Arteriosclerosis, Thrombosis, and Vascular Biology, 2009
Objective— The purpose of this study was to test the association between polymorphisms in genes i... more Objective— The purpose of this study was to test the association between polymorphisms in genes involved in either LDL cholesterol (LDL-C) metabolism or statin pharmacokinetics and LDL-C reduction with statins. Methods and Results— 49 tagging and candidate polymorphisms in 9 genes were genotyped in 1507 post-ACS subjects randomized to atorvastatin or pravastatin. Two polymorphisms (rs7412, rs429358) that define the ε2, ε3, and ε4 isoforms of apolipoprotein E were significantly associated with percent reduction in LDL-C with atorvastatin (ε2 carriers 53.8%, ε3/ε3 48.1%, and ε4 carriers 46.4%, respectively, P =0.00039) and replicated in the pravastatin arm (ε2 carriers 22.1%, ε3/ε3 21.8%, and ε4 carriers 16.6%, respectively, P =0.00038). The proportion of subjects achieving an LDL-C ≤70 mg/dL at day 30 was higher for ε2 than ε4 carriers ( P =1.3×10 −5 ). In the pravastatin group, the triallelic rs2032582 variant (G2677T/A) in ABCB1 was associated with the percent reduction in LDL-C (G...
An important step towards the development of treatments for cognitive impairment in ageing and ne... more An important step towards the development of treatments for cognitive impairment in ageing and neurodegenerative diseases is to identify genetic and environmental modifiers of cognitive function and understand the mechanism by which they exert an effect. In Huntington’s disease, the most common autosomal dominant dementia, a small number of studies have identified intellectual enrichment, i.e. a cognitively stimulating lifestyle and genetic polymorphisms as potential modifiers of cognitive function. The aim of our study was to further investigate the relationship and interaction between genetic factors and intellectual enrichment on cognitive function and brain atrophy in Huntington’s disease. For this purpose, we analysed data from Track-HD, a multi-centre longitudinal study in Huntington’s disease gene carriers and focused on the role of intellectual enrichment (estimated at baseline) and the genes FAN1, MSH3, BDNF, COMT and MAPT in predicting cognitive decline and brain atrophy. ...
Background: Cognitive and motor task performance in premanifest Huntington's disease (HD) gene-ca... more Background: Cognitive and motor task performance in premanifest Huntington's disease (HD) gene-carriers is often within normal ranges prior to clinical diagnosis, despite loss of brain volume in regions involved in these tasks. This indicates ongoing compensation, with the brain maintaining function in the presence of neuronal loss. However, thus far, compensatory processes in HD have not been modeled explicitly. Using a new model, which incorporates individual variability related to structural change and behavior, we sought to identify functional correlates of compensation in premanifest-HD gene-carriers. Methods: We investigated the modulatory effects of regional brain atrophy, indexed by structural measures of disease load, on the relationship between performance and brain activity (or connectivity) using task-based and resting-state functional MRI. Findings: Consistent with compensation, as atrophy increased performance-related activity increased in the right parietal cortex during a working memory task. Similarly, increased functional coupling between the right dorsolateral prefrontal cortex and a left hemisphere network in the resting-state predicted better cognitive performance as atrophy increased. Such patterns were not detectable for the left hemisphere or for motor tasks. Interpretation: Our findings provide evidence for active compensatory processes in premanifest-HD for cognitive demands and suggest a higher vulnerability of the left hemisphere to the effects of regional atrophy.
The earliest white matter changes in Huntington's disease are seen before disease onset in th... more The earliest white matter changes in Huntington's disease are seen before disease onset in the premanifest stage around the striatum, within the corpus callosum, and in posterior white matter tracts. While experimental evidence suggests that these changes may be related to abnormal gene transcription, we lack an understanding of the biological processes driving this regional vulnerability. Here, we investigate the relationship between regional transcription in the healthy brain, using the Allen Institute for Brain Science transcriptome atlas, and regional white matter connectivity loss at three time points over 24 months in subjects with premanifest Huntington's disease relative to control participants. The baseline cohort included 72 premanifest Huntington's disease participants and 85 healthy control participants. We show that loss of corticostriatal, interhemispheric, and intrahemispheric white matter connections at baseline and over 24 months in premanifest Huntingto...
