The Mediterranean diet is not associated with neuroimaging or cognition in middle-aged adults: a cross-sectional analysis of the PREVENT dementia programme.

BACKGROUND AND PURPOSE: The Mediterranean diet (MedDiet) has been associated with reduced dementia incidence in several studies. It is important to understand if diet is associated with brain health in midlife, when Alzheimer's disease and related dementias are known to begin. METHODS: This study used data from the PREVENT dementia programme. Three MedDiet scores were created (the Pyramid, Mediterranean Diet Adherence Screener [MEDAS] and MEDAS continuous) from a self-reported food frequency questionnaire. Primary outcomes were hippocampal volume and cube-transformed white matter hyperintensity volume. Secondary outcomes included cornu ammonis 1 and subiculum hippocampal subfield volumes, cortical thickness and measures of cognition. Sex-stratified analyses were run to explore differential associations between diet and brain health by sex. An exploratory path analysis was conducted to study if any associations between diet and brain health were mediated by cardiovascular risk factors for dementia. RESULTS: In all, 504 participants were included in this analysis, with a mean Pyramid score of 8.10 (SD 1.56). There were no significant associations between any MedDiet scoring method and any of the primary or secondary outcomes. There were no differences by sex in any analyses and no significant mediation between the Pyramid score and global cognition by cardiovascular risk factors. CONCLUSIONS: Overall, this study did not find evidence for an association between the MedDiet and either neuroimaging or cognition in a midlife population study. Future work should investigate associations between the MedDiet and Alzheimer's disease and related dementias biomarkers as well as functional neuroimaging in a midlife population.

Nutrition for dementia prevention: a state of the art update for clinicians.

BACKGROUND AND OBJECTIVES: Dementia prevalence continues to rise. It is therefore essential to provide feasible and effective recommendations to encourage healthy brain ageing and reduce dementia risk across the population. Appropriate nutrition represents a potential strategy to mitigate dementia risk and could be recommended by clinicians as part of mid-life health checks and other health initiatives to reduce dementia prevalence. The purpose of this review is to provide a clinician-focused update on the current state of the knowledge on nutrition and dementia prevention. METHODS: Narrative review. RESULTS: Strong evidence exists to support the consumption of healthy, plant-based dietary patterns (e.g. Mediterranean, MIND or Nordic diet) for maintaining cognitive function and reducing dementia risk in later life and is supported by dementia prevention guideline from leading public health bodies (e.g. World Health Organization). Emerging evidence suggests potential cognitive benefits of consuming specific nutrients/foods (e.g. n-3 fatty acids or fish, flavonols and B-vitamins) and multi-nutrient compounds (e.g. Fortasyn Connect). Challenges and opportunities for integrating nutritional/dietary interventions for dementia prevention into clinical practice are explored in this review. CONCLUSIONS: Appropriate nutrition represents an important factor to help facilitate healthy cognitive ageing and allay dementia risk. The information provided in this article can help clinicians provide informed opinions on appropriate nutritional strategies as part of mid-life Health Checks and other risk reduction initiatives.

Mediterranean diet adherence is associated with lower dementia risk, independent of genetic predisposition: findings from the UK Biobank prospective cohort study.

BACKGROUND: The identification of effective dementia prevention strategies is a major public health priority, due to the enormous and growing societal cost of this condition. Consumption of a Mediterranean diet (MedDiet) has been proposed to reduce dementia risk. However, current evidence is inconclusive and is typically derived from small cohorts with limited dementia cases. Additionally, few studies have explored the interaction between diet and genetic risk of dementia. METHODS: We used Cox proportional hazard regression models to explore the associations between MedDiet adherence, defined using two different scores (Mediterranean Diet Adherence Screener [MEDAS] continuous and Mediterranean diet Pyramid [PYRAMID] scores), and incident all-cause dementia risk in 60,298 participants from UK Biobank, followed for an average 9.1 years. The interaction between diet and polygenic risk for dementia was also tested. RESULTS: Higher MedDiet adherence was associated with lower dementia risk (MEDAS continuous: HR = 0.77, 95% CI = 0.65-0.91; PYRAMID: HR = 0.86, 95% CI = 0.73-1.02 for highest versus lowest tertiles). There was no significant interaction between MedDiet adherence defined by the MEDAS continuous and PYRAMID scores and polygenic risk for dementia. CONCLUSIONS: Higher adherence to a MedDiet was associated with lower dementia risk, independent of genetic risk, underlining the importance of diet in dementia prevention interventions.

