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.

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.

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.

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.

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.

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.

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.

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.

Multi-compartment analysis of the complex gradient-echo signal quantifies myelin breakdown in premanifest Huntington's disease.

White matter (WM) alterations have been identified as a relevant pathological feature of Huntington's disease (HD). Increasing evidence suggests that WM changes in this disorder are due to alterations in myelin-associated biological processes. Multi-compartmental analysis of the complex gradient-echo MRI signal evolution in WM has been shown to quantify myelin in vivo, therefore pointing to the potential of this technique for the study of WM myelin changes in health and disease. This study first characterized the reproducibility of metrics derived from the complex multi-echo gradient-recalled echo (mGRE) signal across the corpus callosum in healthy participants, finding highest reproducibility in the posterior callosal segment. Subsequently, the same analysis pipeline was applied in this callosal region in a sample of premanifest HD patients (n = 19) and age, sex and education matched healthy controls (n = 21). In particular, we focused on two myelin-associated derivatives: i. the myelin water signal fraction (fm), a parameter dependent on myelin content; and ii. The difference in frequency between myelin and intra-axonal water pools (Δω), a parameter dependent on the ratio between the inner and the outer axonal radii. fm was found to be lower in HD patients (ß = -0.13, p = 0.03), while Δω did not show a group effect. Performance in tests of working memory, executive function, social cognition and movement was also assessed, and a greater age-related decline in executive function was detected in HD patients (ß = -0.06, p = 0.006), replicating previous evidence of executive dysfunction in HD. Finally, the correlation between fm, executive function, and proximity to disease onset was explored in patients, and a positive correlation between executive function and fm was detected (r = 0.542; p = 0.02). This study emphasises the potential of complex mGRE signal analysis for aiding understanding of HD pathogenesis and progression. Moreover, expanding on evidence from pathology and animal studies, it provides novel in vivo evidence supporting myelin breakdown as an early feature of HD.

APOE-ε4-related differences in left thalamic microstructure in cognitively healthy adults.

APOE-ε4 is a main genetic risk factor for developing late onset Alzheimer's disease (LOAD) and is thought to interact adversely with other risk factors on the brain. However, evidence regarding the impact of APOE-ε4 on grey matter structure in asymptomatic individuals remains mixed. Much attention has been devoted to characterising APOE-ε4-related changes in the hippocampus, but LOAD pathology is known to spread through the whole of the Papez circuit including the limbic thalamus. Here, we tested the impact of APOE-ε4 and two other risk factors, a family history of dementia and obesity, on grey matter macro- and microstructure across the whole brain in 165 asymptomatic individuals (38-71 years). Microstructural properties of apparent neurite density and dispersion, free water, myelin and cell metabolism were assessed with Neurite Orientation Density and Dispersion (NODDI) and quantitative magnetization transfer (qMT) imaging. APOE-ε4 carriers relative to non-carriers had a lower macromolecular proton fraction (MPF) in the left thalamus. No risk effects were present for cortical thickness, subcortical volume, or NODDI indices. Reduced thalamic MPF may reflect inflammation-related tissue swelling and/or myelin loss in APOE-ε4. Future prospective studies should investigate the sensitivity and specificity of qMT-based MPF as a non-invasive biomarker for LOAD risk.

Drumming Motor Sequence Training Induces Apparent Myelin Remodelling in Huntington's Disease: A Longitudinal Diffusion MRI and Quantitative Magnetization Transfer Study.

BACKGROUND: Impaired myelination may contribute to Huntington's disease (HD) pathogenesis. OBJECTIVE: This study assessed differences in white matter (WM) microstructure between HD patients and controls, and tested whether drumming training stimulates WM remodelling in HD. Furthermore, it examined whether training-induced microstructural changes are related to improvements in motor and cognitive function. METHODS: Participants undertook two months of drumming exercises. Working memory and executive function were assessed before and post-training. Changes in WM microstructure were investigated with diffusion tensor magnetic resonance imaging (DT-MRI)-based metrics, the restricted diffusion signal fraction (Fr) from the composite hindered and restricted model of diffusion (CHARMED) and the macromolecular proton fraction (MPF) from quantitative magnetization transfer (qMT) imaging. WM pathways linking putamen and supplementary motor areas (SMA-Putamen), and three segments of the corpus callosum (CCI, CCII, CCIII) were studied using deterministic tractography. Baseline MPF differences between patients and controls were assessed with tract-based spatial statistics. RESULTS: MPF was reduced in the mid-section of the CC in HD subjects at baseline, while a significantly greater change in MPF was detected in HD patients relative to controls in the CCII, CCIII, and the right SMA-putamen post-training. Further, although patients improved their drumming and executive function performance, such improvements did not correlate with microstructural changes. Increased MPF suggests training-induced myelin changes in HD. CONCLUSION: Though only preliminary and based on a small sample size, these results suggest that tailored behavioural stimulation may lead to neural benefits in early HD, that could be exploited for delaying disease progression.

