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[Background] Previous studies linked disease-progression variables such as age at onset or survival to both genetic, and non-genetic factors in Parkinson's disease (PD) patients., [Objective] The aim of this study was to assess how genetic and non genetic factors act as modifiers of age at onset and survival and in a cohort of 753 PD patients, and to determine how these variables interact to define the overall risk., [Methods] We analyzed the effect of gender, tobacco, alcohol, type of PD (genetic, gPD or idiopathic, iPD) and three genetic variants rs5848- GRN, rs1042522- TP53 and APOE. We studied two cohorts (PPMI and IPDGC) to replicate positive results., [Results] Regarding age at onset, male smokers PD had a significantly lower mean age compared to non-smoker (p = 0.001). APOE-Ɛ4 carriers had a younger onset-age compared to non-carriers (p = 0.03) in the Spanish cohort, but these results were not replicated in the other cohorts. Concerning survival, PD patients with an early onset (below 50 years) had an increased survival rate (p < 0.001)., [Conclusions] Our study showed how several genetic and non-genetic risk factors influenced the age at onset and survival in PD., Irene Rosas was supported by a grant from Fundación Jose Luis Castaño-SEQC. Sergio Pérez-Oliveira is supported by Fundación Parkinson Asturias-Obra Social Cajastur. This study was supported by grant PI 15/00878 (Fondos Feder) to VA.

Parkinso’s disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for disease intervention. However, the ability to stratify patients who will benefit from such treatment modalities based on shared etiology is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types. We previously found centrosomal deficits in immortalized lymphocytes fromG2019S-LRRK2PD patients. Here, to investigate whether such deficits may serve as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we characterized patient-derived cells from distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early-stage idiopathic PD patients which is mitigated by LRRK2 kinase inhibition, supporting a role for aberrant LRRK2 activity in idiopathic PD. Centrosomal defects are detected inR1441G-LRRK2andG2019S-LRRK2PD patients and in non-manifestingLRRK2mutation carriers, indicating that they acumulate prior to a clinical PD diagnosis. They are present in immortalized cells as well as in primary lymphocytes from peripheral blood. These findings indicate that analysis of centrosomal defects as a blood-based patient stratification biomarker may help nominate PD patients who will benefit from LRRK2-related therapeutics.One-sentence summaryPeripheral blood-derived cells can be employed to stratify Parkinso’s disease patients most likely to respond to LRRK2-related therapeutics.

Elevated urine bis(monoacylglycerol)phosphate (BMP) levels have been found in gain-of-kinase function LRRK2 G2019S mutation carriers. Here, we have expanded urine BMP analysis to other Parkinson’s disease (PD) associated mutations and found them to be consistently elevated in carriers of LRRK2 G2019S and R1441G/C as well as VPS35 D620N mutations. Urine BMP levels are promising biomarkers for patient stratification and potentially target engagement in clinical trials of emerging targeted PD therapies.

In real mobile applications, deactivation of Mn-based catalysts by SO2 is severe and catalysts underperform at temperatures below 200 °C. SO2 deactivates the catalysts' redox function and regeneration is cumbersome.

Funding for this work was provided by King Abdullah University of Science and Technology (KAUST). The authors gratefully thank Sandra Ramirez Cherbuy for the graphical abstract illustration and Dr. Youssef Saih for thorough patents review search and discussion.

Funding for this work was provided by King Abdullah University of Science and Technology (KAUST). The authors wish to acknowledge and thank Sandra Ramirez Cherbuy for the illustration of the graphical abstract.

The effect of copper on various acid saponite supported Ni–Cu bimetallic catalysts, prepared with different Ni : Cu ratios, was studied for the liquid phase hydrogenolysis of glycidol on a batch reactor at 393 and 453 K. Characterization of the catalysts showed that Ni and Cu are in close contact as the XRD measurements evidenced the formation of an alloy. H2 chemisorption results revealed that the measured metallic area progressively decreased with an increase in the wt% of copper. In the presence of high metal activity (higher Ni wt%), the formation of 1,2-propanediol (1,2-PD) outweighed, while acid activity led to the formation of dimerization and oligomerization products. The addition of Cu and the increase of the reaction temperature decreased the diol formation but boosted the 1,3-PD/1,2-PD ratio. This could be explained by an improvement of the collaborative effect between the metal Ni and the H+ of the saponite. Therefore, the presence of an appropriate amount of Cu allowed the control of the hydrogenation capacity of Ni and enhanced the collaborative effect of Ni and H+ favouring the formation of 1,3-propanediol with respect to 1,2-propanediol.

The selective oxidation of CH4 in the aqueous phase to produce valuable chemicals has attracted considerable research attention due to its mild reaction conditions and simple process. As the most widely studied catalyst for this reaction, Fe-containing ZSM-5 zeolite (Fe-ZSM-5) demonstrates high intrinsic activity and selectivity; however, Fe-ZSM-5 prepared using conventional methods has a limited number of active Fe sites, resulting in low CH4 conversion per unit mass of the catalyst. To address this issue, this study reports a facile organic-template-free synthesis strategy that enables the incorporation of more Fe into the zeolite framework with a higher dispersion degree compared to conventional synthesis methods. Because framework Fe incorporated in this way is more readily to transform into isolated extra-framework Fe species under thermal treatment, the overall effect is that Fe-ZSM-5 prepared using this method (Fe-HZ5-TF) has three times as many catalytically active sites as conventional Fe-ZSM-5. When used for the selective oxidation of CH4 (30.5 bar) with 0.5 M H2O2 at 75°C, Fe-HZ5-TF produced a record high C1 oxygenate yield of 106.3 mmol gcat−1 h− 1 (a HCOOH selectivity of 91.3%), surpassing other catalysts reported to date. Spectroscopic characterization and density functional theory calculations revealed that the active sites in Fe-HZ5-TF are mononuclear Fe species in the form of [(H2O)3Fe(IV) = O]2+ bound to Al pairs in the zeolite framework. This differs from conventional Fe-ZSM-5, where binuclear Fe acts as the active site. Analysis of the catalyst and product evolution during the reaction suggests a radical-driven pathway to explain CH4 activation at the mononuclear Fe site and subsequent conversion to C1 oxygenates.

