Biology subjects

Rajah, M. N.

Publications and source records attributed to Rajah, M. N..

14 recordsLinked to original sources

bioRxiv2026

White Matter Lesion Asymmetry and Carotid Intraplaque Hemorrhage: A Novel Imaging Phenotype for Stroke Risk in Older Men

BackgroundWhile identifying high-risk carotid disease remains a significant clinical challenge, the specific role of carotid intraplaque hemorrhage (IPH) is poorly understood. Although IPH has been linked to white matter lesion (WML) burden, current assessments overlook the directional impact of plaque instability on the brain. This study sought to determine whether IPH is an independent driver of asymmetric WML pathology and evaluate if this phenotype can identify a high-risk demographic for TIA and stroke. MethodsThis multi-center retrospective study analyzed 264 participants (mean age 71.8 years) from the Canadian Atherosclerosis Imaging Network (2010-2015). Participants underwent 3T MRI to assess carotid IPH and WMLs. We quantified WMLs using a deep-learning pipeline to extract three biomarkers: volume (WML-ICV), intensity (WML-Intensity), and intensity ratio (WML-IR). The Asymmetry Index Measure (AIM) defined the inter-hemispheric log-ratio, while the association between IPH and AIM was examined using multivariable linear regression adjusted for age, sex, stenosis, and scanner manufacturer. A secondary composite outcome of TIA/stroke was analyzed via logistic regression to evaluate the interaction between IPH, age, and sex. ResultsWhile whole-brain WML burden did not significantly differ by IPH status (p > 0.60), IPH status was a robust independent predictor of hemispheric asymmetry (WML-ICV: p = 0.01; WML-Intensity, p = 0.01). Post-hoc analysis confirmed WML burden was significantly higher in IPH+ older males ([≥] 70 years) compared to younger cohorts (p < 0.04). This older male subgroup also demonstrated 4.57-fold higher adjusted odds of TIA/stroke (p = 0.02) compared to other demographic subgroups (all p > 0.87). ConclusionsCarotid IPH is independently associated with a rightward asymmetric WML phenotype not captured by global metrics. This imaging marker identifies a high-risk demographic of older males with a nearly five-fold increase in clinical events, suggesting that hemispheric-level analysis provides critical prognostic value for stroke risk stratification.

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bioRxiv2025

Longitudinal functional connectivity during rest and task is differentially related to Alzheimer's pathology and episodic memory in older adults

Changes in functional connectivity (FC) strength involving the medial temporal lobe (MTL) and posteromedial cortex (PMC) are related to early Alzheimers pathology and alterations in episodic memory performance in cognitively unimpaired older adults, but their dynamics remain unclear. We examined how longitudinal changes in FC involving MTL and PMC during resting-state, episodic memory encoding, and retrieval relate to subsequent amyloid- and tau- PET burden, longitudinal episodic memory performance, and the APOE4 genotype in 152 cognitively unimpaired older adults from the PREVENT-AD cohort. We found APOE4- and fMRI paradigm-dependent associations of change in FC strength with pathology burden and change in episodic memory performance. Decreasing FC over time, or "hypoconnectivity", within PMC during rest in APOE4 carriers and during retrieval in APOE4 non-carriers was related to more amyloid and tau, respectively. Conversely, increasing FC over time, or "hyperconnectivity", within MTL during encoding in APOE4 carriers and between MTL and PMC during retrieval independent of APOE4 status was related to more tau. Further, increasing FC between MTL and PMC during rest, unlike during encoding, was beneficial for episodic memory. Our study highlights that pathology-related episodic memory network changes manifest differently during rest and task and have differential implications for episodic memory trajectories.

