The effects of musical instrument training on fluid intelligence and executive functions in healthy older adults: A systematic review and meta-analysis.

Intervention studiescombiningcognitive and motor demands have reported far-transfer cognitive benefits in healthy ageing. This systematic review and meta-analysis evaluated the effects of music and rhythm intervention on cognition in older adulthood. Inclusion criteria specified: 1) musical instrument training; 2) healthy, musically-naïve adults (≥60 years); 3) control group; 4) measure of executive function. Ovid, PubMed, Scopus and the Cochrane Library online databases were searched in August 2023. Data from thirteen studies were analysed (N = 502 participants). Study quality was assessed using the Cochrane Risk of Bias tool (RoB 2; Sterne et al., 2019). Random effects models revealed: a low effect on inhibition (d = 0.27,p = .0335); a low-moderate effect on switching (d = -0.39, p = .0021); a low-moderate effect on verbal category switching (d =0.39,p = .0166); and a moderate effect on processing speed (d = 0.47,p < .0001). No effect was found for selective visual attention, working memory, or verbal memory. With regards to overall bias, three studies were rated as "high", nine studies were rated as having "some concerns" and one was rated "low". The meta-analysis suggests that learning to play a musical instrument enhances attention inhibition, switching and processing speed in ageing.

Mutation-related magnetization-transfer, not axon density, drives white matter differences in premanifest Huntington disease: Evidence from in vivo ultra-strong gradient MRI.

White matter (WM) alterations have been observed in Huntington disease (HD) but their role in the disease-pathophysiology remains unknown. We assessed WM changes in premanifest HD by exploiting ultra-strong-gradient magnetic resonance imaging (MRI). This allowed to separately quantify magnetization transfer ratio (MTR) and hindered and restricted diffusion-weighted signal fractions, and assess how they drove WM microstructure differences between patients and controls. We used tractometry to investigate region-specific alterations across callosal segments with well-characterized early- and late-myelinating axon populations, while brain-wise differences were explored with tract-based cluster analysis (TBCA). Behavioral measures were included to explore disease-associated brain-function relationships. We detected lower MTR in patients' callosal rostrum (tractometry: p = .03; TBCA: p = .03), but higher MTR in their splenium (tractometry: p = .02). Importantly, patients' mutation-size and MTR were positively correlated (all p-values < .01), indicating that MTR alterations may directly result from the mutation. Further, MTR was higher in younger, but lower in older patients relative to controls (p = .003), suggesting that MTR increases are detrimental later in the disease. Finally, patients showed higher restricted diffusion signal fraction (FR) from the composite hindered and restricted model of diffusion (CHARMED) in the cortico-spinal tract (p = .03), which correlated positively with MTR in the posterior callosum (p = .033), potentially reflecting compensatory mechanisms. In summary, this first comprehensive, ultra-strong gradient MRI study in HD provides novel evidence of mutation-driven MTR alterations at the premanifest disease stage which may reflect neurodevelopmental changes in iron, myelin, or a combination of these.

A Critical Review of White Matter Changes in Huntington's Disease.

Huntington's disease is a genetic neurodegenerative disorder. White matter alterations have recently been identified as a relevant pathophysiological feature of Huntington's disease, but their etiology and role in disease pathogenesis and progression remain unclear. Increasing evidence suggests that white matter changes in this disorder are attributed to alterations in myelin-associated biological processes. This review first discusses evidence from neurochemical studies lending support to the demyelination hypothesis of Huntington's disease, demonstrating aberrant myelination and changes in oligodendrocytes in the Huntington's brain. Next, evidence from neuroimaging studies is reviewed, the limitations of the described methodologies are discussed, and suggested interpretations of findings from published studies are challenged. Although our understanding of Huntington's associated pathological changes in the brain will increasingly rely on neuroimaging techniques, the shortcomings of these methodologies must not be forgotten. Advances in magnetic resonance imaging techniques and tissue modeling will enable a better in vivo, longitudinal characterization of the biological properties of white matter microstructure. This in turn will facilitate identification of disease-related biomarkers and the specification of outcome measures in clinical trials. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Sex-specific effects of central adiposity and inflammatory markers on limbic microstructure.

