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BackgroundComputerized cognitive assessments may improve Alzheimer's disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers.ObjectiveTo assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3).DesignCross-sectional analysis of cognitive screening data from the A4 study (Anti-Amyloid in Asymptomatic AD).SettingMulti-center international study.ParticipantsClinically normal (CN) older adults (65-85; n=4486).MeasurementsParticipants underwent florbetapir-Positron Emission Tomography for Aβ+/- classification. They completed the C3 and standard paper and pencil measures included in the Preclinical Alzheimer's Cognitive Composite (PACC). The C3 combines memory measures sensitive to change over time (Cogstate Brief Battery-One Card Learning) and measures shown to be declining early in AD including pattern separation (Behavioral Pattern Separation Test- Object- Lure Discrimination Index) and associative memory (Face Name Associative Memory Exam- Face-Name Matching). C3 acceptability and completion rates were assessed using qualitative and quantitative methods. C3 performance was explored in relation to Aβ+/- groups (n=1323/3163) and PACC.ResultsC3 was feasible for CN older adults to complete. Rates of incomplete or invalid administrations were extremely low, even in the bottom quartile of cognitive performers (PACC). C3 was moderately correlated with PACC (r=0.39). Aβ+ performed worse on C3 compared with Aβ- [unadjusted Cohen's d=-0.22 (95%CI: -0.31,-0.13) p

BackgroundComputerized cognitive assessments may improve Alzheimer's disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers.ObjectiveTo assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3).DesignCross-sectional analysis of cognitive screening data from the A4 study (Anti-Amyloid in Asymptomatic AD).SettingMulti-center international study.ParticipantsClinically normal (CN) older adults (65-85; n=4486).MeasurementsParticipants underwent florbetapir-Positron Emission Tomography for Aβ+/- classification. They completed the C3 and standard paper and pencil measures included in the Preclinical Alzheimer's Cognitive Composite (PACC). The C3 combines memory measures sensitive to change over time (Cogstate Brief Battery-One Card Learning) and measures shown to be declining early in AD including pattern separation (Behavioral Pattern Separation Test- Object- Lure Discrimination Index) and associative memory (Face Name Associative Memory Exam- Face-Name Matching). C3 acceptability and completion rates were assessed using qualitative and quantitative methods. C3 performance was explored in relation to Aβ+/- groups (n=1323/3163) and PACC.ResultsC3 was feasible for CN older adults to complete. Rates of incomplete or invalid administrations were extremely low, even in the bottom quartile of cognitive performers (PACC). C3 was moderately correlated with PACC (r=0.39). Aβ+ performed worse on C3 compared with Aβ- [unadjusted Cohen's d=-0.22 (95%CI: -0.31,-0.13) p

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome., Competing Interests: O.H. has received consulting fees for AC Immune, Amylyx, ALZpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens; S.Z. has received consulting fees from Lundbeck; D.M.W. has received consulting fees from Biohaven Therapeutics; E.H. has received consulting fees for Alzheon and Cyclo Therapeutics; A.M.B. has received consulting fees from Cogstate, Cognito Therapeutics, IQVIA, and Cognition Therapeutics., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Unpredictable childhood experiences are an understudied form of early life adversity that impacts neurodevelopment in a sex-specific manner. The neurobiological processes by which exposure to early-life unpredictability impacts development and vulnerability to psychopathology remain poorly understood. The present study investigates the sex-specific consequences of early-life unpredictability on the limbic network, focusing on the hippocampus and the amygdala., Methods: Participants included 150 youth (54% female). Early life unpredictability was assessed using the Questionnaire of Unpredictability in Childhood (QUIC). Participants engaged in a task-fMRI scan between the ages of 8 and 17 (223 total observations) measuring BOLD responses to novel and familiar scenes., Results: Exposure to early-life unpredictability associated with BOLD contrast (novel vs. familiar) in a sex-specific manner. For males, but not females, higher QUIC scores were associated with lower BOLD activation in response to novel vs. familiar stimuli in the hippocampal head and amygdala. Secondary psychophysiological interaction (PPI) analyses revealed complementary sex-specific associations between QUIC and condition-specific functional connectivity between the right and left amygdala, as well as between the right amygdala and hippocampus bilaterally., Conclusion: Exposure to unpredictability in early life has persistent implications for the functional operations of limbic circuits. Importantly, consistent with emerging experimental animal and human studies, the consequences of early life unpredictability differ for males and females. Further, impacts of early-life unpredictability were independent of other risk factors including lower household income and negative life events, indicating distinct consequences of early-life unpredictability over and above more commonly studied types of early life adversity., Competing Interests: Disclosures All authors report no conflicts of interest related to this work.

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., Competing Interests: Conflict of interest: M.A.Y. is Co-founder and Chief Scientific Officer of Augnition Labs, LLC. The authors declare no other competing financial interests.

Adults with Down syndrome are less likely to have hypertension than neurotypical adults. However, whether blood pressure measures are associated with brain health and clinical outcomes in this population has not been studied in detail. Here, we assessed whether pulse pressure is associated with markers of cerebrovascular disease and is linked to a diagnosis of dementia in adults with Down syndrome via structural imaging markers of cerebrovascular disease and atrophy. The study included participants with Down syndrome from the Alzheimer's Disease - Down Syndrome study ( n = 195, age = 50.6 ± 7.2 years, 44% women, 18% diagnosed with dementia). Higher pulse pressure was associated with greater global, parietal and occipital white matter hyperintensity volume but not with enlarged perivascular spaces, microbleeds or infarcts. Using a structural equation model, we found that pulse pressure was associated with greater white matter hyperintensity volume, which in turn was related to increased neurodegeneration, and subsequent dementia diagnosis. Pulse pressure is an important determinant of brain health and clinical outcomes in individuals with Down syndrome despite the low likelihood of frank hypertension., Competing Interests: M.M. is on the scientific advisory board of Brain Neurotherapy Bio, Davis Phinney Foundation for Parksinson’s and Alzheon. A.M.B. has received consulting/advisory fees from Cognition Therapeutics, Cognito Therapeutics and CogState and has a patent for technologies for white matter hyperintensity quantification (867566) issued., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

UK Biobank is a large-scale epidemiological resource for investigating prospective correlations between various lifestyle, environmental, and genetic factors with health and disease progression. In addition to individual subject information obtained through surveys and physical examinations, a comprehensive neuroimaging battery consisting of multiple modalities provides imaging-derived phenotypes (IDPs) that can serve as biomarkers in neuroscience research. In this study, we augment the existing set of UK Biobank neuroimaging structural IDPs, obtained from well-established software libraries such as FSL and FreeSurfer, with related measurements acquired through the Advanced Normalization Tools Ecosystem. This includes previously established cortical and subcortical measurements defined, in part, based on the Desikan-Killiany-Tourville atlas. Also included are morphological measurements from two recent developments: medial temporal lobe parcellation of hippocampal and extra-hippocampal regions in addition to cerebellum parcellation and thickness based on the Schmahmann anatomical labeling. Through predictive modeling, we assess the clinical utility of these IDP measurements, individually and in combination, using commonly studied phenotypic correlates including age, fluid intelligence, numeric memory, and several other sociodemographic variables. The predictive accuracy of these IDP-based models, in terms of root-mean-squared-error or area-under-the-curve for continuous and categorical variables, respectively, provides comparative insights between software libraries as well as potential clinical interpretability. Results demonstrate varied performance between package-based IDP sets and their combination, emphasizing the need for careful consideration in their selection and utilization., (© 2024. The Author(s).)