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bioRxiv2024

Precuneus activity during retrieval is positively associated with amyloid burden in cognitively normal older APOE4 carriers

The precuneus is an early site of amyloid-beta (A{beta}) accumulation. Previous cross-sectional studies reported increased precuneus fMRI activity in older adults with mild cognitive deficits or elevated A{beta}. However, longitudinal studies in early Alzheimers disease (AD) risk stages are lacking and the interaction with Apolipoprotein-E (APOE) genotype is unclear. In the PREVENT-AD cohort, we assessed how precuneus activity during successful memory retrieval at baseline and over time relates to future A{beta} and tau burden and to change in memory performance. We further studied the moderation by APOE4 genotype. We included 165 older adults (age: 62.8{+/-}4.4 years; 113 female; 66 APOE4 carriers) who were cognitively normal at baseline and had a family history of AD. All participants performed task-fMRI at baseline and underwent 18F-flortaucipir-PET and 18F-NAV4694-A{beta}-PET on average 5 years later. We found that higher baseline activity and greater longitudinal change in activity in precuneus were associated with higher subsequent A{beta} in APOE4 carriers but not non-carriers. There were no effects of precuneus activity on tau burden. Finally, APOE4 non-carriers with low baseline activity in the precuneus exhibited better longitudinal performance in an independent memory test compared to APOE4 non-carriers with high baseline activity and APOE4 carriers. Our findings suggest that higher task-related precuneus activity at baseline and over time are associated with subsequent A{beta} burden in cognitively normal APOE4 carriers. Our results further indicate that the absence of hyperactivation and the absence of the APOE4 allele is related with the best future cognitive outcome in cognitively normal older adults at risk for AD. Significance StatementThe precuneus is a brain region involved in episodic memory function and is an early site of amyloid-beta (A{beta}) accumulation. Alterations in task-related activity occur in the precuneus with ageing as well as with Alzheimers disease (AD) pathology even in the absence of cognitive symptoms; however, their course and implications are not well understood. We demonstrate that higher precuneus activity at baseline and its change over time during successful memory retrieval is associated with higher A{beta} burden on average 5 years after baseline in Apolipoprotein-E4 (APOE4) carriers. Lower precuneus baseline activation was related to better memory performance over time in APOE4 non-carriers. Our findings provide novel longitudinal evidence that increased activity in posterior midline regions is linked to early AD pathology in dependence of APOE4 genotype.

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bioRxiv2024

Sex differences emerge after the menopause transition:Females show accelerated decline in episodic memory for spatial context at midlife

Background and ObjectivesThe ability to remember past events in rich contextual detail (episodic memory) declines with advancing age, with accelerated decline around midlife. Past research indicates there may be sex differences in cognitive aging trajectories and risk for age-related neurodegenerative diseases, i.e. Alzheimers Disease. Yet, little is known about how biological sex affects episodic memory in the adult lifespan. We examined age differences in episodic memory for spatial context in males and females. Research Design and Methods192 adults aged 21 to 65 (M=44, SD=13, 134 females) completed a face-location task measuring spatial context memory (correct spatial context retrieval rates) and facial item memory (correct recognition rates), and the California Verbal Learning Test version II (CVLT-II) measuring verbal item memory (long free recall, cued recall, and recognition rates). Changepoint regression analysis was used to estimate the slope of memory across age and any significant shifts in the slope (indicating critical transition periods). ResultsRegression analyses revealed that the best-fitting model for females on spatial context memory accuracy was a one-changepoint model, with gradual decline of 2% (SE=1) fewer correct responses per year of age from age 21 until age 50 (95% CI 41, 58), shifting to more rapid decline of 4% (SE=1) fewer correct responses per year of age until age 65. The best fitting model for males on spatial context memory accuracy was linear, with no significant changes across ages. The best fitting models for both sexes were linear for facial item memory accuracy, spatial context memory and facial item memory reaction times, and verbal item memory accuracy. Discussion and ImplicationMales and females show similar decline on spatial context memory from young adulthood until midlife, after which females show greater decline than males. Importantly, disaggregating by sex indicated that past midlife effects on episodic memory for context may be driven by a specific group of females (post-menopausal), as accelerated decline occurred at the same time as menopause in midlife females and did not occur in midlife males. Translational SignificanceO_ST_ABSProblem AddressedC_ST_ABSWe use changepoint regression to examine how biological sex influences age differences in remembering the context of past events (episodic memory). Main outcomeFemales, but not males, showed significantly greater decline on spatial context memory (i.e., correctly recalling the location of previously learned information) after age 50, which aligns with the time of menopause in midlife females. Implications for TranslationEpisodic memory for spatial context shows accelerated decline in females after midlife compared to before midlife, but not in midlife males, indicating the potential influence of menopause on aging of memory.

