ABSTRACT
Neuroimaging is increasingly being included in clinical trials of Huntington's disease (HD) for a wide range of purposes from participant selection and safety monitoring, through to demonstration of disease modification. Selection of the appropriate modality and associated analysis tools requires careful consideration. On behalf of the EHDN Imaging Working Group, we present current opinion on the utility and future prospects for inclusion of neuroimaging in HD trials. Covering the key imaging modalities of structural-, functional- and diffusion- MRI, perfusion imaging, positron emission tomography, magnetic resonance spectroscopy, and magnetoencephalography, we address how neuroimaging can be used in HD trials to: 1) Aid patient selection, enrichment, stratification, and safety monitoring; 2) Demonstrate biodistribution, target engagement, and pharmacodynamics; 3) Provide evidence for disease modification; and 4) Understand brain re-organization following therapy. We also present the challenges of translating research methodology into clinical trial settings, including equipment requirements and cost, standardization of acquisition and analysis, patient burden and invasiveness, and interpretation of results. We conclude, that with appropriate consideration of modality, study design and analysis, imaging has huge potential to facilitate effective clinical trials in HD.
Subject(s)
Clinical Trials as Topic , Huntington Disease , Neuroimaging , Humans , Huntington Disease/diagnostic imaging , Neuroimaging/methods , Brain/diagnostic imagingABSTRACT
With disease-modifying drugs on the horizon for degenerative ataxias, ecologically valid, finely granulated, digital health measures are highly warranted to augment clinical and patient-reported outcome measures. Gait and balance disturbances most often present as the first signs of degenerative cerebellar ataxia and are the most reported disabling features in disease progression. Thus, digital gait and balance measures constitute promising and relevant performance outcomes for clinical trials.This narrative review with embedded consensus will describe evidence for the sensitivity of digital gait and balance measures for evaluating ataxia severity and progression, propose a consensus protocol for establishing gait and balance metrics in natural history studies and clinical trials, and discuss relevant issues for their use as performance outcomes.
ABSTRACT
INTRODUCTION: Turning in gait digital parameters may be useful in measuring disease progression in Parkinson's disease (PD), however challenges remain over algorithm validation in real-world settings. The influence of clinician observation on turning outcomes is poorly understood. Our objective is to describe a unique in-home video dataset and explore the use of turning parameters as biomarkers in PD. METHODS: 11 participants with PD, 11 control participants stayed in a home-like setting living freely for 5 days (with two sessions of clinical assessment), during which high-resolution video was captured. Clinicians watched the videos, identified turns and documented turning parameters. RESULTS: From 85 hours of video 3869 turns were evaluated, averaging at 22.7 turns per hour per person. 6 participants had significantly different numbers of turning steps and/or turn duration between "ON" and "OFF" medication states. Positive Spearman correlations were seen between the Movement Disorders Society-sponsored revision of the Unified Parkinson's Disease Rating Scale III score with a) number of turning steps (rho = 0.893, p < 0.001), and b) duration of turn (rho = 0.744, p = 0.009) "OFF" medications. A positive correlation was seen "ON" medications between number of turning steps and clinical rating scale score (rho = 0.618, p = 0.048). Both cohorts took more steps and shorter durations of turn during observed clinical assessments than when free-living. CONCLUSION: This study shows proof of concept that real-world free-living turn duration and number of turning steps recorded can distinguish between PD medication states and correlate with gold-standard clinical rating scale scores. It illustrates a methodology for ecological validation of real-world digital outcomes.