Imbalanced basal ganglia connectivity is associated with motor deficits and apathy in Huntington's disease.

The gating of movement depends on activity within the cortico-striato-thalamic loops. Within these loops, emerging from the cells of the striatum, run two opponent pathways-the direct and indirect basal ganglia pathways. Both are complex and polysynaptic, but the overall effect of activity within these pathways is thought to encourage and inhibit movement, respectively. In Huntington's disease, the preferential early loss of striatal neurons forming the indirect pathway is thought to lead to disinhibition, giving rise to the characteristic motor features of the condition. But early Huntington's disease is also associated with apathy, a loss of motivation and failure to engage in goal-directed movement. We hypothesized that in Huntington's disease, motor signs and apathy may be selectively correlated with indirect and direct pathway dysfunction, respectively. We used spectral dynamic casual modelling of resting-state functional MRI data to model effective connectivity in a model of these cortico-striatal pathways. We tested both of these hypotheses in vivo for the first time in a large cohort of patients with prodromal Huntington's disease. Using an advanced approach at the group level we combined parametric empirical Bayes and Bayesian model reduction procedures to generate a large number of competing models and compare them using Bayesian model comparison. With this automated Bayesian approach, associations between clinical measures and connectivity parameters emerge de novo from the data. We found very strong evidence (posterior probability > 0.99) to support both of our hypotheses. First, more severe motor signs in Huntington's disease were associated with altered connectivity in the indirect pathway components of our model and, by comparison, loss of goal-direct behaviour or apathy, was associated with changes in the direct pathway component. The empirical evidence we provide here demonstrates that imbalanced basal ganglia connectivity may play an important role in the pathogenesis of some of commonest and disabling features of Huntington's disease and may have important implications for therapeutics.

Neurofilament light-associated connectivity in young-adult Huntington's disease is related to neuronal genes.

Upregulation of functional network connectivity in the presence of structural degeneration is seen in the premanifest stages of Huntington's disease (preHD) 10-15 years from clinical diagnosis. However, whether widespread network connectivity changes are seen in gene carriers much further from onset has yet to be explored. We characterized functional network connectivity throughout the brain and related it to a measure of disease pathology burden (CSF neurofilament light, NfL) and measures of structural connectivity in asymptomatic gene carriers, on average 24 years from onset. We related these measurements to estimates of cortical and subcortical gene expression. We found no overall differences in functional (or structural) connectivity anywhere in the brain comparing control and preHD participants. However, increased functional connectivity, particularly between posterior cortical areas, correlated with increasing CSF NfL level in preHD participants. Using the Allen Human Brain Atlas and expression-weighted cell-type enrichment analysis, we demonstrated that this functional connectivity upregulation occurred in cortical regions associated with regional expression of genes specific to neuronal cells. This relationship was validated using single-nucleus RNAseq data from post-mortem Huntington's disease and control brains showing enrichment of neuronal-specific genes that are differentially expressed in Huntington's disease. Functional brain networks in asymptomatic preHD gene carriers very far from disease onset show evidence of upregulated connectivity correlating with increased disease burden. These changes occur among brain areas that show regional expression of genes specific to neuronal GABAergic and glutamatergic cells.

The Mediterranean diet is associated with better cardiometabolic health for women in mid-life but not men: A PREVENT dementia cohort cross-sectional analysis.