Midlife obesity is a risk factor of late onset Alzheimer's disease (LOAD) but why this is the case remains unknown. As systemic inflammation is involved in both conditions, obesity-related neuroinflammation may contribute to damage in limbic structures important in LOAD. Here, we investigated the hypothesis that systemic inflammation would mediate central obesity related effects on limbic tissue microstructure in 166 asymptomatic individuals (38-71 years old). We employed MRI indices sensitive to myelin and neuroinflammation [macromolecular proton fraction (MPF) and kf] from quantitative magnetization transfer (qMT) together with indices from neurite orientation dispersion and density imaging (NODDI) to investigate the effects of central adiposity on the fornix, parahippocampal cingulum, uncinate fasciculus (compared with whole brain white matter and corticospinal tract) and the hippocampus. Central obesity was assessed with the Waist Hip Ratio (WHR) and abdominal visceral and subcutaneous fat area fractions (VFF, SFF), and systemic inflammation with blood plasma concentrations of leptin, adiponectin, C-reactive protein and interleukin 8. Men were significantly more centrally obese and had higher VFF than women. Individual differences in WHR and in VFF were negatively correlated with differences in fornix MPF and kf, but not with any differences in neurite microstructure. In women, age mediated the effects of VFF on fornix MPF and kf, whilst in men differences in the leptin and adiponectin ratio fully mediated the effect of WHR on fornix MPF. These results suggest that visceral fat related systemic inflammation may damage myelin-related properties of the fornix, a key limbic structure known to be involved in LOAD.

Dynamics of the Human Structural Connectome Underlying Working Memory Training.

Brain region-specific changes have been demonstrated with a variety of cognitive training interventions. The effect of cognitive training on brain subnetworks in humans, however, remains largely unknown, with studies limited to functional networks. Here, we used a well-established working memory training program and state-of-the art neuroimaging methods in 40 healthy adults (21 females, mean age 26.5 years). Near and far-transfer training effects were assessed using computerized working memory and executive function tasks. Adaptive working memory training led to improvement on (non)trained working memory tasks and generalization to tasks of reasoning and inhibition. Graph theoretical analysis of the structural (white matter) network connectivity ("connectome") revealed increased global integration within a frontoparietal attention network following adaptive working memory training compared with the nonadaptive group. Furthermore, the impact on the outcome of graph theoretical analyses of different white matter metrics to infer "connection strength" was evaluated. Increased efficiency of the frontoparietal network was best captured when using connection strengths derived from MR metrics that are thought to be more sensitive to differences in myelination (putatively indexed by the [quantitative] longitudinal relaxation rate, R1) than previously used diffusion MRI metrics (fractional anisotropy or fiber-tracking recovered streamlines). Our findings emphasize the critical role of specific microstructural markers in providing important hints toward the mechanisms underpinning training-induced plasticity that may drive working memory improvement in clinical populations. SIGNIFICANCE STATEMENT: This is the first study to explore training-induced changes in the structural connectome using a well-controlled design to examine cognitive training with up-to-date neuroimaging methods. We found changes in global integration based on white matter connectivity within a frontoparietal attention network following adaptive working memory training compared with a nonadaptive comparison group. Furthermore, the impact of different diffusion MR metrics and more specific markers of white matter on the graph theoretical findings was evaluated. An increase in network global efficiency following working memory training was best captured when connection strengths were weighted by MR relaxation rates (influenced by myelination). These results are important for the optimization of cognitive training programs for healthy individuals and people with brain disease.

Dynamics of White Matter Plasticity Underlying Working Memory Training: Multimodal Evidence from Diffusion MRI and Relaxometry.