Introduction: Virtually all people with Down syndrome (DS) develop neuropathology associated with Alzheimer's disease (AD). Atrophy of the hippocampus and entorhinal cortex (EC), as well as elevated plasma concentrations of neurofilament light chain (NfL) protein, are markers of neurodegeneration associated with late-onset AD. We hypothesized that hippocampus and EC gray matter loss and increased plasma NfL concentrations are associated with memory in adults with DS., Methods: T1-weighted structural magnetic resonance imaging (MRI) data were collected from 101 participants with DS. Hippocampus and EC volume, as well as EC subregional cortical thickness, were derived. In a subset of participants, plasma NfL concentrations and modified Cued Recall Test scores were obtained. Partial correlation and mediation were used to test relationships between medial temporal lobe (MTL) atrophy, plasma NfL, and episodic memory., Results: Hippocampus volume, left anterolateral EC (alEC) thickness, and plasma NfL were correlated with each other and were associated with memory. Plasma NfL mediated the relationship between left alEC thickness and memory as well as hippocampus volume and memory., Discussion: The relationship between MTL gray matter and memory is mediated by plasma NfL levels, suggesting a link between neurodegenerative processes underlying axonal injury and frank gray matter loss in key structures supporting episodic memory in people with DS., Competing Interests: The authors declare no conflicts of interest relevant to this manuscript., (© 2024 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

This study examined whether a 3-month mild-exercise intervention could improve executive function in healthy middle-aged and older adults in a randomized control trial. Ultimately, a total of 81 middle-aged and older adults were randomly assigned to either an exercise group or a control group. The exercise group received 3 months of mild cycle exercise intervention (3 sessions/week, 30-50 min/session). The control group was asked to behave as usual for the intervention period. Before and after the intervention, participants did color-word matching Stroop tasks (CWST), and Stroop interference (SI)-related reaction time (RT) was assessed as an indicator of executive function. During the CWST, prefrontal activation was monitored using functional near-infrared spectroscopy (fNIRS). SI-related oxy-Hb changes and SI-related neural efficiency (NE) scores were assessed to examine the underlying neural mechanism of the exercise intervention. Although the mild-exercise intervention significantly decreased SI-related RT, there were no significant effects of exercise intervention on SI-related oxy-Hb changes or SI-related NE scores in prefrontal subregions. Lastly, changes in the effects of mild exercise on NE with advancing age were examined. The 81 participants were divided into two subgroups (younger-aged subgroup [YA], older-aged subgroup [OA], based on median age [68 years.]). Interestingly, SI-related RT significantly decreased, and SI-related NE scores in all ROIs of the prefrontal cortex significantly increased only in the OA subgroup. These results reveal that a long-term intervention of very light-intensity exercise has a positive effect on executive function especially in older adults, possibly by increasing neural efficiency in the prefrontal cortex., (© 2023. The Author(s).)

Enhanced memory for emotional experiences is hypothesized to depend on amygdala-hippocampal interactions during memory consolidation. Here we show using intracranial recordings from the human amygdala and the hippocampus during an emotional memory encoding and discrimination task increased awake ripples after encoding of emotional, compared to neutrally-valenced stimuli. Further, post-encoding ripple-locked stimulus similarity is predictive of later memory discrimination. Ripple-locked stimulus similarity appears earlier in the amygdala than in hippocampus and mutual information analysis confirms amygdala influence on hippocampal activity. Finally, the joint ripple-locked stimulus similarity in the amygdala and hippocampus is predictive of correct memory discrimination. These findings provide electrophysiological evidence that post-encoding ripples enhance memory for emotional events., (© 2024. The Author(s).)

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., (© 2023. The Author(s).)

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., (© 2023 Chwiesko et al.; Published by Cold Spring Harbor Laboratory Press.)

Older adults may harbor large amounts of amyloid-β (Aβ) pathology, yet still perform at age-normal levels on memory assessments. We tested whether functional brain networks confer resilience or compensatory mechanisms to support memory in the face of Aβ pathology. Sixty-five cognitively normal older adults received high-resolution resting state fMRI to assess functional networks, 18F-florbetapir-PET to measure Aβ, and a memory assessment. We characterized functional networks with graph metrics of local efficiency (information transfer), modularity (specialization of functional modules), and small worldness (balance of integration and segregation). There was no difference in functional network measures between older adults with high Aβ (Aβ+) compared to those with no/low Aβ (Aβ-). However, in Aβ+ older adults, increased local efficiency, modularity, and small worldness were associated with better memory performance, while this relationship did not occur Aβ- older adults. Further, the association between increased local efficiency and better memory performance in Aβ+ older adults was localized to local efficiency of the default mode network and hippocampus, regions vulnerable to Aβ and involved in memory processing. Our results suggest functional networks with modular and efficient structures are associated with resilience to Aβ pathology, providing a functional target for intervention., (© 2023. Springer Nature Limited.)

