ABSTRACT
BACKGROUND: Hip fracture is a common injury in the geriatric population. Despite surgical repair and subsequent rehabilitation programmes, functional recovery is often limited, particularly in individuals with multi-morbidity. This leads to high care dependency and subsequent use of healthcare services. Fear of falling has a negative influence on recovery after hip fracture, due to avoidance of activity and subsequent restriction in mobility. Although fear of falling is highly prevalent after hip fracture, no structured treatment programme is currently available. This trial will evaluate whether targeted treatment of fear of falling in geriatric rehabilitation after hip fracture using a multi-component cognitive behavioural intervention (FIT-HIP), is feasible and (cost) effective in reducing fear of falling and associated activity restriction and thereby improves physical functioning. METHODS/DESIGN: This multicentre cluster randomised controlled trial will be conducted among older patients with hip fracture and fear of falling who are admitted to a multidisciplinary inpatient geriatric rehabilitation programme in eleven post-acute geriatric rehabilitation units. Fifteen participants will be recruited from each site. Recruitment sites will be allocated by computer randomisation to either the control group, receiving usual care, or to the intervention group receiving the FIT-HIP intervention in addition to usual care. The FIT-HIP intervention is conducted by physiotherapists and will be embedded in usual care. It consists of various elements of cognitive behavioural therapy, including guided exposure to feared activities (that are avoided by the participants). Participants and outcome assessors are blinded to group allocation. Follow-up measurements will be performed at 3 and 6 months after discharge from geriatric rehabilitation. (Cost)-effectiveness and feasibility of the intervention will be evaluated. Primary outcome measures are fear of falling and mobility. DISCUSSION: Targeted treatment of fear of falling may improve recovery and physical and social functioning after hip fracture, thereby offering benefits for patients and reducing healthcare costs. Results of this study will provide insight into whether fear of falling is modifiable in the (geriatric) rehabilitation after hip fracture and whether the intervention is feasible. TRIAL REGISTRATION: Netherlands Trial Register: NTR 5695 .
Subject(s)
Accidental Falls , Cognitive Behavioral Therapy , Fear , Hip Fractures/psychology , Hip Fractures/rehabilitation , Aged , Aged, 80 and over , Cost-Benefit Analysis , Female , Hospitalization , Humans , Male , Netherlands , Treatment OutcomeABSTRACT
OBJECTIVES: To investigate both cross-sectional and time-related changes of striatal and whole-brain microstructural properties in different stages of Huntington's disease (HD) using diffusion tensor imaging. EXPERIMENTAL DESIGN: From the TRACK-HD study, premanifest gene carriers (preHD), early manifest HD and controls were scanned at baseline and 2-year follow-up. Stratification of the preHD group into a far (preHD-A) and near (preHD-B) to predicted disease onset was performed. Age-corrected histograms of whole-brain white matter (WM), gray matter (GM) and striatal diffusion measures were computed and normalised by the number of voxels in each subject's data set. PRINCIPLE OBSERVATIONS: Higher cross-sectional mean, axial and radial diffusivities were found in both WM (P ≤ 0.001) and GM (P ≤ 0.001) of the manifest HD compared to the preHD and control groups. In preHD, only WM axial diffusivity (AD) was higher than in controls (P ≤ 0.01). This finding remained valid only in preHD-B (P ≤ 0.001). AD was also higher in the striatum of preHD-B compared to controls and preHD-A (P ≤ 0.01). Fractional anisotropy (FA) lacked sensitivity in differentiating between the groups. Histogram peak heights were generally lower in manifest HD compared to the preHD and control groups. No longitudinal differences were found in the degree of diffusivity change between the groups in the two year follow-up. There was a significant relationship between diffusivity and neurocognitive measures. CONCLUSIONS: Alterations in cross-sectional diffusion profiles between manifest HD subjects and controls were evident, both in whole-brain and striatum. In the preHD stage, only AD alterations were found, a finding suggesting that this metric is a sensitive marker for early change in HD prior to disease manifestation. The individual diffusivities were superior to FA in revealing pathologic microstructural brain alterations. Diffusion measures were well related to clinical functioning and disease stage.
