Parkinson's Disease : From Genetics to Clinical Practice

Breakthroughs in genetics over the last decade have radically advanced our understanding of the etiological basis of Parkinson's disease (PD). Although much research remains to be done, the main genetic causes of this neurodegenerative disorder are now partially unraveled, allowing us to feel more confident that our knowledge about the genetic architecture of PD will continue to increase exponentially. How and when these discoveries will be introduced into general clinical practice, however, remains uncertain. In this review, we provide a general summary of the progress in the genetics of PD and discuss how this knowledge will contribute to the diagnosis and clinical management of patients with, or at risk of this disorder

Análisis y propuesta de mejora de los patrocinios deportivos a la asociación ‘MotoStudent Unizar’

Mi proyecto se basa en una investigación de mercados donde procedo a desarrollar un análisis de contenido basado en la observación de los actuales patrocinios deportivos que encontramos en las asociaciones ‘MotoStudent’ del resto de España.Una vez evaluados y, tras una previa entrevista a los alumnos que conforman el equipo, se establece un plan de marketing basado en diferentes estrategias y acciones para impulsar a las posibles empresas patrocinadoras.<br /

Using the Neandertal and Denisova Genetic Data to Understand the Common \u3cem\u3eMAPT\u3c/em\u3e 17q21 Inversion in Modern Humans

The polymorphic inversion on 17q21, that includes the MAPT gene, represents a unique locus in the human genome characterized by a large region with strong linkage disequilibrium. Two distinct haplotypes, H1 and H2, exist in modern humans, and H1 has been unequivocally related to several neurodegenerative disorders. Recent data indicates that recurrent inversions of this genomic region have occurred through primate evolution, with the H2 haplotype being the ancestral state. Neandertals harbored the H1 haplotype, however until now no data was available for the Denisova hominin. Neandertals and Denisovans are sister groups that share a common ancestor with modern humans. We analyzed the MAPT sequence and assessed the differences between modern humans, Neandertals, Denisovans, and great apes. Our analysis indicated that the Denisova hominin carried the H1 haplotype and the Neandertal and Denisova common ancestor probably shared the same subhaplotype (H1j). We also found 68 intronic variants within the MAPT gene, 23 exclusive to Denisova hominin, 6 limited to Neandertals and 24 exclusive to present-day humans. Our results reinforce previous data suggesting that the 17q21 inversion arose within the modern human lineage. The data also indicates that archaic hominins that coexisted in Eurasia probably shared the same MAPT subhaplotype, hat can be found in almost 2% of chromosomes from European ancestry

Altered microRNAs related to synaptic function as potential plasma biomarkers for Alzheimer's disease

Altres ajuts: This work was supported by grants from , Fundació La Marató TV3 (TV3-2014-3610), CIBERNED (CB06/05/0042 and PI2017/01) to JRA. DSW was supported by the Fundació La Marató TV3. JCS is a recipient of a Ph.D. Fellowship from the Ministerio de Ciencia, Innovación y Universidades. CF is a recipient of a Ph.D. Fellowship from the Department of Biochemistry and Molecular Biology of the Universitat Autònoma de Barcelona.Several evidences suggest that failure of synaptic function occurs at preclinical stages of Alzheimer's disease (AD) preceding neuronal loss and the classical AD pathological hallmarks. Nowadays, there is an urgent need to identify reliable biomarkers that could be obtained with non-invasive methods to improve AD diagnosis at early stages. Here, we have examined plasma levels of a group of miRNAs related to synaptic proteins in a cohort composed of cognitive healthy controls (HC), mild cognitive impairment (MCI) and AD subjects. Plasma and brain levels of miRNAs were analysed in two different cohorts including 38 HC, 26 MCI, 56 AD dementia patients and 27 frontotemporal dementia (FTD) patients. D'Agostino and Pearson and Shapiro-Wilk tests were used to evaluate data normality. miRNA levels between groups were compared using a two-sided nonparametric Mann-Whitney test and sensitivity and specificity was determined by receiver operating characteristic curve analysis. Significant upregulation of miR-92a-3p, miR-181c-5p and miR-210-3p was found in the plasma of both MCI and AD subjects. MCI patients that progress to AD showed higher plasma levels of these miRNAs. By contrast, no changes in miR-92a-3p, miR-181c-5p or miR-210-3p levels were observed in plasma obtained from a cohort of FTD. Our study shows that plasma miR-92a-3p, miR-181c-5p and miR-210-3p constitute a specific molecular signature potentially useful as a potential biomarker for AD. The online version of this article (10.1186/s13195-019-0501-4) contains supplementary material, which is available to authorized users

