Mario Ezquerra
University of Barcelona
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Featured researches published by Mario Ezquerra.
Movement Disorders | 2009
Yaroslau Compta; María José Martí; Naroa Ibarretxe-Bilbao; Carme Junqué; Francesc Valldeoriola; Esteban Muñoz; Mario Ezquerra; José Ríos; Eduardo Tolosa
Alzheimers disease (AD)‐pathology may play a role in Parkinsons disease (PD)‐related dementia (PDD). The aim of this study was to assess cerebrospinal fluid (CSF) levels of tau, phospho‐tau, and beta‐amyloid, proposed AD biomarkers, and their relationship with cognitive function in PD. Forty PD patients [20 nondemented (PDND); 20 PDD] and 30 controls underwent CSF tau, phospho‐tau, and beta‐amyloid analysis using specific ELISA techniques. All PD patients and 15 controls underwent neuropsychological testing of fronto‐subcortical (attention, fluency) and neocortical (memory, naming, visuoperceptive) functions. CSF markers levels were compared between groups, and compared and correlated with neuropsychological measures in PDND and PDD separately and as a continuum (PD). CSF tau and phospho‐tau were higher in PDD than in PDND and controls (P < 0.05). CSF beta‐amyloid ranged from high (controls) to intermediate (PDND) and low (PDD) levels (P < 0.001). In all PD and PDD patients, high CSF tau and phospho‐tau were associated with impaired memory and naming. In PDND, CSF beta‐amyloid was related with phonetic fluency. These findings suggest underlying AD‐pathology in PDD in association with cortical cognitive dysfunction, and that low CSF beta‐amyloid in PDND patients with impaired phonetic fluency can constitute an early marker of cognitive dysfunction.
Annals of Neurology | 2000
Pau Pastor; Mario Ezquerra; Esteban Muñoz; María José Martí; Rafael Blesa; E. Tolosa; Rafael Oliva
A significant association between the tau gene A0/A0 genotype and progressive supranuclear palsy has been reported recently. To determine if the presence of a tau polymorphism could constitute a risk factor for the development of sporadic and familial Parkinson’s disease, a dinucleotide repeat marker at intron 11 was genotyped in 152 patients with PD, 52 patients with Alzheimers disease, and 150 healthy controls. We detected a significant difference in A0 allelic frequency in the Parkinsons disease group (79.27%) compared with the control group (71%) and the Alzheimers disease group (73.07%). Individuals homozygous for the A0 allele were also detected significantly more frequently in the Parkinsons disease group (63.8%) compared with the control group (52.66%) and the Alzheimers disease group (48.07%). These results suggest a possible involvement of the tau gene in the pathogenesis of some cases of Parkinsons disease. Ann Neurol 2000;47:242–245
Journal of Neurology, Neurosurgery, and Psychiatry | 2007
Carles Gaig; María José Martí; Mario Ezquerra; María Jesús Rey; Adriana Cardozo; Eduardo Tolosa
The G2019S leucine-rich repeat kinase 2 gene (LRRK2) mutation has been identified in a significant proportion of familial and sporadic cases of Parkinson’s disease (PD). Until now, information on the neuropathological changes associated with the G2019S LRRK2 mutation has been sparse. We report a 77-year-old patient who presented with a 14 year history of PD but, unexpectedly, histopathological examination disclosed mild neuronal loss in the substantia nigra without α-synuclein, tau or ubiquitin cytoplasmic inclusions. A G2019S LRRK2 mutation was eventually detected. The present case confirms that clinical PD caused by G2019S mutations can be associated with non-specific nigral degeneration without Lewy bodies.
Neuroscience Letters | 1999
Mario Ezquerra; Pau Pastor; Francesc Valldeoriola; José Luis Molinuevo; Rafael Blesa; E. Tolosa; Rafael Oliva
An intronic polymorphism and other changes in the transcribed region of the tau gene forming a haplotype have been previously described associated to progressive supranuclear palsy (PSP). These results raised the possibility that a change at or near the tau gene could be responsible for an increased risk to develop PSP. We initiated the present work in research for potential changes in the promoter region of the tau gene that could further extend the previously described haplotype. The tau promoter region was analyzed through single strand conformation polymorphism followed by direct sequencing in PSP patients (n = 35), in controls (n = 195) and in Alzheimers disease (AD; n = 74) patients. We have been able to identify a G to C change at position -221 of the tau gene promoter region. The CC genotype has been detected to be present with a significantly higher frequency in PSP patients (91.4%; P < 0.00001; OR = 11.8), but not in AD patients, as compared with controls (49.74%). Subsequently we have detected that the CC -221 tau promoter genotype is significantly associated to the tau intronic A0/A0 genotype (P < 0.00001). The detected -221 tau G to C change occurs within a potential c-myb proto-oncogene element present in the promoter region. Thus, in addition to extending the previously described haplotype associated to PSP, this -221 G to C change is an interesting candidate that could provide a potential explanation for the association of the haplotype to increased risk for developing PSP.