Subject(s)
Brain/pathology , Huntington Disease/pathology , Adult , Anisotropy , Diffusion Tensor Imaging , Female , Follow-Up Studies , Gray Matter/pathology , Humans , Longitudinal Studies , Male , Middle Aged , White Matter/pathologyABSTRACT
BACKGROUND: We previously demonstrated that in the premanifest stage of Huntington's disease (preHD), a reduced functional connectivity exists compared to healthy controls. In the current study, we look at possible changes in functional connectivity occurring longitudinally over a period of 3 years, with the aim of assessing the potential usefulness of this technique as a biomarker for disease progression in preHD. METHODS: Twenty-two preHD and 17 healthy control subjects completed resting state functional magnetic resonance imaging (fMRI) scans in two visits with 3 years in between. Differences in resting state connectivity were examined for eight networks of interest using FSL with three different analysis types: a dual regression method, region of interest approach, and an independent component analysis. To evaluate a possible combined effect of gray matter volume change and the change in blood oxygenation level dependent signal, the analysis was performed with and without voxel-wise correction for gray matter volume. To evaluate possible correlations between functional connectivity change and the predicted time to disease onset, the preHD group was classed as preHD-A if ≥10.9 years and preHD-B if <10.9 years from predicted disease onset. Possible correlations between burden of pathology score and functional connectivity change in preHD were also assessed. Finally, longitudinal change in whole brain and striatal volumetric measures was assessed in the studied cohort. RESULTS: Longitudinal analysis of the resting state-fMRI (RS-fMRI) data revealed no differences in the degree of connectivity change between the groups over a period of 3 years, though a significantly higher rate of striatal atrophy was found in the preHD group compared to controls in the same period. DISCUSSION: Based on the results found in this study, the provisional conclusion is that RS-fMRI lacks sensitivity in detecting changes in functional connectivity in HD gene carriers prior to disease manifestation over a 3-year follow-up period.
Subject(s)
Brain Mapping , Brain/blood supply , Huntington Disease/diagnosis , Magnetic Resonance Imaging , Rest , Adult , Brain/pathology , Disease Progression , Female , Humans , Huntington Disease/genetics , Image Processing, Computer-Assisted , Longitudinal Studies , Male , Middle Aged , Neuropsychological Tests , Oxygen/blood , Severity of Illness Index , Statistics, NonparametricABSTRACT
OBJECTIVE: Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness caused by DMD gene mutations leading to absence of the full-length dystrophin protein in muscle. Multiple dystrophin isoforms are expressed in brain, but little is known about their function. DMD is associated with specific learning and behavioral disabilities that are more prominent in patients with mutations in the distal part of the DMD gene, predicted to affect expression of shorter protein isoforms. We used quantitative magnetic resonance (MR) imaging to study brain microstructure in DMD. METHODS: T1-weighted and diffusion tensor images were obtained on a 3T MR scanner from 30 patients and 22 age-matched controls (age = 8-18 years). All subjects underwent neuropsychological examination. Group comparisons on tissue volume and diffusion tensor imaging parameters were made between DMD patients and controls, and between 2 DMD subgroups that were classified according to predicted Dp140 isoform expression (DMD_Dp140(+) and DMD_Dp140(-) ). RESULTS: DMD patients had smaller total brain volume, smaller gray matter volume, lower white matter fractional anisotropy, and higher white matter mean and radial diffusivity than healthy controls. DMD patients also performed worse on neuropsychological examination. Subgroup analyses showed that DMD_Dp140(-) subjects contributed most to the gray matter volume differences and performed worse on information processing. INTERPRETATION: Both gray and white matter is affected in boys with DMD at a whole brain level. Differences between the DMD_Dp140(-) subgroup and controls indicate an important role for the Dp140 dystrophin isoform in cerebral development.
