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Background TRACK-HD is an international multi-site study of premanifest and early Huntington's disease (HD) which aims to investigate a range of biomarkers for use in future therapeutic trials. Detecting subtle brain changes in slowly progressive heterogeneous diseases such as HD is a challenge. Manual techniques, the current ‘gold standard’, are time consuming, reliant on the rater skill and impractical for large scale use. Linear registration of serial MRI has successfully been used to detect whole brain and caudate atrophy in HD using the boundary shift integral (BSI). However, it is less robust when applied to structures without brain–CSF boundaries. Non-linear (fluid) registration allows assessment of within subject change across the entire brain so may be applicable to a wider array of structures, thus providing more regionally specific information. Aims To develop and apply a fully automated technique sensitive to 1 year global and regional volumetric changes in premanifest and early HD subjects using fluid registration of serial MRI. Methods/techniques T1 weighted 3T MR images were acquired at baseline and 1 year from 303 subjects (97 controls; 110 premanifest; 96 early HD) in the TRACK-HD study. Regions of interest (ROI) were generated on the baseline scans using the automated FSL software. Fluid registration was used to model within subject voxel level change over the scanning interval and the 1 year volume change was quantified by summing voxel change within each ROI. Results/outcome Preliminary fluid derived results (whole brain and caudate) show good group discrimination, consistent with BSI findings. We will present fluid derived regional and global atrophy rates, group differences and a comparison of our data with BSI results where appropriate. Conclusions We describe a technique which has the potential to provide fully automated global and regional measures of atrophy using multi site data. This may have utility as an outcome measure for future therapeutic trials in HD. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM PUBLISHER]

Background/aims TRACK-HD is a multinational prospective, observational study of Huntington's disease (HD) that aims to examine longitudinal change in premanifest carriers of the mutant HTT gene and subjects with early stage disease (Tabrizi 2009). New data from the first follow-up assessment are reported here, and build on previous findings from baseline 3T MRI and novel clinical, cognitive, quantitative motor, oculomotor and neuropsychiatric assessments. Of 366 subjects enrolled at baseline, 345 (115 controls, 116 premanifest (preHD) and 114 early HD) completed 12 months of follow-up. Statistical analysis was performed to assess annualised change in all modalities. Methods/techniques Annualised rates of global and regional atrophy were higher in both the pre- and early HD groups than in controls (p≤0.007). Whole brain atrophy rates were 0.3%, 0.5% and 0.9%, and caudate atrophy rates 0.6%, 2.0% and 3.5%, in controls, pre and early HD, respectively, over 1 year. Whole brain image analysis techniques also revealed striking cortical and subcortical grey and white matter atrophy over just 1 year even in subjects furthest from predicted disease onset. Quantitative imaging showed significant associations with disease burden and total functional capacity, a widely used clinical measure of disease severity. Cognitive deterioration was detectable in both HD groups. However, rates of decline in cognitive, quantitative motor and oculomotor tasks were greater after onset of motor signs. Results/outcome HD is characterised by a long premanifest state, slow progression and a disease course of around 20 years. After 1 year, we have identified robust change in a range of measures across modalities in both premanifest and early stage HD. Quantitative imaging showed the greatest differentiation across the spectrum of the disease and a number of functional measures of decline were sensitive in early HD with cognitive impairment also detectable in the pre-HD group. Conclusions TRACK-HD is the first multi-site study to report whole brain, regional and subcortical atrophy in premanifest subjects many years from predicted disease onset using 3T MR imaging; and demonstrates the feasibility of obtaining quantifiable endpoints which show robust change over just 1 year thus showing potential as endpoints for future therapeutic trials. [ABSTRACT FROM PUBLISHER]

Background and Purpose: Inherited prion diseases represent over 15% of human prion cases and are a frequent cause of early onset dementia. The purpose of this study was to define the distribution of changes in cerebral volumetric and microstructural parenchymal tissues in a specific inherited human prion disease mutation combining VBM with VBA of cerebral MTR and MD., Materials and Methods: VBM and VBA of cerebral MTR and MD were performed in 16 healthy control participants and 9 patients with the 6-OPRI mutation. An analysis of covariance consisting of diagnostic grouping with age and total intracranial volume as covariates was performed., Results: On VBM, there was a significant reduction in gray matter volume in patients compared with control participants in the basal ganglia, perisylvian cortex, lingual gyrus, and precuneus. Significant MTR reduction and MD increases were more anatomically extensive than volume differences on VBM in the same cortical areas, but MTR and MD changes were not seen in the basal ganglia., Conclusions: Gray matter and WM changes were seen in brain areas associated with motor and cognitive functions known to be impaired in patients with the 6-OPRI mutation. There were some differences in the anatomic distribution of MTR-VBA and MD-VBA changes compared with VBM, likely to reflect regional variations in the type and degree of the respective pathophysiologic substrates. Combined analysis of complementary multiparameter MR imaging data furthers our understanding of prion disease pathophysiology.

