Anterior Temporal Research Articles

Longitudinal hippocampal axis in large-scale cortical systems underlying development and episodic memory

The hippocampus is functionally specialized along its longitudinal axis with intricate interactions with cortical systems, which is crucial for understanding development and cognition. Using a well-established connectopic mapping technique on two large resting-state functional MRI datasets, we systematically quantified topographic organization of the hippocampal functional connectivity (hippocampal gradient) and its cortical interaction in developing brains. We revealed hippocampal functional hierarchy within the large-scale cortical brain systems, with the anterior hippocampus preferentially connected to an anterior temporal (AT) pathway and the posterior hippocampus embedded in a posterior medial (PM) pathway. We examined the developmental effects of the primary gradient and its whole-brain functional interaction. We observed increased functional specialization along the hippocampal long axis and found a general whole-brain connectivity shift from the posterior to the anterior hippocampus during development. Using phenotypic predictive modeling, we further delineated how the hippocampus is differentially integrated into the whole-brain cortical hierarchy underlying episodic memory and identified several key nodes within PM/AT systems. Our results highlight the importance of hippocampal gradient and its cortical interaction in development and for supporting episodic memory.

Anterior–temporal hippocampal network mechanisms of left angular gyrus-navigated rTMS for memory improvement in aMCI: A sham-controlled study

IntroductionNeuro-navigated repetitive transcranial magnetic stimulation (rTMS) of the left angular gyrus has been broadly investigated for the treatment of amnestic mild cognitive impairment (aMCI). Although abnormalities in two hippocampal networks, the anterior–temporal (AT) and posterior–medial (PM) networks, are consistent with aMCI and are potential therapeutic targets for rTMS, the underlying mechanisms of the therapeutic effects of rTMS on hippocampal network connections remain unknown. Here, we assessed the impact of left angular gyrus rTMS on activity in these networks and explored whether the treatment response was due to the distance between the clinically applied target (the group average optimal site) and the personalized target in patients with aMCI. MethodsSixty subjects clinically diagnosed with aMCI participated in this study after 20 sessions of sham-controlled rTMS targeting the left angular gyrus. Resting-state functional magnetic resonance imaging and neuropsychological assessments were performed before and after rTMS. Functional connectivity alterations in the PM and AT networks were assessed using seed-based functional connectivity analysis and two-factor repeated measures analysis of variance (ANOVA). We then computed the correlations between the functional connectivity changes and clinical rating scales. Finally, we examined whether the Euclidean distance between the clinically applied and personalized targets predicted the subsequent treatment response. ResultsCompared with the sham group, the active rTMS group showed rTMS-induced deactivation of functional connectivity within the medial temporal lobe-AT network, with a negative correlation with episodic memory score changes. Moreover, the active rTMS lowers the interdependency of changes in the PM and AT networks. Finally, the Euclidean distance between the clinically applied and personalized target distances could predict subsequent network lever responses in the active rTMS group. ConclusionsNeuro-navigated rTMS selectively modulates widespread functional connectivity abnormalities in the PM and AT hippocampal networks in aMCI patients, and the modulation of hippocampal-AT network connectivity can efficiently reverse memory deficits. The results also highlight the necessity of personalized targets for fMRI.

Age-related enhancement of the association between episodic memory and gray matter volume in medial temporal and frontal lobes

BackgroundEpisodic memory (EM) deteriorates as a result of normal aging as well as Alzheimer’s disease. The neural underpinnings of such age-related memory impairments in older individuals are not well-understood. Although previous research has unveiled the association between gray matter volume (GMV) and EM in the elderly population, such findings exhibit variances across distinct age cohorts. Consequently, an investigation into the dynamic evolution of this relationship with advancing age is imperative.ResultThe present study utilized a sliding window approach to examine how the correlation between EM and GMV varied with age in a cross-sectional sample of 926 Chinese older adults. We found that both verbal EM (VEM) and spatial EM (SEM) exhibited positive correlations with GMV in extensive areas primarily in the temporal and frontal lobes and that these correlations typically became stronger with older age. Moreover, there were variations in the strength of the correlation between EM and GMV with age, which differed based on sex and the specific type of EM. Specifically, the association between VEM and GMVs in the insula and parietal regions became stronger with age for females but not for males, whereas the association between SEM and GMVs in the parietal and occipital regions became stronger for males but not for females. At the brain system level, there is a significant age-related increase in the correlations between both types of EM and the GMV of both the anterior temporal (AT) system and the posterior medial (PM) system in male group. In females, both types of EM show stronger age-related correlations with the GMV of the AT system compared to males.ConclusionsOur study revealed a significant positive correlation between GMV in most regions associated with EM and age, particularly in the frontal and temporal lobes. This discovery offers new insights into the connection between brain structure and the diminishing episodic memory function among older individuals.