Subject(s)
Gray Matter/pathology , Magnetic Resonance Imaging/methods , Muscular Dystrophy, Duchenne/pathology , White Matter/pathology , Adolescent , Cerebral Cortex/pathology , Child , Diffusion Tensor Imaging/instrumentation , Diffusion Tensor Imaging/methods , Dystrophin/genetics , Humans , Magnetic Resonance Imaging/instrumentation , Male , Muscular Dystrophy, Duchenne/genetics , Muscular Dystrophy, Duchenne/physiopathology , Mutation/genetics , Nerve Fibers, Myelinated/pathology , Protein Isoforms/geneticsABSTRACT
BACKGROUND: Iron accumulation has been linked to neuronal injury following cerebral ischemia. In animals, a hypointense signal on T2*-weighted (T2*-w) MRI correlated with iron deposits in remote brain regions following ischemic stroke. We aim to assess whether such signal changes are present in remote brain structures following ischemic stroke in humans. METHODS: We analyzed T2*-w images of 36 patients with unilateral ischemic stroke and 36 healthy controls. Regions of interest (ROIs) consisted of the thalamus, putamen, globus pallidus, caudate nucleus and white matter. To quantify signal intensity in ROIs ipsilateral to the infarct, signal intensity was measured in the ROIs in both hemispheres and a ratio of signal intensity was calculated. Signal asymmetry was compared between patients and controls and its relation with time after stroke onset was assessed. RESULTS: In 34 (94%) patients, the thalamus ipsilateral to the infarct was hypointense compared to the contralateral thalamus. Ipsilateral thalamic signal hypointensity was significantly different between patients and controls (p < 0.001) and was present as early as 1 day after stroke onset. In other ROIs, no difference was found between patients and controls. No association was found between intensity asymmetry and time. CONCLUSION: We demonstrated that, as early as days after ischemic stroke, T2*-w signal intensity was decreased in the ipsilateral thalamus. This finding might indicate pathophysiologic changes in regions outside the infarcted area, possibly reflecting toxic iron accumulation.
Subject(s)
Brain Ischemia/metabolism , Iron/metabolism , Magnetic Resonance Imaging , Stroke/metabolism , Thalamus/metabolism , Adult , Aged , Brain Ischemia/diagnosis , Databases, Factual , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies , Stroke/diagnosis , Time FactorsABSTRACT
The authors report the inter-rater reliability and factor structure of the Short Problem Behaviors Assessment (PBA-s), a semistructured interview to measure severity and frequency of behavioral problems in Huntington's disease. Video recordings of 410 PBA-s interviews were rescored by an independent rater, and Cohen's kappa calculated to assess inter-rater reliability. The mean kappa was 0.74 for severity and 0.76 for frequency scores, whereas weighted kappa (allowing scores to differ by 1 point) was 0.94 for severity and 0.92 for frequency scores. The results of factor analysis were consistent with previous studies using other measures. The authors conclude that the PBA-s is a reliable measure.
Subject(s)
Huntington Disease/complications , Mental Disorders/diagnosis , Mental Disorders/etiology , Psychiatric Status Rating Scales , Europe , Female , Humans , International Cooperation , Longitudinal Studies , Male , Registries , Reproducibility of Results , Severity of Illness Index , Statistics, Nonparametric , Video RecordingABSTRACT
Motor disturbances can be present in both manifest and premanifest Huntington's disease (HD). We aimed to investigate the role of motor functioning on executive functioning to better understand the progression of cognitive dysfunction in HD. Forty patients with manifest HD, 21 patients with premanifest HD, and a group of 28 controls were tested twice with a 1-year interval. For the Symbol Digit Modalities Test and the Figure Fluency Test, extra conditions were designed to measure motor involvement. Subtraction of this motor score from the original test score resulted in isolation of the cognitive component. Groups were compared on motor, cognitive, and original test scores using multilevel regression analysis. Manifest patients had lower baseline scores of 0.53 standard deviations (SD) on the original Symbol Digit Modalities Test (P = 0.03) and 0.71 SD on the motor isolation part (P = 0.006), and they showed a deterioration of 0.47 SD over 1 year of follow-up on the original Symbol Digit Modalities Test (P = 0.001) compared with controls. Premanifest patients had lower baseline scores of 0.67 SD on the Symbol Digit Modalities motor part (P = 0.008) and deterioration of 0.48 SD on the original (P = 0.001) and cognitive isolation (P = 0.02) parts. Secondary analyses revealed that the premanifest deterioration resulted from the close-to-predicted-onset group. Motor disturbances have a negative influence on performance on the Symbol Digit Modalities Test. Isolation of the cognitive component of this test revealed cognitive deterioration in the premanifest group only, caused by deteriorating scores for patients who were close to their predicted clinical disease onset. The Figure Fluency Test did not prove sensitive to cognitive change.