Background HD is an autosomal dominant, hereditary, and neurodegenerative disease that presents neurological, psychiatric, and cognitive impairment, with visual cognition being one of the affected areas. Aims This study aims to analyze the visual cognition profile of asymptomatic and symptomatic carriers of Huntington’s disease (HD), compared with healthy controls (HC), and to evaluate the differences between asymptomatic and symptomatic patients with different years of progression of HD. Methods We evaluated 99 participants, 51 HD carriers [17 asymptomatic, 13 symptomatic ( 5 years of evolution)] and 48 HC matched by sex and educational level. Motor function was rated with UHDRS scale, the general cognitive status was assessed with MoCA test, and a comprehensive battery of visual cognitive instruments was used. The following visual cognitive domains were assessed: visual memory, visuospatial skills and visuoconstructive abilities. One- way ANOVA and Tukey’s test for post hoc analysis were performed to analyze and compare the cognitive performance between the four groups. Results Statistically significant differences were found in the motor function (F(3.1)=14.129; p Conclusions Findings suggest that both symptomatic and asymptomatic HD patients present an increased visual cognitive impairment compared to HC. This impairment worsens with HD progression.

Confining metal active species in the voids of porous solid matrices such as zeolites, metal–organic frameworks (MOFs), and carbon nanotubes (CNTs) can bring fascinating key advantages in the field of selective hydrogenation reactions. Confined metal species act as intermolecular selective catalysts capable of discriminating reagents based on their molecular size and shape. They also exhibit intramolecular selectivity by converting one or more functional groups selectively in the presence of others. In this review, we present a comprehensive overview of the different synthetic methods for confining active metal species in the voids of zeolites, MOFs, CNTs, and other porous structures. We then emphasize the strong influence of metal confinement on steering catalytic selectivity in a wide range of selective hydrogenation reactions. Finally, we share our opinion on the different synthesis methods for potential practical applications and on future research directions.

Utilization of multi-functional catalysis is fast becoming the method of choice to boost the production of valuable chemicals from CO2. Here, we present a possible route to increase selectivity to light olefins by modifying the acidity of the zeolitic component of a multi-functional catalyst. This is carried out via incorporation of Ca on the zeolite ZSM-5 by incipient wetness impregnation. This incorporation, while straightforward, leads to reduced Bronsted acidity and the formation of multiple Lewis acidic species inside the zeolite. NMR investigations point towards incorporation of CO/ketene into the zeolite leading to the creation of surface acetate species, which augments the production of light olefins. Additionally, the suppression of oligomerization due to the reduction of Bronsted acid sites also produces more light olefins at the expense of longer chain hydrocarbons.

Background Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls. Methods Cancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients. Results Although cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients. Conclusions The increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. (c) 2019 International Parkinson and Movement Disorder Society

Heterozygous gain-of-kinase function variants in LRRK2 (leucine-rich repeat kinase 2) cause 1–2% of all cases of Parkinson’s disease (PD) albeit with incomplete and age-dependent penetrance. All pathogenic LRRK2 mutations reside within the two catalytic domains of LRRK2—either in its kinase domain (e.g. G2019S) with modest effect or its ROC-COR GTPase domain (e.g. R1441G/H) with large effect on LRRK2 kinase activity. We have previously reported assays to interrogate LRRK2 kinase pathway activity in human bio-samples measuring phosphorylation of its endogenous substrate Rab10, that mirrors LRRK2 kinase activation status. Here, we isolated neutrophils from fresh peripheral blood from 101 participants including 42 LRRK2 mutation carriers (21 with the G2019S and 21 with the R1441G mutations), 27 patients with idiopathic PD, and 32 controls. Using a dual approach, LRRK2 dependent Rab10 phosphorylation at Threonine 73 (pRab10Thr73) was measured by quantitative multiplexed immunoblotting for pRab10Thr73/total Rab10 as well as targeted mass-spectrometry for absolute pRab10Thr73 occupancy. We found a significant over fourfold increase in pRab10Thr73 phosphorylation in carriers of the LRRK2 R1441G mutation irrespective of clinical disease status. The effect of the LRRK2 G2019S mutation did not reach statistical significance. Furthermore, we show that LRRK2 phosphorylation at Serine 935 is not a marker for LRRK2 kinase activity in human neutrophils. When analysing pRab10Thr73 phosphorylation in post-mortem brain samples, we observed overall high variability irrespective of clinical and LRRK2 mutation status and attributed this mainly to the adverse effect of the peri- and post-mortem period on the stability of posttranslational modifications such as protein phosphorylation. Overall, in vivo LRRK2 dependent pRab10Thr73 phosphorylation in human peripheral blood neutrophils is a specific, robust and promising biomarker for significant LRRK2 kinase hyperactivation, as with the LRRK2 R1441G mutation. Additional readouts and/or assays may be needed to increase sensitivity to detect modest LRRK2 kinase activation, as with the LRRK2 G2019S mutation. Our assays could be useful for patient stratification and target engagement studies for LRRK2 kinase inhibitors.