Genetic risk of dementia modifies obesity effects on white matter myelin in cognitively healthy adults.

APOE-ε4 is a major genetic risk factor for late-onset Alzheimer's disease that interacts with other risk factors, but the nature of such combined effects remains poorly understood. We quantified the impact of APOE-ε4, family history (FH) of dementia, and obesity on white matter (WM) microstructure in 165 asymptomatic adults (38-71 years old) using quantitative magnetization transfer and neurite orientation dispersion and density imaging. Microstructural properties of the fornix, parahippocampal cingulum, and uncinate fasciculus were compared with those in motor and whole-brain WM regions. Widespread interaction effects between APOE, FH, and waist-hip ratio were found in the myelin-sensitive macromolecular proton fraction from quantitative magnetization transfer. Among individuals with the highest genetic risk (FH+ and APOE-ε4), obesity was associated with reduced macromolecular proton fraction in the right parahippocampal cingulum, whereas no effects were present for those without FH. Risk effects on apparent myelin were moderated by hypertension and inflammation-related markers. These findings suggest that genetic risk modifies the impact of obesity on WM myelin consistent with neuroglia models of aging and late-onset Alzheimer's disease.

Visuo-Perceptual and Decision-Making Contributions to Visual Hallucinations in Mild Cognitive Impairment in Lewy Body Disease: Insights from a Drift Diffusion Analysis.

Background: Visual hallucinations (VH) are a common symptom in dementia with Lewy bodies (DLB); however, their cognitive underpinnings remain unclear. Hallucinations have been related to cognitive slowing in DLB and may arise due to impaired sensory input, dysregulation in top-down influences over perception, or an imbalance between the two, resulting in false visual inferences. Methods: Here we employed a drift diffusion model yielding estimates of perceptual encoding time, decision threshold, and drift rate of evidence accumulation to (i) investigate the nature of DLB-related slowing of responses and (ii) their relationship to visuospatial performance and visual hallucinations. The EZ drift diffusion model was fitted to mean reaction time (RT), accuracy and RT variance from two-choice reaction time (CRT) tasks and data were compared between groups of mild cognitive impairment (MCI-LB) LB patients (n = 49) and healthy older adults (n = 25). Results: No difference was detected in drift rate between patients and controls, but MCI-LB patients showed slower non-decision times and boundary separation values than control participants. Furthermore, non-decision time was negatively correlated with visuospatial performance in MCI-LB, and score on visual hallucinations inventory. However, only boundary separation was related to clinical incidence of visual hallucinations. Conclusions: These results suggest that a primary impairment in perceptual encoding may contribute to the visuospatial performance, however a more cautious response strategy may be related to visual hallucinations in Lewy body disease. Interestingly, MCI-LB patients showed no impairment in information processing ability, suggesting that, when perceptual encoding was successful, patients were able to normally process information, potentially explaining the variability of hallucination incidence.

A randomised feasibility study of computerised cognitive training as a therapeutic intervention for people with Huntington's disease (CogTrainHD).