BACKGROUND AND AIMS: The Mediterranean diet (MedDiet) has been associated with better cardiovascular health in a number of studies. This study aimed to explore cross-sectional associations between MedDiet adherence in the PREVENT Dementia (PREVENT) programme, stratified by sex. METHODS AND RESULTS: Three MedDiet scores were calculated (MEDAS, MEDAS continuous and Pyramid) alongside a Western diet score. We used linear regression and linear mixed effects models to test for associations between the MEDAS score and cardiovascular health. Propensity scores were calculated to strengthen causality inferences from the data, and used as covariates along with total energy intake and Western diet scores. Exploratory analysis repeated the linear regression models for each individual food component. This study included 533 participants, with a mean age 51.25 (±5.40) years, and a majority of women (60.0%). Women had higher MedDiet scores across all three scoring methods, had a lower Western diet score and consumed fewer total calories. Higher MedDiet scores were associated with lower blood pressure, body mass index (BMI) and lower cardiovascular risk scores. When stratified by sex, women had significant positive associations between MedDiet scores and lower blood pressure, BMI and glycemia, whereas men only had a significant association with lower BMI. CONCLUSION: There were significant associations between higher MedDiet scores and a number of cardiovascular health outcome measures. These associations were seen more consistently for women compared to men, which may have implications for the development of personalised nutritional recommendations to improve cardiovascular health.

Therapeutic implications of hypothalamic-pituitaryadrenal-axis modulation in Alzheimer's disease: A narrative review of pharmacological and lifestyle interventions.

With disease-modifying treatments for Alzheimer's disease (AD) still elusive, the search for alternative intervention strategies has intensified. Growing evidence suggests that dysfunction in hypothalamic-pituitaryadrenal-axis (HPAA) activity may contribute to the development of AD pathology. The HPAA, may therefore offer a novel target for therapeutic action. This review summarises and critically evaluates animal and human studies investigating the effects of pharmacological and non-pharmacological intervention on HPAA modulation alongside cognitive performance. The interventions discussed include glucocorticoid receptor antagonists and 11ß-hydroxysteroid dehydrogenase inhibitors as well as lifestyle treatments such as physical activity, diet, sleep and contemplative practices. Pharmacological HPAA modulators improve pathology and cognitive deficit in animal AD models, but human pharmacological trials are yet to provide definitive support for such benefits. Lifestyle interventions may offer promising strategies for HPAA modification and cognitive health, but several methodological caveats across these studies were identified. Directions for future research in AD studies are proposed.

Self-reported diabetes is associated with allocentric spatial processing in the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study.

Type 2 diabetes is a robust predictor of cognitive impairment. Impairment in allocentric processing may help identify those at increased risk for Alzheimer's disease dementia. The objective of this study was to investigate the performance of participants with and without diabetes on a task of allocentric spatial processing. This was a cross-sectional secondary data analysis study using baseline data from the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS). Participants were aged 50 years and above and were free of dementia at baseline. Participants with no missing data on the variables of interest were included in this study. Our exposure variable was diabetes reported in the medical history. Our primary outcome was the Four Mountains Test (4MT), a novel task of allocentric processing. Covariates included demographics (age, sex, family history of dementia and years of education), APOEε4 carrier status, cognitive status (Clinical Dementia Rating scale), cerebrospinal fluid phosphorylated tau and amyloid-beta 1-42. Of 1324 participants (mean age = 65.95 (±7.45)), 90 had diabetes. Participants with diabetes scored 8.32 (±2.32) on the 4MT compared with 9.24 (±2.60) for participants without diabetes. In a univariate model, diabetes was significantly associated with worse 4MT total scores (ß = -.92, p = .001), remaining significant in a fully adjusted model (ß = -.64, p = .01). Cerebrospinal fluid phosphorylated tau was significantly higher in participants with diabetes compared with those without. Novel cognitive tests, such as the 4MT, may be appropriate to identify early cognitive changes in this high-risk group. Identifying those at greatest risk for future neurodegeneration is key to prevention efforts.

Dietary nitrate, aging and brain health: the latest evidence.

