Biology subjects

Metzler-Baddeley, C.

Publications and source records attributed to Metzler-Baddeley, C..

10 recordsLinked to original sources

bioRxiv2026

Feasibility of PIANO-Cog for older adults: A randomised controlled pilot trial exploring changes in cognition and brain microstructure.

BackgroundExecutive functions are a key target of cognitive interventions for older adults due to their central role in daily functioning and maintaining a good quality of life. Piano training has been proposed as an ecologically valid method of improving cognition and brain structure in older adults. The primary aims of this study were to (i) evaluate the feasibility and acceptability of Piano Instruction for Adult Novices as an Online Cognitive Intervention (PIANO-Cog), a novel bespoke 8-week self-guided piano training programme for adults over 50 years of age, and (ii) assess the feasibility of conducting a fully-powered randomised controlled trial (RCT), including recruitment, retention, and adherence. Secondary aims explored effects of PIANO-Cog on executive functions and brain microstructure using advanced diffusion-weighted imaging (DWI). MethodThirty-three healthy music novices aged 51-80 years (M = 63.73, SD = 7.94) participated in a two-arm unblinded feasibility RCT. Participants were assigned by stratified allocation for age and sex to either (i) 8 weeks of PIANO-Cog, requiring 30 minutes of practice, 5 days per week, or (ii) a passive control group. Cognitive assessment and MRI scanning were conducted before and after the intervention using a strong-gradient (300mT/m) 3T Connectom scanner to acquire multi-shell DWI data with b-values ranging from 200 to 6,000 s/mm{superscript 2}. Grey and white matter microstructure were modelled with Soma And Neurite Density Imaging (SANDI) and Neurite Orientation Density and Dispersion Imaging (NODDI). ResultsAccording to predefined criteria, feasibility was established for recruitment (91.6%), retention (75%) and adherence (>100%) rates. Preliminary observations suggest that piano training compared with control was associated with improvements in verbal fluency and multiple changes in brain microstructure including increases in apparent soma size and radius and reductions in extracellular signal in frontal and temporal cortical regions, larger apparent neurite density in right inferior frontal gyrus and changes in neurite dispersion in left middle temporal and right precentral gyri. DiscussionThe results demonstrate that short-term remote piano training is a feasible cognitive intervention for healthy adults over 50. Preliminary evidence suggest that PIANO-Cog was associated cognitive improvements and changes in brain microstructure in executive, auditory and motor regions.

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bioRxiv2023

Age-related fornix decline predicts conservative response strategy-based slowing in perceptual decision-making

Aging leads to increased response latencies but the underpinning cognitive and neural mechanisms remain elusive. We modelled older and younger adults response time (RT) data from a 2-choice flanker task with a diffusion drift model (DDM) and employed multi-shell diffusion weighted magnetic resonance imaging and spectroscopy to study neurobiological predictors of DDM components thought to govern RTs: drift rate, boundary separation and non-decision time. Microstructural indices of fractional anisotropy (FA), diffusivities and the restricted signal fraction (FR) from the Composite Hindered and Restricted Model of Diffusion (CHARMED) were derived from white matter pathways of visuo-perceptual and attention networks (optic radiation, inferior and superior longitudinal fasciculi, fornix) and estimates of metabolite concentrations [N-acetyl aspartate (NAA), glutamate (Glx), {gamma}-aminobutyric acid (GABA), creatine (Cr), choline (Cho) and myoinositol (mI)] were measured from occipital (OCC), anteri- or and posterior cingulate cortices (ACC, PPC). Ageing was associated with increased RT, boundary separation, and non-decision time. Differences in boundary separation but not non-decision time mediated age-related response slowing. Regression analyses revealed a network of brain regions involved in top-down (fornix FA, diffusivities in right SLF) and bottom-up processing (mI in OCC, AD in left optic radiation) and verbal intelligence as significant predictors of RTs and non-decision time (NAA in ACC, AD in the right ILF, creatine in the OCC) while fornix FA was the only predictor for boundary separation. Fornix FA mediated the effects of age on RTs but not vice versa. These results provide novel insights into the cognitive and neural underpinnings of age-related slowing.