Annals of Neurology | 2004
Pau Pastor; Mario Ezquerra; J. Christian Perez; Sumi Chakraverty; Joanne Norton; Brad A. Racette; Dan McKeel; Joel S. Perlmutter; Eduardo Tolosa; Alison Goate
Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are sporadic neurodegenerative diseases presenting as atypical parkinsonian disorders, characterized by the presence of tau‐positive neurofibrillary tangles. Recently, an extended haplotype (H1E) of 787.6kb that comprises several genes including MAPT showed increased association with PSP. The objective of this study was to determine the size of the H1E haplotype associated with PSP and CBD in different populations and to identify specific subhaplotypes in the background of H1E haplotype. Nineteen single nucleotide polymorphisms (SNPs) in the 17q21 region were genotyped in two case–control samples. The SNPs that were associated with higher risk for the disease in the homozygous state delimit a region of more that 1Mb. Haplotype analyses in the Spanish sample showed that the most frequent haplotype found among the patients (H1E′), which extends 1.04Mb and contains several genes such as MAPT, CRHR1, IMP5, Saitohin, WTN3, and NSF. A specific subhaplotype (H1E′A) was present in 16% of PSP patients but was not observed in the controls. Furthermore, the H2E′A haplotype, was rarely present in the disease group suggesting that it plays a protective role. The identification of these specific subhaplotypes that modify risk for PSP/CBD supports the hypothesis that a pathogenic allele exists in a subgroup of PSP patients. Ann Neurol 2004;56:249–258
Movement Disorders | 2002
Pau Pastor; Mario Ezquerra; Eduardo Tolosa; Esteban Muñoz; María José Martí; Francesc Valldeoriola; José Luis Molinuevo; Matilde Calopa; Rafael Oliva
The recent finding of disequilibrium among several polymorphisms along the tau gene and the strong association of one of the two haplotypes formed by these polymorphisms (H1) with progressive supranuclear palsy (PSP) suggests that a single allele in or near the tau gene at 17q21 is responsible for increased risk in most of the PSP cases. We sought to determine whether mutations in the tau gene are responsible for the disease in 45 sporadic PSP patients. Furthermore, we analyzed some markers located in the common region of linkage (D17S800‐D17S791), associated with some cases of familial frontotemporal dementia (FTDP‐17), and the SNPs rs1816 and rs937 close to the tau gene, to determine their possible association with sporadic PSP. We did not find pathogenic mutations in exons 9, 10, 12, or 13 of the tau gene, indicating that tau mutations in both the splice‐site region of the exon 10 and in the microtubule‐binding region of tau gene are not a cause of PSP in this study group. We found significant overrepresentation of the haplotypes H1, extended up to the promoter of the tau gene (H1P), in PSP patients as compared with controls. In addition, a significant overrepresentation of the D17S810 2/2 and 3/2 genotypes, of the SNP rs1816 A/A, and of the SNP rs937 delG/delG genotypes was detected in PSP, further extending the haplotype described previously. These results are consistent with the hypothesis that a change either in the 5′ or in the 3′ flanking regions of the tau gene, or even other genes contained in the H1E haplotype, could increase the genetic susceptibility to PSP.