Increased medial temporal lobe functional connectivity is critical in Alzheimer’s disease: evidences from longitudinal analyses across the whole cognitive continuum

AbstractBackgroundThe medial temporal lobe is extensively connected to the whole brain through two functional networks: the anterior‐temporal (AT) and posterior‐medial (PM) systems. While both increased and decreased functional connectivity (FC) have been reported in Alzheimer’s disease (AD), the specific changes in each network and their clinical relevance throughout AD stages remain to be elucidated. To fill this gap, we aimed to provide a comprehensive overview of AT‐ and PM‐FC changes, and links with AD imaging‐biomarkers, clinical severity and dementia onset, using longitudinal data covering the whole cognitive continuum.MethodLongitudinal data were acquired in 209 cognitively unimpaired (CU) adults aged 19‐85 (n = 56 Aβ‐ over 60), 26 Aβ+ patients with mild cognitive impairment (MCI) (n = 18 AD‐converters), and 26 Aβ+ AD‐demented patients, all followed up to 4 years. All underwent resting‐state (rs)‐fMRI, T1‐w MRI, Florbetapir‐ and FDG‐PET. Connectivity maps were generated from seed‐to‐voxels analyses applied to rs‐fMRI using individual ROIs (AT = perirhinal cortex, PM = parahippocampal cortex). The networks were defined by comparing baseline CU Aβ‐ AT to PM maps (and vice‐versa) using paired permutation t‐tests with FWE correction. Mean FC was then extracted from these masks for each participant. Generalized additive and linear mixed models were run to assess AT‐ and PM‐FC changes across the whole cognitive continuum, and their relationships with i)‐amyloid uptake, ii)‐glucose metabolism, iii)‐hippocampal volume and iv)‐cognitive deficit within participants>60yo, and v)‐AD‐conversion time in MCI patients.ResultResults showed that AT‐FC linearly increased from younger to Aβ+ AD‐demented adults while PM‐FC decreased along the healthy lifespan and then remained stable across the AD continuum (Aβ+ individuals). Higher AT‐FC was associated with i)‐higher amyloid uptake, ii)‐lower glucose metabolism, iii)‐smaller hippocampal volume, iv)‐lower MMSE/Mattis scores and v)‐faster AD‐dementia onset. No such relationships were found with PM‐FC.ConclusionBy encompassing the whole cognitive continuum and assessing longitudinal changes, we highlighted that AT‐ and PM‐FC alterations differ in aging and AD. While reduced PM connectivity seems restricted to age‐related processes (corroborated by no correlation with AD‐signature changes), increased AT connectivity seems to result from specific AD‐related mechanisms. Importantly, we evidenced that AT hyper‐connectivity appears critical in AD and might predict clinical and pathological outcomes.

Age‐related and AD pathology‐related differences in neural activation and neural specificity in memory

AbstractBackgroundBeta‐amyloid (Aß) and tau deposition is spatially selective in the early stages of Alzheimer’s Disease (AD), with Aß depositing predominately in posterior‐medial (PM) regions and tau accumulating in the medial temporal lobe (MTL) with increasing age before spreading to anterior‐temporal (AT) regions. Functionally, AT and PM are linked to object and scene processing, respectively, and the hippocampus in the MTL is important for integration and forming associations between objects and scenes. Given the differential vulnerability of AT, PM, and MTL to Aß and tau, we examined the behavioral and neural differences in memory for objects, scenes, and object‐in‐scene pairs between young and cognitively normal older adults with and without AD pathologies.MethodTwenty‐three young (19‐34 yrs) and 32 older (60‐91 yrs) participants completed an incidental encoding task on object, scene, and object‐in‐scene pair images during fMRI and a recognition test outside the scanner (Fig.1). Thirty older participants underwent PiB and FTP PET that measured Aß and tau. We conducted univariate whole‐brain analysis and multi‐voxel pattern analysis (MVPA) of AT, PM, and the hippocampus. The MVPA trains a support vector machine to classify the stimulus category (object, scene, pair) based on the ROI’s activation pattern. A higher classification accuracy represents informative neural representation that reflects functional specificity of the region.ResultBehaviorally, older people had worse object (ps<.027) and pair (ps<.017) memory. Greater temporal meta‐ROI tau was related to worse object (p = .032) and pair (p = .022) memory. Whole‐brain analyses showed activations in AT and PM networks for object and scene processing, and additional frontal, temporal, and occipital regions for pair processing (Fig.2A‐C) where older adults, compared to younger adults, showed activation reductions in fusiform, parahippocampal, precuneus, and occipital regions (Fig.2D). The MVPA revealed age‐related reductions in classification accuracy for pairs (Fig.3A) and that greater Aß and tau were related to lower accuracy in the hippocampus (Fig.3B).ConclusionWe found evidence supporting specific vulnerabilities in object and associative memory in older adults correlated with tau pathology. FMRI findings suggest both lower neural activation and lower neural specificity in older adults when processing complex associations. AD pathology appears to contribute to lower neural specificity in the hippocampus.