Subject(s)
Executive Function/physiology , Huntington Disease/physiopathology , Motor Neuron Disease/physiopathology , Adult , Aged , Cognition/physiology , Disease Progression , Female , Humans , Huntington Disease/complications , Male , Middle Aged , Motor Neuron Disease/etiology , Neuropsychological TestsABSTRACT
PURPOSE: To develop a framework for quantitative detection of between-group textural differences in ultrahigh field T2*-weighted MR images of the brain. MATERIALS AND METHODS: MR images were acquired using a three-dimensional (3D) T2*-weighted gradient echo sequence on a 7 Tesla MRI system. The phase images were high-pass filtered to remove phase wraps. Thirteen textural features were computed for both the magnitude and phase images of a region of interest based on 3D Gray-Level Co-occurrence Matrix, and subsequently evaluated to detect between-group differences using a Mann-Whitney U-test. We applied the framework to study textural differences in subcortical structures between premanifest Huntington's disease (HD), manifest HD patients, and controls. RESULTS: In premanifest HD, four phase-based features showed a difference in the caudate nucleus. In manifest HD, 7 magnitude-based features showed a difference in the pallidum, 6 phase-based features in the caudate nucleus, and 10 phase-based features in the putamen. After multiple comparison correction, significant differences were shown in the putamen in manifest HD by two phase-based features (both adjusted P values=0.04). CONCLUSION: This study provides the first evidence of textural heterogeneity of subcortical structures in HD. Texture analysis of ultrahigh field T2*-weighted MR images can be useful for noninvasive monitoring of neurodegenerative diseases.
Subject(s)
Diffusion Magnetic Resonance Imaging/methods , Huntington Disease/pathology , Image Interpretation, Computer-Assisted , Imaging, Three-Dimensional , Adult , Case-Control Studies , Female , Humans , Huntington Disease/diagnosis , Male , Middle Aged , Pattern Recognition, Automated , Reference Values , Statistics, NonparametricABSTRACT
Neuropathological studies in Huntington disease (HD) have demonstrated neuronal loss in the striatum, as well as in other brain regions including the cortex. With diffusion tensor MRI we evaluated the hypothesis that the clinical dysfunction in HD is related to regionally specific lesions of circuit-specific cortico-basal ganglia networks rather than to the striatum only. We included 27 HD and 24 controls from the TRACK-HD Paris cohort. The following assessments were used: self-paced tapping tasks, trail B making test (TMT), University of Pennsylvania smell identification test (UPSIT), and apathy scores from the problem behaviors assessment. Group comparisons of fractional anisotropy and mean diffusivity and correlations were performed using voxel-based analysis. In the cortex, HD patients showed significant correlations between: (i) self paced tapping and mean diffusivity in the parietal lobe at 1.8 Hz and prefrontal areas at 3 Hz, (ii) UPSIT and mean diffusivity in the parietal, and median temporal lobes, the cingulum and the insula, and fractional anisotropy in the insula and the external capsule, (iii) TMT B and mean diffusivity in the white matter of the superior frontal, orbital, temporal, superior parietal and post central areas, and (iv) apathy and fractional anisotropy in the white matter of the rectus gyrus. In the basal ganglia, we found correlations between the self paced tapping, UPSIT, TMT tests, and mean diffusivity in the anterior part of the putamen and the caudate nucleus. In conclusion, disruption of motor, associative and limbic cortico-striatal circuits differentially contribute to the clinical signs of the disease.
Subject(s)
Brain Mapping , Brain/pathology , Brain/physiopathology , Huntington Disease/pathology , Huntington Disease/physiopathology , Apathy/physiology , Cognition/physiology , Cognition Disorders/etiology , Cognition Disorders/pathology , Cognition Disorders/physiopathology , Diffusion Magnetic Resonance Imaging , Female , Humans , Huntington Disease/complications , Image Interpretation, Computer-Assisted , Male , Middle Aged , Neuropsychological Tests , Psychomotor Performance/physiologyABSTRACT
Increased iron in subcortical structures in patients with Huntington's Disease (HD) has been suggested as a causal factor of neuronal degeneration. The present study examines iron accumulation, measured using magnetic resonance imaging (MRI), in premanifest gene carriers and in early HD patients as compared to healthy controls. In total 27 early HD patients, 22 premanifest gene carriers and 25 healthy controls, from the Leiden site of the TRACK-HD study, underwent 3T MRI including high resolution 3D T(1)- and T(2)-weighted and asymmetric spin echo (ASE) sequences. Magnetic Field Correlation (MFC) maps of iron levels were constructed to assess magnetic field inhomogeneities and compared between groups in the caudate nucleus, putamen, globus pallidus, hippocampus, amygdala, accumbens nucleus, and thalamus. Subsequently the relationship of MFC value to volumetric data and disease state was examined. Higher MFC values were found in the caudate nucleus (p<0.05) and putamen (p<0.005) of early HD compared to controls and premanifest gene carriers. No differences in MFC were found between premanifest gene carriers and controls. MFC in the caudate nucleus and putamen is a predictor of disease state in HD. No correlation was found between the MFC value and volume of these subcortical structures. We conclude that Huntington's disease patients in the early stages of the disease, but not premanifest gene carriers, have higher iron concentrations in the caudate nucleus and putamen. We have demonstrated that the iron content of these structures relates to disease state in gene carriers, independently of the measured volume of these structures.