Subject(s)
Parkinson Disease , Humans , Parkinson Disease/complications , Gait , Mental Status and Dementia Tests , Disease Progression , AlgorithmsABSTRACT
The use of wearable sensors allows continuous recordings of physical activity from participants in free-living or at-home clinical studies. The large amount of data collected demands automatic analysis pipelines to extract gait parameters that can be used as clinical endpoints. We introduce a deep learning-based automatic pipeline for wearables that processes tri-axial accelerometry data and extracts gait events-bout segmentation, initial contact (IC), and final contact (FC)-from a single sensor located at either the lower back (near L5), shin or wrist. The gait events detected are posteriorly used for gait parameter estimation, such as step time, length, and symmetry. We report results from a leave-one-subject-out (LOSO) validation on a pilot study dataset of five participants clinically diagnosed with Parkinson's disease (PD) and six healthy controls (HC). Participants wore sensors at three body locations and walked on a pressure-sensing walkway to obtain reference gait data. Mean absolute errors (MAE) for the IC events ranged from 22.82 to 33.09 milliseconds (msecs) for the lower back sensor while for the shin and wrist sensors, MAE ranges were 28.56-64.66 and 40.19-72.50 msecs, respectively. For the FC-event detection, MAE ranges were 29.06-48.42, 40.19-72.70 and 36.06-60.18 msecs for the lumbar, wrist and shin sensors, respectively. Intraclass correlation coefficients, ICC(2,k), between the estimated parameters and the reference data resulted in good-to-excellent agreement (ICC ≥ 0.84) for the lumbar and shin sensors, excluding the double support time (ICC = 0.37 lumbar and 0.38 shin) and swing time (ICC = 0.55 lumbar and 0.59 shin). The wrist sensor also showed good agreements, but the ICCs were lower overall than for the other two sensors. Our proposed analysis pipeline has the potential to extract up to 100 gait-related parameters, and we expect our contribution will further support developments in the fields of wearable sensors, digital health, and remote monitoring in clinical trials.
Subject(s)
Parkinson Disease , Wearable Electronic Devices , Gait , Gait Analysis , Humans , Parkinson Disease/diagnosis , Pilot ProjectsABSTRACT
Volumetric magnetic resonance imaging (vMRI) has been widely studied in Huntington's disease (HD) and is commonly used to assess treatment effects on brain atrophy in interventional trials. Global and regional trajectories of brain atrophy in HD, with early involvement of striatal regions, are becoming increasingly understood. However, there remains heterogeneity in the methods used and a lack of widely-accessible multisite, longitudinal, normative datasets in HD. Consensus for standardized practices for data acquisition, analysis, sharing, and reporting will strengthen the interpretation of vMRI results and facilitate their adoption as part of a pathobiological disease staging system. The Huntington's Disease Regulatory Science Consortium (HD-RSC) currently comprises 37 member organizations and is dedicated to building a regulatory science strategy to expedite the approval of HD therapeutics. Here, we propose four recommendations to address vMRI standardization in HD research: (1) a checklist of standardized practices for the use of vMRI in clinical research and for reporting results; (2) targeted research projects to evaluate advanced vMRI methodologies in HD; (3) the definition of standard MRI-based anatomical boundaries for key brain structures in HD, plus the creation of a standard reference dataset to benchmark vMRI data analysis methods; and (4) broad access to raw images and derived data from both observational studies and interventional trials, coded to protect participant identity. In concert, these recommendations will enable a better understanding of disease progression and increase confidence in the use of vMRI for drug development.
ABSTRACT
Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder that is caused by expansion of a CAG-repeat tract in the huntingtin gene and characterized by motor impairment, cognitive decline, and neuropsychiatric disturbances. Neuropathological studies show that disease progression follows a characteristic pattern of brain atrophy, beginning in the basal ganglia structures. The HD Regulatory Science Consortium (HD-RSC) brings together diverse stakeholders in the HD community-biopharmaceutical industry, academia, nonprofit, and patient advocacy organizations-to define and address regulatory needs to accelerate HD therapeutic development. Here, the Biomarker Working Group of the HD-RSC summarizes the cross-sectional evidence indicating that regional brain volumes, as measured by volumetric magnetic resonance imaging, are reduced in HD and are correlated with disease characteristics. We also evaluate the relationship between imaging measures and clinical change, their longitudinal change characteristics, and within-individual longitudinal associations of imaging with disease progression. This analysis will be valuable in assessing pharmacodynamics in clinical trials and supporting clinical outcome assessments to evaluate treatment effects on neurodegeneration.