Journal of Neurology, Neurosurgery & Psychiatry, 2010
Background/aims Visuomotor integration deficits have been documented in manifest Huntington's... more Background/aims Visuomotor integration deficits have been documented in manifest Huntington's disease, with disproportionate impairments when indirect visual cues are relied upon. Visuomotor integration in premanifest gene expansion carriers has not been studied under such conditions. Methods 239 gene expansion carriers spanning over a decade before predicted onset until early stage disease and 122 control subjects were administered a circle tracing task. Performance was guided by direct or indirect visual cues. Outcome measures targeted accuracy, speed and speed of error detection and correction. Predictor variables included disease group and disease burden (age×(CAG−35.5)). Correlations with 3T MRI voxel based morphometry of grey and white matter volume reduction were computed. Results Increased HD disease burden was associated with reduced accuracy and slowed performance in both direct and indirect circle tracing conditions. Expansion carriers who were more than a decade before predicted clinical onset showed deficits in performance compared with controls. Comparing performance in the indirect with the direct condition, expansion carriers had a disproportionate increase in errors than controls. Expansion carriers showed greater latencies in detecting an error when heading away from target, and in correcting an error when heading back to target. Slowed performance in the indirect circle tracing condition was associated with grey matter volume reduction within the left somatosensory cortex in voxel based morphometry analyses. Conclusions Visuomotor integration deficits appear in expansion carriers many years before onset with the use of indirect visual cues especially appearing to impact adversely on accuracy. Slowed performance under indirect visual cues appears to be associated with atrophy of the left hemisphere somatosensory cortex, which likely reflects the proprioceptive demands of the task.
Deficits in motor functioning are one of the hallmarks of Huntington's disease (HD), a geneti... more Deficits in motor functioning are one of the hallmarks of Huntington's disease (HD), a genetically caused neurodegenerative disorder. We applied functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM) to assess changes that occur with disease progression in the neural circuitry of key areas associated with executive and cognitive aspects of motor control. Seventy-seven healthy controls, 62 pre-symptomatic HD gene carriers (preHD), and 16 patients with manifest HD symptoms (earlyHD) performed a motor finger-tapping fMRI task with systematically varying speed and complexity. DCM was used to assess the causal interactions among seven pre-defined regions of interest, comprising primary motor cortex, supplementary motor area (SMA), dorsal premotor cortex, and superior parietal cortex. To capture heterogeneity among HD gene carriers, DCM parameters were entered into a hierarchical cluster analysis using Ward's method and squared Euclidian distance as a measu...
Journal of Neurology, Neurosurgery & Psychiatry, 2012
Background/Aims We investigated the ability of composite scores developed using statistical model... more Background/Aims We investigated the ability of composite scores developed using statistical models to differentiate progressive cognitive deterioration in Huntington's disease (HD) from natural decline in healthy controls. Methods Using data from TRACK-HD the optimal combination of 24-month changes in quantitative cognitive measures to differentiate early stage HD individuals from controls was determined using logistic regression. Composite scores were calculated from the parameters of the model. Linear regression models were used to calculate effect sizes (ES) quantifying the difference in longitudinal change in the composite over 24 months between premanifest and early stage HD groups and controls respectively. This ES was compared with those for individual cognitive outcomes and other measures used in HD research. 0.632 bootstrap methodology was used to allow for biases which result from developing and testing models in the same sample. Results The composite score gave an ES for the difference in rate of 24-month change between early HD and controls of 1.14 (95% CI 0.90 to 1.39): larger than that for any of the individual cognitive outcomes and those for the UHDRS TFC and TMS. Additionally the composite gave a statistically significant difference in the rate of change in premanifest HD compared to controls over 24-months (ES: 0.24; 95% CI 0.04 to 0.44), despite none of the individual cognitive outcomes having 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.