Does ALS-FUS without FUS mutation represent ALS-FET? Report of three cases

Altres ajuts: This study was partially funded by Fundacio Marató de TV3 (grant no. 20143810 to RSV, no. 20141610 to EG and no. 201437.10 to RRG) and Fondo Europeo de Desarrollo Regional (FEDER) (PI16/01673 to JG and PI15/01618 to RRG). We are indebted to the Neurological Tissue Bank of the Biobanc-Hospital Clinic-IDIBAPS, Barcelona, Spain, for data and sample procurement. We thank Sara Charif, Veronica Santiago, Carmen Schweiger, Leire Etxarri and Abel Muñoz for technical assistance

Genetic risk score predicting accelerated progression from mild cognitive impairment to Alzheimer's disease

Aside from APOE, the genetic factors that influence in the progression from mild cognitive impairment (MCI) to Alzheimer´s disease (AD) remain largely unknown. We assessed whether a genetic risk score (GRS), based on 8 non-APOE genetic variants previously associated with AD risk in genome-wide association studies, is associated with either risk of conversion or with rapid progression from MCI to AD. Among 288 subjects with MCI, follow-up (mean 26.3 months) identified 118 MCI-converters to AD and 170 MCI-nonconverters. We genotyped ABCA7 rs3764650, BIN1 rs744373, CD2AP rs9296559, CLU rs1113600, CR1 rs1408077, MS4A4E rs670139, MS4A6A rs610932, and PICALM rs3851179. For each subject we calculated a cumulative GRS, defined as the number of risk alleles (range 0-16) with each allele weighted by the AD risk odds ratio. GRS was not associated with risk of conversion from MCI to AD. However, MCI-converters to AD harboring 6 or more risk alleles (second and third GRS tertiles) progressed 2-fold more rapidly to AD when compared with those with less than 6 risk alleles (first GRS tertile). Our GRS is a first step toward development of prediction models for conversion from MCI to AD that incorporate aggregate genetic factors

Methylglyoxal Produced by Amyloid- Peptide-Induced Nitrotyrosination of Triosephosphate Isomerase Triggers Neuronal Death in Alzheimer’s Disease

Amyloid-β peptide (Aβ) aggregates induce nitro-oxidative stress, contributing to the characteristic neurodegeneration found in Alzheimer's disease (AD). One of the most strongly nitrotyrosinated proteins in AD is the triosephosphate isomerase (TPI) enzyme which regulates glycolytic flow, and its efficiency decreased when it is nitrotyrosinated. The main aims of this study were to analyze the impact of TPI nitrotyrosination on cell viability and to identify the mechanism behind this effect. In human neuroblastoma cells (SH-SY5Y), we evaluated the effects of Aβ42 oligomers on TPI nitrotyrosination. We found an increased production of methylglyoxal (MG), a toxic byproduct of the inefficient nitro-TPI function. The proapoptotic effects of Aβ42 oligomers, such as decreasing the protective Bcl2 and increasing the proapoptotic caspase-3 and Bax, were prevented with a MG chelator. Moreover, we used a double mutant TPI (Y165F and Y209F) to mimic nitrosative modifications due to Aβ action. Neuroblastoma cells transfected with the double mutant TPI consistently triggered MG production and a decrease in cell viability due to apoptotic mechanisms. Our data show for the first time that MG is playing a key role in the neuronal death induced by Aβ oligomers. This occurs because of TPI nitrotyrosination, which affects both tyrosines associated with the catalytic center

Weight loss in the healthy elderly might be a non-cognitive sign of preclinical Alzheimer's disease

