Human Prion Diseases in The Netherlands (1998–2009): Clinical, Genetic and Molecular Aspects

Prion diseases are rare and fatal neurodegenerative disorders that can be sporadic, inherited or acquired by infection. Based on a national surveillance program in the Netherlands we describe here the clinical, neuropathological, genetic and molecular characteristics of 162 patients with neuropathologically confirmed prion disease over a 12-year period (1998–2009). Since 1998, there has been a relatively stable mortality of Creutzfeldt-Jakob disease (CJD) in the Netherlands, ranging from 0.63 to 1.53 per million inhabitants per annum. Genetic analysis of the codon 129 methionine/valine (M/V) polymorphism in all patients with sporadic CJD (sCJD) showed a trend for under-representation of VV cases (7.0%), compared with sCJD cohorts in other Western countries, whereas the MV genotype was relatively over-represented (22,4%). Combined PrPSc and histopathological typing identified all sCJD subtypes known to date, except for the VV1 subtype. In particular, a “pure" phenotype was demonstrated in 60.1% of patients, whereas a mixed phenotype was detected in 39.9% of all sCJD cases. The relative excess of MV cases was largely accounted for by a relatively high incidence of the MV 2K subtype. Genetic analysis of the prion protein gene (PRNP) was performed in 161 patients and showed a mutation in 9 of them (5.6%), including one FFI and four GSS cases. Iatrogenic CJD was a rare phenomenon (3.1%), mainly associated with dura mater grafts. Three patients were diagnosed with new variant CJD (1.9%) and one with variably protease-sensitive prionopathy (VPSPr). Post-mortem examination revealed an alternative diagnosis in 156 patients, most commonly Alzheimer's disease (21.2%) or vascular causes of dementia (19.9%). The mortality rates of sCJD in the Netherlands are similar to those in other European countries, whereas iatrogenic and genetic cases are relatively rare. The unusual incidence of the VV2 sCJD subtype compared to that reported to date in other Western countries deserves further investigation

Comparison of temporal judgments in sighted and visually impaired children

Aim: We studied visually impaired and blind children to investigate the effects of visual damage on time perception. Methods: Sixty-three children (11 blind, 16 visually impaired, 20 sighted and 16 sighted but blindfolded) performed a temporal bisection task, which consisted of judging different temporal intervals presented in the auditory modality. Results: The visually impaired children showed lower constant error than sighted children but higher variability (Weber ratio). The blindfolded children had a temporal estimation comparable to the clinical groups and time sensitivity comparable to the controls. Conclusion: These findings are interpreted in the light of inter-modality interference, assuming that the coexistence of both sensory modalities, present only in controls, leads to a trade-off between the two senses with an indirect contribution of sight, which does not happen either in the clinical groups or in the blindfolded children, despite the single sensory task

Comparison of temporal judgments in sighted and visually impaired children

Aim: We studied visually impaired and blind children to investigate the effects of visual damage on time perception. Methods: Sixty-three children (11 blind, 16 visually impaired, 20 sighted and 16 sighted but blindfolded) performed a temporal bisection task, which consisted of judging different temporal intervals presented in the auditory modality. Results: The visually impaired children showed lower constant error than sighted children but higher variability (Weber ratio). The blindfolded children had a temporal estimation comparable to the clinical groups and time sensitivity comparable to the controls. Conclusion: These findings are interpreted in the light of inter-modality interference, assuming that the coexistence of both sensory modalities, present only in controls, leads to a trade-off between the two senses with an indirect contribution of sight, which does not happen either in the clinical groups or in the blindfolded children, despite the single sensory task

Ultrafast Roaming Mechanisms in Ethanol Probed by Intense Extreme Ultraviolet Free-Electron Laser Radiation: Electron Transfer versus Proton Transfer

Ultrafast H$_2$$^+$ and H$_3$$^+$ formation from ethanol is studied using pump-probe spectroscopy with an extreme ultraviolet (XUV) free-electron laser. The first pulse creates a dication, triggering H2 roaming that leads to H$_2$$^+$ and H$_3$$^+$ formation, which is disruptively probed by a second pulse. At photon energies of 28 and 32 eV, the ratio of H$_2$$^+$ to H$_3$$^+$ increases with time delay, while it is flat at a photon energy of 70 eV. The delay-dependent effect is ascribed to a competition between electron and proton transfer. High-level quantum chemistry calculations show a flat potential energy surface for H$_2$ formation, indicating that the intermediate state may have a long lifetime. The ab initio molecular dynamics simulation confirms that, in addition to the direct emission, a small portion of H$_2$ undergoes a roaming mechanism that leads to two competing pathways: electron transfer from H2 to C$_2$H$_4$O$_2$$^+$ and proton transfer from C$_2$H$_4$O$_2$$^+$ to H$_2$

A synchronized VUV light source based on high-order harmonic generation at FLASH

Ultrafast measurements in the extreme ultraviolet (XUV) spectral region targeting femtosecond timescales rely until today on two complementary XUV laser sources: free electron lasers (FELs) and high-harmonic generation (HHG) based sources. The combination of these two source types was until recently not realized. The complementary properties of both sources including broad bandwidth, high pulse energy, narrowband tunability and femtosecond timing, open new opportunities for two-color pump-probe studies. Here we show first results from the commissioning of a high-harmonic beamline that is fully synchronized with the free-electron laser FLASH, installed at beamline FL26 with permanent end-station including a reaction microscope (REMI). An optical parametric amplifier synchronized with the FEL burst mode drives the HHG process. First commissioning tests including electron momentum measurements using REMI, demonstrate long-term stability of the HHG source over more than 14 hours. This realization of the combination of these light sources will open new opportunities for time-resolved studies targeting different science cases including core-level ionization dynamics or the electron dynamics during the transformation of a molecule within a chemical reaction probed on femtosecond timescales in the ultraviolet to soft X-ray spectral region

A synchronized VUV beamline for time domain two-color dynamic studies at FLASH2

We present a HHG-based vacuum ultraviolet (VUV) source at the free electron laser FLASH2. The source provides ultrashort pulses from 10 to 40 eV, coupled to the REMI end-station (beamline FL26) for VUV-FEL pump-probe experiments

Synchronized HHG based source at FLASH

We present a VUV beamline installed as pump-probe source at the free-electron laser FLASH. The source is based on high-order harmonic generation driven by femtosecond near-infrared laser pulses synchronized with the FEL burst mode

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.

A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the () mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation. The human disease mainly affected the cerebellum, spinal motor neurons, and peripheral nerves. We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in mice, which thus recapitulated key features of the human disease. Our findings link human neurodegeneration to tubulin polyglutamylation, entailing this post-translational modification as a potential target for drug development for neurodegenerative disorders