Background: Neuropsychiatric symptoms in Huntington's disease (HD) are often evident prior to cli... more Background: Neuropsychiatric symptoms in Huntington's disease (HD) are often evident prior to clinical diagnosis. Apathy is highly correlated with disease progression, while depression and irritability occur at different stages of the disease, both before and after clinical onset. Little is understood about the neural bases of these neuropsychiatric symptoms and to what extent those neural bases are analogous to neuropsychiatric disorders in the general population. Objective: We used Diffusion Tensor Imaging (DTI) to investigate structural connectivity between brain regions and any putative microstructural changes associated with depression, apathy and irritability in HD. Methods: DTI data were collected from 39 premanifest and 45 early-HD participants in the Track-HD study and analysed using whole-brain Tract-Based Spatial Statistics. We used regression analyses to identify white matter tracts whose structural integrity (as measured by fractional anisotropy, FA) was correlated with HADS-depression, PBA-apathy or PBA-irritability scores in gene-carriers and related to cumulative probability to onset (CPO). Results: For those with the highest CPO, we found significant correlations between depression scores and reduced FA in the splenium of the corpus callosum. In contrast, those with lowest CPO demonstrated significant correlations between irritability scores and widespread FA reductions. There was no significant relationship between apathy and FA throughout the whole brain.
The mismatch repair gene MSH3 has been implicated as a genetic modifier of the CAGÁCTG repeat exp... more The mismatch repair gene MSH3 has been implicated as a genetic modifier of the CAGÁCTG repeat expansion disorders Huntington's disease and myotonic dystrophy type 1. A recent Huntington's disease genome-wide association study found rs557874766, an imputed single nucleotide polymorphism located within a polymorphic 9 bp tandem repeat in MSH3/DHFR, as the variant most significantly associated with progression in Huntington's disease. Using Illumina sequencing in Huntington's disease and myotonic dystrophy type 1 subjects, we show that rs557874766 is an alignment artefact, the minor allele for which corresponds to a three-repeat allele in MSH3 exon 1 that is associated with a reduced rate of somatic CAGÁCTG expansion (P = 0.004) and delayed disease onset (P = 0.003) in both Huntington's disease and myotonic dystrophy type 1, and slower progression (P = 3.86 Â 10 À7) in Huntington's disease. RNA-Seq of whole blood in the Huntington's disease subjects found that repeat variants are associated with MSH3 and DHFR expression. A transcriptome-wide association study in the Huntington's disease cohort found increased MSH3 and DHFR expression are associated with disease progression. These results suggest that variation in the MSH3 exon 1 repeat region influences somatic expansion and disease phenotype in Huntington's disease and myotonic dystrophy type 1, and suggests a common DNA repair mechanism operates in both repeat expansion diseases.
Background TRACK-HD is a multi-center, longitudinal study investigating a range of motor, cogniti... more Background TRACK-HD is a multi-center, longitudinal study investigating a range of motor, cognitive, neuropsychiatric, and imaging measures as potential biomarkers for clinical trials in Huntington's disease (HD). Psychiatric assessments were conducted using a 10-item semi-structured interview, the short version of the Problem Behaviours Assessment for HD (PBA-s). Interviews were video recorded for quality assurance purposes, and a proportion randomly selected for re-scoring at another site. The study therefore provided an opportunity to examine the reliability of the measure between multiple pairs of raters in different cultural and linguistic contexts. Methods The study included 360 subjects (120 affected, 120 premanifest gene carriers, 120 controls), and 185 interviews were selected for re-scoring by an expert rater. Digital video recordings were uploaded to the TRACK-HD Web portal and selected for re-scoring by an independent investigator blind to the subjects' diagnosis. A further 73 interviews were obtained from the REGISTRY clinic in Manchester and used for training the expert raters. Results Complete agreement between raters was achieved for 86% of scores (κ = 0.733), and 97.6% were within one point of the expert rating, the standard for quality assurance purposes. Agreement levels for individual pairs of raters ranged from 75% to 94% (κ = 0.59–0.86); agreement within one point ranged from 92% to 99%. Complete agreement for the 20 individual ratings (10 symptoms * frequency and severity) ranged from 67% to 100% (κ = 0.56–0.97); agreement within one point ranged from 94% to 100%. Conclusions The overall results indicate substantial agreement between all raters, whereas the κ-statistic for individual rater pairs ranged from ‘moderate' to ‘almost perfect' agreement, with almost all raters achieving at least a ‘substantial' level of agreement. These data suggest that the PBA-s, with appropriate training, is a reliable measure of psychiatric symptoms in the HD population.
