐0.28, p = 0.02; Fig3B).ConclusionEntorhinal tau pathology and memory performance are closely related to microstructural integrity and structural connectivity of the MTL, suggesting tau‐related MTL neurodegeneration may drive early memory decline.

Examining the diagnostic value of the mnemonic discrimination task for classification of cognitive status and amyloid-beta burden

Alzheimer's disease (AD) is the most common type of dementia, characterized by early memory impairments and gradual worsening of daily functions. AD-related pathology, such as amyloid-beta (Aβ) plaques, begins to accumulate many years before the onset of clinical symptoms. Predicting risk for AD via related pathology is critical as the preclinical stage could serve as a therapeutic time window, allowing for early management of the disease and reducing health and economic costs. Current methods for detecting AD pathology, however, are often expensive and invasive, limiting wide and easy access to a clinical setting. A non-invasive, cost-efficient platform, such as computerized cognitive tests, could be potentially useful to identify at-risk individuals as early as possible. In this study, we examined the diagnostic value of an episodic memory task, the mnemonic discrimination task (MDT), for predicting risk of cognitive impairment or Aβ burden. We constructed a random forest classification algorithm, utilizing MDT performance metrics and various neuropsychological test scores as input features, and assessed model performance using area under the curve (AUC). Models based on MDT performance metrics achieved classification results with an AUC of 0.83 for cognitive status and an AUC of 0.64 for Aβ status. Our findings suggest that mnemonic discrimination function may be a useful predictor of progression to prodromal AD or increased risk of Aβ load, which could be a cost-efficient, noninvasive cognitive testing solution for potentially wide-scale assessment of AD pathological and cognitive risk.

Parsing memory and nonmemory contributions to age-related declines in mnemonic discrimination performance: a hierarchical Bayesian diffusion decision modeling approach.

The mnemonic discrimination task (MDT) is a widely used cognitive assessment tool. Performance in this task is believed to indicate an age-related deficit in episodic memory stemming from a decreased ability to pattern-separate among similar experiences. However, cognitive processes other than memory ability might impact task performance. In this study, we investigated whether nonmnemonic decision-making processes contribute to the age-related deficit in the MDT. We applied a hierarchical Bayesian version of the Ratcliff diffusion model to the MDT performance of 26 younger and 31 cognitively normal older adults. It allowed us to decompose decision behavior in the MDT into different underlying cognitive processes, represented by specific model parameters. Model parameters were compared between groups, and differences were evaluated using the Bayes factor. Our results suggest that the age-related decline in MDT performance indicates a predominantly mnemonic deficit rather than differences in nonmnemonic decision-making processes. In addition, this mnemonic deficit might also involve a slowing in processes related to encoding and retrieval strategies, which are relevant for successful memory as well. These findings help to better understand what cognitive processes contribute to the age-related decline in MDT performance and may help to improve the diagnostic value of this popular task.

6 Posterior cerebral artery-defined white matter hyperintensities are associated with object domain memory and transentorhinal volume independently of global beta-amyloid burden