Within‐network Functional Connectivity of Intrinsic Networks in SuperAgers

AbstractBackgroundMemory decline in late life is a hallmark of aging, yet SuperAgers are individuals age 80 or older with episodic memory performance at least as good as cognitively average 50‐to‐60‐year‐olds. Neuroimaging analyses have found SuperAgers to have thicker cortices and slower atrophy rates compared to similarly aged controls (Controls). This project extended the anatomical findings by examining the functional integrity of seven intrinsic networks spanning the entire cortex and two memory‐specific systems identified from task‐based and resting state studies.MethodsWithin‐network functional connectivity (FC) of seven large‐scale networks and two memory systems were compared between 25 SuperAgers and 16 Controls using resting state functional MRI (rs‐fMRI) and T1‐weighted structural imaging from a single visit. Classification of SuperAgers/Controls was determined based on measures of episodic memory, executive functioning, verbal fluency, and picture naming (Harrison et al., 2012). Inclusion criteria required stable cognitive status across two visits. In the first analysis, we included all seven networks from a common resting‐state atlas (Schaefer et al., 2018). Within‐network FCs for all networks were defined as the average FCs between all within‐network regions (Figure 1A). In the second analysis, we investigated two memory‐specific networks: the anterior temporal (AT) and posterior medial (PM) systems. AT and PM cortical maps (Figure 1B) were identified from prior research (de Flores et al., 2022). Within‐network FC of the AT and PM systems were defined as the FC between AT‐to‐anterior‐hippocampus and PM‐to‐posterior‐hippocampus, respectively. For both analyses, FCs were compared across groups using two‐sample independent t‐tests and corrected for multiple comparisons (Benjamini‐Hochberg false discovery rate).ResultsWe found no significant between‐group differences in demographic characteristics including age, sex, and education. Performance on neuropsychological measures was significantly different for episodic memory, verbal fluency, and picture naming. Group differences in within‐network FCs for large‐scale networks and memory systems were nonsignificant.ConclusionAt the group‐level, within‐network FC of large‐scale networks and memory‐specific systems were not a primary differentiator between cognitively average aging and SuperAging phenotypes. Person‐specific functional connectome approaches may be important for understanding network organizational features of SuperAgers.

Aging and Alzheimer’s Disease Have Dissociable Effects on Local and Regional Medial Temporal Lobe Connectivity

AbstractBackgroundThe extent to which pathological processes in aging and Alzheimer’s disease (AD) relate to functional disruption of the medial temporal lobe (MTL)‐dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity (FC) alterations between anterior and posterior regions of the MTL and in MTL‐associated functional communities – the Anterior‐Temporal (AT) and Posterior‐Medial (PM) networks – in normal agers, individuals with preclinical AD, and patients with Mild Cognitive Impairment or mild dementia due to AD.MethodIn this cross‐sectional study, we analyzed data from 179 individuals from the Aging Brain Cohort study of the Penn ADRC. Detailed information about participants is provided in Table 1. For intra‐MTL FC comparisons, the MTL subregions were segmented using the automated segmentation of hippocampal subfields‐T1 (ASHS‐T1) pipeline (Fig. 1a). When modeling the MTL’s interactions with the rest of the cortex, we employed four MTL ROIs (left/right × anterior/posterior) derived from an ex vivo atlas of tau accumulation in the MTL. Our functional datasets were preprocessed using a customized fMRIprep pipeline. Sparse network estimations and modularity‐based consensus clustering were used to reconstruct the AT and PM network systems (Fig. 1b). Age effect analyses and group comparisons along the AD continuum were performed using the General Linear Model within the network‐based statistical framework.ResultsThe preclinical stage of AD was characterized by increased FC between the perirhinal cortex and other regions of the MTL, as well as between the anterior MTL and its direct neighbors in the AT network (Fig. 1c‐d). This effect was not present in symptomatic AD. Instead, symptomatic patients displayed reduced hippocampal and intra‐PM connectivity. For normal aging, our results led to three main conclusions (for visuals, see Fig. 2). First, intra‐network connectivity of both the AT and PM networks decreases with age. Second, FC between the anterior and posterior segments of the MTL declines with age. Finally, within the MTL, we observed greater vulnerability of the posterior MTL subregions, particularly the parahippocampal cortex, to age‐associated FC decline.ConclusionTogether, the current results provide evidence for aberrant connectivity in the preclinical stage of AD that may have implications for early AD pathophysiology.