The Lebedev process, in which ethanol is catalytically converted into 1,3-butadiene, is an alternative process for the production of this commodity chemical. Silica–magnesia (SiO2–MgO) is a benchmark catalyst for the Lebedev process. Among the different preparation methods, the SiO2–MgO catalysts prepared by wet-kneading typically perform best owing to the surface magnesium silicates formed during wet-kneading. Although the thermal treatment is of pivotal importance as a last step in the catalyst preparation, the effect of the calcination temperature of the wet-kneaded SiO2–MgO on the Lebedev process has not been clarified yet. Here, we prepared and characterized in detail a series of wet-kneaded SiO2–MgO catalysts using varying calcination temperatures. We find that the thermal treatment largely influences the type of magnesium silicates, which have different catalytic properties. Our results suggest that the structurally ill-defined amorphous magnesium silicates and lizardite are responsible for the production of ethylene. Further, we argue that forsterite, which has been conventionally considered detrimental for the formation of ethylene, favors the formation of butadiene, especially when combined with stevensite., Nanomaterials, 11 (3), ISSN:2079-4991

Gain-of kinase function variants in LRRK2 (leucine-rich repeat kinase 2) cause Parkinson’s disease (PD), albeit with incomplete and age-dependent penetrance, offering the prospect of disease-modifying treatment strategies via LRRK2 kinase inhibition. LRRK2 phosphorylates a subgroup of RabGTPases including Rab10 and pathogenic mutations enhance LRRK2-mediated phosphorylation of Rab10 at Thr73.In this study we analyse LRRK2 dependent Rab10Thr73 phosphorylation in human peripheral blood neutrophils isolated from 101 individuals using quantitative immunoblotting and mass spectrometry. Our cohort includes 42 LRRK2 mutation carriers (21 with the G2019S mutation that resides in the kinase domain and 21 with the R1441G mutation that lies within the ROC-COR domain), 27 patients with idiopathic PD, and 32 controls.We show that LRRK2 dependent Rab10 Thr73 phosphorylation is significantly elevated in all R1441G LRRKR2 mutation carriers irrespective of disease status. PD manifesting and non-manifesting G2019S mutation carriers as well as idiopathic PD samples did not display elevated Rab10 Thr73 phosphorylation. Furthermore, we analysed brain samples of 10 G2019S and 1 R1441H mutation carriers as well as 10 individuals with idiopathic PD and 10 controls. We find high variability for pRab10Thr73 phosphorylation amongst donors irrespective of genetic and disease state.We conclude that in vivo LRRK2 dependent pRab10Thr73 analysis in human peripheral blood neutrophils is a specific and robust biomarker for LRRK2 kinase activation for individuals with mutations such as R1441G that enhance pRab10Thr73 phosphorylation over 2-fold. We provide the first evidence that the LRRK2 R1441G mutation enhances LRRK2 kinase activity in a primary human cell.

The dynamics of the retained species on ZSM-5 and SAPO-18 catalysts are studied by using a combination of temperature-programmed desorption/oxidation, ex situ analysis, and in situ FTIR spectroscopic measurements over the entire conversion range, using fixed-bed and spectroscopic cell reactors, in continuous and discontinuous mode. The results point to the appropriateness of the combined methodologies to track the interconversion of active into deactivating species. A statistically relevant (supported by linear regression and multivariate analysis) association of the observations is found by using the different complementary methodologies. The kinetics of this interconversion depends on the initial conversion (tuned by acidity and space time) and microporous topology, and involve: (i) in the ZSM-5 catalysts, the diffusion of monocyclic aromatics toward the exterior of the zeolite to form coke, and (ii) in the SAPO-18 catalysts, the obstruction of the cavities by aromatics that grow into tetracyclic aromatic islands.

BackgroundParkinson’s disease (PD) involves environmental risk and protective factors as well as genetic variance. Most of the research in genomics has been done in subjects of European ancestry leading to sampling bias and leaving Latin American populations underrepresented.ObjectiveWe sought to phenotype and genotype Costa Rican PD cases and controls.MethodsWe enrolled 118 PD patients with 97 unrelated controls. Collected information included demographics, exposure to risk and protective factors, motor and cognitive assessments. We sequenced coding and untranslated regions in familial PD and atypical parkinsonism-associated genes including GBA, SNCA, VPS35, LRRK2, GCH1, PRKN, PINK1, DJ-1, VPS13C, ATP13A2.ResultsMean age of PD probands was 62.12 ± 13.51 years, 57.6% were male. Prevalence of risk and protective factors reached 30%. Physical activity significantly correlated with better motor performance despite years of disease. Increased years of education were significantly associated with better cognitive function, whereas hallucinations, falls, mood disorders and coffee consumption correlated with worse cognitive performance. We did not identify an association between tested genes and PD or any damaging homozygous or compound heterozygous variants. Rare variants in LRRK2 were nominally associated with PD, six were located between amino acids p.1620-1623 in the C-terminal-of-ROC (COR) domain of LRRK2. Nonsynonymous GBA variants (p.T369M, p.N370S, p.L444P) were identified in three healthy individuals. One PD patient carried a pathogenic GCH1 variant, p.K224R.ConclusionThis is the first study that reports on sociodemographic, risk factors, clinical presentation and genetics of Costa Rican patients with PD.

Background There is a need for biomarkers of dementia in PD. Objectives To determine if the levels of the main CSF proteins and their ratios are associated with deterioration in cognition and progression to dementia in the short to mid term. Methods The Parkinson's Progression Markers Initiative database was used as an exploratory cohort, and a center-based cohort was used as a replication cohort. Amyloid s1-42, total tau, threonine-181 phosphorylated tau, and α-synuclein in the CSF and the ratios of these proteins were assessed. Results In the Parkinson's Progression Markers Initiative cohort (n = 281), the total tau/amyloid s1-42, total tau/α-synuclein, total tau/amyloid s1-42+α-synuclein, and amyloid s1-42/total tau ratios were associated with a risk of progression to dementia over a 3-year follow-up. In the replication cohort (n = 40), the total tau/α-synuclein and total tau/amyloid s1-42+α-synuclein ratios were associated with progression to dementia over a 41-month follow-up. Conclusion Ratios of the main proteins found in PD patient brain inclusions that can be measured in the CSF appear to have value as short- to mid-term predictors of dementia. © 2018 International Parkinson and Movement Disorder Society.