Subject(s)
Brain Chemistry/physiology , Brain/pathology , Huntington Disease/metabolism , Huntington Disease/pathology , Iron/metabolism , Adult , Age of Onset , Aged , Aging/physiology , Atrophy , Caudate Nucleus/metabolism , Disease Progression , Educational Status , Electromagnetic Fields , Female , Heterozygote , Humans , Huntington Disease/genetics , Image Processing, Computer-Assisted , Logistic Models , Magnetic Resonance Imaging , Male , Middle Aged , Putamen/metabolism , Sex CharacteristicsABSTRACT
OBJECTIVES: To investigate the function-structure relationship of white matter within different stages of Huntington's disease (HD) using diffusion tensor imaging (DTI). EXPERIMENTAL DESIGN: From the TRACK-HD study, an early stage HD group and a premanifest gene carrier group (PMGC) were age-matched to two healthy control groups; all underwent 3-T MRI scanning of the brain. Region of interest (ROI) segmentation of the corpus callosum, caudate nucleus, thalamus, prefrontal cortex, and sensorimotor cortex was applied, and the apparent fiber pathways of these regions were analyzed. Functional measures of motor, oculomotor, cognition, and behavior were correlated to DTI measures. PRINCIPLE OBSERVATIONS: In PMGC versus controls, higher apparent diffusion coefficient (ADC) was seen in white matter pathways of the sensorimotor cortex (P < 0.01) and in the ROI of corpus callosum (P < 0.017). In early HD, fiber tract analysis showed higher ADC in pathways of the corpus callosum, thalamus, sensorimotor, and prefrontal region (P < 0.01). ROI analysis showed higher diffusivity in the corpus callosum and caudate nucleus (P < 0.017). Motor, oculomotor, cognition, and probability of onset within 2 and 5 years, correlated well with ADC measures of the corpus callosum (P < 0.01 - P < 0.005), sensorimotor (P < 0.01 - P < 0.005), and prefrontal region (P < 0.01). CONCLUSIONS: Disturbances in the white matter connections of the sensorimotor cortex can be demonstrated not only in manifest HD but also in premanifest gene carriers. Connectivity measures are well related to clinical functioning. DTI measures can be regarded as a potential biomarker for HD, due to their ability to objectify changes in brain structures and their role within brain networks.
Subject(s)
Huntington Disease/pathology , Motor Cortex/pathology , Nerve Fibers, Myelinated/pathology , Adult , Brain/pathology , Brain Mapping , Diffusion Tensor Imaging , Disease Progression , Female , Humans , Huntington Disease/psychology , Male , Middle Aged , Neuropsychological TestsABSTRACT
BACKGROUND: Deterioration of cognitive functioning is a debilitating symptom in many neurodegenerative diseases, such as Huntington's disease (HD). To date, there are no effective treatments for the cognitive problems associated with HD. Cognitive assessment outcomes will have a central role in the efforts to develop treatments to delay onset or slow the progression of the disease. The TRACK-HD study was designed to build a rational basis for the selection of cognitive outcomes for HD clinical trials. METHODS: There were a total of 349 participants, including controls (n=116), premanifest HD (n=117) and early HD (n=116). A standardised cognitive assessment battery (including nine cognitive tests comprising 12 outcome measures) was administered at baseline, and at 12 and 24 months, and consisted of a combination of paper and pencil and computerised tasks selected to be sensitive to cortical-striatal damage or HD. Each cognitive outcome was analysed separately using a generalised least squares regression model. Results are expressed as effect sizes to permit comparisons between tasks. RESULTS: 10 of the 12 cognitive outcomes showed evidence of deterioration in the early HD group, relative to controls, over 24 months, with greatest sensitivity in Symbol Digit, Circle Tracing direct and indirect, and Stroop word reading. In contrast, there was very little evidence of deterioration in the premanifest HD group relative to controls. CONCLUSIONS: The findings describe tests that are sensitive to longitudinal cognitive change in HD and elucidate important considerations for selecting cognitive outcomes for clinical trials of compounds aimed at ameliorating cognitive decline in HD.