Aging and Alzheimer’s Disease Have Dissociable Effects on Local and Regional Medial Temporal Lobe Connectivity

AbstractBackgroundThe extent to which pathological processes in aging and Alzheimer’s disease (AD) relate to functional disruption of the medial temporal lobe (MTL)‐dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity (FC) alterations between anterior and posterior regions of the MTL and in MTL‐associated functional communities – the Anterior‐Temporal (AT) and Posterior‐Medial (PM) networks – in normal agers, individuals with preclinical AD, and patients with Mild Cognitive Impairment or mild dementia due to AD.MethodIn this cross‐sectional study, we analyzed data from 179 individuals from the Aging Brain Cohort study of the Penn ADRC. Detailed information about participants is provided in Table 1. For intra‐MTL FC comparisons, the MTL subregions were segmented using the automated segmentation of hippocampal subfields‐T1 (ASHS‐T1) pipeline (Fig. 1a). When modeling the MTL’s interactions with the rest of the cortex, we employed four MTL ROIs (left/right × anterior/posterior) derived from an ex vivo atlas of tau accumulation in the MTL. Our functional datasets were preprocessed using a customized fMRIprep pipeline. Sparse network estimations and modularity‐based consensus clustering were used to reconstruct the AT and PM network systems (Fig. 1b). Age effect analyses and group comparisons along the AD continuum were performed using the General Linear Model within the network‐based statistical framework.ResultThe preclinical stage of AD was characterized by increased FC between the perirhinal cortex and other regions of the MTL, as well as between the anterior MTL and its direct neighbors in the AT network (Fig. 1c‐d). This effect was not present in symptomatic AD. Instead, symptomatic patients displayed reduced hippocampal and intra‐PM connectivity. For normal aging, our results led to three main conclusions (for visuals, see Fig. 2). First, intra‐network connectivity of both the AT and PM networks decreases with age. Second, FC between the anterior and posterior segments of the MTL declines with age. Finally, within the MTL, we observed greater vulnerability of the posterior MTL subregions, particularly the parahippocampal cortex, to age‐associated FC decline.ConclusionTogether, the current results provide evidence for aberrant connectivity in the preclinical stage of AD that may have implications for early AD pathophysiology.

Greater age‐related cognitive decline in perceptual discrimination of objects than scenes: A cross‐cultural study

AbstractBackgroundAccording to the “PMAT” framework, two distinct cortico‐hippocampal networks – the posterior‐medial (PM) and anterior‐temporal (AT) networks – are involved in the processing of scene and object content respectively (Ranganath & Ritchey, 2012). It has been suggested that aging predominantly affects the AT network (Berron et al., 2018), and recent studies show evidence for early impairment in object relative to scene mnemonic discrimination with age (Reagh et al., 2016; Gusten et al., 2021). Age‐dependent impairments in object discrimination even exist outside the realm of episodic memory tasks, such as in perceptual oddity tasks (Graham et al., 2010). We aim to extend these findings with i) a digital Oddity perceptual discrimination task, and ii) a cross‐cultural sample.MethodWe tested healthy participants in the UK (n = 141) and India (n = 149) aged between 18‐70 years on a novel multi‐category Oddity discrimination task including object and scene categories. Using a combined speed‐accuracy measure, Inverse Efficiency Score (IES), we applied a mixed‐effects modelling approach to analyse the age trajectory of performance across categories.ResultsWe found a significant decline in performance with age across stimulus categories and cultures, and object performance showed a significantly steeper decline than scenes in both cultures.ConclusionThese findings are amongst the first to indicate that the Oddity discrimination task is sensitive and specific to age‐related cognitive decline across cultures. Notably, these findings support the idea that the object/ AT network is more sensitive to age (potentially reflecting tau pathology) than the scene/ PM network (Berron et al., 2020). Therefore, perceptual discrimination tasks may be a promising cross‐cultural assessment tool for the early detection and differential diagnosis of patterns of age‐related cognitive decline.

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.

Mechanisms linking proteins and structural brain integrity to biological markers of Alzheimer’s Disease