Rationale Many patients with epilepsy need a second antiepileptic drug (AED), due either to inefficacy or side effects of the first tried one. We evaluated the efficacy and safety of lacosamide (LCM) as first add-on therapy in the real-life setting. Methods LACONORTE is a multicenter, retrospective, one-year study. Patients with focal epilepsy on monotherapy with another AED who were started on lacosamide as first add-on therapy were included. Clinical data was obtained at 3, 6 and 12 months and then analyzed. Results Seventy-three patients (48.6% men) with a mean age of 50.3 and a median duration of the epilepsy of 3.0 years (range 0–65) were included. At 1 year, 91.8% were responders (with at least 50% reduction in the number of seizures) and 64.4% of all patients and 75.8% of those with secondary generalization were seizure-free. Fifteen patients (20.5%) had adverse events (AE), most of them were transient and no severe AEs were reported. LCM was withdrawn in 2 patients due to intolerance and in 1 patient because of inefficacy. Neither side effects nor withdrawal seemed to be related to total dose or to escalating regimes. Seventy patients (95.9%) continued on LCM after the last visit (median dose 200 mg/day, ranging 100–400). Eighteen (24.7%) converted to monotherapy during the 12-month period, 83.3% of them remaining seizure-free. Conclusions These results of real-life setting show LCM to be efficacious and safe when used as first add-on therapy for focal-onset epilepsy. Most adverse events were mild and/or transient.

Background Penetrance estimates of the leucine-rich repeat kinase 2 (LRRK2) p.G2019S mutation for PD vary widely (24%-100%). The p.G2019S penetrance in individuals of Ashkenazi Jewish ancestry has been estimated as 25%, adjusted for multiple covariates. It is unknown whether penetrance varies among different ethnic groups. The objective of this study was to estimate the penetrance of p.G2019S in individuals of non-Ashkenazi Jewish ancestry and compare penetrance between Ashkenazi Jews and non-Ashkenazi Jews to age 80. Methods The kin-cohort method was used to estimate penetrance in 474 first-degree relatives of 69 non-Ashkenazi Jewish LRRK2 p.G2019S carrier probands at 8 sites from the Michael J. Fox LRRK2 Cohort Consortium. An identical validated family history interview was administered to assess age at onset of PD, current age, or age at death for relatives in different ethnic groups at each site. Neurological examination and LRRK2 genotype of relatives were included when available. Results Risk of PD in non-Ashkenazi Jewish relatives who carry a LRRK2 p.G2019S mutation was 42.5% (95% confidence interval [CI]: 26.3%-65.8%) to age 80, which is not significantly higher than the previously estimated 25% (95% CI: 16.7%-34.2%) in Ashkenazi Jewish carrier relatives. The penetrance of PD to age 80 in LRRK2 p.G2019S mutation carrier relatives was significantly higher than the noncarrier relatives, as seen in Ashkenazi Jewish relatives. Conclusions The similar penetrance of LRRK2 p.G2019S estimated in Ashkenazi Jewish carriers and non-Ashkenazi Jewish carriers confirms that p.G2019S penetrance is 25% to 42.5% at age 80 in all populations analyzed. © 2017 International Parkinson and Movement Disorder Society

Background: No CSF or plasma biomarker has been validated for diagnosis or progression of PD. Objectives: To assess whether the CSF and plasma levels of proteins associated with PD neuropathological inclusions and with neuroinflammation might have value in the diagnosis of PD or in relation to disease severity. Methods: CSF levels of α-synuclein, amyloid-s1-42, total tau, and threonine-181 phosphorylated tau, as well as CSF and plasma levels of cytokines (interleukin-1s, interleukin-2, interleukin, interferon-γ, and tumor necrosis factor α) were studied in 40 PD patients and 40 healthy controls. Plasma levels of cytokines were measured in 51 patients and 26 aditional controls. We also explored the Parkinson's Progression Markers Initiative data set as a replication cohort. Results: CSF levels of α-synuclein, amyloid-s1-42, and tumor necrosis factor α were lower in patients than in controls, and the total tau/α-synuclein, phosphorylated tau/α-synuclein, total tau/amyloid-s1-42+α-synuclein, and phosphorylated tau/amyloid-s1-42+α-synuclein ratios were higher in patients. The best area under the curve value was obtained for the phosphorylated tau/α-synuclein ratio alone (0.86) and also when this was combined with tumor necrosis factor α in CSF (0.91; sensitivity 92.9%, specificity 75% for a cut-off value of ≤ 0.71). Phosphorylated tau/α-synuclein and phosphorylated tau/amyloid-s1-42+α-synuclein were higher in patients than in controls of the Parkinson's Progression Markers Initiative database. Plasma cytokines did not differ between groups, although interleukin-6 levels were positively correlated with UPDRS-I, -II, and -III scores. Conclusions: The CSF phosphorylated tau/α-synuclein ratio alone, and in combination with tumor necrosis factor α and plasma interleukin-6 levels, might serve as biomarkers to diagnose PD and monitor its severity. © 2017 International Parkinson and Movement Disorder Society

DOI: 10.1016/j.apcata.2017.03.018 URL: http://www.sciencedirect.com/science/article/pii/S0926860X17301175 Filiació URV: SI This study explores the use of glycidol, as alternative to glycerol, to improve the selectively to 1,3-propanediol (PrD) by hydrogenolysis. The reaction was performed using Ni (with different Ni wt%) supported on an acid delaminated saponite catalysts which are cheaper compared to the expensive catalysts needed to favor the 1,3-PrD formation by glycerol hydrogenolysis. An increase in metallic area and a decrease in the catalyst acidity resulted in higher conversion and selectivity to propanediols (1,2- + 1,3-PrD). An acid activation of glycidol during hydrogenolysis promoted the 1,3-PrD formation and increased the 1,3-PrD/1,2-PrD ratio. For the catalyst prepared with 40 wt% Ni loading, an increase in the reaction temperature to 423 and 453 K led to higher 1,3-PrD/1,2-PrD ratio. The highest 1,3-PrD yield (29%) and 1,3-PrD/1,2-PrD ratio (0.97) at total conversion were obtained at 453 K, after 1 h. The overall 1,3-PrD yield from glycerol, assuming a two-step synthesis (Glycerol → Glycidol → 1,3-PrD) and a yield of 78% for the first step, should be around 23%. This value is comparable to that reported for the hydrogenolysis of glycerol using noble metal catalysts.

