Dynamic nuclear polarization enhanced solid-state NMR studies of surface modification of gamma-alumina

Dynamic nuclear polarization (DNP) gives large (>100-fold) signal enhancements in solid-state NMR spectra via the transfer of spin polarization from unpaired electrons from radicals implanted in the sample. This means that the detailed information about local molecular environment available for bulk samples from solid-state NMR spectroscopy can now be obtained for dilute species, such as sites on the surfaces of catalysts and catalyst supports. In this paper we describe a DNP-enhanced solid-state NMR study of the widely used catalyst gamma-alumina which is often modified at the surface by the incorporation of alkaline earth oxides in order to control the availability of catalytically active penta-coordinate surface Al sites. DNP-enhanced 27Al solid-state NMR allows surface sites in gamma-alumina to be observed and their 27Al NMR parameters measured. In addition changes in the availability of different surface sites can be detected after incorporation of BaO

Sox-2 Positive Neural Progenitors in the Primate Striatum Undergo Dynamic Changes after Dopamine Denervation.

The existence of endogenous neural progenitors in the nigrostriatal system could represent a powerful tool for restorative therapies in Parkinson's disease. Sox-2 is a transcription factor expressed in pluripotent and adult stem cells, including neural progenitors. In the adult brain Sox-2 is expressed in the neurogenic niches. There is also widespread expression of Sox-2 in other brain regions, although the neurogenic potential outside the niches is uncertain. Here, we analyzed the presence of Sox-2+ cells in the adult primate (Macaca fascicularis) brain in naïve animals (N = 3) and in animals exposed to systemic administration of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine to render them parkinsonian (N = 8). Animals received bromodeoxyuridine (100 mg/kg once a day during five consecutive days) to label proliferating cells and their progeny. Using confocal and electron microscopy we analyzed the Sox-2+ cell population in the nigrostriatal system and investigated changes in the number, proliferation and neurogenic potential of Sox-2+ cells, in control conditions and at two time points after MPTP administration. We found Sox-2+ cells with self-renewal capacity in both the striatum and the substantia nigra. Importantly, only in the striatum Sox-2+ was expressed in some calretinin+ neurons. MPTP administration led to an increase in the proliferation of striatal Sox-2+ cells and to an acute, concomitant decrease in the percentage of Sox-2+/calretinin+ neurons, which recovered by 18 months. Given their potential capacity to differentiate into neurons and their responsiveness to dopamine neurotoxic insults, striatal Sox-2+ cells represent good candidates to harness endogenous repair mechanisms for regenerative approaches in Parkinson's disease

A Spanish Consensus on the Use of Safinamide for Parkinson's Disease in Clinical Practice

Safinamide is an approved drug for the treatment of motor fluctuations in Parkinson's disease (PD). Scarce data are available on its use in clinical practice. A group of Spanish movement disorders specialists was convened to review the use of safinamide across different clinical scenarios that may guide neurologists in clinical practice. Eight specialists with recognized expertise in PD management elaborated the statements based on available evidence in the literature and on their clinical experience. The RAND/UCLA method was carried, with final conclusions accepted after a 2-round modified Delphi process. Higher level of agreement between panellists was reached for the following statements. Safinamide significantly improves mean daily OFF time without troublesome dyskinesias. Adjunctive treatment with safinamide is associated with motor improvements in patients with mid-to-late PD. The efficacy of safinamide on motor fluctuations is maintained at long-term, with no increase over time in dyskinesias severity. The clinical benefits of safinamide on pain and depression remain unclear. Safinamide presents a similar incidence of adverse events compared with placebo. The efficacy and safety of safinamide shown in the pivotal clinical trials are reproduced in clinical practice, with improvement of parkinsonian symptoms, decrease of daily OFF time, control of dyskinesias at the long term, and good tolerability and safety.This study was funded by Zambon S.A.U. Medical writing services were funded by Zambon S.A.U

Parkinson’s Disease Gravity Index: A Method by means of Optimal Scaling

Objective. This study has been designed with the aim of using optimal scaling to perform the allocation of scores and to be able to construct an indicator of the Parkinson’s Disease Gravity Index. Scores were assigned to interrelated dimensions that share information about the patient’s situation, to have an objective, holistic tool which integrates scores so that doctors can have a comprehensive idea of the patient’s situation. Patients and Methods. 120 consecutive patients with Parkinson’s diagnosis were chosen according to the United Kingdom Parkinson’s Disease Society Brain Bank criteria. Subsequently, all the chosen dimensions were transformed into interval variables for which the formula proposed by Sturges was used. Once the dimensions were transformed into interval variables, optimal scaling was carried out. Subsequently, the following attributes were analyzed: quality and acceptability of the data; reliability: internal consistency, reliability index, Cronbach’s alpha, and standard error of measurement; finally, validity: convergent validity and validity for known groups. Results. There were no missing data. An appropriate Cronbach’s alpha value of 0.71 was gathered, and all items were found to be pertinent to the scale. The item homogeneity index was 0.36. Precision evaluated with the standard error of measurement was 7.8. The Parkinson’s Disease Gravity Index discriminant validity (validity for known groups), assessed among the different stages of Hoehn and Yahr scale by the Kruskal–Wallis test, showed major significance (X2 = 32.7, p≤0.001). Conclusions. The Parkinson’s Disease Gravity Index has shown adequate metric properties

Chronic levodopa administration followed by a washout period increased number and induced phenotypic changes in striatal dopaminergic cells in MPTP-monkeys.

