Biology subjects

Roe, J. M.

Publications and source records attributed to Roe, J. M..

13 recordsLinked to original sources

bioRxiv2025

Cortical thickness changes precede high levels of amyloid by at least seven years

Alzheimers disease (AD) is now defined based on its underlying brain pathology1, with the presence of amyloid (A{beta}) plaques at high enough levels sufficient to warrant a diagnosis in the absence of cognitive symptoms. High levels of PET-detectable A{beta} are widely thought to be the first imaging marker, with structural brain changes detectable on MRI scans thought to occur later. We combined 4570 longitudinal MRIs and 1684 A{beta} PET scans from three cognitively healthy cohorts to test the difference in cortical thickness and its change between those that subsequently converted to be A{beta}-positive or stayed A{beta}-negative, using MRIs acquired exclusively in the years before conversion. We found those that subsequently developed elevated A{beta} levels show both thicker cortex and less cortical thinning, even when the last MRI used to estimate their thickness trajectories was acquired at least seven years before conversion. Many effects remained when accounting for quantitative A{beta} levels, suggesting some cortical thickness effects may be partly independent of A{beta}. Differences in cortical thickness and its change between converters and A{beta}-negative individuals showed moderate alignment with patterns of A{beta} deposition, and the timing of thickness changes tracked the temporal progression of A{beta} accumulation. Thus, if amyloid is AD1, we show that high levels of PET-detectable amyloid are not the first imaging marker of AD, as cortical thickness changes can be traced years before pathological amyloid. This has implications for understanding the sequence of events leading up to the earliest stages of AD.

neuroscience↗

bioRxiv2025

Vulnerability to memory decline in aging. A mega-analysis of structural brain change.

Brain atrophy is a key factor behind episodic memory loss in aging, but the nature and ubiquity of this relationship remains poorly understood. This study leveraged 13 longitudinal datasets, including 3,737 cognitively healthy adults (10,343 MRI scans; 13,460 memory assessments), to determine whether brain change-memory change associations are more pronounced with age and genetic risk for Alzheimers Disease. Both factors are associated with accelerated brain decline, yet it remains unclear whether memory loss is exacerbated beyond what atrophy alone would predict. Additionally, we assessed whether memory decline aligns with a global pattern of atrophy or stems from distinct regional contributions. Our mega-analysis revealed a nonlinear relationship between memory decline and brain atrophy, primarily affecting individuals with above-average brain structural decline. The associations were stronger in the hippocampus but also spread across diverse cortical and subcortical regions. The associations strengthened with age, reaching moderate associations in participants in their eighties. While APOE {varepsilon}4 carriers exhibited steeper brain and memory loss, genetic risk had no effect on the change-change associations. These findings support the presence of common biological macrostructural substrates underlying memory function in older age which are vulnerable to multiple age-related factors, even in the absence of overt pathological changes.

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bioRxiv2024

Network Segregation During Episodic Memory Shows Age-Invariant Relations with Memory Performance From 7 to 82 Years

Lower episodic memory capability, as seen in development and aging compared with younger adulthood, may partly depend on lower brain network segregation. Here, our objective was twofold: (1) test this hypothesis using within- and between-network functional connectivity (FC) during episodic memory encoding and retrieval, in two independent samples (n=734, age 7-82 years). (2) Assess associations with age and the ability to predict memory comparing task-general FC and memory-modulated FC. In a multiverse-inspired approach, we performed tests across multiple analytic choices. Results showed that relationships differed based on these analytic choices, were often weak, and mainly present in the cohort with the most data. Significant relationships indicated that (i) memory-modulated FC predicted memory performance and associated with memory in an age-invariant manner. (ii) In line with the so- called neural dedifferentiation view, task-general FC showed lower segregation with higher age in adults which was associated with worse memory performance. In development, although there were only weak signs of a neural differentiation, that is, gradually higher segregation with higher age, we observed similar lower segregation-worse memory relationships. This age-invariant relationships between FC and episodic memory suggest that network segregation is pivotal for memory across the healthy lifespan. Declarations of interestnone. HighlightsO_LIWithin- and between network functional connectivity predict memory performance. C_LIO_LIMultiverse-inspired analyses showed varying results depending on analytic choices. C_LIO_LIMemory associations particularly in the cohort with most data were age-invariant across the lifespan. C_LIO_LIDedifferentiation might be better characterized as degrees of differentiation. C_LI