Physical exercise, even stress-free very-light-intensity exercise such as yoga and very slow running, can have beneficial effects on executive function, possibly by potentiating prefrontal cortical activity. However, the exact mechanisms underlying this potentiation have not been identified. Evidence from studies using pupillometry demonstrates that pupil changes track the real-time dynamics of activity linked to arousal and attention, including neural circuits from the locus coeruleus to the cortex. This makes it possible to examine whether pupil-linked brain dynamics induced during very-light-intensity exercise mediate benefits to prefrontal executive function in healthy young adults. In this experiment, pupil diameter was measured during 10 min of very-light-intensity exercise (30% V˙o 2peak ). A Stroop task was used to assess executive function before and after exercise. Prefrontal cortical activation during the task was assessed using multichannel functional near-infrared spectroscopy (fNIRS). We observed that very-light-intensity exercise significantly elicited pupil dilation, reduction of Stroop interference, and task-related left dorsolateral prefrontal cortex activation compared with the resting-control condition. The magnitude of change in pupil dilation predicted the magnitude of improvement in Stroop performance. In addition, causal mediation analysis showed that pupil dilation during very-light-intensity exercise robustly determined subsequent enhancement of Stroop performance. This finding supports our hypothesis that the pupil-linked mechanisms, which may be tied to locus coeruleus activation, are a potential mechanism by which very light exercise enhances prefrontal cortex activation and executive function. It also suggests that pupillometry may be a useful tool to interpret the beneficial impact of exercise on boosting cognition., Competing Interests: Declaration of Competing Interest The authors do not declare any competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Objective: Cognitive loss in older adults is a growing issue in our society, and there is a need to develop inexpensive, simple, effective in-home treatments. This study was conducted to explore the use of olfactory enrichment at night to improve cognitive ability in healthy older adults., Methods: Male and female older adults ( N  = 43), age 60-85, were enrolled in the study and randomly assigned to an Olfactory Enriched or Control group. Individuals in the enriched group were exposed to 7 different odorants a week, one per night, for 2 h, using an odorant diffuser. Individuals in the control group had the same experience with de minimis amounts of odorant. Neuropsychological assessments and fMRI scans were administered at the beginning of the study and after 6 months., Results: A statistically significant 226% improvement was observed in the enriched group compared to the control group on the Rey Auditory Verbal Learning Test and improved functioning was observed in the left uncinate fasciculus, as assessed by mean diffusivity., Conclusion: Minimal olfactory enrichment administered at night produces improvements in both cognitive and neural functioning. Thus, olfactory enrichment may provide an effective and low-effort pathway to improved brain health., Competing Interests: ML and MY have received travel expenses and compensation following presentations at P&G. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Woo, Miranda, Sathishkumar, Dehkordi-Vakil, Yassa and Leon.)

Acute mild exercise has been observed to facilitate executive function and memory. A possible underlying mechanism of this is the upregulation of the ascending arousal system, including the catecholaminergic system originating from the locus coeruleus (LC). Prior work indicates that pupil diameter, as an indirect marker of the ascending arousal system, including the LC, increases even with very light-intensity exercise. However, it remains unclear whether the LC directly contributes to exercise-induced pupil-linked arousal. Here, we examined the involvement of the LC in the change in pupil dilation induced by very light-intensity exercise using pupillometry and neuromelanin imaging to assess the LC integrity. A sample of 21 young males performed 10 min of very light-intensity exercise, and we measured changes in the pupil diameters and psychological arousal levels induced by the exercise. Neuromelanin-weighted magnetic resonance imaging scans were also obtained. We observed that pupil diameter and psychological arousal levels increased during very light-intensity exercise, which is consistent with previous findings. Notably, the LC contrast, a marker of LC integrity, predicted the magnitude of pupil dilation and psychological arousal enhancement with exercise. These relationships suggest that the LC-catecholaminergic system is a potential a mechanism for pupil-linked arousal induced by very light-intensity exercise., (© The Author(s) 2023. Published by Oxford University Press.)

Introduction: We tested whether Alzheimer's disease (AD) pathology predicts memory deficits in non-demented older adults through its effects on medial temporal lobe (MTL) subregional volume., Methods: Thirty-two, non-demented older adults with cerebrospinal fluid (CSF) (amyloid-beta [Aβ] 42 /Aβ 40 , phosphorylated tau [p-tau] 181 , total tau [t-tau]), positron emission tomography (PET; 18F-florbetapir), high-resolution structural magnetic resonance imaging (MRI), and neuropsychological assessment were analyzed. We examined relationships between biomarkers and a highly granular measure of memory consolidation, retroactive interference (RI)., Results: Biomarkers of AD pathology were related to RI. Dentate gyrus (DG) and CA3 volume were uniquely associated with RI, whereas CA1 and BA35 volume were related to both RI and overall memory recall. AD pathology was associated with reduced BA35, CA1, and subiculum volume. DG volume and Aβ were independently associated with RI, whereas CA1 volume mediated the relationship between AD pathology and RI., Discussion: Integrity of distinct hippocampal subfields demonstrate differential relationships with pathology and memory function, indicating specificity in vulnerability and contribution to different memory processes., Competing Interests: Michael A. Yassa is Co‐founder and Chief Scientific Officer of Augnition Labs, LLC. No other authors have conflicts of interest or disclosures. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Classic models consider working memory (WM) and long-term memory as distinct mental faculties that are supported by different neural mechanisms. Yet, there are significant parallels in the computation that both types of memory require. For instance, the representation of precise item-specific memory requires the separation of overlapping neural representations of similar information. This computation has been referred to as pattern separation, which can be mediated by the entorhinal-DG/CA3 pathway of the medial temporal lobe (MTL) in service of long-term episodic memory. However, although recent evidence has suggested that the MTL is involved in WM, the extent to which the entorhinal-DG/CA3 pathway supports precise item-specific WM has remained elusive. Here, we combine an established orientation WM task with high-resolution fMRI to test the hypothesis that the entorhinal-DG/CA3 pathway retains visual WM of a simple surface feature. Participants were retrospectively cued to retain one of the two studied orientation gratings during a brief delay period and then tried to reproduce the cued orientation as precisely as possible. By modeling the delay-period activity to reconstruct the retained WM content, we found that the anterior-lateral entorhinal cortex (aLEC) and the hippocampal DG/CA3 subfield both contain item-specific WM information that is associated with subsequent recall fidelity. Together, these results highlight the contribution of MTL circuitry to item-specific WM representation., Competing Interests: WX, MC, MY, EE, KZ, WZ No competing interests declared

White matter hyperintensities are a marker of small vessel cerebrovascular disease that are strongly related to cognition in older adults. Similarly, medial temporal lobe atrophy is well-documented in aging and Alzheimer's disease and is associated with memory decline. Here, we assessed the relationship between lobar white matter hyperintensities, medial temporal lobe subregional volumes, and hippocampal memory in older adults. We collected MRI scans in a sample of 139 older adults without dementia (88 females, mean age (SD) = 76.95 (10.61)). Participants were administered the Rey Auditory Verbal Learning Test (RAVLT). Regression analyses tested for associations among medial temporal lobe subregional volumes, regional white matter hyperintensities and memory, while adjusting for age, sex, and education and correcting for multiple comparisons. Increased occipital white matter hyperintensities were related to worse RAVLT delayed recall performance, and to reduced CA1, dentate gyrus, perirhinal cortex (Brodmann area 36), and parahippocampal cortex volumes. These medial temporal lobe subregional volumes were related to delayed recall performance. The association of occipital white matter hyperintensities with delayed recall performance was fully mediated statistically only by perirhinal cortex volume. These results suggest that white matter hyperintensities may be associated with memory decline through their impact on medial temporal lobe atrophy. These findings provide new insights into the role of vascular pathologies in memory loss in older adults and suggest that future studies should further examine the neural mechanisms of these relationships in longitudinal samples., 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. Published by Elsevier Inc.)