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bioRxiv2023

Differences in white matter detected by ex vivo 9.4T MRI are associated with axonal changes in the R6/1 model of Huntington's Disease

White matter (WM) volume loss has been reported in people with Huntingtons disease (HD), but the cellular basis of this deficit remains to be elucidated. To address this, we assessed ex vivo WM microstructure in the transgenic R6/1 mouse model of HD with magnetic resonance imaging (MRI) and studied the neurobiological basis of the MRI brain signals with histological and electron microscopy analyses in a separate cohort of age- and sex-matched mice. Differences in the macromolecular proton fraction (MPF) from quantitative magnetization transfer (qMT) as a proxy myelin measure, and the intra-axonal signal fraction (FR) from the composite hindered and restricted model of diffusion (CHARMED) as a proxy marker of axon density, were assessed alongside diffusion tensor imaging (DTI) parameters. A tractometry approach was employed to inspect region-specific differences across the corpus callosum (CC). Furthermore, voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) were used to explore brain-wise WM macro- and microstructure abnormalities. To gain insight into disease-associated impairments in attentional and visuospatial processing, a third cohort of age-matched mice was assessed with the 5-choice serial reaction time task (5-CSRTT). We report cognitive impairments in R6/1 mice and, by evaluating MRI and light and electron microscopy results, we show that this HD mouse model presents disruptions in axonal morphology (i.e. less complex, thinner axons) and organization (i.e. more densely packed axons). Furthermore, we show that, at least early in disease progression, R6/1 mice present a reduction in the expression or content of myelin-associated proteins without significant alterations in the structure of myelin sheaths. Finally, our findings indicate that neuroinflammation-driven glial and axonal swelling might also affect this mouse model early in disease progression. Crucially, we demonstrate the potential of FR, an in vivo estimate of axon density, as a novel MRI biomarker of HD-associated changes in WM microstructure.

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bioRxiv2022

Age-related changes in brain metabolites underlie slowing of speed-accuracy trade-off

Aging leads to response slowing but the underpinning cognitive and neural mechanisms remain elusive. We studied cognitive components of response speed with a diffusion drift model to estimate nondecision, boundary-separation, and drift-rate contributions to choice reaction times of older (62-80 years) and younger (18-29 years) adults (n=25 each). We characterised age-related differences in the metabolic and microstructural profile of cortical regions and white matter (WM) pathways of visuo-perceptual and attention networks with magnetic resonance spectroscopy and multi-shell diffusion-weighted imaging. Aging was associated with increased non-decision time and boundary-separation, reduced N-acetyl aspartate (NAA) concentrations in anterior cingulate (ACC) and posterior parietal cortices, and reduced WM microstructure in the optic radiation (OR), inferior and superior longitudinal fasciculus (ILF, SLF) and fornix. NAA in ACC and diffusivities in OR and SLF predicted non-decision time, while restricted diffusivity signal fraction in the ILF and fornix, and diffusivity in OR predicted boundary-separation. These results suggest that age-related deterioration of neuronal health and WM microstructure in visuo-perceptual and attention networks contribute to response slowing in aging.

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bioRxiv2021

Mutation-related apparent myelin, not axon density, drives white matter differences in premanifest Huntington's disease: Evidence from in vivo ultra-strong gradient MRI

White matter (WM) alterations have been observed early in Huntingtons disease (HD) progression but their role in the disease-pathophysiology remains unknown. We exploited ultra-strong-gradient MRI to tease apart contributions of myelin (with the magnetization transfer ratio), and axon density (with the restricted volume fraction from the Composite Hindered and Restricted Model of Diffusion) to WM differences between premanifest HD patients and age- and sex-matched controls. Diffusion tensor MRI (DT-MRI) measures were also assessed. We used tractometry to investigate region-specific changes across callosal segments with well-characterized early- and late-myelinating axonal populations, while brain-wise alterations were explored with tract-based cluster analysis (TBCA). Behavioural measures were included to explore disease-associated brain-function relationships. We detected lower myelin in the rostrum of patients (tractometry: p = 0.0343; TBCA: p = 0.030), but higher myelin in their splenium (p = 0.016). Importantly, patients myelin and mutation size were positively associated (all p-values < 0.01), indicating that increased myelination might be a direct result of the mutation. Finally, myelin was higher than controls in younger patients but lower in older patients (p = 0.003), suggesting detrimental effects of increased myelination later in the course of the disease. Higher FR in patients left cortico-spinal tract (CST) (p = 0.03) was detected, and was found to be positively associated with MTR in the posterior callosum (p = 0.033), possibly suggesting compensation to myelin alterations. This comprehensive, ultra-strong gradient MRI investigation provides novel evidence of CAG-driven myelin alterations in premanifest HD which may reflect neurodevelopmental, rather than neurodegenerative disease-associated changes.

