Ubiquitin-negative mini-pick-like bodies in the dentate gyrus in p301l tauopathy
Authors: Ferrer, Isidro | Hernández, Isabel | Puig, Berta | Jesús Rey, María | Ezquerra, Mario | Tolosa, Eduardo | Boada, Merce
Article Type: Research Article
Abstract: Neuropathological and biochemical findings are reported in a patient who had suffered from frontotemporal dementia associated with a P310L mutation in the tau gene and included in the H1 haplotype. tau accumulation, as revealed with phospho-specific anti-tau antibodies Thr181, Ser199, Ser202, Ser214, Ser262, Ser396, Ser422 and AT8 (Ser202 and Thr205), was found in neurons with pre-tangles, and astrocytes and oligodendrocytes through the brain. The most characteristic feature was tau immunoreactivity decorating the perinuclear region and small cytoplasmic aggregates designed as mini-Pick-like bodies, mainly in the dentate gyrus. Inclusions were not stained with anti-ubiquitin antibodies and did not recruit tubulins. Tau …accumulation in individual cells was associated with increased expression of kinases linked with tau phosphorylation, mainly active (phosphorylated) stress kinases SAPK/JNK and p38 (SAPK/JNK-P and p38-P). Phosphorylated GSK-3β at Ser9 (GSK-3β-P), that inactivates the kinase, was particularly abundant in mini-Pick-like bodies, thus suggesting alternative roles of GSK-3 probably involved in cell survival. Western blots of sarkosyl-insoluble fractions revealed a double band pattern of phospho-tau of 68/66 kDa and 64 kDa in the hippocampus and white matter in the P310L mutation. Sarkosyl-insoluble fractions of the hippocampus were enriched in p38-P and GSK-3β-P in Alzheimer's disease (AD) cases, processed in parallel for comparative purposes, but not in the P310L mutation. In addition, no bands of high molecular weight were found in P310L in contrast with AD in these fractions. These findings indicate that the major sites of tau phosphorylation, and the expression of kinases involved in tau phosphorylation are active in P310L mutation as in AD and other tauopathies. Yet the P310L mutation has particular phospho-tau inclusions that are not tag with ubiquitin and appear to be rather soluble when compared with AD. Show more
DOI: 10.3233/JAD-2003-5604
Citation: Journal of Alzheimer's Disease, vol. 5, no. 6, pp. 445-454, 2003
Association of TMEM106B rs1990622 Marker and Frontotemporal Dementia: Evidence for a Recessive Effect and Meta-Analysis
Authors: Hernández, Isabel | Rosende-Roca, Maitée | Alegret, Montserrat | Mauleón, Ana | Espinosa, Ana | Vargas, Liliana | Sotolongo-Grau, Oscar | Tárraga, Lluís | Boada, Mercè | Ruiz, Agustín
Article Type: Research Article
Abstract: Transmembrane Protein 106B SNP rs1990622 was recently shown to modify the risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTD-TDP). An independent replication study of this genetic variant was performed in 381 individuals from Catalonia (Spain). By applying a recessive model, a tendency toward an association with FTD risk was observed in our case-control study (age- and gender-adjusted odds ratio = 0.57; p = 0.082). Importantly, meta-analysis of available studies also supports a recessive effect for rs1990622 CC genotype (OR = 0.70; CI 95% [0.57–0.85]; p = 0.0003) and demonstrates the existence of statistical heterogeneity due to an inherent pathological …heterogeneity between series (p = 0.00014). We conclude that TMEM106B is associated with FTD, although the extent of this effect is difficult to be estimated by using clinical FTD series. Show more
Keywords: Frontotemporal dementia, genetics, genome-wide association study, molecular epidemiology, TMEM106B
DOI: 10.3233/JAD-132432
Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 325-334, 2015
A Longitudinal Follow-Up of 550 Mild Cognitive Impairment Patients: Evidence for Large Conversion to Dementia Rates and Detection of Major Risk Factors Involved
Authors: Espinosa, Ana | Alegret, Montserrat | Valero, Sergi | Vinyes-Junqué, Georgina | Hernández, Isabel | Mauleón, Ana | Rosende-Roca, Maitée | Ruiz, Agustín | López, Oscar | Tárraga, Lluís | Boada, Mercè
Article Type: Research Article
Abstract: The most recent studies about mild cognitive impairment (MCI) are focused on the search for factors that make patients more vulnerable to conversion to dementia, mainly Alzheimer's disease (AD). The aim of this study was to determine which neuropsychological test performances, including episodic memory profiles, and genetic risk factors (APOE ε4) better predict early conversion to dementia among the four MCI subtypes. Data from 550 MCI patients were analyzed for the purpose of this study and were classified according to Petersen's criteria (2004), and also taking into account the absence (probable MCI) or presence (possible MCI) of comorbidities that could …explain cognitive deficits. MCI cases were divided into Probable amnestic (Pr-aMCI) (n = 115), probable non-amnestic (Pr-naMCI) (n = 37), possible amnestic (Pss-aMCI) (n = 234), and possible non-amnestic (Pss-naMCI) (n = 164), single or multiple domain. In the whole MCI sample, regression analysis showed that low performances on Orientation, Verbal Delayed Recall of the Word List Learning test from WMS-III, and Luria's Clock test were associated with conversion to dementia, independently of APOE ε4 allele. Cox proportional-hazards showed that the Probable MCI subtype, presence of storage memory impairment, multiple domain condition, and presence of at least one ε4 allele increased the risk of conversion to dementia. Multivariate survival and Kapplan-Meier analyses showed that the Pr-aMCI with storage memory impairment had the most and closest risk of conversion to dementia. In conclusion, the Pr-aMCI subset of patients had 8.5 times more risk of converting to dementia than the Pss-naMCI group, who displayed the slowest conversion rate to dementia. Show more