PURPOSE OF REVIEW: With an increasing population age, cognitive decline and age-associated neurodegenerative diseases are becoming increasingly prevalent and burdensome in society. Dietary supplementation with inorganic nitrate, which serves as a nitric oxide precursor, has been suggested as a potential nutritional strategy to improve brain health in older adults. In this review, we discuss recent findings in this area. RECENT FINDINGS: A number of studies have emerged in the past 12-18 months exploring the effects of dietary nitrate supplementation on cognitive function, with typically (although not exclusively) null findings emerging. This research is characterized by small, acute/short-term studies, although observational studies and longer-duration randomised controlled trials are beginning to emerge. From the limited research reporting benefits of nitrate supplementation on cognitive function, one important discovery has been the identification of a potential pathway through which nitrate could impact cognitive health, involving modulation of the oral microbiome, which warrants further investigation. SUMMARY: Despite some promising early findings, there is currently insufficient evidence to recommend increased dietary nitrate intake for the purpose of improving brain health. However, longer-term, larger-scale trials in potentially responsive groups are warranted to provide definitive evidence in this area.

Robust Markers and Sample Sizes for Multicenter Trials of Huntington Disease.

OBJECTIVE: The identification of sensitive biomarkers is essential to validate therapeutics for Huntington disease (HD). We directly compare structural imaging markers across the largest collective imaging HD dataset to identify a set of imaging markers robust to multicenter variation and to derive upper estimates on sample sizes for clinical trials in HD. METHODS: We used 1 postprocessing pipeline to retrospectively analyze T1-weighted magnetic resonance imaging (MRI) scans from 624 participants at 3 time points, from the PREDICT-HD, TRACK-HD, and IMAGE-HD studies. We used mixed effects models to adjust regional brain volumes for covariates, calculate effect sizes, and simulate possible treatment effects in disease-affected anatomical regions. We used our model to estimate the statistical power of possible treatment effects for anatomical regions and clinical markers. RESULTS: We identified a set of common anatomical regions that have similarly large standardized effect sizes (>0.5) between healthy control and premanifest HD (PreHD) groups. These included subcortical, white matter, and cortical regions and nonventricular cerebrospinal fluid (CSF). We also observed a consistent spatial distribution of effect size by region across the whole brain. We found that multicenter studies were necessary to capture treatment effect variance; for a 20% treatment effect, power of >80% was achieved for the caudate (n = 661), pallidum (n = 687), and nonventricular CSF (n = 939), and, crucially, these imaging markers provided greater power than standard clinical markers. INTERPRETATION: Our findings provide the first cross-study validation of structural imaging markers in HD, supporting the use of these measurements as endpoints for both observational studies and clinical trials. ANN NEUROL 2020;87:751-762.

Fronto-striatal circuits for cognitive flexibility in far from onset Huntington's disease: evidence from the Young Adult Study.

OBJECTIVES: Cognitive flexibility, which is key for adaptive decision-making, engages prefrontal cortex (PFC)-striatal circuitry and is impaired in both manifest and premanifest Huntington's disease (pre-HD). The aim of this study was to examine cognitive flexibility in a far from onset pre-HD cohort to determine whether an early impairment exists and if so, whether fronto-striatal circuits were associated with this deficit. METHODS: In the present study, we examined performance of 51 pre-HD participants (mean age=29.22 (SD=5.71) years) from the HD Young Adult Study cohort and 53 controls matched for age, sex and IQ, on the Cambridge Neuropsychological Test Automated Battery (CANTAB) Intra-Extra Dimensional Set-Shift (IED) task. This cohort is unique as it is the furthest from disease onset comprehensively studied to date (mean years=23.89 (SD=5.96) years). The IED task measures visual discrimination learning, cognitive flexibility and specifically attentional set-shifting. We used resting-state functional MRI to examine whether the functional connectivity between specific fronto-striatal circuits was dysfunctional in pre-HD, compared with controls, and whether these circuits were associated with performance on the critical extradimensional shift stage. RESULTS: Our results demonstrated that the CANTAB IED task detects a mild early impairment in cognitive flexibility in a pre-HD group far from onset. Attentional set-shifting was significantly related to functional connectivity between the ventrolateral PFC and ventral striatum in healthy controls and to functional connectivity between the dorsolateral PFC and caudate in pre-HD participants. CONCLUSION: We postulate that this incipient impairment of cognitive flexibility may be associated with intrinsically abnormal functional connectivity of fronto-striatal circuitry in pre-HD.