neuroscience↗

bioRxiv2024

Left-Right Brain-Wide Asymmetry of Neuroanatomy in the Mouse Brain

Left-right asymmetry of the human brain is widespread through its anatomy and function. However, limited microscopic understanding of it exists, particularly for anatomical asymmetry where there are few well-established animal models. In humans, most brain regions show subtle, population-average regional asymmetries in thickness or surface area, alongside a macro-scale twisting called the cerebral petalia in which the right hemisphere protrudes anteriorly past the left. Here, we ask whether neuroanatomical asymmetries can be observed in mice, leveraging 6 mouse neuroimaging cohorts from 5 different research groups ([~]3,500 animals). We found an anterior-posterior pattern of volume asymmetry with anterior regions larger on the right and posterior regions larger on the left. This pattern appears driven by similar trends in surface area and positional asymmetries, with the results together indicating a small brain-wide twisting pattern, similar to the human cerebral petalia. Furthermore, the results show no apparent relationship to known functional asymmetries in mice, emphasizing the complexity of the structure-function relationship in brain asymmetry. By establishing a signature of anatomical brain asymmetry in mice, we aim to provide a foundation for future studies to probe the mechanistic underpinnings of brain asymmetry seen in humans - a feature of the brain with extremely limited understanding. Significance StatementThe human brain shows significant left-right anatomical asymmetry. Understanding its microscopic basis has implications for studies of autism and schizophrenia, evolution, embryonic brain development, and the relationship between structure and function in the brain. One of the biggest challenges to understanding this aspect of the brain is that animal models are limited. Here we show a brain-wide twisting pattern of asymmetry in the mouse brain using over 3,500 animals from six independent cohorts. These findings provide a basis for using mice to interrogate the microscopic underpinnings of anatomical asymmetry in humans and a roadmap for exploring anatomical asymmetry in additional species.

neuroscience↗

bioRxiv2024

Reliability of structural brain change in cognitively healthy adult samples.

In neuroimaging research, tracking individuals over time is key to understanding the interplay between brain changes and genetic, environmental, or cognitive factors across the lifespan. Yet, the extent to which we can estimate the individual trajectories of brain change over time with precision remains uncertain. In this study, we estimated the reliability of structural brain change in cognitively healthy adults from multiple samples and assessed the influence of follow-up time and number of observations. Estimates of cross-sectional measurement error and brain change variance were obtained using the longitudinal FreeSurfer processing stream. Our findings showed, on average, modest longitudinal reliability with two years of follow-up. Increasing the follow-up time was associated with a substantial increase in longitudinal reliability while the impact of increasing the number of observations was comparatively minor. On average, 2-year follow-up studies require {approx}2.7 and {approx}4.0 times more individuals than designs with follow-ups of 4 and 6 years to achieve comparable statistical power. Subcortical volume exhibited higher longitudinal reliability compared to cortical area, thickness, and volume. The reliability estimates were comparable to those estimated from empirical data. The reliability estimates were affected by both the cohorts age where younger adults had lower reliability of change, and the preprocessing pipeline where the FreeSurfers longitudinal stream was notably superior than the cross-sectional. Suboptimal reliability inflated sample size requirements and compromised the ability to distinguish individual trajectories of brain aging. This study underscores the importance of long-term follow-ups and the need to consider reliability in longitudinal neuroimaging research.

neuroscience↗

bioRxiv2023

Accelerated brain change in healthy adults is associated with genetic risk for Alzheimer's disease and uncovers adult lifespan memory decline