Friedreich ataxia, an autosomal recessive mitochondrial disease, is the most frequent inherited a... more Friedreich ataxia, an autosomal recessive mitochondrial disease, is the most frequent inherited ataxia. Many studies have attempted to identify cognitive and affective changes associated with the disease, but conflicting results have been obtained, depending on the tests used and because many of the samples studied were very small. We investigated personality and neuropsychological characteristics in a cohort of 47 patients with genetically confirmed disease. The neuropsychological battery assessed multiple cognition domains: processing speed, attention, working memory, executive functions, verbal memory, vocabulary, visual reasoning, emotional recognition, and social cognition. Personality was assessed with the Temperament and Character Inventory, and depressive symptoms were assessed with the Beck Depression Inventory. We found deficits of sustained attention, processing speed, semantic capacities, and verbal fluency only partly attributable to motor deficit or depressed mood. Vis...
The Journal of Neuropsychiatry and Clinical Neurosciences, 2015
The authors report the inter-rater reliability and factor structure of the Short Problem Behavior... more 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.
Visuomotor integration deficits have been documented in Huntington disease (HD), with disproporti... more Visuomotor integration deficits have been documented in Huntington disease (HD), with disproportionately more impairment when direct visual feedback is unavailable. Visuomotor integration under direct and indirect visual feedback conditions has not been investigated in the stage before clinical onset ('premanifest'). However, given evidence of posterior cortical atrophy in premanifest HD, we predicted visuomotor integration would be adversely affected, with greater impairment under conditions of indirect visual feedback. 239 subjects with the HD CAG expansion, ranging from more than a decade before predicted clinical onset until early stage disease, and 122 controls, completed a circle-tracing task, which included both direct and indirect visual feedback conditions. Measures included accuracy, speed, and speed of error detection and correction. Using brain images acquired with 3T magnetic resonance imaging (MRI), we generated grey and white matter volumes with voxel-based morphometry, and analyzed correlations with circle-tracing performance. Compared with controls, early HD was associated with lower accuracy and slower performance in both circle-tracing conditions. Premanifest HD was associated with lower accuracy in both conditions and fewer rotations in the direct condition. Comparing performance in the indirect condition with the direct condition, HD gene expansion-carriers exhibited a disproportionate increase in errors relative to controls. Premanifest and early HD groups required longer to detect and correct errors, especially in the indirect condition. Slower performance in the indirect condition was associated with lower grey matter volumes in the left somatosensory cortex in VBM analyses. Visuomotor integration deficits are evident many years before the clinical onset of HD, with deficits in speed, accuracy, and speed of error detection and correction. The visuomotor transformation demands of the indirect condition result in a disproportionate decrease in accuracy in the HD groups. Slower performance under indirect visual feedback was associated with atrophy of the left-hemisphere somatosensory cortex, which may reflect the proprioceptive demands of the task.
Visuomotor integration deficits have been documented in Huntington disease (HD), with disproporti... more Visuomotor integration deficits have been documented in Huntington disease (HD), with disproportionately more impairment when direct visual feedback is unavailable. Visuomotor integration under direct and indirect visual feedback conditions has not been investigated in the stage before clinical onset ('premanifest'). However, given evidence of posterior cortical atrophy in premanifest HD, we predicted visuomotor integration would be adversely affected, with greater impairment under conditions of indirect visual feedback. 239 subjects with the HD CAG expansion, ranging from more than a decade before predicted clinical onset until early stage disease, and 122 controls, completed a circle-tracing task, which included both direct and indirect visual feedback conditions. Measures included accuracy, speed, and speed of error detection and correction. Using brain images acquired with 3T magnetic resonance imaging (MRI), we generated grey and white matter volumes with voxel-based morphometry, and analyzed correlations with circle-tracing performance. Compared with controls, early HD was associated with lower accuracy and slower performance in both circle-tracing conditions. Premanifest HD was associated with lower accuracy in both conditions and fewer rotations in the direct condition. Comparing performance in the indirect condition with the direct condition, HD gene expansion-carriers exhibited a disproportionate increase in errors relative to controls. Premanifest and early HD groups required longer to detect and correct errors, especially in the indirect condition. Slower performance in the indirect condition was associated with lower grey matter volumes in the left somatosensory cortex in VBM analyses. Visuomotor integration deficits are evident many years before the clinical onset of HD, with deficits in speed, accuracy, and speed of error detection and correction. The visuomotor transformation demands of the indirect condition result in a disproportionate decrease in accuracy in the HD groups. Slower performance under indirect visual feedback was associated with atrophy of the left-hemisphere somatosensory cortex, which may reflect the proprioceptive demands of the task.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2009
Objective— The purpose of this study was to test the association between polymorphisms in genes i... more Objective— The purpose of this study was to test the association between polymorphisms in genes involved in either LDL cholesterol (LDL-C) metabolism or statin pharmacokinetics and LDL-C reduction with statins. Methods and Results— 49 tagging and candidate polymorphisms in 9 genes were genotyped in 1507 post-ACS subjects randomized to atorvastatin or pravastatin. Two polymorphisms (rs7412, rs429358) that define the ε2, ε3, and ε4 isoforms of apolipoprotein E were significantly associated with percent reduction in LDL-C with atorvastatin (ε2 carriers 53.8%, ε3/ε3 48.1%, and ε4 carriers 46.4%, respectively, P =0.00039) and replicated in the pravastatin arm (ε2 carriers 22.1%, ε3/ε3 21.8%, and ε4 carriers 16.6%, respectively, P =0.00038). The proportion of subjects achieving an LDL-C ≤70 mg/dL at day 30 was higher for ε2 than ε4 carriers ( P =1.3×10 −5 ). In the pravastatin group, the triallelic rs2032582 variant (G2677T/A) in ABCB1 was associated with the percent reduction in LDL-C (G...