Composite UHDRS Correlates With Progression of Imaging Biomarkers in Huntington's Disease.

BACKGROUND: The composite Unified Huntington's Disease Rating Scale (cUHDRS) is a multidimensional measure of progression in Huntington's disease (HD) being used as a primary outcome in clinical trials investigating potentially disease-modifying huntingtin-lowering therapies. OBJECTIVE: Evaluating volumetric and structural connectivity correlates of the cUHDRS. METHODS: One hundred and nineteen premanifest and 119 early-HD participants were included. Gray and white matter (WM) volumes were correlated with cUHDRS cross-sectionally and longitudinally using voxel-based morphometry. Correlations between baseline fractional anisotropy (FA); mean, radial, and axial diffusivity; and baseline cUHDRS were examined using tract-based spatial statistics. RESULTS: Worse performance in the cUHDRS over time correlated with longitudinal volume decreases in the occipito-parietal cortex and centrum semiovale, whereas lower baseline scores correlated with decreased volume in the basal ganglia and surrounding WM. Lower cUHDRS scores were also associated with reduced FA and increased diffusivity at baseline. CONCLUSION: The cUHDRS correlates with imaging biomarkers and tracks atrophy progression in HD supporting its biological relevance. © 2021 International Parkinson and Movement Disorder Society.

Diffusion imaging in Huntington's disease: comprehensive review.

Huntington's disease (HD) is a monogenic disorder with 100% penetrance. With the advent of genetic testing in adults, disease-related, structural brain changes can be investigated from the earliest, premorbid stages of HD. While examining macrostructural change characterises global neuronal damage, investigating microstructural alterations provides information regarding brain organisation and its underlying biological properties. Diffusion MRI can be used to track the progression of microstructural anomalies in HD decades prior to clinical disease onset, providing a greater understanding of neurodegeneration. Multiple approaches, including voxelwise, region of interest and tractography, have been used in HD cohorts, showing a centrifugal pattern of white matter (WM) degeneration starting from deep brain areas, which is consistent with neuropathological studies. The corpus callosum, longer WM tracts and areas that are more densely connected, in particular the sensorimotor network, also tend to be affected early during premanifest stages. Recent evidence supports the routine inclusion of diffusion analyses within clinical trials principally as an additional measure to improve understanding of treatment effects, while the advent of novel techniques such as multitissue compartment models and connectomics can help characterise the underpinnings of progressive functional decline in HD.

Trauma and depressive symptomatology in middle-aged persons at high risk of dementia: the PREVENT Dementia Study.

OBJECTIVE: Depression and trauma are associated with changes in brain regions implicated in Alzheimer's disease. The present study examined associations between childhood trauma, depression, adult cognitive functioning and risk of dementia. METHODS: Data from 378 participants in the PREVENT Dementia Study aged 40-59 years. Linear and logistic models were used to assess associations between childhood trauma, depression, dementia risk, cognitive test scores and hippocampal volume. RESULTS: Childhood trauma was associated with depression and reduced hippocampal volume but not current cognitive function or dementia risk. Poorer performance on a delayed face/name recall task was associated with depression. Childhood trauma was associated with lower hippocampal volume however poorer cognitive performance was mediated by depression rather than structural brain differences. CONCLUSION: Depressive symptomatology may be associated with dementia risk via multiple pathways, and future studies should consider subtypes of depressive symptomatology when examining its relationship to dementia.

Longitudinal Structural MRI in Neurologically Healthy Adults.

