Biology subjects

Molloy, E. N.

Publications and source records attributed to Molloy, E. N..

7 recordsLinked to original sources

bioRxiv2026

Mesoscale medial temporal lobe connectivity patterns relate to tau pathology and memory in older adults

The medial temporal lobe (MTL) is crucial for episodic memory. Tau pathology is a hallmark of Alzheimer's disease (AD) and accumulates in layer-specific patterns in the MTL during aging. It is, however, unclear whether early AD pathology relates to mesoscale network signatures distinct from non-pathological aging. To address this gap, we acquired 7 Tesla submillimeter-resolution resting-state fMRI, plasma-based AD biomarkers, glial fibrillary acidic protein (GFAP) levels, APOE genotype, regional [18F]PI-2620 tau PET burden, and longitudinal episodic memory data in 75 cognitively unimpaired older adults. Older age was associated with lower perirhinal-hippocampal connectivity and lower network segregation, whereas higher plasma-based AD pathology was associated with higher perirhinal-hippocampal connectivity. Furthermore, temporal-lobe tau burden was related to altered connectivity patterns in tau-vulnerable MTL subfields and layers, dependent on GFAP levels. Retrosplenial tau burden was associated with higher hippocampal-retrosplenial connectivity consistent with tau spread along canonical hippocampal output pathways. Finally, higher connectivity within the hippocampus attenuated the negative association between temporal-lobe tau burden and memory performance but predicted unfavorable memory trajectories. Our findings show differential associations of age and AD pathology with mesoscale MTL-connectivity patterns. Importantly, increased hippocampal connectivity may support memory function in the short term while contributing to subsequent memory decline.

neuroscience↗

bioRxiv2025

Harmonized Protocol for Segmentation of the Hippocampal Tail on High-Resolution in vivo MRI from the Hippocampal Subfields Group (HSG)

The hippocampus is a heterogeneous structure with cytoarchitectonically distinct subfields that exhibit heterogeneous lifespan trajectories and are differentially susceptible to diseases. Advances in high-resolution imaging have accelerated research on these structures, yet variability in segmentation protocols limits cross-study comparability. The Hippocampal Subfields Group (HSG) is an international consortium addressing this challenge by developing a reliable, accessible, and freely available segmentation protocol for high-resolution T2-weighted 3 tesla MRI scans (http://www.hippocampalsubfields.com). Here, we present the harmonized protocol for the posterior portion of the hippocampus (the "tail"), complementing the previously established "body" protocol, and with an anterior "head" protocol under development. The tail protocol provides standardized definitions of the external boundaries for the posterior-most extent of the hippocampus, facilitating consistent segmentation from surrounding tissues. The research community was extensively involved through an online survey that incorporated comprehensive protocol details, feasibility assessments, tutorial videos, and illustrative segmentations. Through this collaborative process, consensus emerged to exclude subfield labeling in the hippocampal tail due to limited visibility of internal landmarks and substantial anatomical variability in this region. All proposed boundary guidelines were deemed clear and agreed upon via a Delphi procedure. The harmonized tail protocol has high intra-(Averaged ICC(2,1) > 0.98; Averaged Dice Similarity Coefficient = 0.92) and inter-rater reliability (Averaged ICC(2,k) > 0.98; Averaged Dice Similarity Coefficient = 0.86) and offers a practical framework for replicable segmentation. By establishing standardized guidelines, this protocol enhances comparability of findings across developmental, aging, and clinical research and is compatible with ongoing technological advances.

neuroscience↗

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.

neuroscience↗

bioRxiv2025

Hippocampal-cortical connectivity relates to inter-individual differences and training gains in distinguishing similar memories