Higher aerobic fitness during late midlife is associated with higher white matter (WM) microstructure. Compared with individuals engaged in irregular exercise, those who engage in regular aerobic exercise show higher fractional anisotropy (FA), a diffusion tenor imaging (DTI) measure that provides an index of WM microstructural integrity. However, whether other types of exercise, such as Tai Chi, can also facilitate WM changes in adults during late midlife remains unknown. The present study compares two types of exercise, Tai Chi and walking, with a sedentary control group, in order to examine the effects of exercise on WM microstructure and determine the regional specificity of WM differences. Thirty-six healthy adults between the ages of 55 and 65 years participated in the study. Based on the participants' exercise habits, they were allocated into three groups: Tai Chi, walking, or sedentary control. All participants were required to complete physical fitness measurements and completed magnetic reasoning imaging (MRI) scans. Our results revealed that the Tai Chi group exhibited a higher FA value in the left cerebral peduncle, compared to the sedentary control group. We also observed that both the Tai Chi and walking groups exhibited higher FA values in the right uncinate fasciculus and the left external capsule, in comparison to the sedentary control group. Increased FA values in these regions was positively correlated with higher levels of physical fitness measurements (i.e., peak oxygen uptake [VO 2 peak], muscular endurance/number of push-up, agility, power). These findings collectively suggest that regular exercise is associated with improved WM microstructural integrity, regardless of the exercise type, which could guide the development and application of future prevention and intervention strategies designed to address age-related cognitive impairments during late midlife., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Soya, Yassa, Li, Chu, Chen, Hung and Chang.)

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 18 F-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., (Copyright © 2022 the authors.)

A child's death is a profound loss for mothers and affects hundreds of thousands of women. Mothers report inconsolable and progressive grief that is distinct from depression and impacts daily emotions and functions. The brain mechanisms responsible for this relatively common and profound mental health problem are unclear, hampering its clinical recognition and care. In an initial exploration of this condition, we used resting state functional MRI (fMRI) scans to examine functional connectivity in key circuits, and task-based fMRI to examine brain network activity in grieving mothers in response to pictures of their deceased child and as well as recognizable deceased celebrities and unfamiliar individuals. We compared nine mothers who had lost an adult child and aged-matched control mothers with a living child of a similar age. Additionally, we collected diffusion imaging scans to probe structural connectivity and complemented the imaging studies with neuropsychological assessments. Increased functional activation in Ventral Attention/Salience Networks accompanied by a reduced activation in the medial prefrontal cortex in response to the deceased child's picture robustly distinguished the grieving mothers from controls. Heightened resting-state functional connectivity between the paraventricular thalamic nucleus (PVT) and the amygdala distinguished the grieving mothers from the controls and correlated with subjective grief severity. Structurally, maternal grief and its severity were associated with alterations in corticolimbic white matter tracts. Finally, grieving mothers performed worse than controls on neuropsychological tests of learning, memory, and executive function, linked with grief severity. Reduced activation in cortical regions inhibiting emotions and changes in the PVT circuitry-a region involved in long-term emotional memories and decision making under conflict-distinguish grieving mothers from controls. Notably, the magnitude of neurobiological changes correlates with the subjective severity of grief. Together, these new discoveries delineate a prevalent and under-recognized mental health syndrome and chart a path for its appreciation and care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kark, Adams, Sathishkumar, Granger, McMillan, Baram and Yassa.)

Research suggests a link between Alzheimer's Disease in Down Syndrome (DS) and the overproduction of amyloid plaques. Using Positron Emission Tomography (PET) we can assess the in-vivo regional amyloid load using several available ligands. To measure amyloid distributions in specific brain regions, a brain atlas is used. A popular method of creating a brain atlas is to segment a participant's structural Magnetic Resonance Imaging (MRI) scan. Acquiring an MRI is often challenging in intellectually-imparied populations because of contraindications or data exclusion due to significant motion artifacts or incomplete sequences related to general discomfort. When an MRI cannot be acquired, it is typically replaced with a standardized brain atlas derived from neurotypical populations (i.e. healthy individuals without DS) which may be inappropriate for use in DS. In this project, we create a series of disease and diagnosis-specific (cognitively stable (CS-DS), mild cognitive impairment (MCI-DS), and dementia (DEM-DS)) probabilistic group atlases of participants with DS and evaluate their accuracy of quantifying regional amyloid load compared to the individually-based MRI segmentations. Further, we compare the diagnostic-specific atlases with a probabilistic atlas constructed from similar-aged cognitively-stable neurotypical participants. We hypothesized that regional PET signals will best match the individually-based MRI segmentations by using DS group atlases that aligns with a participant's disorder and disease status (e.g. DS and MCI-DS). Our results vary by brain region but generally show that using a disorder-specific atlas in DS better matches the individually-based MRI segmentations than using an atlas constructed from cognitively-stable neurotypical participants. We found no additional benefit of using diagnose-specific atlases matching disease status. All atlases are made publicly available for the research community., Highlight: Down syndrome (DS) joint-label-fusion atlases provide accurate positron emission tomography (PET) amyloid measurements.A disorder-specific DS atlas is better than a neurotypical atlas for PET quantification.It is not necessary to use a disease-state-specific atlas for quantification in aged DS.Dorsal striatum results vary, possibly due to this region and dementia progression., Competing Interests: The authors do not have any conflict of interest to declare., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

The hippocampus is known to play a critical role in processing information about temporal context. However, it remains unclear how hippocampal oscillations are involved, and how their functional organization is influenced by connectivity gradients. We examined local field potential activity in CA1 as rats performed a nonspatial odor sequence memory task. We found that odor sequence processing epochs were characterized by distinct spectral profiles and proximodistal CA1 gradients of theta and 20-40 Hz power than track running epochs. We also discovered that 20-40 Hz power was predictive of sequence memory performance, particularly in proximal CA1 and during the plateau of high power observed in trials in which animals had to maintain their decision until instructed to respond. Altogether, these results provide evidence that dynamics of 20-40 Hz power along the CA1 axis are linked to trial-specific processing of nonspatial information critical to order judgments and are consistent with a role for 20-40 Hz power in gating information processing., Competing Interests: SG, GE, JJ, MY, NF No competing interests declared, (© 2022, Gattas et al.)

