Evaluation of multi-modal, multi-site neuroimaging measures in Huntington's disease: Baseline results from the PADDINGTON study.

BACKGROUND: Macro- and micro-structural neuroimaging measures provide valuable information on the pathophysiology of Huntington's disease (HD) and are proposed as biomarkers. Despite theoretical advantages of microstructural measures in terms of sensitivity to pathology, there is little evidence directly comparing the two. METHODS: 40 controls and 61 early HD subjects underwent 3 T MRI (T1- and diffusion-weighted), as part of the PADDINGTON study. Macrostructural volumetrics were obtained for the whole brain, caudate, putamen, corpus callosum (CC) and ventricles. Microstructural diffusion metrics of fractional anisotropy (FA), mean-, radial- and axial-diffusivity (MD, RD, AD) were computed for white matter (WM), CC, caudate and putamen. Group differences were examined adjusting for age, gender and site. A formal comparison of effect sizes determined which modality and metrics provided a statistically significant advantage over others. RESULTS: Macrostructural measures showed decreased regional and global volume in HD (p < 0.001); except the ventricles which were enlarged (p < 0.01). In HD, FA was increased in the deep grey-matter structures (p < 0.001), and decreased in the WM (CC, p = 0.035; WM, p = 0.053); diffusivity metrics (MD, RD, AD) were increased for all brain regions (p < 0.001). The largest effect sizes were for putamen volume, caudate volume and putamen diffusivity (AD, RD and MD); each was significantly larger than those for all other metrics (p < 0.05). CONCLUSION: The highest performing macro- and micro-structural metrics had similar sensitivity to HD pathology quantified via effect sizes. Region-of-interest may be more important than imaging modality, with deep grey-matter regions outperforming the CC and global measures, for both volume and diffusivity. FA appears to be relatively insensitive to disease effects

Genetic topography and cortical cell loss in Huntington's disease link development and neurodegeneration

Cortical cell loss is a core feature of Huntington Disease (HD), beginning many years before clinical motor diagnosis, during the premanifest stage. However, it is unclear how genetic topography relates to cortical cell loss. Here, we explore the biological processes and cell types underlying this relationship and validate this using cell-specific post-mortem data. Eighty premanifest participants on average 15 years from disease onset and 71 controls were included. Using volumetric and diffusion MRI we extracted HD-specific whole brain maps where lower grey matter volume and higher grey matter mean diffusivity, relative to controls, were used as proxies of cortical cell loss. These maps were combined with gene expression data from the Allen Human Brain Atlas (AHBA) to investigate the biological processes relating genetic topography and cortical cell loss. Cortical cell loss was positively correlated with the expression of developmental genes (i.e. higher expression correlated with greater atrophy and increased diffusivity) and negatively correlated with the expression of synaptic and metabolic genes that have been implicated in neurodegeneration. These findings were consistent for diffusion MRI and volumetric HD-specific brain maps. As wild type Huntingtin is known to play a role in neurodevelopment, we explored the association between wild type Huntingtin (HTT) expression and developmental gene expression across the AHBA. Co-expression network analyses in 134 human brains free of neurodegenerative disorders was also performed. HTT expression was correlated with the expression of genes involved in neurodevelopment while co-expression network analyses also revealed that HTT expression was associated with developmental biological processes. Expression weighted cell-type enrichment (EWCE) analyses were used to explore which specific cell-types were associated with HD cortical cell loss and these associations were validated using cell specific single nucleus RNAseq (snRNAseq) data from post-mortem HD brains. The developmental transcriptomic profile of cortical cell loss in preHD was enriched in astrocytes and endothelial cells, while the neurodegenerative transcriptomic profile was enriched for neuronal and microglial cells. Astrocyte-specific genes differentially expressed in HD post-mortem brains relative to controls using snRNAseq were enriched in the developmental transcriptomic profile, while neuronal and microglial-specific genes were enriched in the neurodegenerative transcriptomic profile Our findings suggest that cortical cell loss in preHD may arise from dual pathological processes, emerging as a consequence of neurodevelopmental changes, at the beginning of life, followed by neurodegeneration in adulthood, targeting areas with reduced expression of synaptic and metabolic genes. These events result in age-related cell death across multiple brain cell types

Progressive alterations in white matter microstructure across the timecourse of Huntington's disease

BACKGROUND: Whole-brain longitudinal diffusion studies are crucial to examine changes in structural connectivity in neurodegeneration. Here, we investigated the longitudinal alterations in white matter (WM) microstructure across the timecourse of Huntington's disease (HD). METHODS: We examined changes in WM microstructure from premanifest to early manifest disease, using data from two cohorts with different disease burden. The TrackOn-HD study included 67 controls, 67 premanifest, and 10 early manifest HD (baseline and 24-month data); the PADDINGTON study included 33 controls and 49 early manifest HD (baseline and 15-month data). Longitudinal changes in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity from baseline to last study visit were investigated for each cohort using tract-based spatial statistics. An optimized pipeline was employed to generate participant-specific templates to which diffusion tensor imaging maps were registered and change maps were calculated. We examined longitudinal differences between HD expansion-carriers and controls, and correlations with clinical scores, including the composite UHDRS (cUHDRS). RESULTS: HD expansion-carriers from TrackOn-HD, with lower disease burden, showed a significant longitudinal decline in FA in the left superior longitudinal fasciculus and an increase in MD across subcortical WM tracts compared to controls, while in manifest HD participants from PADDINGTON, there were significant widespread longitudinal increases in diffusivity compared to controls. Baseline scores in clinical scales including the cUHDRS predicted WM microstructural change in HD expansion-carriers. CONCLUSION: The present study showed significant longitudinal changes in WM microstructure across the HD timecourse. Changes were evident in larger WM areas and across more metrics as the disease advanced, suggesting a progressive alteration of WM microstructure with disease evolution