An important step towards the development of treatments for cognitive impairment in ageing and ne... more An important step towards the development of treatments for cognitive impairment in ageing and neurodegenerative diseases is to identify genetic and environmental modifiers of cognitive function and understand the mechanism by which they exert an effect. In Huntington’s disease, the most common autosomal dominant dementia, a small number of studies have identified intellectual enrichment, i.e. a cognitively stimulating lifestyle and genetic polymorphisms as potential modifiers of cognitive function. The aim of our study was to further investigate the relationship and interaction between genetic factors and intellectual enrichment on cognitive function and brain atrophy in Huntington’s disease. For this purpose, we analysed data from Track-HD, a multi-centre longitudinal study in Huntington’s disease gene carriers and focused on the role of intellectual enrichment (estimated at baseline) and the genes FAN1, MSH3, BDNF, COMT and MAPT in predicting cognitive decline and brain atrophy. ...
Background: Cognitive and motor task performance in premanifest Huntington's disease (HD) gene-ca... more Background: Cognitive and motor task performance in premanifest Huntington's disease (HD) gene-carriers is often within normal ranges prior to clinical diagnosis, despite loss of brain volume in regions involved in these tasks. This indicates ongoing compensation, with the brain maintaining function in the presence of neuronal loss. However, thus far, compensatory processes in HD have not been modeled explicitly. Using a new model, which incorporates individual variability related to structural change and behavior, we sought to identify functional correlates of compensation in premanifest-HD gene-carriers. Methods: We investigated the modulatory effects of regional brain atrophy, indexed by structural measures of disease load, on the relationship between performance and brain activity (or connectivity) using task-based and resting-state functional MRI. Findings: Consistent with compensation, as atrophy increased performance-related activity increased in the right parietal cortex during a working memory task. Similarly, increased functional coupling between the right dorsolateral prefrontal cortex and a left hemisphere network in the resting-state predicted better cognitive performance as atrophy increased. Such patterns were not detectable for the left hemisphere or for motor tasks. Interpretation: Our findings provide evidence for active compensatory processes in premanifest-HD for cognitive demands and suggest a higher vulnerability of the left hemisphere to the effects of regional atrophy.
The earliest white matter changes in Huntington's disease are seen before disease onset in th... more The earliest white matter changes in Huntington's disease are seen before disease onset in the premanifest stage around the striatum, within the corpus callosum, and in posterior white matter tracts. While experimental evidence suggests that these changes may be related to abnormal gene transcription, we lack an understanding of the biological processes driving this regional vulnerability. Here, we investigate the relationship between regional transcription in the healthy brain, using the Allen Institute for Brain Science transcriptome atlas, and regional white matter connectivity loss at three time points over 24 months in subjects with premanifest Huntington's disease relative to control participants. The baseline cohort included 72 premanifest Huntington's disease participants and 85 healthy control participants. We show that loss of corticostriatal, interhemispheric, and intrahemispheric white matter connections at baseline and over 24 months in premanifest Huntingto...