Objective:White matter hyperintensities (WMH) are a radiological marker of small vessel cerebrovascular disease that are related to cognition and memory decline in aging and Alzheimer’s disease (AD). However, the mechanisms that link WMH to memory impairment and whether they interact with or act independently of AD pathophysiology are unclear. The transentorhinal cortex (BA35) is among the earliest anatomical regions to show tau deposition and subsequent atrophy, and baseline posterior WMH is related to longitudinal cortical thinning of the entorhinal cortex. However, it is unclear whether regional WMH are related to BA35 volume specifically, and whether this relationship is influenced by amyloid-β (Aβ) burden. We hypothesized that WMH in the vascular territory of the posterior cerebral artery (PCA), which perfuses both posterior and medial temporal lobe regions, would be associated with reduced BA35 volume and with lower memory in older adults independently of Aβ.Participants and Methods:114 older adults without dementia, aged 60 to 98 years (mean (SD) = 78.31 (11.02), 71 (62.8%) women), were included. Regional WMH volumes were derived from T2-FLAIR images using ANTs, a vascular territory atlas and manual editing. Global Aβ was assessed with 18F-florbetapir PET, using SUVR of a cortical composite region (FBP mean SUVR) with a cerebellar reference region. Total transentorhinal (BA35) volume was derived using T1 and T2-weighted images using ASHS. To assess hippocampal pattern separation ability, an index of episodic memory, participants completed both object (MDT-O) and spatial (MDT-S) versions of a mnemonic discrimination task, with the lure discrimination index as the outcome. Using linear regressions, we first tested for associations among PCA-defined WMH, Aβ, BA35 volume, and MDT-S and MDT-O scores. We then tested whether the relationship between PCA-defined WMH and MDT-O performance was mediated by BA35 volume and whether this mediation was moderated by Aβ. All models adjusted for age, sex, and education.Results:PCA-defined WMH were related to higher FBP mean SUVR (b=0.287, p=0.042) and lower BA35 volume (b=-0.222, p=0.038). PCA-defined WMH were also negatively related to MDT-O performance (b=-0.229, p=0.044), but not to MDT-S (b=-0.171, p=0.118). FBP mean SUVR was not related to BA35 volume (b=-0.131, p=0.344) or MDT performance (MDT-S: b=-0.138, p=0.348; MDT-O: b=0.059, p=0.690). Furthermore, FBP mean SUVR did not interact with PCA-defined WMH to predict memory performance (interaction b=-0.039, p=0.973), nor BA35 volume (interaction b=-0.140, p=0.894). The association of PCA-defined WMH to MDT-O was fully mediated by BA35 volume (indirect effect b=-0.0005, 95% CI (-0.0014, -0.0003)). This mediation was not moderated by FBP mean SUVR (indirect effect b=-0.00001, 95% CI (-0.001, 0.001)).Conclusions:We found that PCA-defined WMH were related to memory performance in older adults, and this association is fully mediated by transentorhinal volume. While PCA-defined WMH are related to higher global Aβ burden, there is no interaction between PCA-defined WMH and Aβ on BA35 volume. These findings point to an amyloid-independent vascular pathway towards memory decline in aging and AD. Future work should examine whether the pathway linking PCA-defined WMH to transentorhinal cortex atrophy and subsequent memory decline is mediated by regional tau pathology.

A novel face-name mnemonic discrimination task with naturalistic stimuli

Difficulty remembering faces and names is a common struggle for many people and gets more difficult as we age. Subtle changes in appearance from day to day, common facial characteristics across individuals, and overlap of names may contribute to the difficulty of learning face-name associations. Computational models suggest the hippocampus plays a key role in reducing interference across experiences with overlapping information by performing pattern separation, which enables us to encode similar experiences as distinct from one another. Thus, given the nature of overlapping features within face-name associative memory, hippocampal pattern separation may be an important underlying mechanism supporting this type of memory. Furthermore, cross-species approaches find that aging is associated with deficits in hippocampal pattern separation. Mnemonic discrimination tasks have been designed to tax hippocampal pattern separation and provide a more sensitive measure of age-related cognitive decline compared to traditional memory tasks. However, traditional face-name associative memory tasks do not parametrically vary overlapping features of faces and names to tax hippocampal pattern separation and often lack naturalistic facial features (e.g., hair, accessories, similarity of features, emotional expressions). Here, we developed a face-name mnemonic discrimination task where we varied face stimuli by similarity, race, sex, and emotional expression as well as the similarity of name stimuli. We tested a sample of healthy young and older adults on this task and found that both age groups showed worsening performance as face-name interference increased. Overall, older adults struggled to remember faces and face-name pairs more than young adults. However, while young adults remembered emotional faces better than neutral faces, older adults selectively remembered positive faces. Thus, the use of a face-name association memory task designed with varying levels of face-name interference as well as the inclusion of naturalistic face stimuli across race, sex, and emotional expressions provides a more nuanced approach relative to traditional face-name association tasks toward understanding age-related changes in memory.

Perceived antidepressant efficacy associated with reduced negative and enhanced neutral mnemonic discrimination.

While antidepressants are one of the first-line treatments for depression, the mechanisms underlying antidepressant action are unclear. Furthermore, the extent to which antidepressants impact emotional and cognitive dysfunction in depression requires more fine-grained approaches toward measuring these impacts in humans. Depression is associated with emotion and mood dysregulation in addition to cognitive deficits. Depressed individuals experience general memory impairment as well as a negativity bias in episodic memory, where negative events are better remembered than positive or neutral events. One potential mechanism hypothesized to underlie the negativity bias in memory is dysfunctional hippocampal pattern separation, in which depressed individuals tend to show impaired general pattern separation but enhanced negative pattern separation. Mnemonic discrimination tasks have been designed to tax hippocampal pattern separation in humans and provide a powerful approach to develop a mechanistic account for cognitive dysfunction in depression. While antidepressants have been examined primarily in rodent models in the context of hippocampal pattern separation, this has yet to be examined in humans. Here, we investigated how antidepressant usage and their perceived efficacy was associated with emotional mnemonic discrimination, given our prior work indicating a negativity bias for mnemonic discrimination in individuals with greater depressive symptoms. We found that individuals who reported a greater improvement in their depressive symptoms after taking antidepressants (responders) showed reduced negative and enhanced neutral mnemonic discrimination compared to those with little to no improvement (non-responders). Perceived antidepressant efficacy was the strongest predictor of a reduction in the negativity bias for mnemonic discrimination, even when controlling for current depressive symptoms, antidepressant type, and other relevant factors. These results suggest that antidepressants, when effective, can shift memory dynamics toward healthy function.