Subject(s)
Cognition Disorders/etiology , Huntington Disease/complications , Adolescent , Adult , Age Factors , Aged , Disease Progression , Female , Humans , Longitudinal Studies , Male , Middle Aged , Neuropsychological Tests , Severity of Illness Index , Sex Factors , Time Factors , Young AdultABSTRACT
Background: Huntington's disease (HD) is characterized by motor and behavioral symptoms, and cognitive decline. HD gene carriers and their caregivers report the behavioral and cognitive symptoms as the most burdensome. Apathy is the most common behavioral symptom of HD and is related to clinical measures of disease progression, like functional capacity. However, it is unknown whether apathy is directly related to the neurodegenerative processes in HD. Objective: The aim is to investigate whether an association between atrophy of subcortical structures and apathy is present in HD, at baseline and after 2â¯years follow-up. Method: Volumes of 7 subcortical structures were measured using structural T1 MRI in 171 HD gene carriers of the TRACK-HD study and apathy was assessed with the Problem Behaviors Assessment-Short, at baseline and follow-up visit. At baseline, logistic regression was used to evaluate whether volumes of subcortical brain structures were associated with the presence of apathy. Linear regression was used to assess whether subcortical atrophy was associated with the degree of apathy at baseline and with an increase in severity of apathy over time. Results: At baseline, smaller volume of the thalamus showed a higher probability of the presence of apathy in HD gene carriers, but none of the subcortical structures was associated with the degree of apathy. Over time, no association between atrophy of any subcortical structures and change in degree of apathy was found. Conclusion: The presence of apathy is associated with atrophy of the thalamus in HD, suggesting that apathy has an underlying neural cause and might explain the high incidence of apathy in HD. However, no association was found between atrophy of these subcortical structures and increase in severity of apathy over a 2-year time period.
Subject(s)
Apathy/physiology , Atrophy/pathology , Brain/pathology , Huntington Disease/pathology , Adult , Aged , Atrophy/physiopathology , Disease Progression , Female , Follow-Up Studies , Humans , Huntington Disease/genetics , Huntington Disease/physiopathology , Logistic Models , Magnetic Resonance Imaging/methods , Male , Middle AgedABSTRACT
BACKGROUND: In Huntington's Disease (HD) cognitive decline can occur before unequivocal motor signs become apparent. As cognitive decline often starts early in the course of the disease and has a progressive nature over time, cognition can be regarded as a key target for symptomatic treatment. The specific progressive profile of cognitive decline over time is unknown. OBJECTIVE: The aim of this study is to quantify the progression of cognitive decline across all HD stages, from pre-motormanifest to advanced HD, and to investigate if CAG length mediates cognitive decline. METHODS: In the European REGISTRY study 2669 HD expansion gene carriers underwent annual cognitive assessment. General linear mixed models were used to model the cognitive decline for each cognitive task across all disease stages. Additionally, a model was developed to evaluate the cognitive decline based on CAG length and age rather than disease stage. RESULTS: There was significant cognitive decline on all administered tasks throughout pre-motormanifest (close to estimated disease onset) participants and the subsequent motormanifest participants from stage 1 to stage 4. Performance on the Stroop Word and Stroop Color tests additionally declined significantly across the two pre-motormanifest groups: far and close to estimated disease onset. The evaluation of cognition performance in relation to CAG length and age revealed a more rapid cognitive decline in participants with longer CAG length than participants with shorter CAG length over time. CONCLUSION: Cognitive performance already shows decline in pre-motormanifest HD gene expansion carriers and gradually worsens to late stage HD. HD gene expansion carriers with certain CAG length have their own cognitive profile, i.e., longer CAG length is associated with more rapid decline.
