Short-interval observational data to inform clinical trial design in Huntington's disease.

OBJECTIVES: To evaluate candidate outcomes for disease-modifying trials in Huntington's disease (HD) over 6-month, 9-month and 15-month intervals, across multiple domains. To present guidelines on rapid efficacy readouts for disease-modifying trials. METHODS: 40 controls and 61 patients with HD, recruited from four EU sites, underwent 3 T MRI and standard clinical and cognitive assessments at baseline, 6 and 15 months. Neuroimaging analysis included global and regional change in macrostructure (atrophy and cortical thinning), and microstructure (diffusion metrics). The main outcome was longitudinal effect size (ES) for each outcome. Such ESs can be used to calculate sample-size requirements for clinical trials for hypothesised treatment efficacies. RESULTS: Longitudinal changes in macrostructural neuroimaging measures such as caudate atrophy and ventricular expansion were significantly larger in HD than controls, giving rise to consistently large ES over the 6-month, 9-month and 15-month intervals. Analogous ESs for cortical metrics were smaller with wide CIs. Microstructural (diffusion) neuroimaging metrics ESs were also typically smaller over the shorter intervals, although caudate diffusivity metrics performed strongly over 9 and 15 months. Clinical and cognitive outcomes exhibited small longitudinal ESs, particularly over 6-month and 9-month intervals, with wide CIs, indicating a lack of precision. CONCLUSIONS: To exploit the potential power of specific neuroimaging measures such as caudate atrophy in disease-modifying trials, we propose their use as (1) initial short-term readouts in early phase/proof-of-concept studies over 6 or 9 months, and (2) secondary end points in efficacy studies over longer periods such as 15 months.

Vaccination with anti-idiotype antibody ganglidiomab mediates a GD(2)-specific anti-neuroblastoma immune response.

PURPOSE: Immunotherapy targeting disialoganglioside GD(2) emerges as an important treatment option for neuroblastoma, a pediatric malignancy characterized by poor outcome. Here, we report the induction of a GD(2)-specific immune response with ganglidiomab, a new anti-idiotype antibody to anti-GD(2) antibodies of the 14.18 family. EXPERIMENTAL DESIGN AND RESULTS: Ganglidiomab was generated following immunization of Balb/c mice with 14G2a, and splenocytes were harvested to generate hybridoma cells. Clones were screened by ELISA for mouse antibody binding to hu14.18. One positive clone was selected to purify and characterize the secreted IgG protein (κ, IgG(1)). This antibody bound to anti-GD(2) antibodies 14G2a, ch14.18/CHO, hu14.18, and to immunocytokines ch14.18-IL2 and hu14.18-IL2 as well as to NK-92 cells expressing scFv(ch14.18)-zeta receptor. Binding of these anti-GD(2) antibodies to the nominal antigen GD(2) as well as GD(2)-specific lysis of neuroblastoma cells by NK-92-scFv(ch14.18)-zeta cells was competitively inhibited by ganglidiomab, proving GD(2) surrogate function and anti-idiotype characteristics. The dissociation constants of ganglidiomab from anti-GD(2) antibodies ranged from 10.8 ± 5.01 to 53.5 ± 1.92 nM as determined by Biacore analyses. The sequences of framework and complementarity-determining regions of ganglidiomab were identified. Finally, we demonstrated induction of a GD(2)-specific humoral immune response after vaccination of mice with ganglidiomab effective in mediating GD(2)-specific killing of neuroblastoma cells. CONCLUSION: We generated and characterized a novel anti-idiotype antibody ganglidiomab and demonstrated activity against neuroblastoma.

Body fat distribution as a risk factor for cerebrovascular disease: an MRI-based body fat quantification study.

BACKGROUND: While adiposity is a well-established risk factor for cardiovascular disease, the association between adiposity and cerebrovascular disease is not entirely understood. For example, common methods to quantify body fat volume such as body mass index, waist circumference and waist-to-hip ratio are not suitable to identify the complex distribution patterns of body fat and its relation to cerebrovascular pathology. In view of a better understanding of the association between fat distribution and cerebrovascular disorders, the aim of the study was to perform measurements of body fat distribution patterns and body fat volumes in correlation to arteriosclerosis of the brain-feeding arteries and white matter lesion load (WMLL). METHODS: In this study we performed a magnetic resonance imaging (MRI)-based volumetric differential analysis of subcutaneous and visceral body fat distribution in 25 patients with MRI-proven hyperacute ischemic stroke. For the measurement of adipose tissue volume and tissue distribution automatic labeling analysis software was used. A correlation analysis of MRI volumetric measurements of subcutaneous and visceral body fat, atherosclerotic plaque load of the brain-feeding arteries measured by computed tomography angiography, and WMLL measured by MRI volumetry of the whole brain was performed. RESULTS: The normalized total abdominal adipose tissue and the normalized subcutaneous abdominal adipose tissue showed no significant correlation with either WMLL or total plaque volume. In contrast, the normalized visceral adipose tissue showed a significant correlation with WMLL volume. Visceral adipose tissue as a percentage of total adipose tissue showed a significant correlation with WMLL. In particular, the percentage of visceral adipose tissue rather than total body fat volume strongly correlated with atherosclerosis and ischemic cerebral lesions. Furthermore, the volume of both soft and calcified plaques correlated significantly with WMLL. CONCLUSIONS: Our results contribute to existing studies about the association of different patterns of fat distribution with atherosclerosis of the brain-feeding arteries, in particular highlighting the importance of visceral adiposity as a risk factor for cerebrovascular disease. The percentage of visceral adipose tissue in total adipose tissue has the potential of a sensitive parameter and might become a relevant new epidemiological marker, showing highly significant correlations with well-established markers of cerebrovascular disease. In conclusion, the percentage of visceral adipose tissue by itself has to be regarded as a risk factor for both small vessel cerebrovascular disease and cerebral atherosclerosis of the large-to-medium-sized arteries.

Diffusion tensor imaging and tractwise fractional anisotropy statistics: quantitative analysis in white matter pathology.

BACKGROUND: Information on anatomical connectivity in the brain by measurements of the diffusion of water in white matter tracts lead to quantification of local tract directionality and integrity. METHODS: The combination of connectivity mapping (fibre tracking, FT) with quantitative diffusion fractional anisotropy (FA) mapping resulted in the approach of results based on group-averaged data, named tractwise FA statistics (TFAS). The task of this study was to apply these methods to group-averaged data from different subjects to quantify differences between normal subjects and subjects with defined alterations of the corpus callosum (CC). RESULTS: TFAS exhibited a significant FA reduction especially in the CC, in agreement with region of interest (ROI)-based analyses. CONCLUSION: In summary, the applicability of the TFAS approach to diffusion tensor imaging studies of normal and pathologically altered brains was demonstrated.