Effect of Alzheimer's Pathology on Task-Related Brain Network Reconfiguration in Aging.

Large-scale brain networks undergo widespread changes with older age and in neurodegenerative diseases such as Alzheimer's disease (AD). Research in young adults (YA) suggest that the underlying functional architecture of brain networks remains relatively consistent between rest and task states. However, it remains unclear whether the same is true in aging and to what extent any changes may be related to accumulation of AD pathology such as β-amyloid (Aβ) and tau. Here, we examined age-related differences in functional connectivity (FC) between rest and an object-scene mnemonic discrimination task using fMRI in young and older adults (OA; both females and males). We used an a priori episodic memory network (EMN) parcellation scheme associated with object and scene processing, that included anterior-temporal regions and posterior-medial regions. We also used positron emission topography to measure Aβ and tau in older adults. The correlation between rest and task FC (i.e., FC similarity) was reduced in older compared with younger adults. Older adults with lower FC similarity in EMN had higher levels of tau in the same EMN regions and performed worse during object, but not scene, trials during the fMRI task. These findings link AD pathology, particularly tau, to a less stable functional architecture in memory networks. They also suggest that smaller changes in FC organization between rest and task states may facilitate better performance in older age. Interpretations are limited by methodological factors related to different acquisition directions and durations between rest and task scans.SIGNIFICANCE STATEMENT The brain's large-scale network organization is relatively consistent between rest and task states in young adults (YA). We found that memory networks in older adults (OA) were less correlated between rest and (memory) task states compared with young adults. Older adults with less correlated brain networks also had higher levels of Alzheimer's disease (AD) pathology in the same regions, suggesting that a less stable network architecture may reflect the early evolution of AD. Older adults with less correlated brain networks also performed worse during the memory task suggesting that more similar network organization between rest and task states may facilitate better performance in older age.

The effect of age on mnemonic discrimination is fully mediated by posterior cerebral artery‐defined white matter hyperintensities

AbstractBackgroundPrevious work has observed a decline in memory performance with age on mnemonic discrimination tasks (MDT). Other studies have recognized the contributions of white matter hyperintensities (WMH), a marker of cerebrovascular disease, on age and Alzheimer’s disease‐related memory decline. Here, we asked whether WMH, defined within vascular territories, particularly the posterior cerebral artery (PCA) defined territory, would mediate the association between age and MDT performance.MethodA sample of 120 older adults (mean age (SD) = 76.6 (10.43) years, age range: 59‐98 years, 74 (61.7%) females) were included in these analyses. Regional WMH volumes were derived from T2‐FLAIR (Figure 1A) images using ANTs, a vascular territory atlas (Figure 1B) and manual editing. The MDT was administered to assess episodic memory and pattern separation ability within both the object (MDT‐O) and spatial (MDT‐S) domains. Adjusting for sex and education, we tested for associations among age, regional WMH volumes, MDT‐S, and MDT‐O scores, correcting for multiple comparisons. Results were then used to assess the mediating role of regional WMH on the relationship between age and MDT. Lastly, we compared the accuracy of the different vascular territory WMH volumes, along with total WMH volume, in classifying cognitive impairment (MCI, QCI, CIND) using area under the receiver operating characteristic curve (ROC).ResultAge was associated with MDT‐S (β=‐0.247, p=0.005), but not MDT‐O performance (β=‐0.130, p=0.177). Only PCA‐defined WMH volume was associated with MDT‐S (β=‐0.252, p=0.005) and MDT‐O (b=‐0.229, p=0.016). PCA‐defined WMH fully mediated the association between age and MDT‐S (indirect effect: β=‐0.001, 95% CI (‐0.003, ‐0.001); Figure 2A). Similarly, PCA‐defined WMH fully mediated the association between age and MDT‐O (β=‐0.001, 95% CI (‐0.002, ‐0.003); Figure 2B). PCA‐defined WMH volume more accurately classified cognitively impaired from non‐impaired (AUC=0.780, p<0.001; Figure 3) compared with total WMH (AUC=0.624, p=0.113), ACA‐defined WMH volume (AUC=0.618, p=.130) or MCA‐defined WMH (AUC=0.592, p=0.237).ConclusionPCA‐defined WMH mediate the relationship between age and memory performance and is a better diagnostic of cognitive impairment than whole brain or other vascular territory WMH volumes. This study demonstrates that defining WMH within vascular territories provides a useful way to characterize the impact of aging on memory impairment.