Journal of Neuroscience Research | 2014
Xavier Morató; Yaroslau Compta; Juan José Lozano; Neus Falgas; Francesc Valldeoriola; Claustre Pont-Sunyer; Dolores Vilas; Lourdes Mengual; Manel Fernández; José Luis Molinuevo; Anna Antonell; María José Martí; Rubén Fernández-Santiago; Mario Ezquerra
Blood‐cell‐free circulating micro‐RNAs (miRNAs) have been proposed as potential accessible biomarkers for neurodegenerative diseases such as Parkinsons disease (PD). Here we analyzed the serum levels of 377 miRNAs in a discovery set of 10 idiopathic Parkinsons disease (IPD) patients, 10 PD patients carriers of the LRRK2 G2019S mutation (LRRK2 PD), and 10 controls by using real‐time quantitative PCR‐based TaqMan MicroRNA arrays. We detected candidate differentially expressed miRNAs, which were further tested in a first validation set consisting of 20 IPD, 20 LRRK2 PD, and 20 control samples. We found four statistically significant miRNAs that were downregulated in either LRRK2 or IPD (miR‐29a, miR‐29c, miR‐19a, and miR‐19b). Subsequently, we validated these findings in a third set of samples consisting of 65 IPD and 65 controls and confirmed the association of downregulated levels of miR‐29c, miR‐29a, and miR‐19b in IPD. Differentially expressed miRNAs are predicted to target genes belonging to pathways related to ECM–receptor interaction, focal adhesion, MAPK, Wnt, mTOR, adipocytokine, and neuron projection. Results from our exploratory study indicate that downregulated levels of specific circulating serum miRNAs are associated with PD and suggest their potential use as noninvasive biomarkers for PD. Future studies should further confirm the association of these miRNAs with PD.
Neuroscience Letters | 2008
Mario Ezquerra; Jaume Campdelacreu; Carles Gaig; Yaroslau Compta; Esteban Muñoz; María José Martí; Francesc Valldeoriola; Eduardo Tolosa
Some APOE or tau gene polymorphisms have been associated with Alzheimers disease (AD), progressive supranuclear palsy (PSP) and Parkinsons disease (PD). The reports of a possible association between the APOE 4 allele and dementia in PD are controversial, and some studies suggest that the tau H1/H1 genotype may increase the risk of dementia in PD. Here we analysed these APOE and tau polymorphisms in 86 clinically diagnosed PD patients with dementia (PDD), in 138 clinically diagnosed non-demented PD (PDND) patients, and in 91 healthy controls. Genomic DNA isolated from blood was used for PCR and subsequent RFLP analysis. We examined the possible genetic association of these polymorphisms with dementia in PD, but found no differences in genotypic distributions between the PDND, PDD, and control groups. The effects of tau and APOE polymorphisms on the age at dementia onset were studied using Kaplan-Meier survival analysis but no significant association were found. The lack of association between the APOE 4 allele and PDD suggests that the pathological process involved in the development of dementia in PD is different from the one that occurs in AD.
Movement Disorders | 2011
Carles Gaig; Francesc Valldeoriola; Ellen Gelpi; Mario Ezquerra; Sara Llufriu; Mariateresa Buongiorno; María Jesús Rey; María José Martí; Francesc Graus; Eduardo Tolosa
Lewy body syndromes (mainly Parkinsons disease and dementia with Lewy bodies) share many clinical features and usually have a slowly progressive course. Some patients may show rapid symptoms progression.
Neurology | 1999
Mario Ezquerra; Cristóbal Carnero; Rafael Blesa; J.L. Gelpí; Francisca Ballesta; Rafael Oliva
Objective: To characterize the mutation responsible for early-onset AD in a large Spanish kindred. Background: Mutations in the presenilin 1 (PS1) gene have been identified and are known to be responsible for 18 to 50% of familial early-onset AD cases. Methods: Patients were characterized clinically. The proband was further studied with EEG, CSF analysis, CT, brain biopsy, and histology. Other members were studied using EEG, CT, MRI, and SPECT. Genetic analysis of PS1 was performed using PCR amplification of PS1 exons and direct sequencing followed by PS1 modeling of the normal and mutant PS1 proteins. Results: A novel mutation (Ser169Pro) in exon 6 of the PS1 gene was identified in different affected members. The Ser169Pro mutation is located at a site of the PS1 protein that is not a cluster of mutations. The mutation was not present in 100 general population controls and in 50 unrelated sporadic AD cases. The Ser169Pro mutation is associated with generalized myoclonic seizures several years after the initial symptoms of AD, a very early AD onset (≤35 years), and a rapidly progressive cognitive decline. Conclusions: The absence of the PS1 Ser169Pro mutation in the general population and in sporadic AD cases together with its detection in the affected members of this kindred suggests that it is a pathogenic mutation. The serine to proline change predicts a kink in the α-helix of the transmembrane domain of the PS1 protein that could radically disrupt its normal structure. Further characterization of the effect of this mutation could help identify the function of the PS1 protein and the pathogenic mechanisms of AD.