Adaptive working memory (WM) training may lead to cognitive benefits that are associated with white matter plasticity in parietofrontal networks, but the underlying mechanisms remain poorly understood. We investigated white matter microstructural changes after adaptive WM training relative to a nonadaptive comparison group. Microstructural changes were studied in the superior longitudinal fasciculus, the main parietofrontal connection, and the cingulum bundle as a comparison pathway. MRI-based metrics were the myelin water fraction and longitudinal relaxation rate R1 from multicomponent relaxometry (captured with the mcDESPOT approach) as proxy metrics of myelin, the restricted volume fraction from the composite hindered and restricted model of diffusion as an estimate of axon morphology, and fractional anisotropy and radial diffusivity from diffusion tensor imaging. PCA was used for dimensionality reduction. Adaptive training was associated with benefits in a "WM capacity" component and increases in a microstructural component (increases in R1, restricted volume fraction, fractional anisotropy, and reduced radial diffusivity) that predominantly loaded on changes in the right dorsolateral superior longitudinal fasciculus and the left parahippocampal cingulum. In contrast, nonadaptive comparison activities were associated with the opposite pattern of reductions in WM capacity and microstructure. No group differences were observed for the myelin water fraction metric suggesting that R1 was a more sensitive "myelin" index. These results demonstrate task complexity and location-specific white matter microstructural changes that are consistent with tissue alterations underlying myelination in response to training.

Cholinergic basal forebrain structure influences the reconfiguration of white matter connections to support residual memory in mild cognitive impairment.

The fornix and hippocampus are critical to recollection in the healthy human brain. Fornix degeneration is a feature of aging and Alzheimer's disease. In the presence of fornix damage in mild cognitive impairment (MCI), a recognized prodrome of Alzheimer's disease, recall shows greater dependence on other tracts, notably the parahippocampal cingulum (PHC). The current aims were to determine whether this shift is adaptive and to probe its relationship to cholinergic signaling, which is also compromised in Alzheimer's disease. Twenty-five human participants with MCI and 20 matched healthy volunteers underwent diffusion MRI, behavioral assessment, and volumetric measurement of the basal forebrain. In a regression model for recall, there was a significant group × fornix interaction, indicating that the association between recall and fornix structure was weaker in patients. The opposite trend was present for the left PHC. To further investigate this pattern, two regression models were generated to account for recall performance: one based on fornix microstructure and the other on both fornix and left PHC. The realignment to PHC was positively correlated with free recall but not non-memory measures, implying a reconfiguration that is beneficial to residual memory. There was a positive relationship between realignment to PHC and basal forebrain gray matter volume despite this region demonstrating atrophy at a group level, i.e., the cognitive realignment to left PHC was most apparent when cholinergic areas were relatively spared. Therefore, cholinergic systems appear to enable adaptation to injury even as they degenerate, which has implications for functional restoration.

Task complexity and location specific changes of cortical thickness in executive and salience networks after working memory training.

Novel activities and experiences shape the brain's structure and organisation and, hence, our behaviour. However, evidence from structural plasticity studies remains mixed and the neural correlates of learning and practice are still poorly understood. We conducted a robustly designed study into grey matter plasticity following 2 months of working memory training. We generated a priori hypotheses regarding the location of plastic effects across three cognitive control networks (executive, anterior salience and basal ganglia networks), and compared the effects of adaptive training (n=20) with a well-matched active control group (n=20) which differed in training complexity and included extensive cognitive assessment before and after the training. Adaptive training relative to control activities resulted in a complex pattern of subtle and localised structural changes: Training was associated with increases in cortical thickness in right-lateralised executive regions, notably the right caudal middle frontal cortex, as well as increases in the volume of the left pallidum. In addition the training group showed reductions of thickness in the right insula, which were correlated with training-induced improvements in backward digit span performance. Unexpectedly, control activities were associated with reductions in thickness in the right pars triangularis. These results suggest that the direction of activity-induced plastic changes depend on the level of training complexity as well as brain location. These observations are consistent with the view that the brain responds dynamically to environmental demands by focusing resources on task relevant networks and eliminating irrelevant processing for the purpose of energy reduction.