19 páginas, 4 figuras, 2 tablas; material suplementario con 3 figuras. 2 tablas de material suplementario en: http://dx.doi.org/10.18632/aging.103992, The research of new biomarkers for Parkinson's disease is essential for accurate and precocious diagnosis, as well as for the discovery of new potential disease mechanisms and drug targets. The main objective of this work was to identify metabolic changes that might serve as biomarkers for the diagnosis of this neurodegenerative disorder. For this, we profiled the plasma metabolome from mice with neurotoxin-induced Parkinson's disease as well as from patients with familial or sporadic Parkinson's disease. By using mass spectrometry technology, we analyzed the complete metabolome from healthy volunteers compared to patients with idiopathic or familial (carrying the G2019S or R1441G mutations in the LRRK2 gene) Parkinson's disease, as well as, from mice treated with 6-hydroxydopamine to induce Parkinson disease. Both human and murine Parkinson was accompanied by an increase in plasma levels of unconjugated bile acids (cholic acid, deoxycholic acid and lithocholic acid) and purine base intermediary metabolites, in particular hypoxanthine. The comprehensive metabolomic analysis of plasma from Parkinsonian patients underscores the importance of bile acids and purine metabolism in the pathophysiology of this disease. Therefore, plasma measurements of certain metabolites related to these pathways might contribute to the diagnosis of Parkinson's Disease., This research was supported by “Instituto de Salud Carlos III”, “Fondo de Investigaciones Sanitarias” (PI15/0034), “CIBERNED” (CB06/05/0041 and 2015/03), “MINECO” (SAF2014-52940-R and SAF2017-85199-P) and partially supported by “European Regional Development Fund (ERDF)” from the European Union. SMSY-D was supported by “Isabel Gemio Foundation”. JMB-SP and MN-S were funded by “Ramon y Cajal Program” (RYC-2018-025099-I) and (RYC-2016-20883), respectively. GM-C was supported by “ONCE Foundation”. EU-C is supported by an FPU predoctoral fellowship (FPU16/00684) from “Ministerio de Educación, Cultura y Deporte”. JMF received research support from the “Instituto de Salud Carlos III”; “Fondo de Investigaciones Sanitarias” (PI15/0034) and CIBERNED (CB06/05/0041 and 2015/03). AP-C was supported by MINECO (SAF2014-52940-R and SAF2017-85199- P). JR-M and MZ were supported by Institute de Salud Carlos III, Fondo de Investigaciones Sanitarias (PI19/01653), CIBERNED and PPMI Initiative. JP-T received funding from CIBERNED (CB06/05/1123 and 2015/03). This work was also partially supported by “Fondo Europeo de Desarrollo Regional” (FEDER) from the European Union. GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Association “Le Cancer du Sein, Parlons-en!”; Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM); a donation by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085), Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology (ANR-18-IDEX-0001); the RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM).

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting millions of people. Genome-wide association studies (GWAS) have found >25 genetic risk factors and at least 15 loci directly associated with PD. Recent advances in new next-generation DNA sequencing technologies, such as the semiconductor-based Ion Torrent platform, make multigene sequencing cheaper, faster, and more reliable. Our objective was to test the power of this next-generation sequencing technology to analyze large samples by screening the majority of the most relevant PD-related genes known for single and compound mutations. To archive a rapid, robust, and cost-effective genetic analysis of a PD cohort, we designed a multiplex, polymerase chain reaction (PCR)-based primer panel to amplify and sequence coding exons of 15 PD-associated genes (SNCA, LRRK2, PARK2, PINK1, PARK7, GIGYF2, ATP13A2, UCHL1, PLA2G6, FBXO7, EIF4G1, VPS35, ACMSD, APOE, and GBA). We conducted parallel sequencing using the Ion Torrent Personal Genome Machine® system to detect mutations in 92 blood DNA samples from PD patients. After bioinformatics analysis and filtering, 95.13 % coverage of the targeted region was obtained at >40-fold mean coverage. The results revealed 44 previously documented variants in these 15 genes, with five revealed as pathogenic. We also discovered six novel variants, five of which had an in silico prediction of being pathogenic. Benchtop next-generation sequencing is a powerful method for genetic screening for PD. Our results indicated that it yielded a high frequency of discovery (66 %; n = 92) of variants in carriers from an enriched Spanish PD sample.

In this Perspective, we highlight the main challenges to be addressed in the development of heterogeneous catalysts for the direct functionalization of methane. Along with our personal view on current developments in this field, we outline the main mechanistic, engineering, and catalyst design issues that have hampered implementation of new technologies and highlight possible paths to overcome these problems.

Background The objective of this study was to study motor and nonmotor symptoms and striatal dopaminergic denervation, as well as the relationship between them, in a cohort of asymptomatic relatives of patients with Parkinson's disease (PD) with the R1441G-leucine-rich repeat kinase 2 mutation. Methods Asymptomatic relatives of patients with PD and this mutation were tested for the presence of the mutation and evaluated for striatal, putamenal, and caudate dopaminergic transporters using 123I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane single-photon emission computed tomography binding ratios. Clinical and neuropsychological evaluations including timed motor tests, a smell identification test, and global cognition, attention, executive, visuospatial, and memory functions as well as depression, constipation, and rapid eye movement sleep behavior disorder were also assessed. Results Twenty-seven carriers and 19 noncarriers were studied. Compared with noncarriers, mutation carriers had significantly lower 123I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropan mean striatal (P = 0.03), mean putamenal (P = 0.01), and lowest putamenal (P = 0.01) binding ratios. Multiple linear regression analysis showed that the carrier status and the execution of timed tests significantly predicted striatal 123I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane binding. The proportion of variation accounted for by the regression model of these variables was 69% for the putamen and 53% for the caudate nucleus. Conclusions Asymptomatic carriers of the R1441G-leucine-rich repeat kinase 2 mutation have evidence of dopaminergic nigrostriatal denervation, mainly in the putamen, which is associated with a decline in the execution of complex motor tests. These tests could be early indicators of the ongoing dopaminergic deficit in this group at risk of PD. © 2015 International Parkinson and Movement Disorder Society