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bioRxiv2024

Menopause status and sex affect memory for spatial context information and white matter microstructure at midlife

Decline in spatial context memory emerges in midlife, the time when most females transition from pre-to post-menopause. Recent evidence suggests that, among post-menopausal females, advanced age is associated with functional brain alterations and lower spatial context memory. However, it is unknown whether similar effects are evident for white matter (WM) and, moreover, whether such effects contribute to sex differences at midlife. To address this, we conducted a study on 96 cognitively unimpaired middle-aged adults (30 males, 32 pre-menopausal females, 34 post-menopausal females). Spatial context memory was assessed using a face-location memory paradigm, while WM microstructure was assessed using diffusion tensor imaging. Behaviorally, advanced age was associated with lower spatial context memory in post-menopausal females but not pre-menopausal females or males. Additionally, advanced age was associated with microstructural variability in predominantly frontal WM (e.g., anterior corona radiata, genu of corpus callosum), which was related to lower spatial context memory among post-menopausal females. Our findings suggest that post-menopausal status enhances vulnerability to age effects on the brains WM and episodic memory.

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bioRxiv2023

The influence of chronological age and menopause status on the functional neural correlates of spatial context memory in middle-aged females.

Reductions in the ability to encode and retrieve past experiences in rich spatial contextual detail (episodic memory) are apparent by midlife - a time when most females experience spontaneous menopause. Yet, little is known about how menopause status affects episodic memory-related brain activity at encoding and retrieval in middle-aged pre- and post-menopausal females, and whether any observed group differences in brain activity and memory performance correlate with chronological age within group. We conducted an event-related task fMRI study of episodic memory for spatial context to address this knowledge gap. Multivariate behavioral partial least squares (PLS) was used to investigate how chronological age and retrieval accuracy correlated with brain activity in 31 premenopausal (age range: 39.55 - 53.30 yrs, Mage = 44.28 yrs, SDage = 3.12 yrs) and 41 postmenopausal females (age range: 46.70 to 65.14 yrs, Mage = 57.56 yrs, SDage = 3.93 yrs). We found that postmenopausal status, and advanced age within post-menopause, was associated with lower spatial context memory. The fMRI analysis showed that only in postmenopausal females, advanced age was correlated with decreased activity in occipitotemporal, parahippocampal, and inferior parietal during encoding and retrieval, and poorer spatial context memory performance. In contrast, only premenopausal females exhibited an overlap in encoding and retrieval activity in angular gyrus, midline cortical regions, and prefrontal cortex, which correlated with better spatial context retrieval accuracy. These results highlight how menopause status and chronological age, nested within menopause group, affect episodic memory and its neural correlates at midlife. Significance StatementThis is the first fMRI study to examine how pre- and post-menopause status affects the neural correlates of episodic memory encoding and retrieval, and how chronological age contributes to any observed group similarities and differences. We found that both menopause status (endocrine age) and chronological age affect spatial context memory and its neural correlates. Menopause status directly affected the direction of age- and performance-related correlations with brain activity in inferior parietal, parahippocampal and occipitotemporal cortices across encoding and retrieval. Moreover, we found that only premenopausal females exhibited cortical reinstatement of encoding-related activity in midline cortical, prefrontal, and angular gyrus, at retrieval. This suggests that spatial context memory abilities may rely on distinct brain systems at pre-compared to post-menopause.