The status of the precommissural and postcommissural fornix in normal ageing and mild cognitive impairment: An MRI tractography study.

The fornix connects the hippocampal formation with structures beyond the temporal lobe. Previous tractography studies have typically reconstructed the fornix as one unified bundle. However, the fornix contains two rostral divisions: the precommissural fornix and the postcommissural fornix. Each division has distinct anatomical connections and, hence, potentially distinct functions. Diffusion weighted MRI and spherical deconvolution based tractography were employed to reconstruct these separate fornix divisions and to examine their microstructural properties in both healthy ageing and Mild Cognitive Impairment (MCI). Reliable reconstructions of precommissural and postcommissural fibres were achieved in both groups, with their fibres retaining largely separate locations within the anterior body of the fornix. Ageing and MCI had comparable effects on the two segments. Ageing was associated with changes in mean, axial and radial diffusivity but not with alterations of fibre population-specific diffusion properties, estimated with the hindrance modulated orientational anisotropy (HMOA). Individual HMOA variation in postcommissural, but not precommissural, fibres correlated positively (and unrelated to age) with visual recall performance. This provides novel evidence for a role of postcommissural fibres, which connect structures of the extended hippocampal network, in episodic memory function. Separating the fornix into its two principal divisions brings new opportunities for distinguishing different hippocampal networks.

Increased fractional anisotropy in the motor tracts of Parkinson's disease suggests compensatory neuroplasticity or selective neurodegeneration.

OBJECTIVE: To determine the differences in motor pathways and selected non-motor pathways of the basal ganglia in Parkinson's disease (PD) patients compared to healthy controls (HCs). METHODS: We analysed diffusion weighted imaging data of 24 PD patients and 26 HCs. We performed deterministic tractography analysis using the spherical deconvolution-based damped Richardson-Lucy algorithm and subcortical volume analysis. RESULTS: We found significantly increased fractional anisotropy (FA) in the motor pathways of PD patients: the bilateral corticospinal tract (right; corrected p = 0.0003, left; corrected p = 0.03), bilateral thalamus-motor cortex tract (right; corrected p = 0.02, left; corrected p = 0.004) and the right supplementary area-putamen tract (corrected p = 0.001). We also found significantly decreased FA in the right uncinate fasiculus (corrected p = 0.01) and no differences of FA in the bilateral supero-lateral medial forebrain bundles (p > 0.05) of PD patients compared to HCs. There were no subcortical volume differences (p > 0.05) between the PD patients and HCs. CONCLUSION: These results can inform biological models of neurodegeneration and neuroplasticity in PD. We suggest that increased FA values in the motor tracts in PD may reflect compensatory reorganization of neural circuits indicative of adaptive or extended neuroplasticity. KEY POINTS: • Fractional anisotropy was higher in motor pathways of PD patients compared to healthy controls. • Fractional anisotropy was lower in the uncinate fasciculus of PD patients compared to healthy controls. • Increased fractional anisotropy could suggest adaptive neuroplasticity or selective neurodegeneration.

CSF contamination contributes to apparent microstructural alterations in mild cognitive impairment.