Although in the last two decades there has been considerable progress in understanding the genetic basis of Parkinson's disease (PD), the majority of PD is sporadic and its genetic causes are largely unknown. In an attempt to identify novel genetic causes of PD, whole-exome sequencing and subsequent analyses were performed in a family featuring late-onset PD with cognitive impairment. A novel genetic variant (p.Arg610Gly) in the GIGYF2 gene, previously known to be associated with PD, was identified as potential disease-causing mutation. The GIGYF2 p.Arg610Gly mutation situated in the GYF domain of the encoding protein was predicted to be pathogenic and to disrupt the GYF's ligand-binding abilities. Although further research is still required, this finding may shed light on the GIGYF2-associated mechanisms that lead to PD and suggests insulin dysregulation as a disease-specific mechanism for both PD and cognitive dysfunction.

To describe clinical characteristics of diabetes mellitus (DM) in a group of patients with Wolfram Syndrome (WS). Descriptive, cross-sectional observational design. The sample consisted of 50 patients diagnosed with WS. Clinical criteria contributing to WS diagnosis were analyzed: diabetes mellitus (DM), optic nerve atrophy (OA), sensorineural deafness, urological and neurological dysfunction, among others. These parameters were assessed according to their presence/absence, age of onset, and various clinical-analytical parameters. All the patients studied presented DM and OA, with a mean age of onset of 5.4 ± .9 (1–14) years and 9 ± .9 (1–16) years, respectively. The remaining criteria were present with a variable frequency: 77% had diabetes insipidus, 66.7% auditory alterations, 77.8% neurogenic bladder, 61.1% neurological involvement, and 27.8% hypogonadism. A 16.7% of the patients had positive albuminuria (urinary albumin/creatinine ratio > 30 mg/g) and 72.2% had hyporreflexia. There were no significant differences in the age of diagnosis nor of the presence of different pathologies according to sex. The early presence of a non-autoimmune insulin dependent DM, should alert us of an “infrequent” diabetes syndrome. Wolfram’s presumptive diagnosis could be established if juvenile-onset DM occurs concomitantly with OA, and this visual impairment is not attributable to diabetic retinopathy. Despite the long period of evolution of DM and altered values of HbA1c, the prevalence of microvascular complications in the sample are low.

Background Mutations in LRRK2 are a common genetic cause of Parkinson’s disease (PD). LRRK2 interacts with and phosphorylates a subset of Rab proteins including Rab8a, a protein which has been implicated in various centrosome-related events. However, the cellular consequences of such phosphorylation remain elusive. Methods Human neuroblastoma SH-SY5Y cells stably expressing wildtype or pathogenic LRRK2 were used to test for polarity defects in the context of centrosomal positioning. Centrosomal cohesion deficits were analyzed from transiently transfected HEK293T cells, as well as from two distinct peripheral cell types derived from LRRK2-PD patients. Kinase assays, coimmunoprecipitation and GTP binding/retention assays were used to address Rab8a phosphorylation by LRRK2 and its effects in vitro. Transient transfections and siRNA experiments were performed to probe for the implication of Rab8a and its phosphorylated form in the centrosomal deficits caused by pathogenic LRRK2. Results Here, we show that pathogenic LRRK2 causes deficits in centrosomal positioning with effects on neurite outgrowth, cell polarization and directed migration. Pathogenic LRRK2 also causes deficits in centrosome cohesion which can be detected in peripheral cells derived from LRRK2-PD patients as compared to healthy controls, and which are reversed upon LRRK2 kinase inhibition. The centrosomal cohesion and polarity deficits can be mimicked when co-expressing wildtype LRRK2 with wildtype but not phospho-deficient Rab8a. The centrosomal defects induced by pathogenic LRRK2 are associated with a kinase activity-dependent increase in the centrosomal localization of phosphorylated Rab8a, and are prominently reduced upon RNAi of Rab8a. Conclusions Our findings reveal a new function of LRRK2 mediated by Rab8a phosphorylation and related to various centrosomal defects., S.H. was supported by the Michael J. Fox Foundation, the BBVA Foundation, FEDER, and the Spanish Ministry of Economy and Competitiveness (SAF2014–58653-R). E.G. was funded by the Michael J. Fox Foundation. J-M.T. and M.-C. C.-H. were funded by the Michael J. Fox Foundation, and M.-C.C.-H. was supported by Inserm, CHU de Lille, Lille University and the Ministère de la Recherche et de la Santé (PHRC Convergence). We gratefully acknowledge funding from the European Union’s Horizon 2020 research and innovation programme (Marie Sklodowska-Curie Action Individual Fellowship to J.-M.T.). A.C.N. was supported by the Dept. of the Army (USAMRAA W23RYX-9049-N610) and NIH (DA10044). This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (to M.R.C.).

The oxidative dehydrogenation of various aliphatic amines to their corresponding nitrile compounds using RuO2/Al2O3 catalysts in air was successfully applied to a continuous flow reaction. Conversions of amines (up to >99%) and yields of nitriles (up to 77%) varied depending on reaction conditions and the amine utilised. The presence of water was found to be important for the activity and stability of the RuO2/Al2O3 catalyst. The Hammett relationship and in situ infrared spectroscopy were applied to divulge details about the catalytic mechanism of the oxidative dehydrogenation of amines over RuO2/Al2O3 catalysts.

There is a need for biomarkers of dementia in PD.To determine if the levels of the main CSF proteins and their ratios are associated with deterioration in cognition and progression to dementia in the short to mid term.The Parkinson's Progression Markers Initiative database was used as an exploratory cohort, and a center-based cohort was used as a replication cohort. Amyloid ß1-42, total tau, threonine-181 phosphorylated tau, and α-synuclein in the CSF and the ratios of these proteins were assessed.In the Parkinson's Progression Markers Initiative cohort (n = 281), the total tau/amyloid ß1-42, total tau/α-synuclein, total tau/amyloid ß1-42+α-synuclein, and amyloid ß1-42/total tau ratios were associated with a risk of progression to dementia over a 3-year follow-up. In the replication cohort (n = 40), the total tau/α-synuclein and total tau/amyloid ß1-42+α-synuclein ratios were associated with progression to dementia over a 41-month follow-up.Ratios of the main proteins found in PD patient brain inclusions that can be measured in the CSF appear to have value as short- to mid-term predictors of dementia. © 2018 International Parkinson and Movement Disorder Society.