Examining the diagnostic utility of the mnemonic discrimination task for classification of cognition and amyloid‐β burden

AbstractBackgroundDeveloping non‐invasive diagnostics that can effectively predict amyloid‐β (Aβ) burden is crucial, as this technology could help to identify individuals with increased risk for AD and provide a window for potential treatment or intervention. Mnemonic discrimination tasks (MDTs) are designed to assess the ability to discriminate highly similar episodic memory representations (e.g., objects or spatial locations). The relationship between the MDT performance and Aβ burden, however, has not yet been directly tested. In this study, we investigated whether MDT performance can successfully classify cognitive status or Aβ load in older adults.MethodA sample of 85 older adults (60‐91 yrs old) with normal cognition and 9 older adults with a clinical diagnosis of Mild Cognitive Impairment (MCI) (62 ‐89 yrs old) underwent either cerebrospinal fluid (CSF) lumbar punctures or 18F‐florbetapir‐PET imaging. Cognitively normal individuals were stratified into Aβ+ and Aβ‐ subgroups based on quantitative thresholds for Aβ positivity (SUVR >1.11, CSF Ab1‐42/1‐40 < 0.062). Participants performed the object and spatial versions of the MDT. We used a random forest classification algorithm, including MDT performance metrics and demographic factors (age, gender, education) as features to classify cognitive status (normal vs. MCI) and Aβ status (positive vs. negative). We evaluated the area under the receiver operating characteristic curve (AUC) using the classifiers in a leave‐one‐out cross validation design.ResultFor classification of cognitive status, the best model performance was achieved by including all the features of object and spatial MDT metrics and demographics (AUC = 0.80). For classification of Aβ status in cognitively normal participants, the best model performance was also achieved by including all the features of object and spatial MDT metrics and demographics (AUC = 0.65).ConclusionOur findings suggest that MDT performance measures may have clinical utility as a diagnostic tool to predict cognitive status and in vivo Aβ burden in preclinical older adults.

Multi‐modal biomarkers improve prediction of memory function in cognitively unimpaired older adults

AbstractBackgroundIdentifying biomarkers that predict current and future cognition may improve estimates of Alzheimer’s disease risk among cognitively unimpaired older adults (CU). In vivo measures of amyloid and tau protein burden and task‐based functional MRI measures of core memory mechanisms, such as the strength of cortical reinstatement during remembering, have each been linked to individual differences in memory in CU. This study assesses whether combining CSF biomarkers with fMRI indices of cortical reinstatement improves estimation of memory function in CU, assayed using three unique tests of hippocampal‐dependent memory.MethodParticipants were 157 CU (90F, aged 60‐88 years, CDR=0) enrolled in the Stanford Aging and Memory Study (SAMS). Cortical reinstatement was quantified using multivoxel pattern analysis of fMRI data collected during completion of a paired associate cued recall task. Memory was assayed by associative cued recall, a delayed recall composite, and a mnemonic discrimination task that involved discrimination between studied ‘target’ objects, novel ‘foil’ objects, and perceptually similar ‘lure’ objects. CSF Aβ42, Aβ40, and p‐tau181 were measured with the automated Lumipulse G system (N=115). Regression analyses examined cross‐sectional relationships between memory performance in each task and a) the strength of cortical reinstatement in the Default Network (comprised of posterior medial, medial frontal, and lateral parietal regions) during associative cued recall and b) CSF Aβ42/Aβ40 and p‐tau181, controlling for age, sex, and education. For mnemonic discrimination, linear mixed effects models were used to examine the relationship between discrimination (d’) and each predictor as a function of target‐lure similarity.ResultStronger cortical reinstatement was associated with better performance across all three memory assays. Age and higher CSF p‐tau181 were each associated with poorer associative memory and a diminished improvement in mnemonic discrimination as target‐lure similarity decreased. When combined in a single model, CSF p‐tau181 and Default Network reinstatement strength, but not age, explained unique variance in associative memory and mnemonic discrimination performance, outperforming the single‐modality models.ConclusionCombining fMRI measures of core memory functions with protein biomarkers of Alzheimer’s disease significantly improved prediction of individual differences in memory performance in CU. Leveraging multimodal biomarkers may enhance future prediction of risk for cognitive decline.

