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

The clinical utility of verbal fluency assessment in Huntington’s disease

Introduction. Verbal fluency (VF) tests are widely used in the neuropsychological assessment mainly because of their sensitivity to various cognitive impairments and their brevity. VF deficits are well documented in Huntington’s disease (HD). Aim. The paper aims at presenting the clinical utility of VF tests in HD in the context of differential diagnosis, cognitive screening and longitudinal observation.Discussion. VF deficits are observed in various degenerative disorders and may be attributed to distinct neuropsychological deficits. Both, phonemic and semantic fluency deficits are observed in HD. Deficient VF in HD is an indicator of impaired executive function, psychomotor slowing and generalized cognitive decline. It is unclear whether language impairment significantly contributes to deficient VF performance. Progressive reduction in switching observed in HD documents the executive aspect of failure on VF tasks. The literature lacks in data on action and alternating fluency in HD. As they seem to be sensitive to frontostriatal dysfunction in Parkinson’s disease and are more demanding than traditional fluency tasks, their utility in HD may be limited to preclinical and early clinical stages. Conclusions. VF tasks are useful at the preclinical and clinical stages of HD unless severe dysarthria occurs in HD course. Semantic fluency tasks can document the progression of cognitive deficits when floor effect is observed on phonemic fluency tasks. Alternating and action fluency in HD requires further study

Kliniczne zastosowanie prób fluencji słownej w chorobie Huntingtona

Introduction. Verbal fluency (VF) tests are widely used in the neuropsychological assessment mainly because of their sensitivity to various cognitive impairments and their brevity. VF deficits are well documented in Huntington’s disease (HD). Aim. The paper aims at presenting the clinical utility of VF tests in HD in the context of differential diagnosis, cognitive screening and longitudinal observation.Discussion. VF deficits are observed in various degenerative disorders and may be attributed to distinct neuropsychological deficits. Both, phonemic and semantic fluency deficits are observed in HD. Deficient VF in HD is an indicator of impaired executive function, psychomotor slowing and generalized cognitive decline. It is unclear whether language impairment significantly contributes to deficient VF performance. Progressive reduction in switching observed in HD documents the executive aspect of failure on VF tasks. The literature lacks in data on action and alternating fluency in HD. As they seem to be sensitive to frontostriatal dysfunction in Parkinson’s disease and are more demanding than traditional fluency tasks, their utility in HD may be limited to preclinical and early clinical stages. Conclusions. VF tasks are useful at the preclinical and clinical stages of HD unless severe dysarthria occurs in HD course. Semantic fluency tasks can document the progression of cognitive deficits when floor effect is observed on phonemic fluency tasks. Alternating and action fluency in HD requires further study

Shelter in Smoleń III - A unique example of stratified Holocene clastic cave sediments in Central Europe, a lithostratigraphic stratotype and a record of regional paleoecology.

A cave site Shelter in Smoleń III (southern Poland) contains an approximately 2-m-thick stratified sequence of Upper Pleistocene and Holocene clastic sediments, unique for Central Europe. The sequence contents abundant fossil fauna, including mollusk, rodent and bat remains. The cave sites with long profiles of subfossil fauna present a great value for reconstructions of regional terrestrial paleoenvironment. We explore the stratigraphy of this site through analyses of the lithology and geochemistry of sediments, radiocarbon dating of faunal and human remains and charcoals, and archaeological study, as well as the paleoecology derived from the taxonomic composition of fossil faunal assemblages. Our data show that the entire period of the Holocene is recorded in the rockshelter, which makes that site an exceptional and highly valuable case. We present paleoenvironmental reconstructions of regional importance, and we propose to regard Shelter in Smoleń III as a regional stratigraphic stratotype of Holocene clastic cave sediments

Late Glacial and Holocene paleoecology and paleoenvironmental changes in the northern Carpathians foreland : the Żarska Cave (southern Poland) case study