BACKGROUND: Structural brain MRI measures are frequently examined in both healthy and clinical groups, so an understanding of how these measures vary over time is desirable. PURPOSE: To test the stability of structural brain MRI measures over time. POPULATION: In all, 112 healthy volunteers across four sites. STUDY TYPE: Retrospective analysis of prospectively acquired data. FIELD STRENGTH/SEQUENCE: 3 T, magnetization prepared - rapid gradient echo, and single-shell diffusion sequence. ASSESSMENT: Diffusion, cortical thickness, and volume data from the sensorimotor network were assessed for stability over time across 3 years. Two sites used a Siemens MRI scanner, two sites a Philips scanner. STATISTICAL TESTS: The stability of structural measures across timepoints was assessed using intraclass correlation coefficients (ICC) for absolute agreement, cutoff ≥0.80, indicating high reliability. Mixed-factorial analysis of variance (ANOVA) was used to examine between-site and between-scanner type differences in individuals over time. RESULTS: All cortical thickness and gray matter volume measures in the sensorimotor network, plus all diffusivity measures (fractional anisotropy plus mean, axial and radial diffusivities) for primary and premotor cortices, primary somatosensory thalamic connections, and the cortico-spinal tract met ICC. The majority of measures differed significantly between scanners, with a trend for sites using Siemens scanners to produce larger values for connectivity, cortical thickness, and volume measures than sites using Philips scanners. DATA CONCLUSION: Levels of reliability over time for all tested structural MRI measures were generally high, indicating that any differences between measurements over time likely reflect underlying biological differences rather than inherent methodological variability. LEVEL OF EVIDENCE: 4. TECHNICAL EFFICACY STAGE: 1.

Improving review of housebound people with diabetes through competency-based training.

People with diabetes who are housebound often fall between services and, therefore, do not always receive all of their key care processes, including insulin delivery. As part of a review of all such patients within a clinical commissioning group (CCG) in Kent, this project was conducted to train unregistered practitioners to carry out annual review. The aim was to improve knowledge and competencies among unregistered practitioners in order for them to be able to carry out some components of the diabetes annual review. Six unregistered practitioners employed by the GP practice or the community health trust participated in the project. Each practitioner achieved nine competencies, based on the TREND-UK competency framework. Competencies were achieved through classroom-based learning delivered by a nurse consultant in diabetes, as well as practical supervision of tasks and skills associated with carrying out an annual review. Reflective work and discussion demonstrated not only new skills learned but also how to put these into practice. It is hoped that the training of unregistered practitioners as part of the overall project not only improved their understanding and knowledge but also improved the standard of care delivered to this vulnerable group of people with diabetes.

In vivo characterization of white matter pathology in premanifest huntington's disease.

OBJECTIVE: Huntington's disease (HD) is a monogenic, fully penetrant neurodegenerative disorder, providing an ideal model for understanding brain changes occurring in the years prior to disease onset. Diffusion tensor imaging (DTI) studies show widespread white matter disorganization in the early premanifest stages (pre-HD). However, although DTI has proved informative, it provides only limited information about underlying changes in tissue properties. Neurite orientation dispersion and density imaging (NODDI) is a novel magnetic resonance imaging (MRI) technique for characterizing axonal pathology more specifically, providing metrics that separately quantify axonal density and axonal organization. Here, we provide the first in vivo characterization of white matter pathology in pre-HD using NODDI. METHODS: Diffusion-weighted MRI data that support DTI and NODDI were acquired from 38 pre-HD and 45 control participants. Using whole-brain and region-of-interest analyses, NODDI metrics were compared between groups and correlated with clinical scores of disease progression. Whole-brain changes in DTI metrics were also examined. RESULTS: The pre-HD group displayed widespread reductions in axonal density compared with control participants; this correlated with measures of clinical disease progression in the body and genu of the corpus callosum. There was also evidence in the pre-HD group of increased coherence of axonal packing in the white matter surrounding the basal ganglia. INTERPRETATION: Our findings suggest that reduced axonal density is one of the major factors underlying white matter pathology in pre-HD, coupled with altered local organization in areas surrounding the basal ganglia. NODDI metrics show promise in providing more specific information about the biological processes underlying HD and neurodegeneration per se. Ann Neurol 2018;84:497-504.

Testing a longitudinal compensation model in premanifest Huntington's disease.

