Progression of microstructural damage in spinocerebellar Ataxia Type 2: A longitudinal DTI study

BACKGROUND AND PURPOSE: The ability of DTI to track the progression of microstructural damage in patients with inherited ataxias has not been explored so far. We performed a longitudinal DTI study in patients with spinocerebellar ataxia type 2. MATERIALS AND METHODS: Ten patients with spinocerebellar ataxia type 2 and 16 healthy age-matched controls were examined twice with DTI (mean time between scans, 3.6 years [patients] and 3.3 years [controls]) on the same 1.5T MR scanner. Using tract-based spatial statistics, we analyzed changes in DTI-derived indices: mean diffusivity, axial diffusivity, radial diffusivity, fractional anisotropy, and mode of anisotropy. RESULTS: At baseline, the patients with spinocerebellar ataxia type 2, as compared with controls, showed numerous WM tracts with significantly increased mean diffusivity, axial diffusivity, and radial diffusivity and decreased fractional anisotropy and mode of anisotropy in the brain stem, cerebellar peduncles, cerebellum, cerebral hemisphere WM, corpus callosum, and thalami. Longitudinal analysis revealed changes in axial diffusivity and mode of anisotropy in patients with spinocerebellar ataxia type 2 that were significantly different than those in the controls. In patients with spinocerebellar ataxia type 2, axial diffusivity was increased in WM tracts of the right cerebral hemisphere and the corpus callosum, and the mode of anisotropy was extensively decreased in hemispheric cerebral WM, corpus callosum, internal capsules, cerebral peduncles, pons and left cerebellar peduncles, and WM of the left paramedian vermis. There was no correlation between the progression of changes in DTI-derived indices and clinical deterioration. CONCLUSIONS: DTI can reveal the progression of microstructural damage of WM fibers in the brains of patients with spinocerebellar ataxia type 2, and mode of anisotropy seems particularly sensitive to such changes. These results support the potential of DTI-derived indices as biomarkers of disease progression

Consensus Paper: Radiological Biomarkers of Cerebellar Diseases

Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Axial diffusivity is increase in the degenerating superior cerebellar peduncles of Friedreich\u2019s ataxia

INTRODUCTION: Decreased fractional anisotropy (FA) demonstrated by diffusion tensor MR imaging (DTI) in areas of white matter (WM) damage is generally associated with increase of radial diffusivity, while axial diffusivity is reported to be decreased, unchanged, or increased. Aiming to better define the type of axial diffusivity change occurring in a typical human neurodegenerative disease, we investigated axial and radial diffusivity in Friedreich's ataxia (FRDA) which is characterized by selective neuronal loss of the dentate nuclei and atrophy and decreased FA of the superior cerebellar peduncles (SCPs). METHODS: Axial and radial diffusivity of the whole-brain WM were evaluated in 14 patients with FRDA and 14 healthy volunteers using DTI at 1.5 T and the tract-based spatial statistics (TBSS) method, part of FSL software. RESULTS: TBSS analysis showed a single area in the central midbrain corresponding to the decussation of the SCPs which exhibited lower FA in patients than in controls. In this area, a significant increase of both axial and radial diffusivity was observed. No clusters of significantly decreased axial diffusivity were observed, while additional clusters of increase of radial diffusivity were present throughout the brain. CONCLUSIONS: The selective decrease of FA in SCPs of FRDA patients reflecting chronic WM tract damage is associated with increase of both the axial and radial diffusivity, the latter more pronounced than the former. The ultrastructural and biophysical bases of the increased axial diffusivity in chronically degenerating WM tracts deserve further studies

Self-paced frequency of a simple motor task and brain activation. A fMRI study in healthy subjects using an on-line monitor device.