Diffusion MRI is used widely to probe microstructural alterations in neurological and psychiatric disease. However, ageing and neurodegeneration are also associated with atrophy, which leads to artefacts through partial volume effects due to cerebrospinal-fluid contamination (CSFC). The aim of this study was to explore the influence of CSFC on apparent microstructural changes in mild cognitive impairment (MCI) at several spatial levels: individually reconstructed tracts; at the level of a whole white matter skeleton (tract-based spatial statistics); and histograms derived from all white matter. 25 individuals with MCI and 20 matched controls underwent diffusion MRI. We corrected for CSFC using a post-acquisition voxel-by-voxel approach of free-water elimination. Tracts varied in their susceptibility to CSFC. The apparent pattern of tract involvement in disease shifted when correction was applied. Both spurious group differences, driven by CSFC, and masking of true differences were observed. Tract-based spatial statistics were found to be robust across much of the skeleton but with some localised CSFC effects. Diffusivity measures were affected disproportionately in MCI, and group differences in fornix microstructure were exaggerated. Group differences in white matter histogram measures were also partly driven by CSFC. For diffusivity measures, up to two thirds of observed group differences were due to CSFC. Our results demonstrate that CSFC has an impact on quantitative differences between MCI and controls. Furthermore, it affects the apparent spatial pattern of white matter involvement. Free-water elimination provides a step towards disentangling intrinsic and volumetric alterations in individuals prone to atrophy.

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

Aging leads to response slowing but the underpinning cognitive and neural mechanisms remain elusive. We modelled older and younger adults' response times (RT) from a flanker task with a diffusion drift model (DDM) and employed diffusion-weighted magnetic resonance imaging and spectroscopy to study neurobiological predictors of DDM components (drift-rate, boundary separation, non-decision time). Microstructural indices were derived from white matter pathways involved in visuo-perceptual and attention processing [optic radiation, inferior and superior longitudinal fasciculi (ILF, SLF), fornix]. Estimates of metabolite concentrations [N-acetyl aspartate (NAA), glutamate (Glx), and γ-aminobutyric acid (GABA), creatine (Cr), choline (Cho), myoinositol (mI)] were measured from occipital (OCC), anterior cingulate (ACC) and posterior parietal cortices (PPC). Age-related increases in RT, boundary separation, and non-decision time were observed with response conservatism acounting for RT slowing. Aging was associated with reductions in white matter microstructure (lower fractional anisotropy and restricted signal fraction, larger diffusivities) and in metabolites (NAA in ACC and PPC, Glx in ACC). Regression analyses identified brain regions involved in top-down (fornix, SLF, ACC, PPC) and bottom-up (ILF, optic radiation OCC) processing as predictors for DDM parameters and RT. Fornix FA was the strongest predictor for increases in boundary separation (beta = -0.8) and mediated the effects of age on RT. These findings demonstrate that response slowing in visual discrimination is driven by the adoption of a more conservative response strategy. Age-related fornix decline may result in noisier communication of contextual information from the hippocampus to anterior decision-making regions and thus contribute to the conservative response strategy shift.

Protocol for a randomised controlled unblinded feasibility trial of HD-DRUM: a rhythmic movement training application for cognitive and motor symptoms in people with Huntington's disease.

INTRODUCTION: Huntington's disease (HD) is an inherited neurodegenerative disease causing progressive cognitive and motor decline, largely due to basal ganglia (BG) atrophy. Rhythmic training offers promise as therapy to counteract BG-regulated deficits. We have developed HD-DRUM, a tablet-based app to enhance movement synchronisation skills and improve cognitive and motor abilities in people with HD. This paper outlines a randomised controlled unblinded trial protocol to determine the feasibility of a larger effectiveness trial for HD-DRUM. Additionally, the trial investigates cognitive and motor function measures, along with brain microstructure, aiming to advance our understanding of the neural mechanisms underlying training effects. METHODS, DESIGN AND ANALYSIS: 50 individuals with HD, confirmed by genetic testing, and a Total Functional Capacity (TFC) score of 9-13, will be recruited into a two-arm randomised controlled feasibility trial. Consenting individuals with HD will be randomised to the intervention group, which entails 8 weeks of at-home usage of HD-DRUM or a usual-activity control group. All participants will undergo cognitive and motor assessments, alongside ultra-strong gradient (300 mT/m) brain microstructural MRI before and after the 8-week period. The feasibility assessment will encompass recruitment, retention, adherence and acceptability of HD-DRUM following prespecified criteria. The study will also evaluate variations in cognitive and motor performance and brain microstructure changes resulting from the intervention to determine effect size estimates for future sample size calculations. ETHICS AND DISSEMINATION: The study has received favourable ethical opinion from the Wales Research Ethics Committee 2 (REC reference: 22/WA/0147) and is sponsored by Cardiff University (SPON1895-22) (Research Integrity, Governance and Ethics Team, Research & Innovation Services, Cardiff University, second Floor, Lakeside Building, University Hospital of Wales, Cardiff, CF14 4XW). Findings will be disseminated to researchers and clinicians in peer-reviewed publications and conference presentations, and to participants, carers and the general public via newsletters and public engagement activities. Data will be shared with the research community via the Enroll-HD platform. TRIAL REGISTRATION NUMBER: ISRCTN11906973.