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INTRODUCTION: The impact of disease-modifying agents on disease progression in Parkinson's disease is largely assessed in clinical trials using clinical rating scales. These scales have drawbacks in terms of their ability to capture the fluctuating nature of symptoms while living in a naturalistic environment. The SPHERE (Sensor Platform for HEalthcare in a Residential Environment) project has designed a multi-sensor platform with multimodal devices designed to allow continuous, relatively inexpensive, unobtrusive sensing of motor, non-motor and activities of daily living metrics in a home or a home-like environment. The aim of this study is to evaluate how the SPHERE technology can measure aspects of Parkinson's disease. METHODS AND ANALYSIS: This is a small-scale feasibility and acceptability study during which 12 pairs of participants (comprising a person with Parkinson's and a healthy control participant) will stay and live freely for 5 days in a home-like environment embedded with SPHERE technology including environmental, appliance monitoring, wrist-worn accelerometry and camera sensors. These data will be collected alongside clinical rating scales, participant diary entries and expert clinician annotations of colour video images. Machine learning will be used to look for a signal to discriminate between Parkinson's disease and control, and between Parkinson's disease symptoms 'on' and 'off' medications. Additional outcome measures including bradykinesia, activity level, sleep parameters and some activities of daily living will be explored. Acceptability of the technology will be evaluated qualitatively using semi-structured interviews. ETHICS AND DISSEMINATION: Ethical approval has been given to commence this study; the results will be disseminated as widely as appropriate.
Subject(s)
Parkinson Disease , Activities of Daily Living , Feasibility Studies , Humans , Outcome Assessment, Health Care , Parkinson Disease/diagnosis , Symptom Assessment , TechnologyABSTRACT
ABSTRACTBackground:40% of people with dementia have disturbed sleep but there are currently no known effective treatments. Studies of sleep hygiene and light therapy have not been powered to indicate feasibility and acceptability and have shown 40-50% retention. We tested the feasibility and acceptability of a six-session manualized evidence-based non-pharmacological therapy; Dementia RElAted Manual for Sleep; STrAtegies for RelaTives (DREAMS-START) for sleep disturbance in people with dementia. METHODS: We conducted a parallel, two-armed, single-blind randomized trial and randomized 2:1 to intervention: Treatment as Usual. Eligible participants had dementia and sleep disturbances (scoring ≥4 on one Sleep Disorders Inventory item) and a family carer and were recruited from two London memory services and Join Dementia Research. Participants wore an actiwatch for two weeks pre-randomization. Trained, clinically supervised psychology graduates delivered DREAMS-START to carers randomized to intervention; covering Understanding sleep and dementia; Making a plan (incorporating actiwatch information, light exposure using a light box); Daytime activity and routine; Difficult night-time behaviors; Taking care of your own (carer's) sleep; and What works? Strategies for the future. Carers kept their manual, light box, and relaxation recordings post-intervention. Outcome assessment was masked to allocation. The co-primary outcomes were feasibility (≥50% eligible people consenting to the study) and acceptability (≥75% of intervention group attending ≥4 intervention sessions). RESULTS: In total, 63out of 95 (66%; 95% CI: 56-76%) eligible referrals consented between 04/08/2016 and 24/03/2017; 62 (65%; 95% CI: 55-75%) were randomized, and 37 out of 42 (88%; 95% CI: 75-96%) adhered to the intervention. CONCLUSIONS: DREAM-START for sleep disorders in dementia is feasible and acceptable.