Objective: Motor signs are functionally disabling features of Huntington disease. Characteristic motor signs define disease manifestation. Their severity and onset are assessed by the Total Motor Score of the Unified Huntington's Disease Rating Scale, a categorical scale limited by interrater variability and insensitivity in premanifest subjects. More objective, reliable, and precise measures are needed which permit clinical trials in premanifest populations. We hypothesized that motor deficits can be objectively quantified by force-transducer-based tapping and correlate with disease burden and brain atrophy., Methods: A total of 123 controls, 120 premanifest, and 123 early symptomatic gene carriers performed a speeded and a metronome tapping task in the multicenter study TRACK-HD. Total Motor Score, CAG repeat length, and MRIs were obtained. The premanifest group was subdivided into A and B, based on the proximity to estimated disease onset, the manifest group into stages 1 and 2, according to their Total Functional Capacity scores. Analyses were performed centrally and blinded., Results: Tapping variability distinguished between all groups and subgroups in both tasks and correlated with 1) disease burden, 2) clinical motor phenotype, 3) gray and white matter atrophy, and 4) cortical thinning. Speeded tapping was more sensitive to the detection of early changes., Conclusion: Tapping deficits are evident throughout manifest and premanifest stages. Deficits are more pronounced in later stages and correlate with clinical scores as well as regional brain atrophy, which implies a link between structure and function. The ability to track motor phenotype progression with force-transducer-based tapping measures will be tested prospectively in the TRACK-HD study.

Background and Purpose: Longitudinal MR imaging measures provide an opportunity to track progression in HD before the emergence of clinical symptoms. This may prove useful in assessing disease-modifying treatments. We investigated how caudate and global volumes change as HD progresses from premanifest to early disease., Materials and Methods: Forty HD gene-positive individuals and 19 controls underwent serial volumetric MR imaging (baseline, 12 and 27 months; 2 or 3 scans per person). At baseline, 3 patients with HD were premanifest but developed overt motor features during the study, and 37 had early HD. All had dates of motor onset recorded. Caudates, lateral ventricles, and TIVs were measured using semiautomated procedures. Linear mixed models were used to investigate differences between HD and controls in relation to motor onset, controlling for TIV, sex, and age., Results: Extrapolating backwards in time, we found that differences in caudate and ventricular volumes between patients with HD and controls were evident 14 and 5 years, respectively, before motor onset (P < .05). At onset, caudate volume was 2.58 mL smaller than that in controls (P < .0001); ventricular volume was 9.27 mL larger (P < .0001). HD caudate atrophy rates were linear, showed low variability between subjects, and were approximately 10-fold higher than those in controls (P < .001). HD ventricular enlargement rates were variable between subjects, were approximately 4-fold higher than those in controls at onset (P < .001), and accelerated with disease duration (P = .02)., Conclusions: We provide evidence of acceleration of global atrophy in HD with disproportionate caudate involvement. Both caudate and global measures may be of use as early markers of HD pathology.

Background and Purpose: VBM is increasingly used in the study of neurodegeneration, and recently there has been interest in its potential as a biomarker. However, although it is largely "automated," VBM is rarely implemented consistently across studies, and changing user-specified options can alter the results in a way similar to the very biologic differences under investigation., Materials and Methods: This work uses data from patients with HD to demonstrate the effects of several user-specified VBM parameters and analyses: type and level of statistical correction, modulation, smoothing kernel size, adjustment for brain size, subgroup analysis, and software version., Results: The results demonstrate that changing these options can alter results in a way similar to the biologic differences under investigation., Conclusions: If VBM is to be useful clinically or considered for use as a biomarker, there is a need for greater recognition of these issues and more uniformity in its application for the method to be both reproducible and valid.

We measured hippocampi on baseline-, 6- and 12-month scans in a group of AD (n=36) and control subjects (n=20). We found that mean annualised atrophy rates using 6-month intervals were comparable at a group level to those generated from a 12-month interval. Higher variance was seen using shorter intervals, although this was only significant in the control group. This has implications where shorter inter-scan intervals may be advantageous, such as rapid diagnosis, and tracking of disease progression including in a clinical trial.

Dementia represents one of the major public health problems facing ageing populations, with 20% of those over 80 years of age suffering from this disorder. The advent of therapeutic agents has brought about an increasing demand for a more accurate and earlier diagnosis, and the value of neuroimaging in improving the diagnostic process is becoming widely accepted. Neuroimaging assessments may add weight to a diagnosis of neurodegeneration as opposed to healthy ageing, improve the differential diagnosis, aid in the prediction of conversion to dementia in individuals at a higher risk of developing the disorder, track disease progression and provide an outcome measure for assessment of drug efficacy.