We determined the extent to which obstructive sleep apnea (OSA) is associated with increased cerebrovascular disease and amyloid burden, and the relation of the two processes across clinical Alzheimer's disease (AD) diagnostic groups in adults with Down syndrome (DS). Adults with DS from the Biomarkers of Alzheimer's Disease in Down Syndrome (ADDS) study were included given available research MRI ( n = 116; 50 ± 8 years; 42% women) and amyloid PET scans ( n = 71; 50 ± 7 years; 39% women) at the time of analysis. Participants were characterized as cognitively stable (CS; 64%), with mild cognitive impairment-DS (MCI-DS; 23%), with possible AD dementia (5%), or with definite AD dementia (8%). OSA was determined via medical records and interviews. Models tested the effect of OSA on MRI-derived cerebrovascular biomarkers and PET-derived amyloid burden, and the moderating effect of OSA and AD diagnosis on biomarkers. OSA was reported in 39% of participants, which did not differ by clinical AD diagnostic group. OSA was not associated with cerebrovascular biomarkers but was associated with greater cortical amyloid burden. White matter hyperintensity (WMH) volume (primarily in the parietal lobe), enlarged perivascular spaces, and cortical and striatal amyloid burden were greater across clinical AD diagnostic groups (CS

Introduction: We investigated whether monthly assessments of a computerized cognitive composite (C3) could aid in the detection of differences in practice effects (PE) in clinically unimpaired (CU) older adults, and whether diminished PE were associated with Alzheimer's disease (AD) biomarkers and annual cognitive decline. Materials and Methods: N = 114 CU participants (age 77.6 ± 5.0, 61% female, MMSE 29 ± 1.2) from the Harvard Aging Brain Study completed the self-administered C3 monthly, at-home, on an iPad for one year. At baseline, participants underwent in-clinic Preclinical Alzheimer's Cognitive Composite-5 (PACC5) testing, and a subsample ( n = 72, age = 77.8 ± 4.9, 59% female, MMSE 29 ± 1.3) had 1-year follow-up in-clinic PACC5 testing available. Participants had undergone PIB-PET imaging (0.99 ± 1.6 years before at-home baseline) and Flortaucipir PET imaging ( n = 105, 0.62 ± 1.1 years before at-home baseline). Linear mixed models were used to investigate change over months on the C3 adjusting for age, sex, and years of education, and to extract individual covariate-adjusted slopes over the first 3 months. We investigated the association of 3-month C3 slopes with global amyloid burden and tau deposition in eight predefined regions of interest, and conducted Receiver Operating Characteristic analyses to examine how accurately 3-month C3 slopes could identify individuals that showed >0.10 SD annual decline on the PACC-5. Results: Overall, individuals improved on all C3 measures over 12 months (β = 0.23, 95% CI [0.21-0.25], p < 0.001), but improvement over the first 3 months was greatest (β = 0.68, 95% CI [0.59-0.77], p < 0.001), suggesting stronger PE over initial repeated exposures. However, lower PE over 3 months were associated with more global amyloid burden ( r = -0.20, 95% CI [-0.38 - -0.01], p = 0.049) and tau deposition in the entorhinal cortex ( r = -0.38, 95% CI [-0.54 - -0.19], p < 0.001) and inferior-temporal lobe ( r = -0.23, 95% CI [-0.41 - -0.02], p = 0.03). 3-month C3 slopes exhibited good discriminative ability to identify PACC-5 decliners (AUC 0.91, 95% CI [0.84-0.98]), which was better than baseline C3 ( p < 0.001) and baseline PACC-5 scores ( p = 0.02). Conclusion: While PE are commonly observed among CU adults, diminished PE over monthly cognitive testing are associated with greater AD biomarker burden and cognitive decline. Our findings imply that unsupervised computerized testing using monthly retest paradigms can provide rapid detection of diminished PE indicative of future cognitive decline in preclinical AD., Competing Interests: RS receives research funding from NIA, Alzheimer's Association, Eli Lilly and Co., and Eisai. She has served as a consultant to AC Immune, Alyn Cytox, Janssen, Neurocentria, Roche, Prothena, and Shionogi but not directly relevant to this study. MY receives research funding from NIA and NIMH, served as a consultant for Pfizer, Eisai, Cognito Therapeutics, Curasen Therapeutics, BPT Pharma and Dart Neuroscience, and is co-founder of Enthorin Therapeutics and Augnition Labs, none of which are directly relevant to this study. PM is employed full time by Cogstate Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jutten, Rentz, Fu, Mayblyum, Amariglio, Buckley, Properzi, Maruff, Stark, Yassa, Johnson, Sperling and Papp.)

Running, compared to pedaling is a whole-body locomotive movement that may confer more mental health via strongly stimulating brains, although running impacts on mental health but their underlying brain mechanisms have yet to be determined; since almost the mechanistic studies have been done with pedaling. We thus aimed at determining the acute effect of a single bout of running at moderate-intensity, the most popular condition, on mood and executive function as well as their neural substrates in the prefrontal cortex (PFC). Twenty-six healthy participants completed both a 10-min running session on a treadmill at 50%[Formula: see text] and a resting control session in randomized order. Executive function was assessed using the Stroop interference time from the color-word matching Stroop task (CWST) and mood was assessed using the Two-Dimensional Mood Scale, before and after both sessions. Prefrontal hemodynamic changes while performing the CWST were investigated using functional near-infrared spectroscopy. Running resulted in significant enhanced arousal and pleasure level compared to control. Running also caused significant greater reduction of Stroop interference time and increase in Oxy-Hb signals in bilateral PFCs. Besides, we found a significant association among pleasure level, Stroop interference reaction time, and the left dorsolateral PFCs: important brain loci for inhibitory control and mood regulation. To our knowledge, an acute moderate-intensity running has the beneficial of inducing a positive mood and enhancing executive function coinciding with cortical activation in the prefrontal subregions involved in inhibitory control and mood regulation. These results together with previous findings with pedaling imply the specificity of moderate running benefits promoting both cognition and pleasant mood., (© 2021. The Author(s).)

Early life adversity (ELA) comprises a wide variety of negative experiences during early life and has been linked to cognitive impairments, reduced experiences of pleasure (anhedonia), and other long-term consequences implying that ELA impacts the reward circuitry. In this study, we focused on the projections from the dorsal raphe (DR) to the ventral tegmental area (VTA) and on to the nucleus accumbens (NAcc), an important pathway within the reward circuit. We hypothesized that ELA alters connectivity within the DR-VTA-NAcc pathway, associated with deficient reward seeking behaviors in adulthood. We used the limited bedding and nesting model to induce ELA in mice and measured reward-related behaviors in adulthood using the three-chamber social interaction and sucrose preference tests. High resolution ex vivo diffusion tensor imaging (DTI) was acquired and processed for regional DTI metrics, including tractography to assess circuit organization. We found brain-wide changes in radial diffusivity (RD) and altered connectivity of the reward circuit in the ELA group. DR-VTA-NAcc circuit tractography and axial diffusivity (AD) along this tract exhibited dispersed organization where AD was increased in the VTA segment. Behaviorally, ELA elicited a social anhedonia-like phenotype in adulthood with decreased direct social approach and time spent with peers in the three-chamber task, and no overt differences in sucrose preference. Our findings suggest that reward circuits, assessed using DTI, are altered following ELA and that these changes may reflect enduring reward deficits., Competing Interests: No competing financial interests or any other conflicts of interest exist., (© 2021 The Authors.)