Subject(s)
Caregivers , Dementia/complications , Sleep Wake Disorders/therapy , Aged , Aged, 80 and over , Cognitive Behavioral Therapy , Cost-Benefit Analysis , Exercise , Feasibility Studies , Female , Humans , Male , Single-Blind Method , Surveys and Questionnaires , Treatment Outcome , United KingdomABSTRACT
BACKGROUND: It has been estimated that between 25% and 40% of people living with dementia suffer from sleep disturbances, and there are currently no known effective treatments. Sleep disturbances may be the direct result of dementia or due to other comorbidities, such as pain and limited mobility. If carers' sleep is also disturbed, carers too can become tired and stressed, and this sometimes results in the breakdown of care in the home. OBJECTIVES: To design an evidence-based manualised non-pharmacological therapy for sleep disturbances and test it for feasibility and acceptability. DESIGN: A single-blind, randomised, parallel-group feasibility trial, with participants randomised 2 : 1 to intervention or treatment as usual (TAU). SETTING: Five memory services in two London NHS trusts and Join Dementia Research (JDR). PARTICIPANTS: The study recruited people with dementia and sleep disturbances (who scored ≥ 4 on at least one question on the Sleep Disorders Inventory) and their primary family carers. INTERVENTION: All participants were given an Actiwatch (CamNtech Ltd, Cambridge, UK) to wear to record their sleep patterns for 2 weeks before randomisation. The intervention group received Dementia RElAted Manual for Sleep; STrAtegies for RelaTives (DREAMS START). This was designed as a six-session, manual-based intervention for carers of people with dementia, delivered by trained and clinically supervised psychology graduates, based on evidence about managing sleep disturbance in people with dementia. It uses the structure of a previous manual-based treatment, STrAtegies for RelaTives (START). Family carers were consulted about structure, content and design. Sessions were interactive, and each involved techniques, tasks to practise between sessions, relaxation and a recapitulation on the previous session. The sessions covered understanding sleep and dementia, making a plan (incorporating information from Actiwatch read-outs and a light box to increase light), daytime activity and routine, difficult night-time behaviours, taking care of your own (carer's) sleep and using the strategies in the future. Carers kept their own manual, light box and relaxation recordings post intervention. RANDOMISATION AND BLINDING: A statistician created an electronic randomisation list, stratified by site, using random permuted blocks. Those assessing the outcome were blinded to allocation; participants were not blinded. MAIN OUTCOME MEASURES: Outcomes were assessed at 3 months. (1) Feasibility, defined as the percentage of eligible people who consented to the study recruitment, with an expected value of 50% [95% confidence interval (CI) 41% to 59%]. (2) Acceptability, defined as the percentage of intervention group participants attending ≥ 4 intervention sessions, with an expected value of 75% (95% CI 59% to 87%). The predetermined criterion for progression to the main trial was acceptability of ≥ 70%. RESULTS: Of 95 eligible patients referred, 63 (66%, 95% CI 56% to 76%) consented between 4 August 2016 and 24 March 2017: 61 from memory clinics and two from JDR. Of these, 62 participants (65%, 95% CI 55% to 75%) were randomised: 42 to the intervention arm and 20 to the TAU arm. Thirty-seven out of 42 participants (88%, 95% CI 75% to 96%) adhered to the intervention. CONCLUSIONS: The results show that the randomised controlled trial is feasible and that the intervention is acceptable. A higher than expected proportion of eligible patients referred consented to the study and adhered to the intervention. LIMITATIONS: Participants were not blinded and were recruited only in London. FUTURE WORK: The results of this trial indicate that a future efficacy trial is warranted. TRIAL REGISTRATION: Current Controlled Trials ISCTRN36983298. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 71. See the NIHR Journals Library website for further project information. Funding was also provided by Camden and Islington NHS Foundation Trust and Barnet, Enfield and Haringey Mental Health NHS Trust to pay for excess treatment costs from therapist training and supervision and intervention delivery.
Subject(s)
Caregivers/psychology , Dementia/therapy , Sleep Wake Disorders/therapy , Treatment Outcome , Actigraphy/methods , Aged , Aged, 80 and over , Cost-Benefit Analysis , Female , Humans , London , Male , Middle Aged , Single-Blind Method , Surveys and Questionnaires , Technology Assessment, BiomedicalABSTRACT
Many people living with dementia experience sleep disturbances yet there are currently no known effective, safe and acceptable treatments. Working with those affected by dementia to co-produce interventions is increasingly promoted to ensure that approaches are fit for purpose and meet the specific needs of target groups. Our aim here is to outline and reflect upon the co-production of Dementia RElAted Manual for Sleep; STrAtegies for RelaTives (DREAMS:START), an intervention to improve sleep for people living with dementia. Our co-production team brought together experts in the development and testing of manualised interventions in dementia care and cognitive behavioural interventions for sleep disorders, with Alzheimer's Society research network volunteers (ASRNVs) whose lives had been affected by dementia. Here we present the process of intervention development. We worked with (ASRNVs) at each stage of the process bringing together 'experts by training' and 'experts by experience'. (ASRNVs)shared their experiences of sleep disturbances in dementia and how they had managed these difficulties, as well as suggestions for how to overcome barriers to putting the intervention into practice; making (DREAMS:START) more accessible and usable for those in need. In this paper we discuss both the benefits and challenges to this process and what we can learn for future work. Collaborating with 'experts by experience' caring for a relative with sleep difficulties helped us to develop a complex intervention in an accessible and engaging way which we have tested and found to be feasible and acceptable in a randomised controlled trial.
