Advances in the understanding of hereditary ataxia - implications for future patients

INTRODUCTION: Hereditary ataxias are caused by mutations in a plethora of different genes. Advances in sequencing technologies have led to an exponential increase in novel gene discoveries, highlighted the genetic overlap with other neurological diseases and improved our understanding of genotype-phenotype relationships. Together, these developments allowed the identification of new therapeutic targets that are subsequently making their way into clinical trials. AREAS COVERED: This review focuses on the shared genetic characteristics and the latest insights into the molecular cause of the most prevalent hereditary ataxias. Furthermore, conventional genetic diagnosis and the gradual implementation of next-generation sequencing (NGS) approaches in clinical practice is discussed. Finally, the latest investigated disease-modifying therapeutic agents are reviewed. A literature search was performed in PubMed and the Cochrane Library. Additional information on previous and on-going trials was obtained from the ClinicalTrials.gov website. EXPERT OPINION: The implementation of NGS in clinical practice has led to an increase in detected sequence variants of unknown clinical significance. Determining their pathogenicity is an expensive and time-consuming process. In accordance with the progresses in genetics, there is a need for the simultaneous definition of novel biomarkers and functional assays that can assist in the interpretation of genetic tests

Diabetes Mellitus and Depression as Risk Factors for Dementia: SADEM Study

Aim: 3Evidence indicates that the comorbidity of dementia with diabetes and depression may affect most cognitive functions. Our chief interest was to examine the patterns of cognitive functioning in individuals diagnosed with dementia, diabetes, and depression as compared with dementia plus diabetes (DDM), or dementia plus depression (DD) and healthy controls

Searches for solar-influenced radioactive decay anomalies using Spacecraft RTGs

Experiments showing a seasonal variation of the nuclear decay rates of a number of different nuclei, and decay anomalies apparently related to solar flares and solar rotation, have suggested that the Sun may somehow be influencing nuclear decay processes. Recently, Cooper searched for such an effect in $^{238}$Pu nuclei contained in the radioisotope thermoelectric generators (RTGs) on board the Cassini spacecraft. In this paper we modify and extend Cooper's analysis to obtain constraints on anomalous decays of $^{238}$Pu over a wider range of models, but these limits cannot be applied to other nuclei if the anomaly is composition-dependent. We also show that it may require very high sensitivity for terrestrial experiments to discriminate among some models if such a decay anomaly exists, motivating the consideration of future spacecraft experiments which would require less precision.Comment: 8 pages, 4 figures (to appear in Astroparticle Physics

Experimental demonstration of the relationship between the second- and third-order polarizabilities of conjugated donor-acceptor molecules

The dependence of the second- and third-order polarizabilities ((beta) and (gamma) ) on ground-state polarization was measured for a series of donor-acceptor polyenes using electric field induced second harmonic generation and third harmonic generation, respectively. The changes in ground-state polarization, associated with the donor/acceptor strength or solvent polarity, were probed by x-ray crystallography, 1H-NMR, electronic absorption, and Raman spectroscopies. The observed behavior of (beta) and (gamma) as a function of ground- state polarization agrees well with theoretical predictions. In particular, positive and negative peaks, as well as sign changes, were observed for both (beta) and (gamma) . The dependences for (beta) and (gamma) are consistent with a derivative relationship between them. In addition, the third-order polarizability of a series of molecules possessing zero bond length alternation was found to be negative, in agreement with predictions based on the relationship between the polarizabilities and ground-state geometry

Topical amitriptyline in healthy volunteers

Background and Objectives: The antidepressant amitriptyline is used as an adjuvant in the treatment of a variety of chronic pain conditions. This drug interacts with many receptors and ion channels, such as Na ϩ channels. In a randomized, double-blinded, and placebo-controlled trial, we investigated whether amitriptyline also is capable of providing cutaneous analgesia when applied topically in 14 healthy volunteers

Comparison of Pittsburgh compound B and florbetapir in cross-sectional and longitudinal studies.

IntroductionQuantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B-based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design.MethodsPittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally.ResultsGlobal amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers.DiscussionAlthough the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 1