Hippocampal CA1 volume is associated with higher p‐tau and diminished memory performance in normal older adults

AbstractBackgroundPrior work has demonstrated that elevated CSF biomarkers in older adults are associated with diminished performance across several hippocampally‐dependent memory tasks. It is unknown whether early structural changes in medial temporal lobe subfields (1) may be impacted by elevated p‐tau181, and (2) mediate the effect of p‐tau181 on memory performance in older adults.MethodThe current study draws on a cohort of 147 cognitively unimpaired older adults (Stanford Aging and Memory Study) that completed both 3T MRI and lumbar punctures. To examine memory performance, participants completed two hippocampally dependent tasks: a paired associate cued recall task and a mnemonic discrimination task (MST) that examined discrimination between previously studied “old” objects, novel “foil” objects and perceptually similar “lure” objects. Lure trials were binned in five difficulty levels, ranging from low to high similarity compared to previously presented stimuli. Hippocampal subregions (CA1, CA3/DG, subiculum) were manually delineated on T2*weighted images following Carr et al., (2017). CSF was processed with Lumipulse to measure Ab42:Ab40 ratio and p‐tau181. Multiple regression was used to assess the associative memory d’ from the paired associate task. Given the repeated measures design of the MST task, linear mixed models were conducted to understand the association between hippocampal subfields and p‐tau181 on performance as a function of similarity strength (Trelle et al., 2021). Age, sex, and education were controlled in all models.ResultP‐tau181 was correlated with reduced left CA1 volume (partial r2=0.043, p = 0.01), but not with volume in other hippocampal subfields. Increased CA1 volume was positively associated with better memory performance, including higher associative memory recall and old‐lure discrimination. After controlling for p‐tau181, CA1 volume was no longer associated with performance on the associative memory task but remained significantly correlated with old/lure discrimination. Notably, increased CA1 volume improved overall discrimination for old/lure trials, independent of the difficulty level, while the association between p‐tau181 and performance was strongest at the lower similarity level.ConclusionReduced CA1 volume and p‐tau explain unique variance in memory performance in older adults. This combination of biofluid biomarkers and high‐resolution MRI has the potential to understand mechanisms underlying age‐related memory decline.

The Effect of Apolipoprotein e4 on Object Mnemonic Discrimination in Healthy Adulthood.

AbstractBackgroundImpairment in mnemonic discrimination is a hallmark feature of the very early stages of Alzheimer’s Disease (AD) and is associated with aberrant hippocampal function. Carriers of an Apolipoprotein (APOE) e4 gene, the most well‐established risk factor for AD, show differences in hippocampal function from youth. The cognitive consequences of altered brain activation in this group, however, remain poorly understood.MethodsAn online web‐platform has been developed – the APOE Memory Bank, which presents a collection of in‐depth behavioural tasks targeting hippocampal (object and spatial mnemonic discrimination) and non‐hippocampal cognitive processes (prospective memory, working memory and executive control). Cognitively healthy adults (aged 45–65 years) were invited to take part from the NIHR BioResource database. Selection processes have ensured a well‐matched, equivalent sample of e4 carriers and non‐carriers.ResultsFour hundred and twenty‐one participants have provided data to the APOE Memory bank to date. Ongoing, pre‐registered analyses will test if APOE e4 carriers show alterations in their ability to discriminate objects in memory, and if genotype differences in the cognitive processes supporting successful mnemonic discrimination underpin disparities. The sample is enriched with a high proportion of homozygous e4 carriers, providing a novel examination of gene‐dose effects at scale.ConclusionsEstablishing which cognitive processes are sensitive to the detrimental effects of APOE e4 will advance understanding of how genotype differences in brain development confer vulnerability in this high‐risk group. To date, indices of mnemonic discrimination have been used to discriminate preclinical or prodromal AD. This research provides a novel test of whether, in mid‐life, a web‐based object mnemonic discrimination task can differentiate risk for subsequent cognitive impairment. Identifying non‐invasive, easy‐to‐administer risk markers will advance future avenues of prophylactic, personalised intervention

Unsupervised mobile app-based cognitive testing in a population-based study of older adults born 1944.