Cingulum microstructure predicts cognitive control in older age and mild cognitive impairment.

Cognitive control, an important facet of human cognition, provides flexibility in response to varying behavioral demands. Previous work has focused on the role of prefrontal cortex, notably the anterior cingulate cortex. However, it is now clear that this is one node of a distributed cognitive network. In this emerging network view, structural connections are inherent elements, but their role has not been emphasized. Furthermore, lesion and functional imaging studies have contributed little knowledge about anatomical segregation, functional specialization, and behavioral importance of white matter connections. The relationship between cognitive control and microstructure of connections within the cingulum, a major white matter tract and conduit of projections to prefrontal sites, was probed in vivo in humans with diffusion MRI. Twenty healthy controls and 25 individuals with amnestic mild cognitive impairment (MCI), an early stage of age-associated cognitive deterioration, underwent cognitive testing, including several measures of cognitive control. For each individual, the anterior, middle, posterior, and parahippocampal portions of the cingulum bundle were reconstructed separately using deterministic tractography and anatomical landmarks. Microstructural variation in the left anterior cingulum was closely related to interindividual control based on verbal or symbolic rules. Errors in a task that involved maintenance of spatial rules were largely restricted to patients with MCI and were related, additionally, to right anterior cingulum microstructure. Cognitive control in MCI was also independently related to posterior parahippocampal connections. These results show how specific subpopulations of connections are critical in cognitive control and illustrate fine-grained anatomical specializations in the white matter infrastructure of this network.

HD-DRUM, a Tablet-Based Drumming Training App Intervention for People With Huntington Disease: App Development Study.

BACKGROUND: Huntington disease (HD) is a neurodegenerative condition that leads to progressive loss of cognitive-executive and motor functions, largely due to basal ganglia (BG) atrophy. Currently, there are no therapeutic interventions tailored to address executive and motor dysfunction in people with HD. Music-based interventions may aid executive abilities by compensating for impaired BG-reliant timing and rhythm generation using external rhythmic beats. Here, we applied an integrated knowledge translation (IKT) framework to co-design a tablet-based rhythmic drumming training app (HD-DRUM) to stimulate executive and motor abilities in people with HD. OBJECTIVE: The primary aim was to develop the HD-DRUM app for at-home use that addressed the accessibility needs of people with HD and allowed for the quantification of performance improvements and adherence for controlled clinical evaluation. METHODS: The IKT framework was applied to iteratively refine the design of HD-DRUM. This process involved 3 phases of knowledge user engagement and co-design: a web-based survey of people with HD (n=29) to inform about their accessibility needs, usability testing of tablet-based touch screens as hardware solutions, and usability testing of the design and build of HD-DRUM to meet the identified accessibility needs of people affected by HD and their clinicians (n=12). RESULTS: The survey identified accessibility problems due to cognitive and motor control impairments such as difficulties in finding and navigating through information and using PC keyboards and mouses to interact with apps. Tablet-based touch screens were identified as feasible and accessible solutions for app delivery. Key elements to ensure that the app design and build met the needs of people with HD were identified and implemented. These included the facilitation of intuitive navigation through the app using large and visually distinctive buttons; the use of audio and visual cues as training guides; and gamification, positive feedback, and drumming to background music as a means to increase motivation and engagement. The co-design development process resulted in the proof-of-concept HD-DRUM app that is described here according to the Template for Intervention Description and Replication checklist. HD-DRUM can be used at home, allowing the quantification of performance improvements and adherence for clinical evaluation, matching of training difficulty to users' performance levels using gamification, and future scale-up to reach a wide range of interested users. CONCLUSIONS: Applying an IKT-based co-design framework involving knowledge user engagement allowed for the iterative refinement of the design and build of the tablet-based HD-DRUM app intervention, with the aim of stimulating BG-reliant cognitive and motor functions. Mapping the intervention against the Template for Intervention Description and Replication framework to describe complex interventions allowed for the detailed description of the HD-DRUM intervention and identification of areas that required refinement before finalizing the intervention protocol.