Journal of Neurology, Neurosurgery & Psychiatry, 2010
Background/aims Visuomotor integration deficits have been documented in manifest Huntington's... more Background/aims Visuomotor integration deficits have been documented in manifest Huntington's disease, with disproportionate impairments when indirect visual cues are relied upon. Visuomotor integration in premanifest gene expansion carriers has not been studied under such conditions. Methods 239 gene expansion carriers spanning over a decade before predicted onset until early stage disease and 122 control subjects were administered a circle tracing task. Performance was guided by direct or indirect visual cues. Outcome measures targeted accuracy, speed and speed of error detection and correction. Predictor variables included disease group and disease burden (age×(CAG−35.5)). Correlations with 3T MRI voxel based morphometry of grey and white matter volume reduction were computed. Results Increased HD disease burden was associated with reduced accuracy and slowed performance in both direct and indirect circle tracing conditions. Expansion carriers who were more than a decade before predicted clinical onset showed deficits in performance compared with controls. Comparing performance in the indirect with the direct condition, expansion carriers had a disproportionate increase in errors than controls. Expansion carriers showed greater latencies in detecting an error when heading away from target, and in correcting an error when heading back to target. Slowed performance in the indirect circle tracing condition was associated with grey matter volume reduction within the left somatosensory cortex in voxel based morphometry analyses. Conclusions Visuomotor integration deficits appear in expansion carriers many years before onset with the use of indirect visual cues especially appearing to impact adversely on accuracy. Slowed performance under indirect visual cues appears to be associated with atrophy of the left hemisphere somatosensory cortex, which likely reflects the proprioceptive demands of the task.
Deficits in motor functioning are one of the hallmarks of Huntington's disease (HD), a geneti... more Deficits in motor functioning are one of the hallmarks of Huntington's disease (HD), a genetically caused neurodegenerative disorder. We applied functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM) to assess changes that occur with disease progression in the neural circuitry of key areas associated with executive and cognitive aspects of motor control. Seventy-seven healthy controls, 62 pre-symptomatic HD gene carriers (preHD), and 16 patients with manifest HD symptoms (earlyHD) performed a motor finger-tapping fMRI task with systematically varying speed and complexity. DCM was used to assess the causal interactions among seven pre-defined regions of interest, comprising primary motor cortex, supplementary motor area (SMA), dorsal premotor cortex, and superior parietal cortex. To capture heterogeneity among HD gene carriers, DCM parameters were entered into a hierarchical cluster analysis using Ward's method and squared Euclidian distance as a measu...
Journal of Neurology, Neurosurgery & Psychiatry, 2012
Background/Aims We investigated the ability of composite scores developed using statistical model... more Background/Aims We investigated the ability of composite scores developed using statistical models to differentiate progressive cognitive deterioration in Huntington's disease (HD) from natural decline in healthy controls. Methods Using data from TRACK-HD the optimal combination of 24-month changes in quantitative cognitive measures to differentiate early stage HD individuals from controls was determined using logistic regression. Composite scores were calculated from the parameters of the model. Linear regression models were used to calculate effect sizes (ES) quantifying the difference in longitudinal change in the composite over 24 months between premanifest and early stage HD groups and controls respectively. This ES was compared with those for individual cognitive outcomes and other measures used in HD research. 0.632 bootstrap methodology was used to allow for biases which result from developing and testing models in the same sample. Results The composite score gave an ES for the difference in rate of 24-month change between early HD and controls of 1.14 (95% CI 0.90 to 1.39): larger than that for any of the individual cognitive outcomes and those for the UHDRS TFC and TMS. Additionally the composite gave a statistically significant difference in the rate of change in premanifest HD compared to controls over 24-months (ES: 0.24; 95% CI 0.04 to 0.44), despite none of the individual cognitive outcomes having 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.