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bioRxiv2021

Trial-by-trial fluctuations in post-stimulus attention during memory encoding predict subsequent associative context memory performance.

Episodic memory formation rate varies over time partly due to fluctuations in attentional state during memory encoding. Emerging evidence suggests that fluctuations in pre- and/or post-stimulus attention during encoding impact subsequent memory performance. It remains unclear how these fluctuations may differentially impact the subsequent retrieval of items alone, compared to items + their contextual details (associative context memory). In this study, we explored this in 30 healthy younger adults (21-34 years old). We developed the Montreal Attention at Encoding (MAET) task where on each encoding trial, participants responded as quickly as possible to a central fixation cross that expanded in size after a random duration. They then had to encode a picture of an object and its spatial location. Memory for the object-location associations was tested during retrieval. Response time (RT) to the fixation cross presented prior to each object gauged pre-stimulus attention levels on a trial-by-trial basis, while RT to the fixation cross that ensued each object indexed post-stimulus attention levels. Within-subject logistic regressions were used to predict context and item memory performance from pre- and post-stimulus RTs. Results revealed that encoding pre-stimulus attentional levels did not differentially predict context vs. item memory. However, post-stimulus RTs did predict subsequent context retrieval such that, longer post-stimulus RT to the fixation was related to poorer subsequent context retrieval. This study introduces a novel paradigm for investigating the impact of attentional state at encoding on subsequent memory performance and indicate a link between post-stimulus delays in attention-related RT and associative encoding success.

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bioRxiv2020

The Impact of the Siemens Trio to Prisma Upgrade and Volumetric Navigators on MRI Indices: A Reliability Study with Implications for Longitudinal Study Designs

Many magnetic resonance imaging (MRI) indices are being studied longitudinally to explore topics such as biomarker detection and clinical staging. A pertinent concern to longitudinal work is MRI scanner upgrades. When upgrades occur during the course of a longitudinal MRI neuroimaging investigation, there may be an impact on the compatibility of pre- and post-upgrade measures. Similarly, subject motion is another issue that may be detrimental to longitudinal MRI work; however, embedding volumetric navigators (vNavs) within acquisition sequences has emerged as a technique that allows for prospective motion correction. Our research group recently implemented an upgrade from a Siemens MAGNETOM 3T Trio system to a Siemens MAGNETOM 3T Prisma Fit system. The goals of the current work were to: 1) investigate the impact of this upgrade on commonly used structural imaging measures and proton magnetic resonance spectroscopy indices ("Prisma Upgrade protocol") and 2) examine structural imaging measures in a sequence with vNavs alongside a standard acquisition sequence ("vNav protocol"). In both protocols, while high reliability was observed for most of the investigated MRI outputs, suboptimal reliability was observed for certain indices. Across the scanner upgrade, increases in frontal, temporal, and cingulate cortical thickness (CT) and thalamus volume, along with decreases in parietal CT, amygdala, globus pallidus, hippocampus, and striatum volumes were observed across the Prisma upgrade, and were linked to increases in signal-to-noise ratios. No significant impact of the upgrade was found in 1H-MRS analyses. Further, CT estimates were found to be larger in MPRAGE acquisitions compared to vNav-MPRAGE acquisitions mainly within temporal areas, while the opposite was found mostly in parietal brain regions. The results from this work should be considered in longitudinal study designs and comparable prospective motion correction investigations are warranted in cases of marked head movement.

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bioRxiv2020

Creation of an Open Science Dataset from PREVENT-AD, a Longitudinal Cohort Study of Pre-symptomatic Alzheimer's Disease.