The initial stages of neurodegeneration are commonly marked by normal levels of cognitive and motor performance despite the presence of structural brain pathology. Compensation is widely assumed to account for this preserved behaviour, but despite the apparent simplicity of such a concept, it has proven incredibly difficult to demonstrate such a phenomenon and distinguish it from disease-related pathology. Recently, we developed a model of compensation whereby brain activation, behaviour and pathology, components key to understanding compensation, have specific longitudinal trajectories over three phases of progression. Here, we empirically validate our explicit mathematical model by testing for the presence of compensation over time in neurodegeneration. Huntington's disease is an ideal model for examining longitudinal compensation in neurodegeneration as it is both monogenic and fully penetrant, so disease progression and potential compensation can be monitored many years prior to diagnosis. We defined our conditions for compensation as non-linear longitudinal trajectories of brain activity and performance in the presence of linear neuronal degeneration and applied our model of compensation to a large longitudinal cohort of premanifest and early-stage Huntington's disease patients from the multisite Track-On HD study. Focusing on cognitive and motor networks, we integrated progressive volume loss, task and resting state functional MRI and cognitive and motor behaviour across three sequential phases of neurodegenerative disease progression, adjusted for genetic disease load. Multivariate linear mixed models were fitted and trajectories for each variable tested. Our conceptualization of compensation was partially realized across certain motor and cognitive networks at differing levels. We found several significant network trends that were more complex than that hypothesized in our model. These trends suggest changes to our theoretical model where the network effects are delayed relative to performance effects. There was evidence of compensation primarily in the prefrontal component of the cognitive network, with increased effective connectivity between the left and right dorsolateral prefrontal cortex. Having developed an operational model for the explicit testing of longitudinal compensation in neurodegeneration, it appears that general patterns of our framework are consistent with the empirical data. With the proposed modifications, our operational model of compensation can be used to test for both cross-sectional and longitudinal compensation in neurodegenerative disease with similar patterns to Huntington's disease.

Natural biological variation of white matter microstructure is accentuated in Huntington's disease.

Huntington's disease (HD) is a monogenic neurodegenerative disorder caused by a CAG-repeat expansion in the Huntingtin gene. Presence of this expansion signifies certainty of disease onset, but only partly explains age at which onset occurs. Genome-wide association studies have shown that naturally occurring genetic variability influences HD pathogenesis and disease onset. Investigating the influence of biological traits in the normal population, such as variability in white matter properties, on HD pathogenesis could provide a complementary approach to understanding disease modification. We have previously shown that while white matter diffusivity patterns in the left sensorimotor network were similar in controls and HD gene-carriers, they were more extreme in the HD group. We hypothesized that the influence of natural variation in diffusivity on effects of HD pathogenesis on white matter is not limited to the sensorimotor network but extends to cognitive, limbic, and visual networks. Using tractography, we investigated 32 bilateral pathways within HD-related networks, including motor, cognitive, and limbic, and examined diffusivity metrics using principal components analysis. We identified three independent patterns of diffusivity common to controls and HD gene-carriers that predicted HD status. The first pattern involved almost all tracts, the second was limited to sensorimotor tracts, and the third encompassed cognitive network tracts. Each diffusivity pattern was associated with network specific performance. The consistency in diffusivity patterns across both groups coupled with their association with disease status and task performance indicates that naturally-occurring patterns of diffusivity can become accentuated in the presence of the HD gene mutation to influence clinical brain function.

Diabetes care in care home and residential settings.

An increasing number of people require insulin to manage their diabetes, many of them in supported environments such as residential care homes. Community nursing teams are likely to have a growing caseload of care home residents who require diabetes care, including insulin injections, and many unregistered practitioners are being asked to take on this role. If community nurse leads, matrons, frailty teams and pharmacy teams work together to provide training to staff in care homes (particularly unregistered practitioners), diabetes care can be improved. This has to be suitable for groups and for people with different levels of understanding, and supported by written resources. Courses are interactive to engage and motivate all learners, and methods of teaching include group work, visual teaching aids and games. Self-assessment around competencies, using a competency framework, not only demonstrates the development of staff but also highlights key areas of diabetes care.