AbstractBackgroundMedial temporal lobe (MTL) networks, including posterior‐medial (PM) and anterior‐temporal (AT) subnetworks, are early affected by Alzheimer’s disease (AD) pathologies (tau, neurodegeneration) and are critical for memory, which declines in AD. The biological pathways linking AD pathology, changes in MTL‐AT‐PM structural connectivity (SC), and cognitive decline, are unknown. Plasma protein levels reflect those in the cerebrospinal fluid, providing a low‐invasive potential means of understanding molecular brain changes that occur in AD. These measures may help explain how AD pathology, MTL‐AT‐PM SC, and cognitive decline are linked at the molecular level. We used predefined aging‐related plasma proteins from a meta‐analysis to explore links between MTL‐AT‐PM SC, AD pathologies, and cognitive decline.MethodMTL‐AT‐PM SC scores and plasma protein levels from 100 participants (Stanford ADRC: mean age = 73.7y, 82 healthy control, 16 mild cognitive impairment, and 2 AD) were entered into an Coupled tensor and matrix factorization algorithm, generating clusters based on shared SC‐protein variance. Linear regression analyses were conducted to evaluate cluster relationships with domains of AD (memory, plasma tau, and neurodegeneration by plasma NfL and cortical thickness index).ResultTwo (out of 12 total) SC‐protein clusters significantly related to both tau and neurodegeneration. Both had similar highly contributing proteins (TNFRSF1B.3152.57.1, TNFRSF1B.8368.102.3, GRN.4992.49.1, TNC.4155.3.2, RPS3A.5484.63.3, CD163.5028.59.1, EFNA4.2614.28.2) and SC regions (bilateral: hippocampus, and left: parahippocampal cortex, precuneus, thalamus, and isthmus cingulate). Hippocampal laterality (bilateral vs. opposite directions for left vs. right) and the direction of their relationship to tau/neurodegeneration differentiated these clusters. A 3rd cluster was uniquely associated with composite memory (SC: bilateral: lateral occipital and parahippocampus, left: inferior temporal and hippocampus; proteins: EGFR.2677.1.1, SFRP1.3221.54.1, FAS.9459.7.3, ERBB3.2617.56.35, CFD.13678.169.3, LRP1.8601.167.3, and LPO.4801.13.3).ConclusionProtein‐SC clusters showed both overlapping and unique associations to AD‐associated memory, tau, and neurodegeneration. Two clusters centered on the hippocampus and proteins related to inflammation showed relationships to both tau and neurodegeneration, suggesting they may be important for linking these two aspects of AD pathology. A memory‐related cluster was dominated by neurogenesis related proteins, and occipital/parahippocampal cortex. These findings suggest molecular pathways may differentially affect the left vs. right hippocampus, and AD‐associated pathologies vs. cognition.

Impaired large-scale cortico-hippocampal network connectivity, including the anterior temporal and posterior medial systems, and its associations with cognition in patients with first-episode schizophrenia.

The cortico-hippocampal network is an emerging neural framework with striking evidence that it supports cognition in humans, especially memory; this network includes the anterior temporal (AT) system, the posterior medial (PM) system, the anterior hippocampus (aHIPPO), and the posterior hippocampus (pHIPPO). This study aimed to detect aberrant patterns of functional connectivity within and between large-scale cortico-hippocampal networks in first-episode schizophrenia patients compared with a healthy control group via resting-state functional magnetic resonance imaging (rs-fMRI) and to explore the correlations of these aberrant patterns with cognition. A total of 86 first-episode, drug-naïve schizophrenia patients and 102 healthy controls (HC) were recruited to undergo rs-fMRI examinations and clinical evaluations. We conducted large-scale edge-based network analysis to characterize the functional architecture of the cortico-hippocampus network and investigate between-group differences in within/between-network functional connectivity. Additionally, we explored the associations of functional connectivity (FC) abnormalities with clinical characteristics, including scores on the Positive and Negative Syndrome Scale (PANSS) and cognitive scores. Compared with the HC group, schizophrenia patients exhibited widespread alterations to within-network FC of the cortico-hippocampal network, with decreases in FC involving the precuneus (PREC), amygdala (AMYG), parahippocampal cortex (PHC), orbitofrontal cortex (OFC), perirhinal cortex (PRC), retrosplenial cortex (RSC), posterior cingulate cortex (PCC), angular gyrus (ANG), aHIPPO, and pHIPPO. Schizophrenia patients also showed abnormalities in large-scale between-network FC of the cortico-hippocampal network, in the form of significantly decreased FC between the AT and the PM, the AT and the aHIPPO, the PM and the aHIPPO, and the aHIPPO and the pHIPPO. A number of these signatures of aberrant FC were correlated with PANSS score (positive, negative, and total score) and with scores on cognitive test battery items, including attention/vigilance (AV), working memory (WM), verbal learning and memory (Verb_Lrng), visual learning and memory (Vis_Lrng), reasoning and problem-solving (RPS), and social cognition (SC). Schizophrenia patients show distinct patterns of functional integration and separation both within and between large-scale cortico-hippocampal networks, reflecting a network imbalance of the hippocampal long axis with the AT and PM systems, which regulate cognitive domains (mainly Vis_Lrng, Verb_Lrng, WM, and RPS), and particularly involving alterations to FC of the AT system and the aHIPPO. These findings provide new insights into the neurofunctional markers of schizophrenia.