Weight loss has been proposed as a sign of pre-clinical Alzheimer Disease (AD). To test this hypothesis, we have evaluated the association between longitudinal changes in weight trajectories, cognitive performance, AD biomarker profiles and brain structure in 363 healthy controls from the Alzheimer's Disease Neuroimaging Initiative (mean follow-up 50.5±30.5 months). Subjects were classified according to body weight trajectory into a weight loss group (WLG; relative weight loss ≥ 5%) and a non-weight loss group (non-WLG; relative weight loss < 5%). Linear mixed effects models were used to estimate the effect of body weight changes on ADAS-Cognitive score across time. Baseline CSF tau/AΔ ratio and AV45 PET uptake were compared between WLG and non-WLG by analysis of covariance. Atrophy maps were compared between groups at baseline and longitudinally at a 2-year follow-up using Freesurfer. WLG showed increased baseline levels of cerebrospinal fluid tau/AΔ ratio, increased PET amyloid uptake and diminished cortical thickness at baseline. WLG also showed faster cognitive decline and faster longitudinal atrophy. Our data support weight loss as a non-cognitive manifestation of pre-clinical AD

Agreement of amyloid PET and CSF biomarkers for Alzheimer's disease on Lumipulse

Altres ajuts: This work was funded by CIBERNED grant ; Fundació la Marató de TV3 grants 20141210;, 20142610;, and 20161431; , and PI18/00435 ; and SLT006/17/95; la Caixa Foundation grant. Instituto de Salud Carlos III grants PI13/01532To determine the cutoffs that optimized the agreement between 18 F-Florbetapir positron emission tomography (PET) and A β 1-42, A β 1-40, tTau, pTau and their ratios measured in cerebrospinal fluid (CSF) on the LUMIPULSE G600II instrument, we quantified the levels of these four biomarkers in 94 CSF samples from participants of the Sant Pau Initiative on Neurodegeneration (SPIN cohort) using the Lumipulse G System with available 18 F-Florbetapir imaging. Participants had mild cognitive impairment (n = 35), AD dementia (n = 12), other dementias or neurodegenerative diseases (n = 41), or were cognitively normal controls (n = 6). Levels of A β 1-42 were standardized to certified reference material. Amyloid scans were assessed visually and through automated quantification. We determined the cutoffs of CSF biomarkers that optimized their agreement with 18 F-Florbetapir PET and evaluated concordance between markers of the amyloid category. A β 1-42, tTau and pTau (but not A β 1-40) and the ratios with A β 1-42 had good diagnostic agreement with 18 F-Florbetapir PET. As a marker of amyloid pathology, the A β 1-42/A β 1-40 ratio had higher agreement and better correlation with amyloid PET than A β 1-42 alone. CSF biomarkers measured with the Lumipulse G System show good agreement with amyloid imaging in a clinical setting with heterogeneous presentations of neurological disorders. Combination of A β 1-42 with A β 1-40 increases the agreement between markers of amyloid pathology

A Common Variant in the MC1R Gene (p.V92M) is associated with Alzheimer's Disease Risk.

Despite the recent identification of some novel risk genes for Alzheimer's disease (AD), the genetic etiology of late-onset Alzheimer's disease (LOAD) remains largely unknown. The inclusion of these novel risk genes to the risk attributable to the APOE gene accounts for roughly half of the total genetic variance in LOAD. The evidence indicates that undiscovered genetic factors may contribute to AD susceptibility. In the present study, we sequenced the MC1R gene in 525 Spanish LOAD patients and in 160 controls. We observed that a common MC1R variant p.V92M (rs2228479), not related to pigmentation traits, was present in 72 (14%) patients and 15 (9%) controls and confers increased risk of developing LOAD (OR: 1.99, 95% CI: 1.08-3.64, p = 0.026), especially in those patients whose genetic risk could not be explained by APOE genotype. This association remains and even increased in the subset of 69 patients with typical AD cerebrospinal fluid profile (OR: 3.40 95% CI: 1.40-8.27, p = 0.007). We did not find an association between p.V92M and age of onset of AD. Further studies are necessary to elucidate the role of MC1R in brain cells through the different MC1R pathways