Subject(s)
Cooperative Behavior , Dementia/complications , Sleep Wake Disorders/therapy , Caregivers , Dementia/psychology , HumansABSTRACT
Converging evidence from structural, metabolic and functional connectivity MRI suggests that neurodegenerative diseases, such as Alzheimer's disease, target specific neural networks. However, age-related network changes commonly co-occur with neuropathological cascades, limiting efforts to disentangle disease-specific alterations in network function from those associated with normal ageing. Here we elucidate the differential effects of ageing and Alzheimer's disease pathology through simultaneous analyses of two functional connectivity MRI datasets: (i) young participants harbouring highly-penetrant mutations leading to autosomal-dominant Alzheimer's disease from the Dominantly Inherited Alzheimer's Network (DIAN), an Alzheimer's disease cohort in which age-related comorbidities are minimal and likelihood of progression along an Alzheimer's disease trajectory is extremely high; and (ii) young and elderly participants from the Harvard Aging Brain Study, a cohort in which imaging biomarkers of amyloid burden and neurodegeneration can be used to disambiguate ageing alone from preclinical Alzheimer's disease. Consonant with prior reports, we observed the preferential degradation of cognitive (especially the default and dorsal attention networks) over motor and sensory networks in early autosomal-dominant Alzheimer's disease, and found that this distinctive degradation pattern was magnified in more advanced stages of disease. Importantly, a nascent form of the pattern observed across the autosomal-dominant Alzheimer's disease spectrum was also detectable in clinically normal elderly with clear biomarker evidence of Alzheimer's disease pathology (preclinical Alzheimer's disease). At the more granular level of individual connections between node pairs, we observed that connections within cognitive networks were preferentially targeted in Alzheimer's disease (with between network connections relatively spared), and that connections between positively coupled nodes (correlations) were preferentially degraded as compared to connections between negatively coupled nodes (anti-correlations). In contrast, ageing in the absence of Alzheimer's disease biomarkers was characterized by a far less network-specific degradation across cognitive and sensory networks, of between- and within-network connections, and of connections between positively and negatively coupled nodes. We go on to demonstrate that formalizing the differential patterns of network degradation in ageing and Alzheimer's disease may have the practical benefit of yielding connectivity measurements that highlight early Alzheimer's disease-related connectivity changes over those due to age-related processes. Together, the contrasting patterns of connectivity in Alzheimer's disease and ageing add to prior work arguing against Alzheimer's disease as a form of accelerated ageing, and suggest multi-network composite functional connectivity MRI metrics may be useful in the detection of early Alzheimer's disease-specific alterations co-occurring with age-related connectivity changes. More broadly, our findings are consistent with a specific pattern of network degradation associated with the spreading of Alzheimer's disease pathology within targeted neural networks.
Subject(s)
Aging , Alzheimer Disease/complications , Alzheimer Disease/diagnostic imaging , Brain Mapping , Cognition Disorders/etiology , Neural Pathways/diagnostic imaging , Adult , Aged , Aged, 80 and over , Alzheimer Disease/genetics , Aniline Compounds/pharmacokinetics , Cognition Disorders/diagnostic imaging , Female , Fluorodeoxyglucose F18/pharmacokinetics , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Models, Neurological , Neural Pathways/drug effects , Positron-Emission Tomography , Thiazoles/pharmacokineticsABSTRACT
INTRODUCTION: Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. METHODS: Serial T1-weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point. RESULTS: Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point. DISCUSSION: Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression.