To move Alzheimer Disease (AD) research forward it is essential to collect data from large cohorts, but also make such data available to the global research community. We describe the creation of an open science dataset from the PREVENT-AD (PResymptomatic EValuation of Experimental or Novel Treatments for AD) cohort, composed of cognitively unimpaired older individuals with a parental or multiple-sibling history of AD. From 2011 to 2017, 386 participants were enrolled (mean age 63 years old {+/-} 5) for sustained investigation among whom 349 have retrospectively agreed to share their data openly. Repositories are findable through the unified interface of the Canadian Open Neuroscience Platform (https://portal.conp.ca/) and contain up to five years of longitudinal imaging data, cerebral fluid biochemistry, neurosensory capacities, cognitive, genetic, and medical information. Imaging data can be accessed openly at https://openpreventad.loris.ca while most of the other information, sensitive by nature, is accessible by qualified researchers at https://registeredpreventad.loris.ca. In addition to being a living resource for continued data acquisition, PREVENT-AD offers opportunities to facilitate understanding of AD pathogenesis.

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bioRxiv2019

APOE4 status is related to differences in memory-related brain function in asymptomatic older adults: Baseline analysis of the PREVENT-AD task fMRI dataset

Episodic memory decline is one of the earliest symptoms of late-onset Alzheimers Disease (AD) and older adults with the apolipoprotein E e4 (+APOE4) genetic risk factor for AD may exhibit altered patterns of memory-related brain activity years prior to initial symptom onset. In the current study we report the baseline episodic memory task fMRI results from the PRe-symptomatic EValuation of Experimental or Novel Treatments for Alzheimers Disease (PREVENT-AD) study in Montreal, Canada, in which 327 healthy older adults, within 15 years of the parents conversion to AD, were scanned. During the task fMRI protocol volunteers were scanned as they encoded and retrieved object-location spatial source associations. The task was designed to discriminate between brain activity related to successful spatial source recollection and failures in spatial source recollection, with memory for only item (object) memory. Multivariate task-related partial least squares (task PLS) was used to test the hypothesis that +APOE4 adults with a family history of AD would exhibit altered patterns of brain activity in the recollection-related memory network, comprised of medial frontal, parietal and medial temporal cortices, compared to APOE4 non-carriers (-APOE4). We also tested for group differences in the correlation between event-related brain activity and memory performance in +APOE4 compared to -APOE4 adults using behavioral-PLS (B-PLS). We found group similarities in memory performance and in task-related brain activity in the recollection network. However, the B-PLS results indicated there were group differences in brain activity-behavior correlations in ventral occipito-temporal, medial temporal, and medial prefrontal cortices during episodic encoding. These findings are consistent with previous literature on the influence of APOE4 on brain activity and provide new perspective on potential gene-based differences in brain-behavior relationships in people with parental history of AD. Future research should further investigate the potential to distinguish risk of AD development based on memory performance and associated patterns of brain activity.

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bioRxiv2019

Sex differences in the neural correlates of age-related episodic memory decline

Aging is associated with episodic memory decline and alterations in memory-related brain function. However, it remains unclear if age-related memory decline is associated with similar patterns of brain aging in women and men. In the current task fMRI study, we tested the hypothesis that there are sex differences in the effect of age and memory performance on brain activity during episodic encoding and retrieval of face-location associations (spatial context memory). Forty-one women and 41 men between the ages of 21 to 76 years participated in this study. Between-group multivariate partial least squares (PLS) analysis of the fMRI data was conducted to directly test for sex-group differences and similarities in age-related and performance-related patterns of brain activity. Our behavioural analysis indicated no significant sex differences in retrieval accuracy on the fMRI tasks. In relation to performance effects, we observed similarities and differences in how retrieval accuracy related to brain activity in women and men. Both sexes activated dorsal and lateral prefrontal cortex (PFC), inferior parietal cortex (IPC) and left parahippocampal gyrus (PHG) at encoding and this supported subsequent memory performance. However, there were sex differences in retrieval activity in these same regions and in lateral occipital-temporal and ventrolateral PFC. In relation to age effects, we observed sex differences in the effect of age on memory-related activity within PFC, IPC, PHG and lateral occipital-temporal cortices. Overall, our findings suggest that the neural correlates of age-related spatial context memory decline differ in women compared to men.