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bioRxiv2021

Apolipoprotein ε4 modifies obesity-related atrophy in the hippocampal formation of cognitively healthy adults.

Characterizing age- and risk-related hippocampal vulnerabilities may inform about the neural underpinnings of cognitive decline. We studied the impact of three risk-factors, Apolipoprotein (APOE)-{varepsilon}4, a family history of dementia, and central obesity, on CA1, CA2/3, dentate gyrus (DG) and subiculum in 158 cognitively healthy adults (38-71 years). Subfields were labelled with the Automatic Segmentation of Hippocampal Subfields (ASHS) and FreeSurfer (version 6) protocols. Volumetric and microstructural measurements from quantitative magnetization transfer and Neurite Orientation Density and Dispersion Imaging were extracted for each subfield and reduced to three principal components capturing apparent myelin/neurite packing, size/complexity, and metabolism. Aging was associated with an inverse U-shaped curve on myelin/neurite packing and affected all subfields. Obesity led to reductions in myelin/neurite packing and size/complexity regardless of APOE and FH status. However, amongst individuals with a healthy Waist-Hip-Ratio, APOE {varepsilon}4 carriers showed lower size/complexity than non-carriers. Protocol type did not affect this risk pattern. These findings provide novel evidence for interactive effects between APOE and central obesity on the hippocampal formation of cognitively healthy adults. HighlightsO_LIAge-related inverted U-shaped curve of hippocampal myelin/neurite packing C_LIO_LIObesity-related reductions of hippocampal myelin/neurite packing and size/complexity C_LIO_LIAPOE modifies the effects of obesity on hippocampal size/complexity C_LIO_LIAge-related slowing of spatial navigation C_LIO_LINo APOE, family history, or obesity effects on cognition C_LI

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bioRxiv2020

Dementia risk factors modify hubs but leave other connectivity measures unchanged in asymptomatic individuals: a graph theoretical analysis.

BackgroundAlzheimers Disease (AD) is the most common form of dementia with genetic and environmental risk contributing to its development. Graph theoretical analyses of brain networks constructed from structural and functional MRI measurements have identified connectivity changes in AD and individuals with mild cognitive impairment (MCI). However, brain connectivity in asymptomatic individuals at risk of AD remains poorly understood. MethodsWe analysed diffusion-weighted magnetic resonance imaging (dMRI) data from 160 asymptomatic individuals (38-71 years) from the Cardiff Ageing and Risk of Dementia Study (CARDS). We calculated white matter tracts and constructed whole-brain, default-mode-network and visual structural brain networks that incorporate multiple structural metrics as edge weights. We then calculated the relationship of three AD risk factors, namely Apolipoprotein-E {varepsilon}4 genotype (APOE4), family history (FH) of dementia, and central obesity, on graph theoretical measures and hubs. ResultsWe observed no risk-related differences in clustering coefficients, characteristic path lengths, eccentricity, diameter and radius across the whole-brain, default-mode-network or visual system. However, a hub in the right paracentral lobule was present in all high-risk groups (FH, APOE4, obese) but absent in low-risk groups (no FH, APOE4-ve, healthy weight). DiscussionWe identified no risk-related effects on graph theoretical metrics in the structural brain networks of cognitively healthy individuals. However, high-risk was associated with a hub in the right paracentral lobule, an area with motor and sensory functions related to the lower limb. If this phenotype is shown to predict symptom development in longitudinal studies, it could be used as an early biomarker of AD. Impact StatementAlzheimers Disease is a common form of dementia which to date has no cure. Identifying early biomarkers will aid the discovery and development of treatments that may slow AD progression in the future. In this paper we report that asymptomatic individuals at heightened risk of dementia due to their family history, Apolipoprotein-E {varepsilon}4 genotype and body adiposity have a hub in the right paracentral lobule which is absent in low-risk groups. If this phenotype were to predict the development of symptoms in a longitudinal study of the same cohort, it could provide an early biomarker of disease progression.