Mobile app-based tools have the potential to yield rapid, cost-effective, and sensitive measures for detecting dementia-related cognitive impairment in clinical and research settings. At the same time, there is a substantial need to validate these tools in real-life settings. The primary aim of this study was thus to evaluate the feasibility, validity, and reliability of mobile app-based tasks for assessing cognitive function in a population-based sample of older adults. A total of 172 non-demented (Clinical Dementia Rating 0 and 0.5) older participants (aged 76-77) completed two mobile app-based memory tasks-the Mnemonic Discrimination Task for Objects and Scenes (MDT-OS) and the long-term (24 h) delayed Object-In-Room Recall Task (ORR-LDR). To determine the validity of the tasks for measuring relevant cognitive functions in this population, we assessed relationships with conventional cognitive tests. In addition, psychometric properties, including test-retest reliability, and the participants' self-rated experience with mobile app-based cognitive tasks were assessed. MDT-OS and ORR-LDR were weakly-to-moderately correlated with the Preclinical Alzheimer's Cognitive Composite (PACC5) (r = 0.3-0.44, p < .001) and with several other measures of episodic memory, processing speed, and executive function. Test-retest reliability was poor-to-moderate for one single session but improved to moderate-to-good when using the average of two sessions. We observed no significant floor or ceiling effects nor effects of education or gender on task performance. Contextual factors such as distractions and screen size did not significantly affect task performance. Most participants deemed the tasks interesting, but many rated them as highly challenging. While several participants reported distractions during tasks, most could concentrate well. However, there were difficulties in completing delayed recall tasks on time in this unsupervised and remote setting. Our study proves the feasibility of mobile app-based cognitive assessments in a community sample of older adults, demonstrating its validity in relation to conventional cognitive measures and its reliability for repeated measurements over time. To further strengthen study adherence, future studies should implement additional measures to improve task completion on time.

Entorhinal-Hippocampal Circuit Integrity Is Related to Mnemonic Discrimination and Amyloid-β Pathology in Older Adults.

Mnemonic discrimination, a cognitive process that relies on hippocampal pattern separation, is one of the first memory domains to decline in aging and preclinical Alzheimer's disease. We tested whether functional connectivity (FC) within the entorhinal-hippocampal circuit, measured with high-resolution resting state fMRI, is associated with mnemonic discrimination and amyloid-β (Aβ) pathology in a sample of 64 cognitively normal human older adults (mean age, 71.3 ± 6.4 years; 67% female). FC was measured between entorhinal-hippocampal circuit nodes with known anatomical connectivity, as well as within cortical memory networks. Aβ pathology was measured with 18F-florbetapir-PET, and neurodegeneration was assessed with subregional volume from structural MRI. Participants performed both object and spatial versions of a mnemonic discrimination task outside of the scanner and were classified into low-performing and high-performing groups on each task using a median split. Low object mnemonic discrimination performance was specifically associated with increased FC between anterolateral entorhinal cortex (alEC) and dentate gyrus (DG)/CA3, supporting the importance of this connection to object memory. This hyperconnectivity between alEC and DG/CA3 was related to Aβ pathology and decreased entorhinal cortex volume. In contrast, spatial mnemonic discrimination was not associated with altered FC. Aβ was further associated with dysfunction within hippocampal subfields, particularly with decreased FC between CA1 and subiculum as well as reduced volume in these regions. Our findings suggest that Aβ may indirectly lead to memory impairment through entorhinal-hippocampal circuit dysfunction and neurodegeneration and provide a mechanism for increased vulnerability of object mnemonic discrimination.SIGNIFICANCE STATEMENT Mnemonic discrimination is a critical episodic memory process that is performed in the dentate gyrus (DG) and CA3 subfield of the hippocampus, relying on input from entorhinal cortex. Mnemonic discrimination is particularly vulnerable to decline in older adults; however, the mechanisms behind this vulnerability are still unknown. We demonstrate that object mnemonic discrimination impairment is related to hyperconnectivity between the anterolateral entorhinal cortex and DG/CA3. This hyperconnectivity was associated with amyloid-β pathology and neurodegeneration in entorhinal cortex, suggesting aberrantly increased network activity is a pathological process. Our findings provide a mechanistic explanation of the vulnerability of object compared to spatial mnemonic discrimination in older adults and has translational implications for choice of outcome measures in clinical trials for Alzheimer's disease.