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

Symbioses of lichen-forming fungi with Trentepohlialean algae

Trentepohliaceae are a distinct lineage of green algae frequently found in associations with lichen-forming fungi. We review the current knowledge about the phenotypic diversity of this group of algae which is complemented by currently available molecular data. These data do not confirm the traditional classification of the genera based on morphological inferences. We also present more specific data on the association patterns of epiphyllous representatives in tropical rain forests. Leaf-colonizing Porina species associate specifically with Phycopeltis algae of characteristic growth types. The analysis of partial rbcL sequences of the algal partners suggests that morphologically similar growth types are genetically highly diverse and may represent different species. The fungal species may switch among morphologically similar but genetically distinct algal lineages. This strategy could promote rapid colonization of the ephemeral leaf habitats. Bark-inhabiting lichens of temperate habitats seem to represent a few known morphological species of Trentepohliales, whereas tropical bark lineages seem to be more diverse. Even though Trentepohliales are pending a modern revision before precise figures can be given, their diversity appears to be much higher than thought befor

7 Tesla magnetic resonance imaging to detect cortical pathology in multiple sclerosis.

Neocortical lesions (NLs) are an important pathological component of multiple sclerosis (MS), but their visualization by magnetic resonance imaging (MRI) remains challenging.We aimed at assessing the sensitivity of multi echo gradient echo (ME-GRE) T2*-weighted MRI at 7.0 Tesla in depicting NLs compared to myelin and iron staining.Samples from two MS patients were imaged post mortem using a whole body 7 T MRI scanner with a 24-channel receive-only array. Isotropic 200 micron resolution images with varying T2* weighting were reconstructed from the ME-GRE data and converted into R2* maps. Immunohistochemical staining for myelin (proteolipid protein, PLP) and diaminobenzidine-enhanced Turnbull blue staining for iron were performed.Prospective and retrospective sensitivities of MRI for the detection of NLs were 48% and 67% respectively. We observed MRI maps detecting only a small portion of 20 subpial NLs extending over large cortical areas on PLP stainings. No MRI signal changes suggestive of iron accumulation in NLs were observed. Conversely, R2* maps indicated iron loss in NLs, which was confirmed by histological quantification.High-resolution post mortem imaging using R2* and magnitude maps permits detection of focal NLs. However, disclosing extensive subpial demyelination with MRI remains challenging

NL scheme and PLP staining.

<p>(<b>A</b>) Type-I NL with demyelination of the whole width of the cortex (#) and adjacent WM (*). (<b>B</b>) Type-II intracortical lesion evolving around a vessel. (<b>C</b>) Type-III subpial NL. Demyelination spreads from the pial surface until cortical layer 3. Scale bars represent 500 µm.</p

NLs on MRI and tissue sections stained for PLP and iron.

<p>Examples Examples of NLs from tissue MS1 (<b>A, B and C</b>) identified on MRI magnitude (TE = 25.2 ms) and R₂^* images as well as color-coded PLP-staining and iron staining. Red arrows point towards NLs identified by MRI and confirmed to correspond to area of demyelination by the color-coded PLP staining. Blue arrows point towards NLs identified by the color-coded PLP staining and only retrospectively identified by MRI. Black arrows and black box point towards NLs identified by the color-coded PLP staining and not by MRI even upon a second retrospective image inspection. In the black box we include a large area of demyelination which goes entirely undetected by MRI. In the color-coded PLP staining of figure: green  =  complete WM demyelination, red  =  complete GM demyelination, yellow  =  areas of variably reduced myelin density.</p

NL Occurrence.

<p>*% of 48 total number.</p><p>**% of 45 total number.</p><p>***% of the total number 93.</p><p>NL Occurrence.</p

MRI contrast.

<p>Examples of NLs from tissue MS2 identified on MRI (<b>A</b>) magnitude (TE = 25.2 ms), and (<b>B</b>) R₂^* images. Arrows point towards type-I, type-II and type-III NLs. Examples of intensity profile on of cortical regions with (green box) and without (yellow box) NLs on both magnitude (<b>C and E</b>) and R₂^* maps (<b>D and F</b>). In this example, the WM has a R₂^* value of around 75 Hz, while the inner part of cortex has a R₂^* of around 45 Hz, the outer part of cortex is around 40 Hz and NL is as low as around 30.</p