Across healthy adult life our brains undergo gradual structural change in a pattern of atrophy that resembles accelerated brain changes in Alzheimers disease (AD). Here, using four polygenic risk scores for AD (PRS-AD) in a longitudinal adult lifespan sample aged 30 to 89 years (2-7 timepoints), we show that healthy individuals who lose brain volume faster than expected for their age, have a higher genetic AD risk. We first demonstrate PRS-AD associations with change in early Braak regions, namely hippocampus, entorhinal cortex, and amygdala, and find evidence these extend beyond that predicted by APOE genotype. Next, following the hypothesis that brain changes in ageing and AD are largely shared, we performed machine learning classification on brain change trajectories conditional on age in longitudinal AD patient-control data, to obtain a list of AD-accelerated features and model change in these in adult lifespan data. We found PRS-AD was associated with a multivariate marker of accelerated change in many of these features in healthy adults, and that most individuals above [~]50 years of age are on an accelerated change trajectory in AD-accelerated brain regions. Finally, high PRS-AD individuals also high on a multivariate marker of change showed more adult lifespan memory decline, compared to high PRS-AD individuals with less brain change. Our results support a dimensional account linking normal brain ageing with AD, suggesting AD risk genes speed up the shared pattern of ageing- and AD-related neurodegeneration that starts early, occurs along a continuum, and tracks memory change in healthy adults.

neuroscience↗

bioRxiv2021

Population-level asymmetry of the cerebral cortex: reproducibility, lifespan changes, heritability, and individual differences

Cortical asymmetry is a ubiquitous feature of brain organization that is subtly altered in some neurodevelopmental disorders, yet we lack knowledge of how its development proceeds across life in health. Achieving consensus on the precise cortical asymmetries in humans is necessary to uncover the genetic and later influences that shape them, such as age. Here, we delineate population-level asymmetry in cortical thickness and surface area vertex-wise in 7 datasets and chart asymmetry trajectories longitudinally across life (4-89 years; observations = 3937; 70% longitudinal). We find replicable asymmetry interrelationships, heritability maps, and test asymmetry associations in large-scale data. Cortical asymmetry was robust across datasets. Whereas areal asymmetry is predominantly stable across life, thickness asymmetry grows in childhood and peaks in early adulthood. Areal asymmetry correlates phenotypically and genetically in specific regions, and is low-moderately heritable (max h2SNP [~]19%). In contrast, thickness asymmetry is globally interrelated across the cortex in a pattern suggesting highly left-lateralized individuals tend towards left-lateralization also in population-level right-asymmetric regions (and vice versa), and exhibits low or absent heritability. We find less areal asymmetry in the most consistently lateralized region in humans associates with subtly lower cognitive ability, and confirm small handedness and sex effects. Results suggest areal asymmetry is developmentally stable and arises in early life through genetic but mainly subject-specific stochastic effects, whereas childhood developmental growth shapes thickness asymmetry and may lead to directional variability of global thickness lateralization in the population.

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bioRxiv2021

Left-handedness and its genetic influences are associated with structural asymmetries mapped across the cerebral cortex in 31,864 individuals

Roughly 10% of the human population is left-handed, and this rate is increased in some brain-related disorders. The neuroanatomical correlates of hand preference have remained equivocal. We re-sampled structural brain image data from 28,802 right-handers and 3,062 left-handers (UK Biobank population dataset) to a symmetrical surface template, and mapped asymmetries for each of 8,681 vertices across the cerebral cortex in each individual. Left-handers and right-handers showed average differences of surface area asymmetry within fusiform, anterior insular, anterior-middle-cingulate and precentral cortex. Meta-analyzed functional imaging data implicated these regions in executive functions and language. Polygenic disposition to left-handedness was associated with two of these regional asymmetries, and 18 loci previously linked with left-handedness by genome-wide screening showed associations with one or more of these asymmetries. Implicated genes included six encoding microtubule-related proteins: TUBB, TUBA1B, TUBB3, TUBB4A, MAP2 and NME7 - the latter is mutated in left-right reversal of the visceral organs. There were also two cortical regions where average thickness asymmetry was altered in left-handedness: on the postcentral gyrus and inferior occipital cortex, functionally annotated with hand sensorimotor and visual roles. These cortical thickness asymmetries were not heritable. Heritable surface area asymmetries of language-related regions may link the etiologies of hand preference and language, whereas non-heritable asymmetries of sensorimotor cortex may manifest as consequences of hand preference.