BACKGROUND: Huntington's disease (HD) is associated with a range of cognitive deficits including problems with executive function. In the absence of a disease modifying treatment, cognitive training has been proposed as a means of slowing cognitive decline; however, the impact of cognitive training in HD patient populations remains unclear. The CogTrainHD study assessed the feasibility and acceptability of home-based computerised executive function training, for people impacted by HD. METHODS: Thirty HD gene carriers were recruited and randomised to either executive function training or non-intervention control groups. Participants allocated to the intervention group were asked to complete executive function training three times a week for 30 min for 12 weeks in their own homes. Semi-structured interviews were conducted with participants and friends, family or carers, to determine their views on the study. RESULTS: 26 out of 30 participants completed the baseline assessments and were subsequently randomised: 13 to the control group and 13 to the intervention group. 23 of the 30 participants were retained until study completion: 10/13 in the intervention group and 13/13 in the control group. 4/10 participants fully adhered to the executive function training. All participants in the control group 13/13 completed the study as intended. Interview data suggested several key facilitators including participant determination, motivation, incorporation of the intervention into routine and support from friends and family members. Practical limitations, including lack of time, difficulty and frustration in completing the intervention, were identified as barriers to study completion. CONCLUSIONS: The CogTrainHD feasibility study provides important evidence regarding the feasibility and acceptability of a home-based cognitive training intervention for people with HD. Variable adherence to the cognitive training implies that the intervention is not feasible to all participants in its current form. The study has highlighted important aspects in relation to both the study and intervention design that require consideration, and these include the design of games in the executive function training software, logistical considerations such as lack of time, the limited time participants had to complete the intervention and the number of study visits required. Further studies are necessary before computerised executive function training can be recommended routinely for people with HD. TRIAL REGISTRATION: ClinicalTrials.gov, Registry number NCT02990676.

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.

Precommissural and postcommissural fornix microstructure in healthy aging and cognition.

The fornix is a key tract of the hippocampal formation, whose status is presumed to contribute to age-related cognitive decline. The precommissural and postcommissural fornix subdivisions form respective basal forebrain/frontal and diencephalic networks that may differentially affect aging and cognition. We employed multi-parametric magnetic resonance imaging (MRI) including neurite orientation density and dispersion imaging, quantitative magnetization transfer (qMT), and T1-relaxometry MRI to investigate the microstructural properties of these fornix subdivisions and their relationship with aging and cognition in 149 asymptomatic participants (38-71 years). Aging was associated with increased free water signal and reductions in myelin-sensitive R1 and qMT indices but no apparent axon density differences in both precommissural and postcommissural fibers. Precommissural relative to postcommissural fibers showed a distinct microstructural pattern characterised by larger free water signal and axon orientation dispersion, with lower apparent myelin and axon density. Furthermore, differences in postcommissural microstructure were related to performance differences in object-location paired-associate learning. These results provide novel in vivo neuroimaging evidence for distinct microstructural properties of precommissural and postcommissural fibers that are consistent with their anatomy as found in axonal tracer studies, as well as for a contribution of postcommissural fibers to the learning of spatial configurations.

Author Correction: Fornix white matter glia damage causes hippocampal gray matter damage during age-dependent limbic decline.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Fornix white matter glia damage causes hippocampal gray matter damage during age-dependent limbic decline.

Aging leads to gray and white matter decline but their causation remains unclear. We explored two 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 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 neurite density damage in the fornix and the hippocampus. Mediation analysis supported white matter damage causing gray matter decline; controlling for fornix glia damage, the correlations between age and hippocampal damage disappear, but not vice versa. Fornix and hippocampal differences were both associated with reductions in episodic memory performance. These results suggest that fornix white matter glia damage may cause hippocampal gray matter damage during age-dependent limbic decline.

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.

Myelin Breakdown in Human Huntington's Disease: Multi-Modal Evidence from Diffusion MRI and Quantitative Magnetization Transfer.

Huntington's disease (HD) leads to white matter (WM) degeneration that may be due to an early breakdown in axon myelination but in vivo imaging correlates of demyelination remain relatively unexplored in HD compared to other neurodegenerative diseases. This study investigated HD-related effects on a putative marker of myelin, the macromolecular proton fraction (MMPF) from quantitative magnetization transfer and on fractional anisotropy, axial and radial diffusivity from diffusion tensor MR-imaging. Microstructural differences were studied in WM pathways of the basal ganglia and motor systems known to be impaired in HD: the corpus callosum, the cortico-spinal tract, the anterior thalamic radiation, fibers between prefrontal cortex and caudate and between supplementary motor area and putamen. Principal component analysis was employed for dimensionality reduction. Patients showed reductions in a component with high loadings on MMPF in all WM pathways and a trend for increases in a component loading on axial and radial diffusivities but no differences in a component loading on fractional anisotropy. While patients' performance in executive functioning was impaired, their working memory span was preserved. Inter-individual differences in the diffusivity component correlated with patients' performance in clinical measures of the United Huntington Disease Rating Scale. In summary, HD-related reductions in MMPF suggest that myelin breakdown contributes to WM impairment in human HD and emphasize the potential of quantitative MRI metrics to inform about disease pathogenesis. Disease severity in manifest HD, however, was best captured by non-specific diffusivity metrics sensitive to multiple disease and age-related changes.