Background: Neuropsychiatric symptoms in Huntington's disease (HD) are often evident prior to cli... more Background: Neuropsychiatric symptoms in Huntington's disease (HD) are often evident prior to clinical diagnosis. Apathy is highly correlated with disease progression, while depression and irritability occur at different stages of the disease, both before and after clinical onset. Little is understood about the neural bases of these neuropsychiatric symptoms and to what extent those neural bases are analogous to neuropsychiatric disorders in the general population. Objective: We used Diffusion Tensor Imaging (DTI) to investigate structural connectivity between brain regions and any putative microstructural changes associated with depression, apathy and irritability in HD. Methods: DTI data were collected from 39 premanifest and 45 early-HD participants in the Track-HD study and analysed using whole-brain Tract-Based Spatial Statistics. We used regression analyses to identify white matter tracts whose structural integrity (as measured by fractional anisotropy, FA) was correlated with HADS-depression, PBA-apathy or PBA-irritability scores in gene-carriers and related to cumulative probability to onset (CPO). Results: For those with the highest CPO, we found significant correlations between depression scores and reduced FA in the splenium of the corpus callosum. In contrast, those with lowest CPO demonstrated significant correlations between irritability scores and widespread FA reductions. There was no significant relationship between apathy and FA throughout the whole brain.
The mismatch repair gene MSH3 has been implicated as a genetic modifier of the CAGÁCTG repeat exp... more The mismatch repair gene MSH3 has been implicated as a genetic modifier of the CAGÁCTG repeat expansion disorders Huntington's disease and myotonic dystrophy type 1. A recent Huntington's disease genome-wide association study found rs557874766, an imputed single nucleotide polymorphism located within a polymorphic 9 bp tandem repeat in MSH3/DHFR, as the variant most significantly associated with progression in Huntington's disease. Using Illumina sequencing in Huntington's disease and myotonic dystrophy type 1 subjects, we show that rs557874766 is an alignment artefact, the minor allele for which corresponds to a three-repeat allele in MSH3 exon 1 that is associated with a reduced rate of somatic CAGÁCTG expansion (P = 0.004) and delayed disease onset (P = 0.003) in both Huntington's disease and myotonic dystrophy type 1, and slower progression (P = 3.86 Â 10 À7) in Huntington's disease. RNA-Seq of whole blood in the Huntington's disease subjects found that repeat variants are associated with MSH3 and DHFR expression. A transcriptome-wide association study in the Huntington's disease cohort found increased MSH3 and DHFR expression are associated with disease progression. These results suggest that variation in the MSH3 exon 1 repeat region influences somatic expansion and disease phenotype in Huntington's disease and myotonic dystrophy type 1, and suggests a common DNA repair mechanism operates in both repeat expansion diseases.
Background TRACK-HD is a multi-center, longitudinal study investigating a range of motor, cogniti... more Background TRACK-HD is a multi-center, longitudinal study investigating a range of motor, cognitive, neuropsychiatric, and imaging measures as potential biomarkers for clinical trials in Huntington's disease (HD). Psychiatric assessments were conducted using a 10-item semi-structured interview, the short version of the Problem Behaviours Assessment for HD (PBA-s). Interviews were video recorded for quality assurance purposes, and a proportion randomly selected for re-scoring at another site. The study therefore provided an opportunity to examine the reliability of the measure between multiple pairs of raters in different cultural and linguistic contexts. Methods The study included 360 subjects (120 affected, 120 premanifest gene carriers, 120 controls), and 185 interviews were selected for re-scoring by an expert rater. Digital video recordings were uploaded to the TRACK-HD Web portal and selected for re-scoring by an independent investigator blind to the subjects' diagnosis. A further 73 interviews were obtained from the REGISTRY clinic in Manchester and used for training the expert raters. Results Complete agreement between raters was achieved for 86% of scores (κ = 0.733), and 97.6% were within one point of the expert rating, the standard for quality assurance purposes. Agreement levels for individual pairs of raters ranged from 75% to 94% (κ = 0.59–0.86); agreement within one point ranged from 92% to 99%. Complete agreement for the 20 individual ratings (10 symptoms * frequency and severity) ranged from 67% to 100% (κ = 0.56–0.97); agreement within one point ranged from 94% to 100%. Conclusions The overall results indicate substantial agreement between all raters, whereas the κ-statistic for individual rater pairs ranged from ‘moderate' to ‘almost perfect' agreement, with almost all raters achieving at least a ‘substantial' level of agreement. These data suggest that the PBA-s, with appropriate training, is a reliable measure of psychiatric symptoms in the HD population.