Subject(s)
Alzheimer Disease/complications , Alzheimer Disease/diagnostic imaging , Brain/diagnostic imaging , Adult , Apolipoproteins E/genetics , Atrophy/etiology , Atrophy/pathology , Brain/physiopathology , Female , Humans , Image Processing, Computer-Assisted , Longitudinal Studies , Magnetic Resonance Imaging , Male , Middle Aged , Psychiatric Status Rating Scales , Statistics, Nonparametric , Time FactorsABSTRACT
PURPOSE OF REVIEW: Sleep disorders in dementia cause distress and may lead to families being unable to care for someone with dementia at home. Recent Cochrane reviews found no interventions of proven effectiveness. There was no effect of light therapy and moderate evidence that melatonin was ineffective both given without knowledge of the patient's circadian rhythm. The current article updates this review by considering newer publications on interventions for sleep disorders or abnormalities of the sleep-wake cycle in people with dementia living in the community. RECENT FINDINGS: We searched electronically for new primary research, reviews and meta-analyses and identified 258 articles published between 15/12/2015 and 14/06/2017 on sleep and dementia; 43 of them on nonpharmacological or pharmacological treatments. Fifteen articles reported on the management of sleep disturbances in people with dementia, living at home. Those using pharmacological treatments (melatonin, psychotropic medications, donepezil, memantine) encompassed a meta-analysis, two double-blind RCTs, two uncontrolled trials, two population-based studies, and one case report. The studies of behavioural interventions comprised five uncontrolled trials, one case series, and one qualitative study. We also included three recent reviews on the management of sleep disturbances in Alzheimer's disease; pharmacotherapies for sleep disturbances in dementia, and dementia prevention, intervention and care. None of these found a treatment that showed definitive effectiveness, although there is preliminary work about nonpharmacological interventions, which can be built on. SUMMARY: Clinically effective, safe treatment of sleep disturbances in dementia remains an unresolved challenge. Given the importance of sleep and the many consequences of its disruption, well designed controlled trials are needed to determine acceptable and cost-effective treatment strategies that work for sleep disturbances.
Subject(s)
Dementia/complications , Independent Living/psychology , Sleep Hygiene/physiology , Sleep Wake Disorders , Disease Management , Humans , Needs Assessment , Sleep Wake Disorders/etiology , Sleep Wake Disorders/therapyABSTRACT
Recent brain imaging studies have found changes in subcortical regions in presymptomatic autosomal dominant Alzheimer's disease (ADAD). These regions are also affected in sporadic Alzheimer's disease (sAD), but whether such changes are seen in early-stage disease is still uncertain. In this review, we discuss imaging studies published in the past 12 years that have found evidence of subcortical involvement in early-stage ADAD and/or sAD. Several papers have reported amyloid deposition in the striatum of presymptomatic ADAD mutation carriers, prior to amyloid deposition elsewhere. Altered caudate volume has also been implicated in early-stage ADAD, but findings have been variable. Less is known about subcortical involvement in sAD: the thalamus and striatum have been found to be atrophied in symptomatic patients, but their involvement in the preclinical phase remains unclear, in part due to the difficulties of studying this stage in sporadic disease. Longitudinal imaging studies comparing ADAD mutation carriers with individuals at high-risk for sAD may be needed to elucidate the significance of subcortical involvement in different AD clinical stages.
Subject(s)
Alzheimer Disease/diagnostic imaging , Brain/diagnostic imaging , Alzheimer Disease/physiopathology , Brain/physiopathology , Disease Progression , Humans , NeuroimagingABSTRACT
The current study examined motor timing in frontotemporal dementia (FTD), which manifests as progressive deterioration in social, behavioural and cognitive functions. Twenty-patients fulfilling consensus clinical criteria for behavioural variant FTD (bvFTD), 11 patients fulfilling consensus clinical criteria for semantic-variant primary progressive aphasia (svPPA), four patients fulfilling criteria for nonfluent/agrammatic primary progressive aphasia (naPPA), eight patients fulfilling criteria for Alzheimer׳s disease (AD), and 31 controls were assessed on both an externally- and self-paced finger-tapping task requiring maintenance of a regular, 1500 ms beat over 50 taps. Grey and white matter correlates of deficits in motor timing were examined using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). bvFTD patients exhibited significant deficits in aspects of both externally- and self-paced tapping. Increased mean inter-response interval (faster than target tap time) in the self-paced task was associated with reduced grey matter volume in the cerebellum bilaterally, right middle temporal gyrus, and with increased axial diffusivity in the right superior longitudinal fasciculus, regions and tracts which have been suggested to be involved in a subcortical-cortical network of structures underlying timing abilities. This suggests that such structures can be affected in bvFTD, and that impaired motor timing may underlie some characteristics of the bvFTD phenotype.