Rabies, Still Neglected after 125 Years of Vaccination

International audienceno abstrac

Facilitation or Competition? Tree Effects on Grass Biomass across a Precipitation Gradient

Savanna ecosystems are dominated by two distinct plant life forms, grasses and trees, but the interactions between them are poorly understood. Here, we quantified the effects of isolated savanna trees on grass biomass as a function of distance from the base of the tree and tree height, across a precipitation gradient in the Kruger National Park, South Africa. Our results suggest that mean annual precipitation (MAP) mediates the nature of tree-grass interactions in these ecosystems, with the impact of trees on grass biomass shifting qualitatively between 550 and 737 mm MAP. Tree effects on grass biomass were facilitative in drier sites (MAP≤550 mm), with higher grass biomass observed beneath tree canopies than outside. In contrast, at the wettest site (MAP = 737 mm), grass biomass did not differ significantly beneath and outside tree canopies. Within this overall precipitation-driven pattern, tree height had positive effect on sub-canopy grass biomass at some sites, but these effects were weak and not consistent across the rainfall gradient. For a more synthetic understanding of tree-grass interactions in savannas, future studies should focus on isolating the different mechanisms by which trees influence grass biomass, both positively and negatively, and elucidate how their relative strengths change over broad environmental gradients. © 2013 Moustakas et al

Impacts of savanna trees on forage quality for a large African herbivore

Recently, cover of large trees in African savannas has rapidly declined due to elephant pressure, frequent fires and charcoal production. The reduction in large trees could have consequences for large herbivores through a change in forage quality. In Tarangire National Park, in Northern Tanzania, we studied the impact of large savanna trees on forage quality for wildebeest by collecting samples of dominant grass species in open grassland and under and around large Acacia tortilis trees. Grasses growing under trees had a much higher forage quality than grasses from the open field indicated by a more favourable leaf/stem ratio and higher protein and lower fibre concentrations. Analysing the grass leaf data with a linear programming model indicated that large savanna trees could be essential for the survival of wildebeest, the dominant herbivore in Tarangire. Due to the high fibre content and low nutrient and protein concentrations of grasses from the open field, maximum fibre intake is reached before nutrient requirements are satisfied. All requirements can only be satisfied by combining forage from open grassland with either forage from under or around tree canopies. Forage quality was also higher around dead trees than in the open field. So forage quality does not reduce immediately after trees die which explains why negative effects of reduced tree numbers probably go initially unnoticed. In conclusion our results suggest that continued destruction of large trees could affect future numbers of large herbivores in African savannas and better protection of large trees is probably necessary to sustain high animal densities in these ecosystems

Excess maternal salt intake produces sex-specific hypertension in offspring: putative roles for kidney and gastrointestinal sodium handling.

Hypertension is common and contributes, via cardiovascular disease, towards a large proportion of adult deaths in the Western World. High salt intake leads to high blood pressure, even when occurring prior to birth - a mechanism purported to reside in altered kidney development and later function. Using a combination of in vitro and in vivo approaches we tested whether increased maternal salt intake influences fetal kidney development to render the adult individual more susceptible to salt retention and hypertension. We found that salt-loaded pregnant rat dams were hypernatraemic at day 20 gestation (147±5 vs. 128±5 mmoles/L). Increased extracellular salt impeded murine kidney development in vitro, but had little effect in vivo. Kidneys of the adult offspring had few structural or functional abnormalities, but male and female offspring were hypernatraemic (166±4 vs. 149±2 mmoles/L), with a marked increase in plasma corticosterone (e.g. male offspring; 11.9 [9.3-14.8] vs. 2.8 [2.0-8.3] nmol/L median [IQR]). Furthermore, adult male, but not female, offspring had higher mean arterial blood pressure (effect size, +16 [9-21] mm Hg; mean [95% C.I.]. With no clear indication that the kidneys of salt-exposed offspring retained more sodium per se, we conducted a preliminary investigation of their gastrointestinal electrolyte handling and found increased expression of proximal colon solute carrier family 9 (sodium/hydrogen exchanger), member 3 (SLC9A3) together with altered faecal characteristics and electrolyte handling, relative to control offspring. On the basis of these data we suggest that excess salt exposure, via maternal diet, at a vulnerable period of brain and gut development in the rat neonate lays the foundation for sustained increases in blood pressure later in life. Hence, our evidence further supports the argument that excess dietary salt should be avoided per se, particularly in the range of foods consumed by physiologically immature young

Uncharted waters: rare and unclassified cardiomyopathies characterized on cardiac magnetic resonance imaging

Cardiac magnetic resonance imaging (CMR) has undergone considerable technology advances in recent years, so that it is now entering into mainstream cardiac imaging practice. In particular, CMR is proving to be a valuable imaging tool in the detection, morphological assessment and functional assessment of cardiomyopathies. Although our understanding of this broad group of heart disorders continues to expand, it is an evolving group of entities, with the rarer cardiomyopathies remaining poorly understood or even unclassified. In this review, we describe the clinical and pathophysiological aspects of several of the rare/unclassified cardiomyopathies and their appearance on CMR