Friedreich ataxia, an autosomal recessive mitochondrial disease, is the most frequent inherited a... more Friedreich ataxia, an autosomal recessive mitochondrial disease, is the most frequent inherited ataxia. Many studies have attempted to identify cognitive and affective changes associated with the disease, but conflicting results have been obtained, depending on the tests used and because many of the samples studied were very small. We investigated personality and neuropsychological characteristics in a cohort of 47 patients with genetically confirmed disease. The neuropsychological battery assessed multiple cognition domains: processing speed, attention, working memory, executive functions, verbal memory, vocabulary, visual reasoning, emotional recognition, and social cognition. Personality was assessed with the Temperament and Character Inventory, and depressive symptoms were assessed with the Beck Depression Inventory. We found deficits of sustained attention, processing speed, semantic capacities, and verbal fluency only partly attributable to motor deficit or depressed mood. Vis...
The Journal of Neuropsychiatry and Clinical Neurosciences, 2015
The authors report the inter-rater reliability and factor structure of the Short Problem Behavior... more 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.
Visuomotor integration deficits have been documented in Huntington disease (HD), with disproporti... more Visuomotor integration deficits have been documented in Huntington disease (HD), with disproportionately more impairment when direct visual feedback is unavailable. Visuomotor integration under direct and indirect visual feedback conditions has not been investigated in the stage before clinical onset ('premanifest'). However, given evidence of posterior cortical atrophy in premanifest HD, we predicted visuomotor integration would be adversely affected, with greater impairment under conditions of indirect visual feedback. 239 subjects with the HD CAG expansion, ranging from more than a decade before predicted clinical onset until early stage disease, and 122 controls, completed a circle-tracing task, which included both direct and indirect visual feedback conditions. Measures included accuracy, speed, and speed of error detection and correction. Using brain images acquired with 3T magnetic resonance imaging (MRI), we generated grey and white matter volumes with voxel-based morphometry, and analyzed correlations with circle-tracing performance. Compared with controls, early HD was associated with lower accuracy and slower performance in both circle-tracing conditions. Premanifest HD was associated with lower accuracy in both conditions and fewer rotations in the direct condition. Comparing performance in the indirect condition with the direct condition, HD gene expansion-carriers exhibited a disproportionate increase in errors relative to controls. Premanifest and early HD groups required longer to detect and correct errors, especially in the indirect condition. Slower performance in the indirect condition was associated with lower grey matter volumes in the left somatosensory cortex in VBM analyses. Visuomotor integration deficits are evident many years before the clinical onset of HD, with deficits in speed, accuracy, and speed of error detection and correction. The visuomotor transformation demands of the indirect condition result in a disproportionate decrease in accuracy in the HD groups. Slower performance under indirect visual feedback was associated with atrophy of the left-hemisphere somatosensory cortex, which may reflect the proprioceptive demands of the task.
Visuomotor integration deficits have been documented in Huntington disease (HD), with disproporti... more Visuomotor integration deficits have been documented in Huntington disease (HD), with disproportionately more impairment when direct visual feedback is unavailable. Visuomotor integration under direct and indirect visual feedback conditions has not been investigated in the stage before clinical onset ('premanifest'). However, given evidence of posterior cortical atrophy in premanifest HD, we predicted visuomotor integration would be adversely affected, with greater impairment under conditions of indirect visual feedback. 239 subjects with the HD CAG expansion, ranging from more than a decade before predicted clinical onset until early stage disease, and 122 controls, completed a circle-tracing task, which included both direct and indirect visual feedback conditions. Measures included accuracy, speed, and speed of error detection and correction. Using brain images acquired with 3T magnetic resonance imaging (MRI), we generated grey and white matter volumes with voxel-based morphometry, and analyzed correlations with circle-tracing performance. Compared with controls, early HD was associated with lower accuracy and slower performance in both circle-tracing conditions. Premanifest HD was associated with lower accuracy in both conditions and fewer rotations in the direct condition. Comparing performance in the indirect condition with the direct condition, HD gene expansion-carriers exhibited a disproportionate increase in errors relative to controls. Premanifest and early HD groups required longer to detect and correct errors, especially in the indirect condition. Slower performance in the indirect condition was associated with lower grey matter volumes in the left somatosensory cortex in VBM analyses. Visuomotor integration deficits are evident many years before the clinical onset of HD, with deficits in speed, accuracy, and speed of error detection and correction. The visuomotor transformation demands of the indirect condition result in a disproportionate decrease in accuracy in the HD groups. Slower performance under indirect visual feedback was associated with atrophy of the left-hemisphere somatosensory cortex, which may reflect the proprioceptive demands of the task.
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Papers by Damian Justo