neuroscience↗

bioRxiv2021

Brain age relates to early life factors but not to accelerated brain aging

Brain age is a widely used index for quantifying individuals brain health as deviation from a normative brain aging trajectory. Higher than expected brain age is thought partially to reflect above-average rate of brain aging. We explicitly tested this assumption in two large datasets and found no association between cross-sectional brain age and steeper brain decline measured longitudinally. Rather, brain age in adulthood was associated with early-life influences indexed by birth weight and polygenic scores. The results call for nuanced interpretations of cross-sectional indices of the aging brain and question their validity as markers of ongoing within-person changes of the aging brain. Longitudinal imaging data should be preferred whenever the goal is to understand individual change trajectories of brain and cognition in aging.

neuroscience↗

bioRxiv2020

Asymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer's Disease

Normal aging and Alzheimers Disease (AD) are accompanied by large-scale alterations in brain organization that undermine brain function. Although hemispheric asymmetry is a global organizing feature of cortex thought to promote brain efficiency, current descriptions of cortical thinning in aging and AD have largely overlooked cortical asymmetry. Consequently, the foundational question of whether and where the cerebral hemispheres change at different rates in aging and AD remains open. First, applying vertex-wise data-driven clustering in a longitudinal discovery sample (aged 20-89; 2577 observations; 1851 longitudinal) we identified cortical regions exhibiting similar age-trajectories of asymmetry across the adult lifespan. Next, we sought replication in 4 independent longitudinal aging cohorts. We show that higher-order regions of cortex that exhibit pronounced asymmetry at age ~20 also show asymmetry change in aging. Results revealed that both leftward and rightward asymmetry is progressively lost on a similar time-scale across adult life. Hence, faster thinning of the (previously) thicker homotopic hemisphere is a feature of aging. This simple organizational principle showed high consistency across multiple aging cohorts in the Lifebrain consortium, and both the topological patterns and temporal dynamics of asymmetry-loss were markedly similar across replicating samples. Finally, we show that regions exhibiting gradual asymmetry-loss over healthy adult life exhibit faster asymmetry-change in AD. Overall, our results suggest a system-wide breakdown in the adaptive asymmetric organization of cortex across adult life which is further accelerated in AD, and may implicate thickness asymmetry as a viable marker for declining hemispheric specialization in aging and AD. SignificanceThe brain becomes progressively disorganized with age, and brain alterations accelerated in Alzheimers disease may occur gradually over the lifespan. Although hemispheric asymmetry aids efficient network organization, efforts to identify structural markers of age-related decline have largely overlooked cortical asymmetry. Here we show the hemisphere that is thicker when younger, thins faster. This leads to progressive system-wide loss of regional thickness asymmetry across life. In multiple aging cohorts, asymmetry-loss showed high reproducibility topologically across cortex and similar timing-of-change in aging. Asymmetry-change was further accelerated in AD. Our findings uncover a new principle of brain aging - thicker homotopic cortex thins faster - and suggest we may have unveiled a structural marker for a widely-hypothesized decline in hemispheric specialization in aging and AD.

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bioRxiv2020

Self-reported sleep problems are related to cortical thinning in aging but not memory decline and amyloid-β accumulation - results from the Lifebrain consortium

BackgroundOlder persons with poor sleep are more likely to develop neurodegenerative disease, but the causality underlying this association is unclear. To move towards explanation, we examine whether sleep quality and quantity are similarly associated with brain changes across the adult lifespan. MethodsAssociations between self-reported sleep parameters (Pittsburgh Sleep Quality Index;PSQI) and longitudinal cortical change were tested using five samples from the Lifebrain consortium (n=2205, 4363 MRIs, 18-92 years). Analyses were augmented by considering episodic memory change, gene expression from the Allen Human Brain Atlas, and amyloid-beta (A{beta}) accumulation (n=1980). ResultsPSQI components sleep problems and low sleep quality were related to thinning of the right lateral temporal cortex. The association with sleep problems emerged after 60 years, especially in regions with high expression of genes related to oligodendrocytes and S1 pyramidal neurons. BMI and symptoms of depression had negligible effects. Sleep problems were neither related to longitudinal change in episodic memory function nor to A{beta} accumulation, suggesting that sleep-related cortical changes were independent of AD neuropathology and cognitive decline. ConclusionWorse self-reported sleep in later adulthood was associated with more cortical thinning in regions of high expression of genes related to oligodendrocytes and S1 pyramidal neurons, but not to A{beta} accumulation or memory decline. The relationship to cortical brain change suggests that self-reported sleep parameters are relevant in lifespan studies, but small effect sizes, except for a few restricted regions, indicate that self-reported sleep is not a good biomarker of general cortical degeneration in healthy older adults.