Differential effects of age and sex on medial temporal lobe networks revealed by longitudinal analyses across the adult lifespan

AbstractBackgroundThe medial temporal lobe (MTL) is extensively connected to the rest of the brain through two specific networks which are particularly affected in Alzheimer’s disease (AD): the anterior‐temporal (AT) and posterior‐medial (PM) systems. As the specific and respective effects of age and sex on the functional integrity of these networks are still largely unknown, we sought to fill this gap using longitudinal data spanning the entire adult life.MethodLongitudinal data from 215 cognitively unimpaired adults (aged 19‐85, including 113 females, followed‐up up to 47 months, 419 scans) were analysed. Seed‐based analyses were applied to resting‐state functional magnetic resonance imaging to generate connectivity maps (seeds: the perirhinal cortex for AT and the parahippocampal cortex for PM). The AT and PM networks were defined by comparing baseline maps from adults younger than 40 using a paired permutation t‐test with threshold‐free cluster enhancement (TFCE) and familywise error (FWE) correction (p<.05) (Figure 1). These masks were then used to extract the mean functional connectivity (FC) for each participant. The interaction effects between network, age and sex were investigated using linear mixed models.ResultThere was a significant interaction between age and networks (p<.001), with a decrease of FC with age in PM and an increase in AT (Figure 2). Sex differences were also observed within these two systems (p<.001), with males exhibiting higher FC than females in AT but lower FC in PM (Figure 3). Age‐related trajectories were not modulated by sex differences (p>.05) and were best described by a linear relationship according to model comparison testing different polynomials.ConclusionBy encompassing the entire adult lifespan and assessing longitudinal changes, our study provides strong support that the two MTL networks display differential alterations in the context of aging, as well as sex differences. Since MTL connectivity has been described as particularly affected in the early stages of AD, and age and sex are risk factors, these findings may be helpful to enhance the clinical utility of such biomarkers for the early detection of AD‐related changes.

Differential effects of age and sex on medial temporal lobe networks revealed by longitudinal analyses across the adult lifespan

AbstractBackgroundThe medial temporal lobe (MTL) is extensively connected to the rest of the brain through two specific networks which are particularly affected in Alzheimer’s disease (AD): the anterior‐temporal (AT) and posterior‐medial (PM) systems. As the specific and respective effects of age and sex on the functional integrity of these networks are still largely unknown, we sought to fill this gap using longitudinal data spanning the entire adult life.MethodLongitudinal data from 215 cognitively unimpaired adults (aged 19‐85, including 113 females, followed‐up up to 47 months, 419 scans) were analysed. Seed‐based analyses were applied to resting‐state functional magnetic resonance imaging to generate connectivity maps (seeds: the perirhinal cortex for AT and the parahippocampal cortex for PM). The AT and PM networks were defined by comparing baseline maps from adults younger than 40 using a paired permutation t‐test with threshold‐free cluster enhancement (TFCE) and familywise error (FWE) correction (p<.05) (Figure 1). These masks were then used to extract the mean functional connectivity (FC) for each participant. The interaction effects between network, age and sex were investigated using linear mixed models.ResultThere was a significant interaction between age and networks (p<.001), with a decrease of FC with age in PM and an increase in AT (Figure 2). Sex differences were also observed within these two systems (p<.001), with males exhibiting higher FC than females in AT but lower FC in PM (Figure 3). Age‐related trajectories were not modulated by sex differences (p>.05) and were best described by a linear relationship according to model comparison testing different polynomials.ConclusionBy encompassing the entire adult lifespan and assessing longitudinal changes, our study provides strong support that the two MTL networks display differential alterations in the context of aging, as well as sex differences. Since MTL connectivity has been described as particularly affected in the early stages of AD, and age and sex are risk factors, these findings may be helpful to enhance the clinical utility of such biomarkers for the early detection of AD‐related changes.

Brain atrophy pattern in patients with mild cognitive impairment: MRI study.

We evaluated the accuracy of the quantitative and semiquantitative analysis in detecting regional atrophy patterns and differentiating mild cognitive impairment patients who remain stable (aMCI-S) from patients who develop Alzheimer’s disease (aMCI-AD) at clinical follow-up. Baseline magnetic resonance imaging was used for quantitative and semiquantitative analysis using visual rating scales. Visual rating scores were related to gray matter thicknesses or volume measures of some structures belonging to the same brain regions. Receiver operating characteristic (ROC) analysis was performed to assess measures’ accuracy in differentiating aMCI-S from aMCI-AD. Comparing aMCI-S and aMCI-AD patients, significant differences were found for specific rating scales, for cortical thickness belonging to the middle temporal lobe (MTL), anterior temporal (AT), and fronto-insular (FI) regions, for gray matter volumes belonging to MTL and AT regions. ROC curve analysis showed that middle temporal atrophy, AT, and FI visual scales showed better diagnostic accuracy than quantitative measures also when thickness measures were combined with hippocampal volumes. Semiquantitative evaluation, performed by trained observers, is a fast and reliable tool in differentiating, at the early stage of disease, aMCI patients that remain stable from those patients that may progress to AD since visual rating scales may be informative both about early hippocampal volume loss and cortical thickness reduction.

Medial Temporal Lobe Networks in Alzheimer's Disease: Structural and Molecular Vulnerabilities.