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bioRxiv2019

Genetic risk of dementia modifies the impact of obesity on limbic white matter and spatial navigation behavior in cognitively healthy adults.

A family history (FH) of dementia, APOE-{varepsilon}4 genotype, and obesity are major risk factors for developing Alzheimers disease but their combined effects on the brain and cognition remain elusive. We tested the hypothesis that these risk factors affect apparent white matter (WM) myelin and cognition including spatial navigation and processing speed in 166 asymptomatic individuals (38-71 years). Microstructure in temporal [fornix, parahippocampal cingulum, uncinate fasciculus], motor and whole-brain WM was assessed with myelin-sensitive indices from quantitative magnetization transfer [macromolecular proton fraction (MPF)] and axon density from diffusion imaging. Individuals with the highest genetic risk (FH+ and APOE-{varepsilon}4) compared to those with FH+ alone showed obesity-related reductions in MPF and axon density in the right parahippocampal cingulum. No effects were present for those without FH. Furthermore, FH modulated obesity-related effects on spatial navigation behaviour. In summary, an individuals genetic dementia risk influenced the impact of obesity on WM myelin and cognition.

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bioRxiv2018

The causal structure of age-dependent limbic decline: fornix white matter glia damage causes hippocampal grey matter damage, not vice versa.

Aging leads to gray and white matter decline but their causation remains unclear. We explored two broad classes of models of age and dementia risk related brain changes. The first class of models emphasises the importance of gray matter: age and risk-related processes cause neurodegeneration and this causes damage in associated white matter tracts. The second class of models reverses the direction of causation: aging and risk factors cause white matter damage and this leads to gray matter damage. We compared these models with linear mediation analysis and quantitative multi-modal MRI indices (from diffusion, quantitative magnetization transfer and relaxometry imaging) of tissue properties in two limbic structures implicated in age-related memory decline: the hippocampus and the fornix in 166 asymptomatic individuals (aged 38 - 71 years). Aging was associated with apparent glia but not axon density damage in the fornix. Mediation analysis unambiguously supported white matter damage causing gray matter decline; controlling for fornix glia damage, the correlation between age and hippocampal damage disappears, but not vice versa. Fornix and hippocampal tissue loss were both associated with reductions in episodic memory performance. The implications of these findings for neuroglia and neurodegenerative models of aging and late onset dementia are discussed.

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bioRxiv2018

Adipokines contribute to central-obesity related reductions in myelin-sensitive MRI indices in the fornix.

Midlife obesity is a risk factor of late onset Alzheimers disease (LOAD) but why this is the case remains unknown. As systemic inflammation is involved in both conditions, one possibility is that obesity-related neuroinflammation may contribute to the development of LOAD. Neuroinflammation is closely linked to white matter myelin loss, and this can be measured in vivo with quantitative magnetization transfer (qMT) imaging. Here, we investigated whether differences in obesity measures, i.e., in Waist Hip Ratio (WHR), abdominal visceral and subcutaneous fat volume fractions and Body Mass Index (BMI), were associated with reductions in qMT indices of apparent myelin in temporal white matter pathways involved in LOAD (i.e., the fornix, the parahippocampal cingulum and the uncinate fasciculus compared with whole brain and cortico-spinal white matter) in 166 cognitively healthy individuals (38-71 years of age). Obesity-related effects on myelin-sensitive markers were contrasted with differences in apparent axon density from dual-shell diffusion Neurite Orientation Dispersion and Density Imaging (NODDI). Differences in WHR and in visceral fat volume fractions were negatively correlated with differences in qMT estimates of apparent myelin and tissue metabolism in the fornix but not with any other microstructural components. These correlations were not explained by demographic (age, sex, education), health (hypertension, alcohol consumption, sedentary lifestyle) or genetic (APOE genotype, family history of dementia) risk factors of LOAD. Furthermore, differences in the ratio of plasma concentrations of leptin and adiponectin were also positively correlated with differences in C-Reactive Protein concentrations, and contributed significantly to the correlations between central obesity and myelin-sensitive metrics in the fornix. These results are consistent with the view that visceral fat-related chronic inflammation may damage white matter myelin in limbic regions, known to be vulnerable to LOAD pathology.

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