Mnemonic discrimination (MD) is the ability to distinguish current experiences from similar memories. Research on the brain correlates of MD has focused on how regional neural responses are linked to MD. Here we go beyond this approach to investigate inter-regional functional connectivity patterns related to MD, its inter-individual variability and training-related improvement. Based on prior work we focused on medial temporal lobe (MTL), prefrontal cortex (PFC) and visual regions. We used fMRI to determine how functional connectivity patterns between these regions are related to MD before and after 2-weeks of web-based cognitive training. We identified a functional connectivity signature involving MTL-PFC-visual areas during successful MD. We found that hippocampal-PFC connectivity was negatively associated with interindividual variability in MD performance across two different tasks. Hippocampal-PFC connectivity decrease was also linked to interindividual variability in post-training MD improvement. Additionally, training led to increased connectivity from the lateral occipital cortex to the occipital pole area. Our results point to a hippocampal-PFC connectivity pattern which is a reliable, task-invariant, marker of MD performance. This pattern is further related to MD training gains providing causal evidence for its relevance in distinguishing similar memories. Overall, we show that hippocampal-PFC connectivity constitutes a neural resource for MD that enables training-related improvements and could be targeted in future research to enhance cognition.

neuroscience↗

bioRxiv2024

Differential effects of aging, Alzheimer's pathology, and APOE4 on longitudinal functional connectivity and episodic memory in older adults

INTRODUCTIONBoth aging and Alzheimers disease (AD) affect episodic memory networks. How this relates to region-specific early differences in functional connectivity (FC), however, remains unclear. METHODSWe assessed resting-state FC strength in the medial temporal lobe (MTL) - posteromedial cortex (PMC) - prefrontal network and cognition over two years in cognitively normal older adults from the PREVENT-AD cohort. RESULTSFC strength within PMC and between posterior hippocampus and inferomedial precuneus decreased in "normal" aging (amyloid- and tau-negative adults). Lower FC strength within PMC was associated with poorer longitudinal episodic memory performance. Increasing FC between anterior hippocampus and superior precuneus was related to higher baseline AD pathology. Higher FC strength was differentially associated with memory trajectories depending on APOE4 genotype. DISCUSSIONFindings suggest differential effects of aging and AD pathology on longitudinal FC. MTL-PMC hypoconnectivity was related to aging and cognitive decline. Furthermore, MTL-PMC hyperconnectivity was related to early AD pathology and cognitive decline in APOE4 carriers. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=86 SRC="FIGDIR/small/627967v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@12c0cc9org.highwire.dtl.DTLVardef@fb7c6borg.highwire.dtl.DTLVardef@a56bdforg.highwire.dtl.DTLVardef@4d1773_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract.C_FLOATNO A) "Normal aging" is characterized by a longitudinal decrease in functional connectivity. B) Cognitively unimpaired older adults with more Alzheimers pathology at baseline (measured via cerebrospinal fluid) exhibit a longitudinal increase in functional connectivity. C_FIG

neuroscience↗

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.

neuroscience↗

bioRxiv2021

One-week escitalopram intake shifts excitation-inhibition balance in the healthy female brain

Neural health relies on cortical excitation-inhibition balance (EIB), with disrupted EIB underlying circuit dysfunction in several neuropsychiatric disorders. Previous research suggests links between increased cortical excitation and neuroplasticity induced by selective serotonin reuptake inhibitors (SSRIs). Whether there are modulations of EIB following SSRI-administration in the healthy human brain, however, remains unclear. To this end, we assessed changes in EIB following longitudinal escitalopram-intake. In a randomized, double-blind study protocol, a sample of 59 healthy female individuals on oral contraceptives underwent three resting-state electroencephalography recordings after daily administration of 20 mg escitalopram (n = 28) or placebo (n = 31) at baseline, after single dose, and after 1 week (steady state). We assessed 1/f slope of the power spectrum, a marker of EIB, compared individual trajectories of 1/f slope changes contrasting single dose and 1-week drug intake, and tested the relationship of escitalopram plasma levels and cortical excitatory and inhibitory balance shifts. Escitalopram-intake associated with decreased 1/f slope, indicating an EIB shift in favor of excitation. Furthermore, 1/f slope at baseline and after single dose of escitalopram predicted 1/f slope at steady state. Higher plasma escitalopram levels at single dose associated with better maintenance of these EIB changes throughout the drug administration week. Characterizing changes in 1/f slope during longitudinal SSRI-intake in healthy female individuals, we show that escitalopram shifted EIB in favor of excitation. These findings demonstrate the potential for 1/f slope to predict individual cortical responsivity to SSRIs and widen the neuroimaging lens by testing an interventional psychopharmacological design in a clearly-defined endocrinological state.

neuroscience↗