Frontotemporal connections in episodic memory and aging: a diffusion MRI tractography study.

Human episodic memory is supported by networks of white matter tracts that connect frontal, temporal, and parietal regions. Degradation of white matter microstructure is increasingly recognized as a general mechanism of cognitive deterioration with aging. However, atrophy of gray matter regions also occurs and, to date, the potential role of specific white matter connections has been largely ignored. Changes to frontotemporal tracts may be important for the decline of episodic memory; while frontotemporal cooperation is known to be critical, the precise pathways of interaction are unknown. Diffusion-weighted MRI tractography was used to reconstruct three candidate fasciculi known to link components of memory networks: the fornix, the parahippocampal cingulum, and the uncinate fasciculus. Age-related changes in the microstructure of these tracts were investigated in 40 healthy older adults between the ages of 53 and 93 years. The relationships between aging, microstructure, and episodic memory were assessed for each individual tract. Age-related reductions of mean fractional anisotropy and/or increased mean diffusivity were found in all three tracts. However, age-related decline in recall was specifically associated with degradation of fornix microstructure, consistent with the view that this tract is important for episodic memory. In contrast, a decline in uncinate fasciculus microstructure was linked to impaired error monitoring in a visual object-location association task, echoing the effects of uncinate transection in monkeys. These results suggest that degradation of microstructure in the fornix and the uncinate fasciculus make critical but differential contributions to the mechanisms underlying age-related cognitive decline and subserve distinct components of memory.

How and how not to correct for CSF-contamination in diffusion MRI.

Diffusion MRI is used extensively to investigate changes in white matter microstructure related to brain development and pathology. Ageing, however, is also associated with significant white and grey matter loss which in turn can lead to cerebrospinal fluid (CSF) based partial volume artefacts in diffusion MRI metrics. This is especially problematic in regions prone to CSF contamination, such as the fornix and the genu of corpus callosum, structures that pass through or close to the ventricles respectively. The aim of this study was to model the effects of CSF contamination on diffusion MRI metrics, and to evaluate different post-acquisition strategies to correct for CSF-contamination: Controlling for whole brain volume and correcting on a voxel-wise basis using the Free Water Elimination (FWE) approach. Using the fornix as an exemplar of a structure prone to CSF-contamination, corrections were applied to tract-specific and voxel-based [tract based spatial statistics (TBSS)] analyses of empirical DT-MRI data from 39 older adults (53-93 years of age). In addition to significant age-related decreases in whole brain volume and fornix tissue volume fraction, age was also associated with a reduction in mean fractional anisotropy and increase in diffusivity metrics in the fornix. The experimental data agreed with the simulations in that diffusivity metrics (mean diffusivity, axial and radial diffusivity) were more prone to partial volume CSF-contamination errors than fractional anisotropy. After FWE-based voxel-by-voxel partial volume corrections, the significant positive correlations between age and diffusivity metrics, in particular with axial diffusivity, disappeared whereas the correlation with anisotropy remained. In contrast, correcting for whole brain volume had little effect in removing these spurious correlations. Our study highlights the importance of correcting for CSF-contamination partial volume effects in the structures of interest on a voxel-by-voxel basis prior to drawing inferences about underlying changes in white matter structures and have implications for the interpretation of many recent diffusion MRI results in ageing and disease.