The Advanced Normalizations Tools ecosystem, known as ANTsX, consists of multiple open-source software libraries which house top-performing algorithms used worldwide by scientific and research communities for processing and analyzing biological and medical imaging data. The base software library, ANTs, is built upon, and contributes to, the NIH-sponsored Insight Toolkit. Founded in 2008 with the highly regarded Symmetric Normalization image registration framework, the ANTs library has since grown to include additional functionality. Recent enhancements include statistical, visualization, and deep learning capabilities through interfacing with both the R statistical project (ANTsR) and Python (ANTsPy). Additionally, the corresponding deep learning extensions ANTsRNet and ANTsPyNet (built on the popular TensorFlow/Keras libraries) contain several popular network architectures and trained models for specific applications. One such comprehensive application is a deep learning analog for generating cortical thickness data from structural T1-weighted brain MRI, both cross-sectionally and longitudinally. These pipelines significantly improve computational efficiency and provide comparable-to-superior accuracy over multiple criteria relative to the existing ANTs workflows and simultaneously illustrate the importance of the comprehensive ANTsX approach as a framework for medical image analysis.

The paraventricular thalamic nucleus (PVT) is a small but highly connected nucleus of the dorsal midline thalamus. The PVT has garnered recent attention as a context-sensitive node within the thalamocortical arousal system that modulates state-dependent motivated behaviors. Once considered related to generalized arousal responses with non-specific impacts on behavior, accumulating evidence bolsters the contemporary view that discrete midline thalamic subnuclei belong to specialized corticolimbic and corticostriatal circuits related to attention, emotions, and cognition. However, the functional connectivity patterns of the human PVT have yet to be mapped. Here, we combined high-quality, high-resolution 7T and 3T resting state MRI data from 121 young adult participants from the Human Connectome Project (HCP) and thalamic subnuclei atlas masks to investigate resting state functional connectivity of the human PVT. The 7T results demonstrated extensive positive functional connectivity with the brainstem, midbrain, ventral and dorsal medial prefrontal cortex (mPFC), anterior and posterior cingulate, ventral striatum, hippocampus, and amygdala. These connections persist upon controlling for functional connectivity of the rest of the thalamus. Whole-brain contrasts provided further evidence that, compared to three nearby midline thalamic subnuclei, functional connectivity of the PVT is strong with the hippocampus, amygdala, ventral and dorsal mPFC, and middle temporal gyrus. These findings suggest that, even during rest, the human PVT is functionally coupled with many regions known to be structurally connected to rodent and non-human primate PVT. Further, cosine similarity analysis results suggested the PVT is integrated into the default mode network (DMN), an intrinsic connectivity network associated with episodic memory and self-referential thought. The current work provides a much-needed foundation for ongoing and future work examining the functional roles of the PVT in humans., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kark, Birnie, Baram and Yassa.)

Across species, unpredictable patterns of maternal behavior are emerging as novel predictors of aberrant cognitive and emotional outcomes later in life. In animal models, exposure to unpredictable patterns of maternal behavior alters brain circuit maturation and cognitive and emotional outcomes. However, whether exposure to such signals in humans alters the development of brain pathways is unknown. In mother-child dyads, we tested the hypothesis that exposure to more unpredictable maternal signals in infancy is associated with aberrant maturation of corticolimbic pathways. We focused on the uncinate fasciculus, the primary fiber bundle connecting the amygdala to the orbitofrontal cortex and a key component of the medial temporal lobe-prefrontal cortex circuit. Infant exposure to unpredictable maternal sensory signals was assessed at 6 and 12 months. Using high angular resolution diffusion imaging, we quantified the integrity of the uncinate fasciculus using generalized fractional anisotropy (GFA). Higher maternal unpredictability during infancy presaged greater uncinate fasciculus GFA in children 9-11 years of age ( n = 69, 29 female). In contrast to the uncinate, GFA of a second corticolimbic projection, the hippocampal cingulum, was not associated with maternal unpredictability. Addressing the overall functional significance of the uncinate and cingulum relationships, we found that the resulting imbalance of medial temporal lobe-prefrontal cortex connectivity partially mediated the association between unpredictable maternal sensory signals and impaired episodic memory function. These results suggest that unbalanced maturation of corticolimbic circuits is a mechanism by which early unpredictable sensory signals may impact cognition later in life. SIGNIFICANCE STATEMENT Our prior work across species demonstrated that unpredictable patterns of maternal care are associated with compromised memory function. However, the neurobiological mechanisms by which this occurs in humans remain unknown. Here, we identify an association of exposure to unpredictable patterns of maternal sensory signals with the integrity of corticolimbic circuits involved in emotion and cognition using state-of-the-art diffusion imaging techniques and analyses. We find that exposure to early unpredictability is associated with higher integrity of the uncinate fasciculus with no effect on a second corticolimbic pathway, the cingulum. The resulting imbalance of corticolimbic circuit development is a novel mediator of the association between unpredictable patterns of maternal care and poorer episodic memory., (Copyright © 2021 the authors.)

Introduction: Down syndrome (DS) is associated with elevated risk for Alzheimer's disease (AD) due to amyloid beta (Aβ) lifelong accumulation. We hypothesized that the spatial distribution of brain Aβ predicts future dementia conversion in individuals with DS., Methods: We acquired 18 F-florbetapir positron emission tomography scans from 19 nondemented individuals with DS at baseline and monitored them for 4 years, with five individuals transitioning to dementia. Machine learning classification using an independent test set determined features on 18 F-florbetapir standardized uptake value ratio maps that predicted transition., Results: In addition to "AD signature" regions including the inferior parietal cortex, temporal lobes, and the cingulum, we found that Aβ cortical binding in the prefrontal and superior frontal cortices distinguished subjects who transitioned to dementia. Classification did well in predicting transitioners., Discussion: Our study suggests that specific regional profiles of brain amyloid in older adults with DS may predict cognitive decline and are informative in evaluating the risk for dementia., Competing Interests: The authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest, or non‐financial interest in the subject matter or materials discussed in this article., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: Loss of entorhinal cortex (EC) layer II neurons represents the earliest Alzheimer's disease (AD) lesion in the brain. Research suggests differing functional roles between two EC subregions, the anterolateral EC (aLEC) and the posteromedial EC (pMEC)., Methods: We use joint label fusion to obtain aLEC and pMEC cortical thickness measurements from serial magnetic resonance imaging scans of 775 ADNI-1 participants (219 healthy; 380 mild cognitive impairment; 176 AD) and use linear mixed-effects models to analyze longitudinal associations among cortical thickness, disease status, and cognitive measures., Results: Group status is reliably predicted by aLEC thickness, which also exhibits greater associations with cognitive outcomes than does pMEC thickness. Change in aLEC thickness is also associated with cerebrospinal fluid amyloid and tau levels., Discussion: Thinning of aLEC is a sensitive structural biomarker that changes over short durations in the course of AD and tracks disease severity-it is a strong candidate biomarker for detection of early AD., Competing Interests: The authors declare no conflicts of interest relevant to this article., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Pattern separation (PS) describes the process by which the brain discriminates similar stimuli from previously encoded stimuli. This fundamental process requires the intact processing by specific subfields in the hippocampus and can be examined using mnemonic discrimination tasks. Previous studies reported different patterns for younger and older individuals between mnemonic discrimination performance and hippocampal subfield activation. Here, we investigated the relationship between the lure discrimination index (LDI) and hippocampal subfield volume and activity across the adult lifespan (20-70 years old). Using ultra-high field functional and structural magnetic resonance imaging at 7 T, we found that lower DG volume and higher CA3 activation was associated with worse LDI performance in individuals (>60 years), suggesting that this higher activation may be an indication of aberrant neurodegenerative-related processes. In fact, higher activation in the CA1 and DG was associated with lower volumes in these subfields. For individuals around 40-50 years old, we observed that greater left and right DG volume, and greater activity in the CA3 was associated with lower LDI performance. Taken together, these results suggest that the relationship between memory and hippocampal subfield structure or function varies nonlinearly and possibly reciprocally with age, with midlife being a critically vulnerable period in life.