Objective:Despite the enormous advancements made in deciphering the genetic architecture of Parkinson disease (PD), the majority of PD is idiopathic, with single gene mutations explaining only a small proportion of the cases.Methods:In this study, we clinically evaluated 2 unrelated Spanish families diagnosed with PD, in which known PD genes were previously excluded, and performed whole-exome sequencing analyses in affected individuals for disease gene identification.Results:Patients were diagnosed with typical PD without relevant distinctive symptoms. Two different novel mutations were identified in the CSMD1 gene. The CSMD1 gene, which encodes a complement control protein that is known to participate in the complement activation and inflammation in the developing CNS, was previously shown to be associated with the risk of PD in a genome-wide association study.Conclusions:We conclude that the CSMD1 mutations identified in this study might be responsible for the PD phenotype observed in our examined patients. This, along with previous reported studies, may suggest the complement pathway as an important therapeutic target for PD and other neurodegenerative diseases.

Functional Neuroimaging has been traditionally used in research for patients with different parkinsonian syndromes. However, the emergence of commercial radiotracers together with the availability of single photon emission computed tomography (SPECT) and, more recently, positron emission tomography (PET) have made them available for clinical practice. Particularly, the development of clinical evidence achieved by functional neuroimaging techniques over the past two decades have motivated a progressive inclusion of several biomarkers in the clinical diagnostic criteria for neurodegenerative diseases that occur with parkinsonism. However, the wide range of radiotracers designed to assess the involvement of different pathways in the neurodegenerative process underlying parkinsonian syndromes (dopaminergic nigrostriatal pathway integrity, basal ganglia and cortical neuronal activity, myocardial sympathetic innervation), and the different neuroimaging techniques currently available (scintigraphy, SPECT and PET), have generated some controversy concerning the best neuroimaging test indicated for the differential diagnosis of parkinsonism. In this article, a panel of nuclear medicine and neurology experts has evaluated the functional neuroimaging techniques emphazising practical considerations related to the diagnosis of patients with uncertain origin parkinsonism and the assessment of Parkinson's disease progression.

Functional Neuroimaging has been traditionally used in research for patients with different Parkinsonian syndromes. However, the emergence of commercial radiotracers together with the availability of single photon emission computed tomography (SPECT) and, more recently, positron emission tomography (PET) have made them available for clinical practice. Particularly, the development of clinical evidence achieved by functional neuroimaging techniques over the past two decades have motivated a progressive inclusion of several biomarkers in the clinical diagnostic criteria for neurodegenerative diseases that occur with Parkinsonism. However, the wide range of radiotracers designed to assess the involvement of different pathways in the neurodegenerative process underlying Parkinsonian syndromes (dopaminergic nigrostriatal pathway integrity, basal ganglia and cortical neuronal activity, myocardial sympathetic innervation), and the different neuroimaging techniques currently available (scintigraphy, SPECT and PET), have generated some controversy concerning the best neuroimaging test that should be indicated for the differential diagnosis of Parkinsonism. In this article, a panel of nuclear medicine and neurology experts has evaluated the functional neuroimaging techniques emphazising practical considerations related to the diagnosis of patients with uncertain origin parkinsonism and the assessment Parkinson's disease progression.

An inverse relationship between Parkinson's disease (PD) and cancer has been described. However, the association between cancers and genetic forms of PD, in particular the R1441G mutation in the LRRK2 gene, is not well known. The objective of this work was to analyze cancer prevalence in PD patients with R1441G or G2019S mutations in LRRK2, and in idiopathic PD (iPD). A total of 732 patients with PD (70 and 25 carriers of R1441G or G2019S mutations, respectively), and 177 controls, were linked using a population-based cancer registry of the Spanish province of Gipuzkoa. Cancer prevalence was not significantly higher in PD-G2019S carriers (20%) than in PD-R1441G carriers (14.3%), iPD (13.8%), or controls (12.5%). With the exception of a high prevalence of hematological cancers (crude odds ratio of 7.1) in the R1441G group, specific cancer types were not increased in PD mutation carriers. In both the carrier and iPD groups, cancers were diagnosed after the onset of PD. PD patients had a similar prevalence of cancer to control subjects. There was no increased association between G2019S or R1441G mutations and any type of cancer. Although there was a higher prevalence of hematological cancers in the R1441G group, the low number of such cancers overall makes this finding of uncertain significance. There was a slightly higher but not statistically significant prevalence of non-skin cancers in the G2019S group, suggesting that further study to evaluate the association should be undertaken prior to ascribing an increased cancer risk to this population.

Background Low serum uric acid (UA) levels have been associated with increased Parkinson's disease (PD) risk and accelerated disease progression. We analyzed the effect of polymorphisms in 9 genes influencing serum UA concentration on the risk of PD. Methods We genotyped SLC2A9 rs734553, ABCG2 rs2231142, SLC17A1 rs1183201, SLC22A11 rs17300741, SLC22A12 rs505802, GCKR rs780094, PDZK1 rs12129861, LRRC16A+SCGN rs742132, and SLC16A9 rs12356193 in 1061 PD patients and 754 controls. For each subject we calculated a cumulative genetic risk score (GRS), defined as the total number of PD-risk alleles (range, 2–15) associated to lower serum UA levels. Serum UA levels were measured in a subgroup of 365 PD cases and 132 controls. Results Serum UA levels were significantly lower in men with PD than in controls. Subjects (both men and women) carrying more than 9 risk alleles (third GRS tertile) had a 1.5 higher risk of developing PD than subjects with less than 8 risk alleles (first GRS tertile). An inverse correlation was observed between higher GRS and lower serum UA concentration in both men and women. Conclusions Genetic variability influencing serum UA levels might modify susceptibility to PD. © 2013 International Parkinson and Movement Disorder Society