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bioRxiv2018

Preparing for the worst: Evidence that older adults proactively downregulate negative affect

Age-related differences in processing emotional stimuli are well established. However, previous studies have only assessed the impact of age on emotional processing and encoding in response to, not in anticipation of, emotional stimuli. In the current study, we investigated age-related differences in the impact of emotional anticipation on affective responses and episodic memory for emotional images. Young and older were scanned while encoding negative and neutral images preceded by cues that were either valid or invalid predictors of image valence. Participants were asked to rate the emotional intensity of the images and to complete an episodic recognition task immediately after scanning. Using multivariate behavioral partial least squares (PLS) analysis, we found that young and older adults recruit the same set of brain regions to differentially support emotional processing during the anticipation of emotional images. Specifically, anticipatory recruitment of the amygdala, ventromedial PFC, and hippocampus in older adults predicts reduced memory for negative than neutral images for older adults and the opposite for young adults. Seed PLS analyses further show inverse coupling between the amygdala and ventromedial PFC activation following negative cues, consistent with the top-down spontaneous suppression of negative affect. To the best of our knowledge, this is the first study to provide evidence that the \"positivity effect\" seen in older adults memory performance is related to the spontaneous suppression of negative affect in anticipation of, not just in response to, negative stimuli.

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bioRxiv2018

Cortical thickness in right frontal and left lingual gyri differentially mediate episodic memory for spatial contextual details across the adult lifespan

Healthy aging is associated with declines in episodic memory and with widespread cortical thinning. These parallel declines suggest that age-related changes in cortical thickness may contribute to episodic memory decline with age. The current study uses a cross-sectional study design to examine whether regional cortical thickness mediates the relationship between age and episodic memory, as measured by a context memory task for faces. Mediation and conditional mediation models were tested using bootstrapping in order to determine how age-associated changes in regional cortical thickness mediated age-associated changes in performance on the context memory task. We observed that right superior frontal cortical thickness conditionally mediated spatial context memory only in middle-aged and older adults; and right caudal middle frontal cortical thickness conditionally mediated context memory only in older adults. Left lingual cortical thickness mediated spatial context memory across the adult lifespan, but this effect was most evident at midlife. Right parahippocampal cortical thickness mediated context memory, independent of age. We conclude that our cortical thickness results were generally consistent with the posterior-to-anterior shift in aging hypothesis (Davis et al., 2008) for episodic memory.

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bioRxiv2017

Family history and APOE4 risk for Alzheimer’s Disease impact the neural correlates of episodic memory by early midlife

Episodic memory impairment is a consistent, pronounced deficit in pre-clinical stages of late-onset Alzheimers disease (AD). Individuals with risk factors for AD exhibit altered brain function several decades prior to the onset of AD-related symptoms. In the current event-related fMRI study of spatial context memory we tested the hypothesis that middle-aged adults (MA; 40-58yrs) with a family history of late onset AD (MA+FH), or a combined +FH and apolipoprotein E {varepsilon}4 allele risk factors for AD (MA+FH+APOE4), will exhibit differences in encoding and retrieval-related brain activity, compared to - FH-APOE4 MA controls. We also hypothesized that the two at-risk MA groups will exhibit distinct patterns of correlation between brain activity and memory performance, compared to controls. To test these hypotheses we conducted multivariate task, and behavior, partial least squares analysis of fMRI data obtained during successful context encoding and retrieval. Our results indicate that even though there were no significant group differences in context memory performance, there were significant differences in brain activity and brain-behavior correlations involving hippocampus, left angular gyrus, cingulate, and precuneus in MA with AD risk factors, compared to controls. In addition, we observed that brain activity and brain-behavior correlations in anterior-medial PFC and in ventral visual cortex differentiated the two MA risk groups from each other, and from MAcontrols. This is the first study to show that there are differences in the brain areas engaged during context memory encoding and retrieval in middle-aged adults with +FH and +APOE-4 risk factors for late onset AD, compared to controls.

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