Subject(s)
Cognition , Cognitive Dysfunction/genetics , Heterozygote , Huntington Disease/genetics , Trinucleotide Repeat Expansion , Adult , Aged , Cognitive Dysfunction/complications , Disease Progression , Female , Humans , Huntington Disease/complications , Male , Middle Aged , Neuropsychological TestsABSTRACT
Duchenne muscular dystrophy is caused by dystrophin gene mutations which lead to the absence of the protein dystrophin. A significant proportion of patients suffer from learning and behavioural disabilities, in addition to muscle weakness. We have previously shown that these patients have a smaller total brain and grey matter volume, and altered white matter microstructure compared to healthy controls. Patients with more distal gene mutations, predicted to affect dystrophin isoforms Dp140 and Dp427, showed greater grey matter reduction. Now, we studied if cerebral blood flow in Duchenne muscular dystrophy patients is altered, since cerebral expression of dystrophin also occurs in vascular endothelial cells and astrocytes associated with cerebral vasculature. T1-weighted anatomical and pseudo-continuous arterial spin labeling cerebral blood flow images were obtained from 26 patients and 19 age-matched controls (ages 8-18 years) on a 3 tesla MRI scanner. Group comparisons of cerebral blood flow were made with and without correcting for grey matter volume using partial volume correction. Results showed that patients had a lower cerebral blood flow than controls (40.0 ± 6.4 and 47.8 ± 6.3 mL/100 g/min respectively, p = 0.0002). This reduction was independent of grey matter volume, suggesting that they are two different aspects of the pathophysiology. Cerebral blood flow was lowest in patients lacking Dp140. There was no difference in CBF between ambulant and non-ambulant patients. Only three patients showed a reduced left ventricular ejection fraction. No correlation between cerebral blood flow and age was found. Our results indicate that cerebral perfusion is reduced in Duchenne muscular dystrophy patients independent of the reduced grey matter volume.
Subject(s)
Cerebrovascular Circulation/physiology , Dystrophin/metabolism , Gray Matter/diagnostic imaging , Magnetic Resonance Angiography/methods , Muscular Dystrophy, Duchenne/diagnostic imaging , Adolescent , Child , Female , Gray Matter/pathology , Humans , Male , Muscular Dystrophy, Duchenne/metabolism , Muscular Dystrophy, Duchenne/pathology , Muscular Dystrophy, Duchenne/physiopathologyABSTRACT
BACKGROUND: Earlier research has found cross-sectional attentional control deficits in manifest Huntington's disease (HD) using neuropsychological testing combined with simultaneous P300 registration. In the current pilot-study, we investigate attentional control in pre-manifest and manifest HD over a 3-year follow-up period. METHOD: Five manifest HD (MHD), 9 pre-manifest HD (PMHD), and 12 control subjects were included. Sustained Attention to Response task (SART) and P300 registration resulted in number of errors, reaction time (RT), and P300 amplitude and latency. RT change patterns surrounding No-go trials were also investigated. Within-subject differences were tested using paired-samples t-tests and between-group results with ANCOVA on delta scores (follow-up--baseline scores). RESULTS: Manifest HD made more errors and were slower than controls and PMHD. Longitudinally, MHD showed an overall RT increase and a specific slowing on trials preceding a correct No-go trial (within-group effects). The latter was also seen in PMHD. P300 latency prolongation was found for controls on No-go and for MHD on Go trials. On specific trials surrounding both correct and incorrect No-go trials, MHD became significantly slower over time than controls and PMHD (between-group effects). CONCLUSIONS: Over 3-years, MHD subjects became slower on the SART and showed a prolongation of P300 latency on specific SART trials. Specific slowing of performance over time was also seen in PMHD, suggestive of compensatory mechanisms in this group.
Subject(s)
Attention Deficit Disorder with Hyperactivity/diagnosis , Attention Deficit Disorder with Hyperactivity/etiology , Event-Related Potentials, P300/physiology , Huntington Disease/complications , Reaction Time/physiology , Adult , Analysis of Variance , Cross-Sectional Studies , Electroencephalography , Female , Humans , Longitudinal Studies , Male , Middle Aged , Neuropsychological Tests , Pilot ProjectsABSTRACT
We report a healthy adult male, who underwent, as a control subject, part of a Huntington's disease study, extensive testing during three visits in a two year follow-up, including clinical examination and 3.0 T MRI scans. The T2-weighted MRI sequences revealed the "eye-of-the-tiger-sign". No clinical abnormalities in either motor, cognitive or behavioural domains were observed. PKAN2 and FTL gene mutation analysis were negative. This finding implies that an eye-of-the-tiger sign, which is considered a pathognomonic feature of neurodegeneration with brain iron accumulation (NBIA), can occur without any clinical symptoms.