Subject(s)
Cerebellar Cortex/pathology , Frontotemporal Dementia/physiopathology , Motor Activity/physiology , Time Perception/physiology , Aged , Alzheimer Disease/physiopathology , Aphasia, Primary Progressive/physiopathology , Female , Humans , Male , Middle AgedABSTRACT
Despite considerable interest in improving clinical and neurobiological characterisation of frontotemporal dementia and in defining the role of brain network disintegration in its pathogenesis, information about white matter pathway alterations in frontotemporal dementia remains limited. Here we investigated white matter tract damage using an unbiased, template-based diffusion tensor imaging (DTI) protocol in a cohort of 27 patients with the behavioral variant of frontotemporal dementia (bvFTD) representing both major genetic and sporadic forms, in relation both to healthy individuals and to patients with Alzheimer's disease. Widespread white matter tract pathology was identified in the bvFTD group compared with both healthy controls and Alzheimer's disease group, with prominent involvement of uncinate fasciculus, cingulum bundle and corpus callosum. Relatively discrete and distinctive white matter profiles were associated with genetic subgroups of bvFTD associated with MAPT and C9ORF72 mutations. Comparing diffusivity metrics, optimal overall separation of the bvFTD group from the healthy control group was signalled using radial diffusivity, whereas optimal overall separation of the bvFTD group from the Alzheimer's disease group was signalled using fractional anisotropy. Comparing white matter changes with regional grey matter atrophy (delineated using voxel based morphometry) in the bvFTD cohort revealed co-localisation between modalities particularly in the anterior temporal lobe, however white matter changes extended widely beyond the zones of grey matter atrophy. Our findings demonstrate a distributed signature of white matter alterations that is likely to be core to the pathophysiology of bvFTD and further suggest that this signature is modulated by underlying molecular pathologies.
Subject(s)
Alzheimer Disease/pathology , Brain/pathology , Frontotemporal Dementia/pathology , Nerve Fibers, Myelinated/pathology , White Matter/pathology , Alzheimer Disease/diagnosis , Anisotropy , Atrophy , C9orf72 Protein , Cohort Studies , Diffusion Tensor Imaging , Female , Frontotemporal Dementia/diagnosis , Frontotemporal Dementia/genetics , Genotyping Techniques , Gray Matter/pathology , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Middle Aged , Mutation , Proteins/genetics , Sensitivity and Specificity , tau Proteins/geneticsABSTRACT
OBJECTIVE: To assess regional patterns of gray and white matter atrophy in familial Alzheimer disease (FAD) mutation carriers. METHODS: A total of 192 participants with volumetric T1-weighted MRI, genotyping, and clinical diagnosis were available from the Dominantly Inherited Alzheimer Network. Of these, 69 were presymptomatic mutation carriers, 50 were symptomatic carriers (31 with Clinical Dementia Rating [CDR] = 0.5, 19 with CDR > 0.5), and 73 were noncarriers from the same families. Voxel-based morphometry was used to identify cross-sectional group differences in gray matter and white matter volume. RESULTS: Significant differences in gray matter (p < 0.05, family-wise error-corrected) were observed between noncarriers and mildly symptomatic (CDR = 0.5) carriers in the thalamus and putamen, as well as in the temporal lobe, precuneus, and cingulate gyrus; the same pattern, but with more extensive changes, was seen in those with CDR > 0.5. Significant white matter differences between noncarriers and symptomatic carriers were observed in the cingulum and fornix; these form input and output connections to the medial temporal lobe, cingulate, and precuneus. No differences between noncarriers and presymptomatic carriers survived correction for multiple comparisons, but there was a trend for decreased gray matter in the thalamus for carriers closer to their estimated age at onset. There were no significant increases of gray or white matter in asymptomatic or symptomatic carriers compared to noncarriers. CONCLUSIONS: Atrophy in FAD is observed early, both in areas commonly associated with sporadic Alzheimer disease and also in the putamen and thalamus, 2 regions associated with early amyloid deposition in FAD mutation carriers.
Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/pathology , Cerebrum/pathology , Magnetic Resonance Imaging/methods , Adult , Age of Onset , Atrophy/genetics , Cerebral Cortex/pathology , Cohort Studies , Female , Heterozygote , Humans , Magnetic Resonance Imaging/instrumentation , Male , Middle Aged , Prodromal Symptoms , Prognosis , Young AdultABSTRACT
Errors trigger changes in behavior that help individuals adapt to new situations. The dorsal anterior cingulate cortex (dACC) is thought to be central to this response, but more lateral frontal regions are also activated by errors and may make distinct contributions. We investigated error processing by studying 2 distinct error types: commission and timing. Thirty-five subjects performed a version of the Simon Task designed to produce large number of errors. Commission errors were internally recognized and were not accompanied by explicit feedback. In contrast, timing errors were difficult to monitor internally and were explicitly signaled. Both types of error triggered changes in behavior consistent with increased cognitive control. As expected, robust activation within the dACC and bilateral anterior insulae (the Salience Network) was seen for commission errors. In contrast, timing errors were not associated with activation of this network but did activate a bilateral network that included the right ventral attentional system. Common activation for both error types occurred within the pars operculari and angular gyri. These results show that the dACC does not respond to all behaviorally salient errors. Instead, the error-processing system is multifaceted, and control can be triggered independently of the dACC when feedback is unexpected.
Subject(s)
Attention/physiology , Brain Mapping , Cognition/physiology , Frontal Lobe/physiology , Adult , Female , Humans , Image Interpretation, Computer-Assisted , Magnetic Resonance Imaging , MaleABSTRACT
Efficient behavior involves the coordinated activity of large-scale brain networks, but the way in which these networks interact is uncertain. One theory is that the salience network (SN)--which includes the anterior cingulate cortex, presupplementary motor area, and anterior insulae--regulates dynamic changes in other networks. If this is the case, then damage to the structural connectivity of the SN should disrupt the regulation of associated networks. To investigate this hypothesis, we studied a group of 57 patients with cognitive impairments following traumatic brain injury (TBI) and 25 control subjects using the stop-signal task. The pattern of brain activity associated with stop-signal task performance was studied by using functional MRI, and the structural integrity of network connections was quantified by using diffusion tensor imaging. Efficient inhibitory control was associated with rapid deactivation within parts of the default mode network (DMN), including the precuneus and posterior cingulate cortex. TBI patients showed a failure of DMN deactivation, which was associated with an impairment of inhibitory control. TBI frequently results in traumatic axonal injury, which can disconnect brain networks by damaging white matter tracts. The abnormality of DMN function was specifically predicted by the amount of white matter damage in the SN tract connecting the right anterior insulae to the presupplementary motor area and dorsal anterior cingulate cortex. The results provide evidence that structural integrity of the SN is necessary for the efficient regulation of activity in the DMN, and that a failure of this regulation leads to inefficient cognitive control.
Subject(s)
Brain Injuries/physiopathology , Adolescent , Adult , Behavior , Brain/physiology , Brain Injuries/therapy , Brain Mapping/methods , Diffusion Tensor Imaging/methods , Female , Gyrus Cinguli/physiology , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Models, Biological , Motor Cortex/physiologyABSTRACT
Traumatic brain injury (TBI) frequently produces impairments of attention in humans. These can result in a failure to maintain consistent goal-directed behavior. A predominantly right-lateralized frontoparietal network is often engaged during attentionally demanding tasks. However, lapses of attention have also been associated with increases in activation within the default mode network (DMN). Here, we study TBI patients with sustained attention impairment, defined on the basis of the consistency of their behavioral performance over time. We show that sustained attention impairments in patients are associated with an increase in DMN activation, particularly within the precuneus and posterior cingulate cortex. Furthermore, the interaction of the precuneus with the rest of the DMN at the start of the task, i.e., its functional connectivity, predicts which patients go on to show impairments of attention. Importantly, this predictive information is present before any behavioral evidence of sustained attention impairment, and the relationship is also found in a subgroup of patients without focal brain damage. TBI often results in diffuse axonal injury, which produces cognitive impairment by disconnecting nodes in distributed brain networks. Using diffusion tensor imaging, we demonstrate that structural disconnection within the DMN also correlates with the level of sustained attention. These results show that abnormalities in DMN function are a sensitive marker of impairments of attention and suggest that changes in connectivity within the DMN are central to the development of attentional impairment after TBI.