The medial temporal lobe (MTL) is connected to the rest of the brain through two main networks: the anterior-temporal (AT) and the posterior-medial (PM) systems. Given the crucial role of the MTL and networks in the physiopathology of Alzheimer's disease (AD), the present study aimed at (1) investigating whether MTL atrophy propagates specifically within the AT and PM networks, and (2) evaluating the vulnerability of these networks to AD proteinopathies. To do that, we used neuroimaging data acquired in human male and female in three distinct cohorts: (1) resting-state functional MRI (rs-fMRI) from the aging brain cohort (ABC) to define the AT and PM networks (n = 68); (2) longitudinal structural MRI from Alzheimer's disease neuroimaging initiative (ADNI)GO/2 to highlight structural covariance patterns (n = 349); and (3) positron emission tomography (PET) data from ADNI3 to evaluate the networks' vulnerability to amyloid and tau (n = 186). Our results suggest that the atrophy of distinct MTL subregions propagates within the AT and PM networks in a dissociable manner. Brodmann area (BA)35 structurally covaried within the AT network while the parahippocampal cortex (PHC) covaried within the PM network. In addition, these networks are differentially associated with relative tau and amyloid burden, with higher tau levels in AT than in PM and higher amyloid levels in PM than in AT. Our results also suggest differences in the relative burden of tau species. The current results provide further support for the notion that two distinct MTL networks display differential alterations in the context of AD. These findings have important implications for disease spread and the cognitive manifestations of AD.SIGNIFICANCE STATEMENT The current study provides further support for the notion that two distinct medial temporal lobe (MTL) networks, i.e., anterior-temporal (AT) and the posterior-medial (PM), display differential alterations in the context of Alzheimer's disease (AD). Importantly, neurodegeneration appears to occur within these networks in a dissociable manner marked by their covariance patterns. In addition, the AT and PM networks are also differentially associated with relative tau and amyloid burden, and perhaps differences in the relative burden of tau species [e.g., neurofibriliary tangles (NFTs) vs tau in neuritic plaques]. These findings, in the context of a growing literature consistent with the present results, have important implications for disease spread and the cognitive manifestations of AD in light of the differential cognitive processes ascribed to them.

Effect of Alzheimer’s pathology on the functional architecture of memory networks during rest and task states in aging

AbstractBackgroundIntrinsic brain networks are relatively consistently organized between rest and task states in young individuals. We performed this study in order to determine whether the same is true in aging, and whether measures of AD pathology affect this relationship.MethodWe used task‐based (mnemonic discrimination task with object and scene stimuli) and rest fMRI to measure functional connectivity (FC) in an anterior temporal (AT) and posteromedial (PM) network in older (OA; N=49, 74±5 years, 31F) and younger adults (YA; N=24, 27±4 years, 9F). We calculated the correlation between rest and task FC states by conducting a Pearson’s correlation between the rest and task FC matrices for each participant. We used PiB‐PET to measure global Aβ (using threshold of 1.065 to classify OA as PiB+/‐) and FTP‐PET to measure tau within an AT and PM composite ROI in OA. We also measured recognition memory performance during the mnemonic discrimination task requiring discrimination of repeated stimuli from lures.ResultResting state and task FC in the ATPM network were less correlated in older compared to younger adults. In addition, less correlated rest vs. task FC was associated with higher levels of FTP in ATPM networks in PiB+ older adults. Finally, less correlated rest vs. task FC was associated with worse recognition performance (among all participants and OA alone) during the object trials.ConclusionThese findings link AD pathology to disruption of the functional architecture of intrinsic brain networks during rest and memory task states in OA. They also suggest that memory decline in some older adults may be influenced by the extent of change in functional architecture between rest and task demands. Overall, dynamic FC changes from rest to task may provide a novel mechanism in which aging impacts cognition.

Does rehearsal matter? Left anterior temporal alpha and theta band changes correlate with the beneficial effects of rehearsal on working memory

Rehearsal during working memory (WM) maintenance is assumed to facilitate retrieval. Less is known about how rehearsal modulates WM delay activity. In the present study, 44 participants completed a Sternberg Task with either intact novel scenes or phase-scrambled scenes, which had similar color and spatial frequency but lacked semantic content. During the rehearsal condition participants generated a descriptive label during encoding and covertly rehearsed during the delay period. During the suppression condition participants did not generate a label during encoding and suppressed (repeated “the”) during the delay period. This was easy in the former (novel scenes) but more difficult in the later condition (phase-scrambled scenes) where scenes lacked semantic content. Behavioral performance and EEG delay activity was analyzed as a function of maintenance strategy. Performance during WM revealed a benefit of rehearsal for phase-scrambled but not intact scenes. Examination of the absolute amplitude revealed three underlying sources of activity for rehearsal, including the left anterior temporal (ATL) and left and midline parietal regions. Increases in alpha and theta activity in ATL were correlated with improvement in performance on WM with rehearsal only when labeling was not automatic (e.g., phase-scrambled scenes), which may reflect differences in labeling and rehearsal (i.e., semantic associations vs. shallow labels). We conclude that rehearsal only benefits memory for visual stimuli that lack semantic information, and that this is correlated with changes in alpha and theta rhythms.