Introduction: Down syndrome (DS) is associated with a higher risk of dementia. We hypothesize that amyloid beta (Aβ) in specific brain regions differentiates mild cognitive impairment in DS (MCI-DS) and test these hypotheses using cross-sectional and longitudinal data., Methods: 18F-AV-45 (florbetapir) positron emission tomography (PET) data were collected to analyze amyloid burden in 58 participants clinically classified as cognitively stable (CS) or MCI-DS and 12 longitudinal CS participants., Results: The study confirmed our hypotheses of increased amyloid in inferior parietal, lateral occipital, and superior frontal regions as the main effects differentiating MCI-DS from the CS groups. The largest annualized amyloid increases in longitudinal CS data were in the rostral middle frontal, superior frontal, superior/middle temporal, and posterior cingulate cortices., Discussion: This study helps us to understand amyloid in the MCI-DS transitional state between cognitively stable aging and frank dementia in DS. The spatial distribution of Aβ may be a reliable indicator of MCI-DS in DS., Competing Interests: The Co‐Principal Investigators of the ADDS component of the ABC‐DS program are Nicole Schupf, PhD, Doctor of Public Health (DrPh) (Columbia University), Ira Lott, MD, and Wayne Silverman, PhD (UC Irvine). Co‐Principal Investigators of the NiAD ABC‐DS component are Benjamin Handen, PhD and William Klunk, MD, PhD (University of Pittsburgh), and Bradley Christian, PhD (University of Wisconsin‐Madison), (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of the Alzheimer's Association.)

Detailed representations of past events rely on the ability to form associations between items and their contextual features (i.e., source memory), as well as the ability to distinctly represent a new event from a similar one stored in memory (i.e., pattern separation). These processes are both known to engage the hippocampus, although whether they share similar mechanisms remains unclear. It is also unknown if, and in which region(s), activity related to these processes overlaps and/or interacts. Here, we used high-resolution fMRI to examine the contributions of hippocampal subfields and neocortical areas to pattern separation and source memory with an experimental paradigm that concurrently tested both. During encoding, male and female human subjects incidentally studied items in one of four quadrants on the screen. During test, they viewed repeated items (targets), similar items (lures), and new items (foils) and were asked to indicate whether each item was old, similar, or new. Following each item judgment, subjects were asked to indicate the quadrant in which the original stimulus was presented. Thus, each lure trial had a lure discrimination component (taxing pattern separation) and a location judgment (source memory). We found two main response profiles: (1) pattern separation-related signals in DG/CA3 and perirhinal cortex and (2) source memory signals in posterior CA1, parahippocampal cortex, and angular gyrus. Whole-brain voxelwise analysis revealed that activity related to lure discrimination and source memory was largely nonoverlapping. These findings suggest that distinct processes underlie the retrieval of pattern separated item representations and recollection of source information. SIGNIFICANCE STATEMENT Recalling past events with detail and accuracy depends on the ability to remember the contextual features of an event (i.e., source memory) as well as the ability to distinguish among similar events in memory (i.e., pattern separation). Previous work has shown that these processes are behaviorally dissociable (e.g., people can have clear memory for context but misidentify people or items). However, both processes engage the hippocampus, and it is unclear whether they rely on shared or distinct neural mechanisms. Here, we used high-resolution fMRI to concurrently assess hippocampal and neocortical activity related to source memory and pattern separation. We found that activity related to these processes was largely nonoverlapping, shedding light on two complementary but distinct mechanisms supporting episodic memory., (Copyright © 2020 the authors.)

People often recognize and remember faces of individuals within their own race more easily than those of other races. While behavioral research has long suggested that the Other-Race Effect (ORE) is due to extensive experience with one's own race group, the neural mechanisms underlying the effect have remained elusive. Predominant theories of the ORE have argued that the effect is mainly caused by processing disparities between same and other-race faces during early stages of perceptual encoding. Our findings support an alternative view that the ORE is additionally shaped by mnemonic processing mechanisms beyond perception and attention. Using a "pattern separation" paradigm based on computational models of episodic memory, we report evidence that the ORE may be driven by differences in successful memory discrimination across races as a function of degree of interference or overlap between face stimuli. In contrast, there were no ORE-related differences on a comparable match-to-sample task with no long-term memory load, suggesting that the effect is not simply attributable to visual and attentional processes. These findings suggest that the ORE may emerge in part due to "tuned" memory mechanisms that may enhance same-race, at the expense of other-race face detection.

Preclinical and clinical research indicates that excess corticosteroid is associated with adverse effects on the hippocampus. Animal model data suggest that N-methyl-D-aspartate (NMDA) receptor antagonists may block corticosteroid effect on the hippocampus. This translational clinical trial investigated the effect of memantine vs. placebo on hippocampal subfield volume in humans receiving chronic corticosteroid therapy. Men and women (N = 46) receiving chronic prescription corticosteroid therapy were randomized to memantine or placebo in a double-blind, crossover design (two 24-week treatment periods, separated by a 4-week washout) for 52 weeks. Structural magnetic resonance imaging was obtained at baseline and after each treatment. Data were analyzed using repeated measures analysis of variance. Mean corticosteroid dose was 7.69 ± 6.41 mg/day and mean duration 4.90 ± 5.61 years. Controlling for baseline volumes, the left DG/CA3 region was significantly larger following memantine than placebo (p = .011). The findings suggest that an NMDA receptor antagonist attenuates corticosteroid effect in the same hippocampal subfields in humans as in animal models. This finding has both mechanistic and clinical implications. Attenuation of the effect of corticosteroids on the human DG/CA3 region implicates the NMDA receptor in human hippocampal volume losses with corticosteroids. In addition, by suggesting a drug class that may, at least in part, block the effects of corticosteroids on the human DG/CA3 subfield, these results may have clinical relevance for people receiving prescription corticosteroids, as well as to those with cortisol elevations due to medical or psychiatric conditions.