Subject(s)
Globus Pallidus/pathology , Health Status Indicators , Magnetic Resonance Imaging , Humans , Magnetic Resonance Imaging/methods , Male , Middle AgedABSTRACT
BACKGROUND: Previous cross-sectional magnetic resonance spectroscopy (MRS) studies in Huntington's disease (HD) have demonstrated differences in metabolite concentrations in several regions of interest, especially the putamen and caudate nucleus. OBJECTIVE: To assess metabolite changes in both premanifest and early HD over a two year follow up period using MRS at 7 Tesla in several regions of interest. METHODS: In 13 HD gene carriers (10 premanifest and 3 manifest HD) proton MRS was performed at baseline and after 24 months. At follow up, four of the premanifest HD gene carriers had progressed into manifest HD, as assessed by clinical measures. 7T MR proton spectroscopy was performed in three regions of interest; the caudate nucleus, putamen and prefrontal cortex. Six metabolites were quantified for each region at each time point. Statistical analysis was performed using Wilcoxon signed rank tests. RESULTS: Across all subjects, a longitudinal decrease in the caudate nucleus in creatine (p = 0.038) and myo-inositol (p = 0.015) concentrations was found. A significant decrease in the putamen was seen in the total N-acetylaspartate (tNAA) (p = 0.028) and choline concentrations (p = 0.028). For premanifest HD converters, a non-significant high rate of tNAA decrease in the putamen was found compared to non-converting premanifest HD. CONCLUSION: Over a two year period we have demonstrated metabolite changes in the caudate nucleus and putamen of HD gene carriers around disease onset. This demonstrates the potential of MRS for providing a biomarker of disease progression and for evaluating future therapeutic interventions.
Subject(s)
Huntington Disease/metabolism , Molecular Imaging/methods , Adult , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Caudate Nucleus/chemistry , Caudate Nucleus/metabolism , Creatinine/metabolism , Female , Follow-Up Studies , Humans , Longitudinal Studies , Magnetic Resonance Spectroscopy , Male , Middle Aged , Prefrontal Cortex/chemistry , Prefrontal Cortex/metabolism , Putamen/chemistry , Putamen/metabolismABSTRACT
BACKGROUND: Composite scores derived from joint statistical modelling of individual risk factors are widely used to identify individuals who are at increased risk of developing disease or of faster disease progression. OBJECTIVE: We investigated the ability of composite measures developed using statistical models to differentiate progressive cognitive deterioration in Huntington's disease (HD) from natural decline in healthy controls. METHODS: Using longitudinal data from TRACK-HD, the optimal combinations of quantitative cognitive measures to differentiate premanifest and early stage HD individuals respectively from controls was determined using logistic regression. Composite scores were calculated from the parameters of each statistical model. Linear regression models were used to calculate effect sizes (ES) quantifying the difference in longitudinal change over 24 months between premanifest and early stage HD groups respectively and controls. ES for the composites were compared with ES for individual cognitive outcomes and other measures used in HD research. The 0.632 bootstrap was used to eliminate biases which result from developing and testing models in the same sample. RESULTS: In early HD, the composite score from the HD change prediction model produced an ES for difference in rate of 24-month change relative to controls of 1.14 (95% CI: 0.90 to 1.39), larger than the ES for any individual cognitive outcome and UHDRS Total Motor Score and Total Functional Capacity. In addition, this composite gave a statistically significant difference in rate of change in premanifest HD compared to controls over 24-months (ES: 0.24; 95% CI: 0.04 to 0.44), even though none of the individual cognitive outcomes produced statistically significant ES over this period. CONCLUSIONS: Composite scores developed using appropriate statistical modelling techniques have the potential to materially reduce required sample sizes for randomised controlled trials.
Subject(s)
Cognition Disorders/diagnosis , Cognition Disorders/etiology , Huntington Disease/complications , Adult , Aging/physiology , Cognition Disorders/physiopathology , Disease Progression , Female , Humans , Huntington Disease/physiopathology , Longitudinal Studies , Male , Middle Aged , Models, Statistical , Neuropsychological TestsABSTRACT
Huntington's disease (HD) is a devastating neurological disorder that affects the brain. The cause of HD is an expanded CAG trinucleotide repeat in the Htt gene. The Htt gene is responsible for the protein huntingtin, the exact functions of which have yet to be elucidated. The role of iron in the pathological cascade is usually mentioned in the context of an inability to regulate iron homeostasis, which generates a surplus of reactive iron and free radical toxicity, resulting in increased oxidative stress. In this review, we discuss the role of iron within the existing hypotheses of HD pathology, ex vivo findings in support of increased iron in HD, and finally in vivo MRI findings in manifest and premanifest HD. Both in vivo and ex vivo findings support the notion that excess iron is present in the brain of HD patients. There does not seem to be much evidence that iron accumulation is the initiator of the pathological cascade as little or no evidence can be found for very early increased iron in the HD brain, when neuronal cell loss is already extensive.