Semantic Knowledge of Famous People and Places Is Represented in Hippocampus and Distinct Cortical Networks.

Studies have found that anterior temporal lobe (ATL) is critical for detailed knowledge of object categories, suggesting that it has an important role in semantic memory. However, in addition to information about entities, such as people and objects, semantic memory also encompasses information about places. We tested predictions stemming from the PMAT model, which proposes there are distinct systems that support different kinds of semantic knowledge: an anterior temporal (AT) network, which represents information about entities; and a posterior medial (PM) network, which represents information about places. We used representational similarity analysis to test for activation of semantic features when human participants viewed pictures of famous people and places, while controlling for visual similarity. We used machine learning techniques to quantify the semantic similarity of items based on encyclopedic knowledge in the Wikipedia page for each item and found that these similarity models accurately predict human similarity judgments. We found that regions within the AT network, including ATL and inferior frontal gyrus, represented detailed semantic knowledge of people. In contrast, semantic knowledge of places was represented within PM network areas, including precuneus, posterior cingulate cortex, angular gyrus, and parahippocampal cortex. Finally, we found that hippocampus, which has been proposed to serve as an interface between the AT and PM networks, represented fine-grained semantic similarity for both individual people and places. Our results provide evidence that semantic knowledge of people and places is represented separately in AT and PM areas, whereas hippocampus represents semantic knowledge of both categories.SIGNIFICANCE STATEMENT Humans acquire detailed semantic knowledge about people (e.g., their occupation and personality) and places (e.g., their cultural or historical significance). While research has demonstrated that brain regions preferentially respond to pictures of people and places, less is known about whether these regions preferentially represent semantic knowledge about specific people and places. We used machine learning techniques to develop a model of semantic similarity based on information available from Wikipedia, validating the model against similarity ratings from human participants. Using our computational model, we found that semantic knowledge about people and places is represented in distinct anterior temporal and posterior medial brain networks, respectively. We further found that hippocampus, an important memory center, represented semantic knowledge for both types of stimuli.

Neurodegeneration in medial temporal lobe subregions propagates within distinct functional networks in the AD continuum

AbstractBackgroundThe medial temporal lobe (MTL) is extensively connected to the rest of the brain through two specific networks: the anterior‐temporal (AT) and the posterior‐medial (PM) systems. As neurodegeneration is thought to occur along specific networks, our aim was to evaluate whether atrophy in perirhinal (PRC) vs parahippocampal cortices (PHC) ‐ two MTL nodes of the AT vs PM systems, respectively ‐ covary over time with distinct brain regions reflecting the AT vs PM networks.MethodLongitudinal T1‐weighted images (up to 3 scans, span: 1.73±0.49 years) of 117 Ab‐ Cognitively Normal elderly (CN), 65 Ab+ CN, 148 Ab+ MCI and 19 Ab+ AD individuals from ADNI were included. Annualized atrophy rates of PRC and PHC were estimated with an unbiased deformation‐based morphometry method. Whole‐brain cortical thickness annualized atrophy rates were estimated using ANTs. Voxel‐wise correlations between MTL measures and whole‐brain maps were performed to highlight structural covariance patterns [Pcluster(corr)<0.05, Pvoxel(uncorr)<0.01]. Functional connectivity analyses (seed‐based) were employed to define the AT and PM networks [Pcluster(corr)<0.05, Pvoxel(uncorr)<0.01] in an independent sample of 68 CN older adults. The overlap between structural covariance patterns and the AT and PM networks was visually inspected. T‐maps from the voxel‐wise correlations were used to calculate goodness of fit (GOF) indices with the AT and PM networks (GOF=tinside‐toutside).ResultFunctional connectivity analyses revealed two distinct networks: the AT network encompasses the amygdala and the temporopolar cortex extending posteriorly to inferior and middle temporal gyri while the PM network encompasses the posterior cingulate cortex, the precuneus, the cuneus, the angular and occipital gyri and the right insula (Figure 1‐a). PRC structurally covaried with the amygdala and the left temporopolar cortex, overlapping with the AT network (Figure 1‐b,c). In contrast, PHC covaried with the posterior cingulate cortex, the precuneus, the cuneus and the angular and occipital gyri, overlapping with the PM network (Figure 1‐b,d). PRC covariance showed best GOF with the AT system (1.10 vs ‐0.50 for PM) and PHC covariance showed best GOF with the PM system (0.92 vs ‐0.33 for AT).ConclusionOverall, MTL atrophy propagates within two distinct networks over time, recapitulating the typical atrophy pattern in AD.