Dementia Risk Factors Modify Hubs but Leave Other Connectivity Measures Unchanged in Asymptomatic Individuals: A Graph Theoretical Analysis.

Background: Alzheimer's 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 magnetic resonance imaging (MRI) measurements have identified connectivity changes in AD and individuals with mild cognitive impairment. However, brain connectivity in asymptomatic individuals at risk of AD remains poorly understood. Methods: We analyzed diffusion-weighted MRI data from 161 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 (DMN) 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 ɛ4 (APOE4) genotype, family history of dementia (FH), and central obesity (Waist-Hip-Ratio [WHR]), on graph theoretical measures and hubs. Results: We observed no risk-related differences in clustering coefficients, characteristic path lengths, eccentricity, diameter, and radius across the whole-brain, DMN or visual system. However, a hub in the right paracentral lobule was present in all the high-risk groups (FH, APOE4, obese), but absent in low-risk groups (no FH, APOE4-ve, healthy WHR). Discussion: We 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, a medial fronto-parietal cortical area with motor and sensory functions. This finding is consistent with accumulating evidence for right parietal cortex contributions in AD. If this phenotype is shown to predict symptom development in longitudinal studies, it could be used as an early biomarker of AD. Impact statement Alzheimer's disease (AD) is a common form of dementia that 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 article, we report that asymptomatic individuals at heightened risk of dementia due to their family history, Apolipoprotein-E ɛ4 genotype, and central 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.

Investigating the Anatomy and Microstructure of the Dentato-rubro-thalamic and Subthalamo-ponto-cerebellar Tracts in Parkinson's Disease.

Cerebellar-thalamic connections play a central role in deep brain stimulation-based treatment of tremor syndromes. Here, we used diffusion Magnetic Resonance Imaging (MRI) tractography to delineate the main cerebellar peduncles as well as two main white matter tracts that connect the cerebellum with the thalamus, the dentato-rubro-thalamic tract (DRTT) and the subthalamo-ponto-cerebellar tract (SPCT). We first developed a reconstruction protocol in young healthy adults with high-resolution diffusion imaging data and then demonstrate feasibility of transferring this protocol to clinical studies using standard diffusion MRI data from a cohort of patients with Parkinson's disease (PD) and their matched healthy controls. The tracts obtained closely corresponded to the previously described anatomical pathways and features of the DRTT and the SPCT. Second, we investigated the microstructure of these tracts with fractional anisotropy (FA), radial diffusivity (RD), and hindrance modulated orientational anisotropy (HMOA) in patients with PD and healthy controls. By reducing dimensionality of both the microstructural metrics and the investigated cerebellar and cerebellar-thalamic tracts using principal component analyses, we found global differences between patients with PD and controls, suggestive of higher fractional anisotropy, lower radial diffusivity, and higher hindrance modulated orientational anisotropy in patients. However, separate analyses for each of the tracts did not yield any significant differences. Our findings contribute to the characterization of the distinct anatomical connections between the cerebellum and the diencephalon. Microstructural differences between patients and controls in the cerebellar pathways suggest involvement of these structures in PD, complementing previous functional and diffusion imaging studies.

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)-ε4, a family history of dementia, and central obesity, on the CA1, CA2/3, dentate gyrus and subiculum of 158 cognitively healthy adults (38-71 years). Subfields were labelled with the Automatic Segmentation of Hippocampal Subfields 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 family history of dementia status. However, amongst individuals with a healthy Waist-Hip-Ratio, APOE ε4 carriers showed lower size/complexity than non-carriers. Segmentation protocol type did not affect this risk pattern. These findings reveal interactive effects between APOE and central obesity on the hippocampal formation of cognitively healthy adults.