The study of past environments, their ecology, and detailed changes through time has become an important task of environmental science. Records of paleoenvironment usually vary between regions owing to different influences of local climate, vegetation, relief, and depositional processes. Therefore, studying local sequences thoroughly allows paleoenvironmental and paleoecological reconstructions for particular regions, but it also provides important data that complement the global record. The Żarska Cave is an exceptional site, which owing to its thick and undisturbed Holocene sediments with very rich paleobotanical and paleozoological materials has become the most complete example of the uppermost Upper Pleistocene and Holocene cave deposits in the Polish uplands. The aim of our study was to understand paleoenvironmental changes in southern Poland, from the late Glacial to the late Holocene, which has been targeted by use of a detailed geological analysis accompanied by analysis of a wide range of paleobotanical, paleozoological, and archeological assemblages. All the results obtained have permitted characterization of the paleoenvironmental changes occurring in the area of the Polish Jura during the last >15 ka years. A particularly well-represented sequence covers the Allerød interstadial, which revealed the presence of forests with associated shade-loving mollusks and rodents. The beginning of the Holocene was clearly identified with an increase of shaded forest habitats, which developed in a still relatively cold climate with continental features, and with the first appearance of mesophilous deciduous trees. During the middle Holocene, unusual evidence for maple forests is documented, which developed before the formation of beech forests, typical for the late Holocene. The obtained sequence has great significance not only for the Polish Jura region, but also has wider implications for southern Poland and the vast area of the northern Carpathian foreland

Clinical manifestations of intermediate allele carriers in Huntington disease

Objective: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry. Methods: We assessed a cohort of participants at risk with <36 CAG repeats of the huntingtin (HTT) gene. Outcome measures were the Unified Huntington's Disease Rating Scale (UHDRS) motor, cognitive, and behavior domains, Total Functional Capacity (TFC), and quality of life (Short Form-36 [SF-36]). This cohort was subdivided into IA carriers (27-35 CAG) and controls (<27 CAG) and younger vs older participants. IA carriers and controls were compared for sociodemographic, environmental, and outcome measures. We used regression analysis to estimate the association of age and CAG repeats on the UHDRS scores. Results: Of 12,190 participants, 657 (5.38%) with <36 CAG repeats were identified: 76 IA carriers (11.56%) and 581 controls (88.44%). After correcting for multiple comparisons, at baseline, we found no significant differences between IA carriers and controls for total UHDRS motor, SF-36, behavioral, cognitive, or TFC scores. However, older participants with IAs had higher chorea scores compared to controls (p 0.001). Linear regression analysis showed that aging was the most contributing factor to increased UHDRS motor scores (p 0.002). On the other hand, 1-year follow-up data analysis showed IA carriers had greater cognitive decline compared to controls (p 0.002). Conclusions: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling. ClinicalTrials.gov identifier: NCT01590589

Optimization of adsorptive removal of α-toluic acid by CaO2 nanoparticles using response surface methodology

The present work addresses the optimization of process parameters for adsorptive removal of α-toluic acid by calcium peroxide (CaO2) nanoparticles using response surface methodology (RSM). CaO2 nanoparticles were synthesized by chemical precipitation method and confirmed by Transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) analysis which shows the CaO2 nanoparticles size range of 5–15 nm. A series of batch adsorption experiments were performed using CaO2 nanoparticles to remove α-toluic acid from the aqueous solution. Further, an experimental based central composite design (CCD) was developed to study the interactive effect of CaO2 adsorbent dosage, initial concentration of α-toluic acid, and contact time on α-toluic acid removal efficiency (response) and optimization of the process. Analysis of variance (ANOVA) was performed to determine the significance of the individual and the interactive effects of variables on the response. The model predicted response showed a good agreement with the experimental response, and the coefficient of determination, (R2) was 0.92. Among the variables, the interactive effect of adsorbent dosage and the initial α-toluic acid concentration was found to have more influence on the response than the contact time. Numerical optimization of process by RSM showed the optimal adsorbent dosage, initial concentration of α-toluic acid, and contact time as 0.03 g, 7.06 g/L, and 34 min respectively. The predicted removal efficiency was 99.50%. The experiments performed under these conditions showed α-toluic acid removal efficiency up to 98.05%, which confirmed the adequacy of the model prediction