We describe a method of automatically calculating hippocampal atrophy rates on T1-weighted MR images without manual delineation of hippocampi. This method was applied to a group of Alzheimer's disease (AD) (n=36) and control (n=19) subjects and compared with manual methods (manual segmentation of baseline and repeat-image hippocampi) and semi-automated methods (manual segmentation of baseline hippocampi only). In controls, mean (S.D.) atrophy rates for manual, semi-automated, and automated methods were 18.1 (53.5), 15.3 (50.2) and 11.3 (50.4) mm3 loss per year, respectively. In AD patients these rates were 174.6 (106.5) 159.4 (101.2) and 172.1 (123.1) mm3 loss per year, respectively. The automated method was a significant predictor of disease (p=0.001) and gave similar group discrimination compared with both semi-automated and manual methods. The automated hippocampal analysis in this small study took approximately 20 min per hippocampal pair on a 3.4 GHz Intel Xeon server, whereas manual delineation of each hippocampal pair took approximately 90 min of operator-intensive labour. This method may be useful diagnostically or in studies where analysis of many scans may be required.

Background: Early diagnosis and monitoring of the progression of Alzheimer's disease is important for the development of therapeutic strategies. To detect the earliest structural brain changes, individuals need to be studied before symptom onset. We used an imaging technique known as voxel-compression mapping to localise progressive atrophy in patients with preclinical Alzheimer's disease., Methods: Four symptom-free individuals from families with early-onset Alzheimer's disease with known autosomal dominant mutations underwent serial magnetic resonance imaging (MRI) over 5-8 years. All four became symptomatic during follow-up. 20 individuals with a clinical diagnosis of probable Alzheimer's disease and 20 control participants also underwent serial MR imaging. A non-linear fluid matching algorithm was applied to register repeat scans onto baseline imaging. Jacobian determinants were used to create the voxel-compression maps., Findings: Progressive atrophy was revealed in presymptomatic individuals, with posterior cingulate and neocortical temporoparietal cortical losses, and medial temporal-lobe atrophy. In patients with known Alzheimer's disease, atrophy was widespread apart from in the primary motor and sensory cortices and cerebellum, reflecting the clinical phenomenology., Interpretation: Voxel-compression maps confirmed early involvement of the medial temporal lobes, but also showed posterior cingulate and temporoparietal cortical losses at presymptomatic stage. This technique could be applied diagnostically and used to monitor the effects of therapeutic intervention.

The application of voxel-level three-dimensional registration to serial magnetic resonance imaging (MRI) is described. This fluid registration determines deformation fields modeling brain change, which are consistent with a model describing a viscous fluid. The objective was to validate the measurement of hippocampal volumetric change by fluid registration in Alzheimer's disease (AD) against current methodologies. The hippocampus was chosen for this study because it is difficult to measure reproducibly by manual segmentation and is widely studied; however, the technique is applicable to any structure which can be delineated on a scan. First, suitable values for the viscosity-body-force-ratio, alpha (0.01), and the number of iterations (300), were established and the convergence, repeatability, linearity, and accuracy investigated and compared with expert manual segmentation. A simple model of hippocampal atrophy was used to compare simulated volumetric change against that obtained by fluid registration. Finally the serial segmentation was compared with the current gold standard technique-expert human labeling with a volume repeatability of approximately 4%-in 27 subjects (15 normal controls, 12 clinically diagnosed with Alzheimer's disease). The scan-rescan volumetric consistency of serial segmentation by fluid-registration was shown to be superior to human serial segmentors ( approximately 2%). The mean absolute volume difference between fluid and manual segmentation was 0.7%. Fluid registration has potential importance for tracking longitudinal structural changes in brain particularly in the context of the clinical trial where large numbers of subjects may have multiple MR scans., (Copyright 2001 Academic Press.)

Volumetric magnetic resonance imaging analyses of 30 subjects were undertaken to quantify the global and temporal lobe atrophy in semantic dementia and Alzheimer's disease. Three groups of 10 subjects were studied: semantic dementia patients, Alzheimer's disease patients, and control subjects. The temporal lobe structures measured were the amygdala, hippocampus, entorhinal cortex, parahippocampal gyrus, fusiform gyrus, and superior, middle, and inferior temporal gyri. Semantic dementia and Alzheimer's disease groups did not differ significantly on global atrophy measures. In semantic dementia, there was asymmetrical temporal lobe atrophy, with greater left-sided damage. There was an anteroposterior gradient in the distribution of temporal lobe atrophy, with more marked atrophy anteriorly. All left anterior temporal lobe structures were affected in semantic dementia, with the entorhinal cortex, amygdala, middle and inferior temporal gyri, and fusiform gyrus the most severely damaged. Asymmetrical, predominantly anterior hippocampal atrophy was also present. In Alzheimer's disease, there was symmetrical atrophy of the entorhinal cortex, hippocampus, and amygdala, with no evidence of an anteroposterior gradient in the distribution of temporal lobe or hippocampal atrophy. These data demonstrate that there is a marked difference in the distribution of temporal lobe atrophy in semantic dementia and Alzheimer's disease. In addition, the pattern of atrophy in semantic dementia suggests that semantic memory is subserved by anterior temporal lobe structures, within which the middle and inferior temporal gyri may play a key role.