Application of fMRI to clinical neurology implies the selection of a simple task and control of the task performance. The capability to objectively monitor variables related to task execution is, therefore, important and could improve accuracy of clinical fMRI studies. We assessed the influence of different self-paced frequencies of a simple motor task on brain activation in healthy subjects. A device was developed to measure the force exerted by a subject in pressing an air-filled rubber bulb with the last four fingers of the dominant hand. The task frequency was determined by analysis of the force signal. Nine healthy subjects performed twice the task with self-paced slow (0.35+/-0.09 Hz), intermediate (0.58+/-0.21 Hz) or fast (0.98+/-0.32 Hz) frequency. The device revealed impaired task execution in 1 subject. The coefficient of variation of frequency was 8.7% for slow, 12.2% for intermediate and 15.8% for fast paced task. No significant differences were found comparing the activation maps obtained at slow, intermediate and fast frequencies in the contralateral sensorimotor cortex and ipsilateral cerebellum. Cluster reproducibility was good for location (standard deviation<or=7.3 mm), but poor for signal intensity (coefficient of variation 0-176.8%) and extent (coefficient of variation 1.9-140.6%). In conclusion, self-paced frequency variations of a simple motor task in the 0.2-2 Hz range are not a relevant source of the variability of the fMRI results in healthy subjects. Use of the device for evaluation of the neurologically impaired patients might broaden the clinical applications of fMRI

Multimodal MRI classification in vascular mild cognitive impairment

Vascular mild cognitive impairment (VMCI) is a disorder in which multimodal MRI can add significant value by combining diffusion tensor imaging (DTI) with brain morphometry. In this study we implemented and compared machine learning techniques for multimodal classification between 58 VMCI patients and 29 healthy subjects as well as for discrimination (within the VMCI group) between patients with different cognitive performances. For each subject, a cortical feature vector was constructed based on cortical parcellation and cortical and subcortical volumetric segmentation and a DTI feature vector was formed by combining descriptive statistical metrics related to the distribution of DTI invariants within white matter. We employed both a sequential minimal optimization and a functional tree classifier, using feature selection and 10-fold cross-validation, and compared their performances in monomodal and multimodal classification for both classification problems (healthy subjects vs VMCI and prediction of cognitive performance). While monomodal classification resulted in satisfactory performance in most cases, turning from monomodal to multimodal classification resulted in an improvement of the performance in the discrimination between VMCI patients with low cognitive performance and healthy subjects by up to 10% in sensitivity (leaving specificity unchanged). We therefore are able to confirm the usefulness of machine learning techniques in discriminating diseased states based on neuroimaging data

Whole-brain histogram and voxel-based analyses of Diffusion Tensor Imaging in patients with Leukoaraiosis. Correlation with motor and cognitive impairment

BACKGROUND AND PURPOSE: Cerebral white matter changes, termed leukoaraiosis (LA), appearing as areas of increased signal intensity in T2-weighted MR images, are common in elderly subjects, but the possible correlation of LA with cognitive or motor deficit has not been established. We hypothesized that histogram and voxel-based analyses of whole-brain mean diffusivity (MD) and fractional anisotropy (FA) maps calculated from diffusion tensor imaging (DTI) could be more sensitive tools than visual scales to investigate the clinical correlates of LA. MATERIALS AND METHODS: Thirty-six patients of the Leukoaraiosis and Disability Study were evaluated with fluid-attenuated inversion recovery for LA extension, T1-weighted images for volume, and DTI for MD and FA. The extent of LA was rated visually. The normalized total, gray, and white matter brain volumes were computed, as well as the 25th percentile, 50th percentile, kurtosis, and skewness of the MD and FA maps of the whole brain. Finally, voxel-based analysis on the maps of gray and white matter volume, MD, and FA was performed with SPM2 software. Correlation analyses between visual or computerized data and motor or neuropsychologic scale scores were performed using the Spearman rank test and the SPM2 software. RESULTS: The visual score correlated with some MD and FA histogram metrics (P<.01). However, only the 25th and 50th percentiles, kurtosis, and skewness of the MD and FA histograms correlated with motor or neuropsychologic deficits. Voxel-based analysis revealed a correlation (P<.05 corrected for multiple comparisons) between a large cluster of increased MD in the corpus callosum and pericallosal white matter and motor deficit. CONCLUSIONS: These results are consistent with the hypothesis that histogram and voxel-based analyses of the whole-brain MD and FA maps are more sensitive tools than the visual evaluation for clinical correlation in patients with LA