Background and purpose The presentation of Parkinson's disease patients with mutations in the LRRK2 gene (PDLRRK2) is highly variable, suggesting a strong influence of modifying factors. In this context, inflammation is a potential candidate inducing clinical subtypes. Methods An extensive battery of peripheral inflammatory markers was measured in human serum in a multicentre cohort of 142 PDLRRK2 patients from the MJFF LRRK2 Consortium, stratified by three different subtypes as recently proposed for idiopathic Parkinson's disease: diffuse/malignant, intermediate and mainly pure motor. Results Patients classified as diffuse/malignant presented with the highest levels of the pro-inflammatory proteins interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP-1) and macrophage inflammatory protein 1-β (MIP-1-β) paralleled by high levels of the neurotrophic protein brain-derived neurotrophic factor (BDNF). It was also possible to distinguish the clinical subtypes based on their inflammatory profile by using discriminant and area under the receiver operating characteristic curve analysis. Conclusions Inflammation seems to be associated with the presence of a specific clinical subtype in PDLRRK2 that is characterized by a broad and more severely affected spectrum of motor and non-motor symptoms. The pro-inflammatory metabolites IL-8, MCP-1 and MIP-1-β as well as BDNF are interesting candidates to be included in biomarker panels that aim to differentiate subtypes in PDLRRK2 and predict progression.

Objective: The aim of this study was to analyze autonomic function and cardiac sympathetic innervation in symptomatic and asymptomatic carriers of the E46K alpha-synuclein gene (SNCA) mutation. Patients and methods: Autonomic function tests were performed in six patients, four of whom were symptomatic carriers (ages: 46, 59, 52 and 28-years) and two who were asymptomatic carriers (ages: 52 and 29 years). Autopsy studies were performed on an additional two symptomatic carriers not eligible for autonomic testing. Patients completed the SCOPA autonomic questionnaire, and underwent the head-up tilt test accompanied by measurements of plasma norepinephrine. Valsalva maneuver and deep breathing tests, along with recording of sympathetic skin response (SSR) and cardiac MIBG scintigraphy were carried out. Myocardial tissue sections removed from the two autopsied cases were subjected to routine histological staining and immunohistochemical processing with monoclonal antibodies against tyrosine hydroxylase and alpha-synuclein. Results: Both the four symptomatic and the older asymptomatic carriers reported abnormalities in the SCOPA questionnaire and had markedly diminished cardiac MIBG uptake. Plasma norepinephrine in the supine and tilted positions was normal in all subjects. Only one patient had significant orthostatic hypotension. There was a complete absence of tyrosine hydroxylase immunostaining in the myocardium of the two autopsied cases. Interpretation: We have found imaging and histological evidence of cardiac sympathetic denervation in symptomatic and asymptomatic carriers of the E46K alpha-synuclein gene mutation. The sympathetic denervation appears to be organ-specific, with selective affectation of the heart given that plasma norepinephrine levels and blood pressure were normal.

No CSF or plasma biomarker has been validated for diagnosis or progression of PD.To assess whether the CSF and plasma levels of proteins associated with PD neuropathological inclusions and with neuroinflammation might have value in the diagnosis of PD or in relation to disease severity.CSF levels of α-synuclein, amyloid-ß1-42, total tau, and threonine-181 phosphorylated tau, as well as CSF and plasma levels of cytokines (interleukin-1ß, interleukin-2, interleukin, interferon-γ, and tumor necrosis factor α) were studied in 40 PD patients and 40 healthy controls. Plasma levels of cytokines were measured in 51 patients and 26 aditional controls. We also explored the Parkinson's Progression Markers Initiative data set as a replication cohort.CSF levels of α-synuclein, amyloid-ß1-42, and tumor necrosis factor α were lower in patients than in controls, and the total tau/α-synuclein, phosphorylated tau/α-synuclein, total tau/amyloid-ß1-42+α-synuclein, and phosphorylated tau/amyloid-ß1-42+α-synuclein ratios were higher in patients. The best area under the curve value was obtained for the phosphorylated tau/α-synuclein ratio alone (0.86) and also when this was combined with tumor necrosis factor α in CSF (0.91; sensitivity 92.9%, specificity 75% for a cut-off value of ≤ 0.71). Phosphorylated tau/α-synuclein and phosphorylated tau/amyloid-ß1-42+α-synuclein were higher in patients than in controls of the Parkinson's Progression Markers Initiative database. Plasma cytokines did not differ between groups, although interleukin-6 levels were positively correlated with UPDRS-I, -II, and -III scores.The CSF phosphorylated tau/α-synuclein ratio alone, and in combination with tumor necrosis factor α and plasma interleukin-6 levels, might serve as biomarkers to diagnose PD and monitor its severity. © 2017 International Parkinson and Movement Disorder Society.

It has been observed that immune cell deterioration occurs in the elderly, as well as a chronic low-grade inflammation called inflammaging. These cellular changes must be driven by numerous changes in gene expression and in fact, both protein-coding and non-coding RNA expression alterations have been observed in peripheral blood mononuclear cells from elder people. In the present work we have studied the expression of small non-coding RNA (microRNA and small nucleolar RNA -snoRNA-) from healthy individuals from 24 to 79 years old. We have observed that the expression of 69 non-coding RNAs (56 microRNAs and 13 snoRNAs) changes progressively with chronological age. According to our results, the age range from 47 to 54 is critical given that it is the period when the expression trend (increasing or decreasing) of age-related small non-coding RNAs is more pronounced. Furthermore, age-related miRNAs regulate genes that are involved in immune, cell cycle and cancer-related processes, which had already been associated to human aging. Therefore, human aging could be studied as a result of progressive molecular changes, and different age ranges should be analysed to cover the whole aging process.