In addition to the medium spiny neurons the mammalian striatum contains a small population of GABAergic interneurons that are immunoreactive for tyrosine hydroxylase (TH), which dramatically increases after lesions to the nigrostriatal pathway and striatal delivery of neurotrophic factors. The regulatory effect of levodopa (L-Dopa) on the number and phenotype of these cells is less well understood. Eleven macaques (Macaca fascicularis) were included. Group I (n = 4) received 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and L-Dopa; Group II (n = 4) was treated with MPTP plus vehicle and Group III (n = 3) consist of intact animals (control group). L-Dopa and vehicle were given for 1 year and animals sacrificed 6 months later. Immunohistochemistry against TH was used to identify striatal and nigral dopaminergic cells. Double and triple labeling immunofluorescence was performed to detect the neurochemical characteristics of the striatal TH-ir cells using antibodies against: TH, anti-glutamate decarboxylase (GAD(67)) anti-calretinin (CR) anti-dopa decarboxylase (DDC) and anti-dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32). The greatest density of TH-ir striatal cells was detected in the striatum of the L-Dopa treated monkeys and particularly in its associative territory. None of the striatal TH-ir cell expressed DARPP-32 indicating they are interneurons. The percentages of TH-ir cells that expressed GAD67 and DDC was approximately 50%. Interestingly, we found that in the L-Dopa group the number of TH/CR expressing cells was significantly reduced. We conclude that chronic L-Dopa administration produced a long-lasting increase in the number of TH-ir cells, even after a washout period of 6 months. L-Dopa also modified the phenotype of these cells with a significant reduction of the TH/CR phenotype in favor of an increased number of TH/GAD cells that do not express CR. We suggest that the increased number of striatal TH-ir cells might be involved in the development of aberrant striatal circuits and the appearance of L-Dopa induced dyskinesias

Correction: Sox-2 Positive Neural Progenitors in the Primate Striatum Undergo Dynamic Changes after Dopamine Denervation.

[This corrects the article on p. e66377 in vol. 8.]

Erratum : Pagonabarraga, J.; et al. A Spanish Consensus on the Use of Safinamide for Parkinson's Disease in Clinical Practice. Brain Sci. 2020, 10, 176

We would like to submit the following erratum to our recently published paper [1] due to the errors in the abstract. We request (1) the removal of the word “motor” from the first line of the abstract, so that the sentence reads: “Safinamide is an approved drug for the treatment of fluctuations in Parkinson’s disease (PD)”, and (2) that the word “OFF” is changed to “ON” in line 6 of the abstract, so that the sentence reads: “Safinamide significantly improves the mean daily ON time without troublesome dyskinesias.

Cell renewal and differentiation dynamics of progenitors in the striatum.

<p>Schematic representation of hypothetic dynamics of endogenous striatal progenitors and the effects of MPTP. <b>A.</b> For reference we represented on top, the results of fate mapping of Sox-2⁺ cells in the murine dentate gyrus showing that non-radial Sox-2⁺ progenitors have self-renew potential and give rise to both neurons and astrocytes <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066377#pone.0066377-Muotri1" target="_blank">[26]</a>. <b>B, C.</b> Similarly, we propose than in the normal situation, Sox-2⁺ striatal progenitors (Sox-2⁺/GFAP^−/CR^–) divide to generate new Sox-2⁺ progenitors. Moreover, some Sox-2⁺ progenitors give rise to astrocytes and (few) Sox-2⁺/CR⁺ neurons that after several maturation steps could switch off Sox-2 expression and give rise to different mature phenotypes (including TH⁺). Following MPTP administration the number of Sox-2⁺ progenitors increases while the number of CR⁺ cells that express Sox-2 is decreased. Possible mechanisms are A) MPTP favours gliogenesis from Sox2 progenitors at the expense of neurogenesis. B) MPTP (or lack of dopamine) accelerates maturation of Sox-2⁺/CR⁺ cells. C) Sox-2⁺/CR⁺ cells are susceptible to MPTP toxicity. Abbreviations: 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine: MPTP; calretinin: CR; tyrosine hydroxylase: TH.</p