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bioRxiv2020

The functional foundations of episodic memory remain stable throughout the lifespan

It is suggested that the functional mechanisms behind specific forms of cognition, particularly episodic memory, may be dynamic over the lifespan and that cognitive preservation or decay in older age thus relies on age-specific mechanisms such as compensatory processes. Here instead, we tested whether the functional foundations of successful episodic memory encoding adhere to a principle of lifespan continuity, shaped by developmental, structural and evolutionary influences. We identified the generic lifespan patterns of memory encoding function across the brain (n = 540; age range = 6 - 82 years). The lifespan trajectories of brain activity were organized in a topologically meaningful manner and aligned to fundamental aspects of brain organization, such as large-scale connectivity hierarchies and evolutionary cortical expansion gradients. None of the normative trajectories of encoding function was solely determined by late-life patterns of activity, but rather showed continuities across development and adulthood. Inter-individual differences in activity in age-sensitive regions were predicted by general cognitive abilities and variation in grey matter structure, which are core variables of cognitive and structural change throughout the lifespan. Altogether, the results provide evidence for the lifelong continuity of the functional foundations of episodic memory which are bounded by both brain architecture and core mechanisms of cognitive and structural change over life. We provide novel support for a perspective on memory aging in which maintenance and decay of episodic memory in older age needs to be understood from a comprehensive life-long perspective rather than as a late-life phenomenon only. Significance statementIt is suggested that cognitive function in older age largely relies on late-life specific mechanisms such as compensatory processes. In contrast, here we tested whether and to what degree brain activity during episodic memory encoding adheres to fundamental principles of life-long brain organization and continuity. The results revealed that generic lifespan trajectories of memory encoding function were not specific to late-life. Instead, the age-trajectories showed a continuity through life, were related to fundamental features of brain structure and cognition and to functional and evolutionary hierarchies. We argue that rather than focusing on older-age specific mechanisms, a framework that takes lifespan mechanisms of cognition and brain anatomy into account is necessary to understand episodic memory vulnerability in older age.

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bioRxiv2018

Age-differences in functional asymmetry during memory retrieval revisited: no evidence for contralateral over-activation or compensation

Brain asymmetry is inherent to cognitive processing and seems to reflect processing efficiency. Lower frontal asymmetry is often observed in older adults during memory retrieval, yet it is unclear whether lower asymmetry implies an age-related increase in contralateral recruitment, whether less asymmetry reflects compensation, is limited to frontal regions, or predicts neurocognitive stability or decline. We assessed age-differences in asymmetry across the entire cerebral cortex, using fMRI data from 89 young and 76 older adults during successful retrieval, and surface-based methods that allowed direct homotopic comparison of activity between hemispheres. An extensive left-asymmetric network facilitated retrieval in both young and older adults, whereas diverse frontal and parietal regions exhibited lower asymmetry in older adults. However, lower asymmetry was not associated with age-related increases in contralateral recruitment, but primarily reflected either less deactivation in contralateral regions reliably signalling retrieval failure in the young, or lower recruitment of the dominant hemisphere--suggesting that functional deficits may drive lower asymmetry in older brains, not compensatory activity. Lower asymmetry neither predicted current memory performance, nor the extent of memory change across the preceding [~]8 years in older adults. Together, these findings are inconsistent with a compensation account for lower asymmetry during retrieval and aging.

neuroscience↗