Neuroinflammation in Huntington's Disease: New Insights with 11C-PBR28 PET/MRI.

Huntington's disease is a devastating neurodegenerative genetic disorder that causes progressive motor dysfunction, emotional disturbances, and cognitive impairment. Unfortunately, there is no treatment to cure or slow the progression of the disease. Neuroinflammation is one hallmark of Huntington's disease, and modulation of neuroinflammation has been suggested as a potential target for therapeutic intervention. The relationship between neuroinflammation markers and the disease pathology is still poorly understood. To improve our understanding of neuroinflammation in Huntington's disease, we measured translocator protein (TSPO) expression using 11C-PBR28 and simultaneous PET/MRI. Standardized-uptake-value ratios, normalized by whole brain uptake, were calculated for data acquired 60-90 min after radiotracer administration. We identified distinct patterns of regional neuroinflammation (as defined by TSPO overexpression relative to a control group) in the basal ganglia of Huntington's disease patients. These patterns were observed at the individual level in all patients, with region of interest analysis confirming significant differences between patients and the control group in the putamen and the pallidum. Additionally, we observed further distinct regional and subregional signatures, which may provide insights into phenotypical variability. For example, in certain Huntington's disease patients, we observed in vivo elevation of the level of TSPO binding in subnuclei in the thalamus and brainstem that have been previously associated with visual function, motor function, and motor coordination. Our main result is an objective score, based solely on 11C-PBR28 measurements, that correlates well with measurements of brain atrophy. We conclude that PET/MR imaging using 11C-PBR28 provides a high signal-to-background ratio and has the potential to be used to assess Huntington's disease progression. Our results suggest 11C-PBR28 might prove useful in clinical trials evaluating therapies targeting neuroinflammation.

Joint reconstruction of white-matter pathways from longitudinal diffusion MRI data with anatomical priors.

We consider the problem of reconstructing white-matter pathways in a longitudinal study, where diffusion-weighted and T1-weighted MR images have been acquired at multiple time points for the same subject. We propose a method for joint reconstruction of a subject's pathways at all time points given the subject's entire set of longitudinal data. We apply a method for unbiased within-subject registration to generate a within-subject template from the T1-weighted images of the subject at all time points. We follow a global probabilistic tractography approach, where the unknown pathway is represented in the space of this within-subject template and propagated to the native space of the diffusion-weighted images at all time points to compute its posterior probability given the images. This ensures spatial correspondence of the reconstructed pathway among time points, which in turn allows longitudinal changes in diffusion measures to be estimated consistently along the pathway. We evaluate the reliability of the proposed method on data from healthy controls scanned twice within a month, where no changes in white-matter microstructure are expected between scans. We evaluate the sensitivity of the method on data from Huntington's disease patients scanned repeatedly over the course of several months, where changes are expected between scans. We show that reconstructing white-matter pathways jointly using the data from all time points leads to improved reliability and sensitivity, when compared to reconstructing the pathways at each time point independently.

Uncertainties in predicting rice yield by current crop models under a wide range of climatic conditions.

Predicting rice (Oryza sativa) productivity under future climates is important for global food security. Ecophysiological crop models in combination with climate model outputs are commonly used in yield prediction, but uncertainties associated with crop models remain largely unquantified. We evaluated 13 rice models against multi-year experimental yield data at four sites with diverse climatic conditions in Asia and examined whether different modeling approaches on major physiological processes attribute to the uncertainties of prediction to field measured yields and to the uncertainties of sensitivity to changes in temperature and CO2 concentration [CO2 ]. We also examined whether a use of an ensemble of crop models can reduce the uncertainties. Individual models did not consistently reproduce both experimental and regional yields well, and uncertainty was larger at the warmest and coolest sites. The variation in yield projections was larger among crop models than variation resulting from 16 global climate model-based scenarios. However, the mean of predictions of all crop models reproduced experimental data, with an uncertainty of less than 10% of measured yields. Using an ensemble of eight models calibrated only for phenology or five models calibrated in detail resulted in the uncertainty equivalent to that of the measured yield in well-controlled agronomic field experiments. Sensitivity analysis indicates the necessity to improve the accuracy in predicting both biomass and harvest index in response to increasing [CO2 ] and temperature.

PRECREST: a phase II prevention and biomarker trial of creatine in at-risk Huntington disease.

OBJECTIVE: To assess the safety and tolerability of high-dose creatine, the feasibility of enrolling premanifest and 50% at-risk subjects in a prevention trial, and the potential of cognitive, imaging, and blood markers. METHODS: Sixty-four eligible consenting participants were randomly allocated (1:1) to 15 g twice daily of creatine monohydrate or placebo for a 6-month double-blind phase followed by a 12-month open-label extension. Subjects included premanifest (tested) and at-risk (not tested) individuals without clinical symptoms or signs of Huntington disease (HD). Primary outcomes were safety and tolerability. Exploratory endpoints included fine motor, visuospatial, and memory performance; structural and diffusion MRI; and selected blood markers. RESULTS: Forty-seven HD carriers and 17 non-HD controls were enrolled. Fifteen discontinued treatment (2 assigned to placebo); all were followed for the entire study period. Primary analysis was by intent to treat. The most common adverse events were gastrointestinal. Neuroimaging demonstrated treatment-related slowing of cortical and striatal atrophy at 6 and 18 months. CONCLUSION: We describe a design that preserves the autonomy of subjects not wanting genetic testing while including controls for assessing the specificity of treatment effects. Our results demonstrate the feasibility of prevention trials for HD and the safety of high-dose creatine, provide possible evidence of disease modification, support future studies of creatine, and illustrate the value of prodromal biomarkers. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that high-dose creatine is safe and tolerable.