Currently, over five million Americans suffer with Alzheimer's disease (AD). In the absence of a cure, this number could increase to 13.8 million by 2050. A critical goal of biomedical research is to establish indicators of AD during the preclinical stage (i.e. biomarkers) allowing for early diagnosis and intervention. Numerous advances have been made in developing biomarkers for AD using neuroimaging approaches. These approaches offer tremendous versatility in terms of targeting distinct age-related and pathophysiological mechanisms such as structural decline (e.g. volumetry, cortical thinning), functional decline (e.g. fMRI activity, network correlations), connectivity decline (e.g. diffusion anisotropy), and pathological aggregates (e.g. amyloid and tau PET). In this review, we survey the state of the literature on neuroimaging approaches to developing novel biomarkers for the amnestic form of AD, with an emphasis on combining approaches into multimodal biomarkers. We also discuss emerging methods including imaging epigenetics, neuroinflammation, and synaptic integrity using PET tracers. Finally, we review the complementary information that neuroimaging biomarkers provide, which highlights the potential utility of composite biomarkers as suitable outcome measures for proof-of-concept clinical trials with experimental therapeutics.

How do we remember emotional events? While emotion often leads to vivid recollection, the precision of emotional memories can be degraded, especially when discriminating among overlapping experiences in memory (i.e., pattern separation). Communication between the amygdala and the hippocampus has been proposed to support emotional memory, but the exact neural mechanisms remain unclear. Here, we used intracranial recordings in pre-surgical epilepsy patients to show that successful pattern separation of emotional stimuli is associated with theta band (3-7 Hz)-coordinated bidirectional interactions between the amygdala and the hippocampus. In contrast, discrimination errors (i.e., failure to discriminate similar stimuli) were associated with alpha band (7-13 Hz)-coordinated unidirectional influence from the amygdala to the hippocampus. These findings imply that alpha band synchrony may impair discrimination of similar emotional events via the amygdala-hippocampal directional coupling, which suggests a target for treatments of psychiatric conditions such as post-traumatic stress disorder, in which aversive experiences are often overgeneralized., (Copyright © 2019. Published by Elsevier Inc.)

Stress influences how we remember emotional events and how these events shape future behaviors. However, the impact of stress on memory specificity for emotional events has yet to be examined. To this end, the present study utilized a mnemonic discrimination task that taxes hippocampal pattern separation, the process of distinguishing between overlapping experiences, thereby allowing us to better understand the mechanisms by which stress affects gist versus detail memory of emotional events. Participants encoded scenes composed of negative or neutral objects placed on neutral backgrounds and then underwent a psychosocial stressor or matched control task. Twenty-four hours later during testing, objects were presented separately, with some identical old objects (targets), some new objects (foils), and some similar but not identical objects (lures). Target recognition was enhanced for negative compared to neutral objects in both the stress and control groups. Interestingly, post-encoding stress selectively enhanced mnemonic discrimination of negative versus neutral objects, which was not the case in the control group. Measures of salivary cortisol revealed a quadratic inverted U relationship between negative mnemonic discrimination and cortisol increase. These findings suggest that moderate cortisol release following stress is associated with enhanced memory precision for negative information., (© 2018 Cunningham and Payne; Published by Cold Spring Harbor Laboratory Press.)

Physical exercise has beneficial effects on neurocognitive function, including hippocampus-dependent episodic memory. Exercise intensity level can be assessed according to whether it induces a stress response; the most effective exercise for improving hippocampal function remains unclear. Our prior work using a special treadmill running model in animals has shown that stress-free mild exercise increases hippocampal neuronal activity and promotes adult neurogenesis in the dentate gyrus (DG) of the hippocampus, improving spatial memory performance. However, the rapid modification, from mild exercise, on hippocampal memory function and the exact mechanisms for these changes, in particular the impact on pattern separation acting in the DG and CA3 regions, are yet to be elucidated. To this end, we adopted an acute-exercise design in humans, coupled with high-resolution functional MRI techniques, capable of resolving hippocampal subfields. A single 10-min bout of very light-intensity exercise (30%[Formula: see text]) results in rapid enhancement in pattern separation and an increase in functional connectivity between hippocampal DG/CA3 and cortical regions (i.e., parahippocampal, angular, and fusiform gyri). Importantly, the magnitude of the enhanced functional connectivity predicted the extent of memory improvement at an individual subject level. These results suggest that brief, very light exercise rapidly enhances hippocampal memory function, possibly by increasing DG/CA3-neocortical functional connectivity., Competing Interests: The authors declare no conflict of interest.

The hippocampus plays a critical role in spatial memory. However, the exact neural mechanisms underlying high-fidelity spatial memory representations are unknown. We report findings from presurgical epilepsy patients with bilateral hippocampal depth electrodes performing an object-location memory task that provided a broad range of spatial memory precision. During encoding, patients were shown a series of objects along the circumference of an invisible circle. At test, the same objects were shown at the top of the circle (0°), and patients used a dial to move the object to its location shown during encoding. Angular error between the correct location and the indicated location was recorded as a continuous measure of performance. By registering pre- and postimplantation MRI scans, we were able to localize the electrodes to specific hippocampal subfields. We found a correlation between increased gamma power, thought to reflect local excitatory activity, and the precision of spatial memory retrieval in hippocampal CA1 electrodes. Additionally, we found a similar relationship between gamma power and memory precision in the dorsolateral prefrontal cortex and a directional relationship between activity in this region and in the CA1, suggesting that the dorsolateral prefrontal cortex is involved in postretrieval processing. These results indicate that local processing in hippocampal CA1 and dorsolateral prefrontal cortex supports high-fidelity spatial memory representations., Competing Interests: The authors declare no conflict of interest.

The entorhinal cortex (EC) is among the earliest brain areas to deteriorate in Alzheimer's disease (AD). However, the extent to which functional properties of the EC are altered in the aging brain, even in the absence of clinical symptoms, is not understood. Recent human fMRI studies have identified a functional dissociation within the EC, similar to what is found in rodents. Here, we used high-resolution fMRI to identify a specific hypoactivity in the anterolateral EC (alEC) commensurate with major behavioral deficits on an object pattern separation task in asymptomatic older adults. Only subtle deficits were found in a comparable spatial condition, with no associated differences in posteromedial EC between young and older adults. We additionally linked this condition to dentate/CA3 hyperactivity, and the ratio of activity between the regions was associated with object mnemonic discrimination impairment. These results provide novel evidence of alEC-dentate/CA3 circuit dysfunction in cognitively normal aged humans., (Copyright © 2018 Elsevier Inc. All rights reserved.)