Keywords: Amnestic, cognition, dementia conversion, genetics, mild cognitive impairment, risk factors
DOI: 10.3233/JAD-122002
Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 769-780, 2013
Longitudinal Neuroimaging Analysis in Mild-Moderate Alzheimer’s Disease Patients Treated with Plasma Exchange with 5% Human Albumin
Authors: Cuberas-Borrós, Gemma | Roca, Isabel | Boada, Mercè | Tárraga, Lluís | Hernández, Isabel | Buendia, Mar | Rubio, Lourdes | Torres, Gustavo | Bittini, Ángel | Guzmán-de-Villoria, Juan A. | Pujadas, Francesc | Torres, Mireia | Núñez, Laura | Castell, Joan | Páez, Antonio
Article Type: Research Article
Abstract: Background: Recently, modifications of Aβ1-42 levels in CSF and plasma associated with improvement in memory and language functions have been observed in patients with mild-moderate Alzheimer’s disease (AD) treated with plasma exchange (PE) with albumin replacement. Objective: To detect structural and functional brain changes in PE-treated AD patients as part of a Phase II clinical trial. Methods: Patients received between 3 and 18 PE with albumin (Albutein® 5%, Grifols) or sham-PE (controls) for 21 weeks (divided in one intensive and two maintenance periods) followed by 6-month follow-up. Brain perfusion assessed by SPECT scans using an automated software (NeuroGam® ) and …brain structural changes assessed by MRI were performed at weeks 0 (baseline), 21, and 44 (with additional SPECT at weeks 9 and 33). Statistical parametric mapping (voxel-based analysis, SPM) and Z-scores calculations were applied to investigate changes to baseline. Results: 42 patients were recruited (39 evaluable; 37 analyzed: 18 PE-treated; 19 controls). There was a trend toward decreasing hippocampi and total intracranial volume for both patient groups during the study (p < 0.05). After six months, PE-treated patients had less cerebral perfusion loss than controls in frontal, temporal, and parietal areas, and perfusion stabilization in Brodmann area BA38-R during the PE-treatment period (p < 0.05). SPM analysis showed stabilization or absence of progression of perfusion loss in PE-treated patients until week 21, not observed in controls. Conclusions: Mild-moderate AD patients showed decreased brain volume and impairment of brain perfusion as expected for the progression of the disease. PE-treatment with albumin replacement favored the stabilization of perfusion. Show more
Keywords: Albumin, Alzheimer’s disease, magnetic resonance imaging, plasma exchange, single-photon emission computed tomography
DOI: 10.3233/JAD-170693
Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 321-332, 2018
The Role of Verb Fluency in the Detection of Early Cognitive Impairment in Alzheimer’s Disease
Authors: Alegret, Montserrat | Peretó, Mar | Pérez, Alba | Valero, Sergi | Espinosa, Ana | Ortega, Gemma | Hernández, Isabel | Mauleón, Ana | Rosende-Roca, Maitée | Vargas, Liliana | Rodríguez-Gómez, Octavio | Abdelnour, Carla | Berthier, Marcelo L. | Bak, Thomas H. | Ruíz, Agustín | Tárraga, Lluís | Boada, Mercè
Article Type: Research Article
Abstract: Background: Verb fluency (VF) is the less commonly used fluency test, despite several studies suggesting its potential as a neuropsychological assessment tool. Objective: To investigate the presence of VF deficits in mild cognitive impairment (MCI) and mild Alzheimer’s disease (AD) dementia; to assess the usefulness of VF in the detection of cognitively healthy (CH) people who will convert to MCI, and from MCI to dementia; and to establish the VF cut-offs useful in the cognitive assessment of Spanish population. Methods: 568 CH, 885 MCI, and 367 mild AD dementia individuals were administered the VF test and a complete neuropsychological battery. …Longitudinal analyses were performed in 231 CH and 667 MCI subjects to search for VF predictors of diagnosis conversion. Results: A worsening on VF performance from CH, MCI to AD dementia groups was found. Lower performances on VF were significantly related to conversion from CH to MCI/MCI to dementia. When the effect of time to conversion was analyzed, a significant effect of VF was found on the faster conversion from CH to MCI, but not from MCI to dementia. Moreover, VF cut-off scores and sensitivity/specificity values were calculated for 6 conditions (3 age ranges by 2 educational levels). Conclusion: The VF test may be a useful tool for the differential diagnosis of cognitive failure in the elderly. Since VF deficits seem to take place in early stages of the disease, it is a suitable neuropsychological tool for the detection not only of CH people who will convert to MCI, but also from MCI to dementia. Show more
Keywords: Alzheimer’s disease, cognitively healthy, mild cognitive impairment, verb fluency, verbal fluency
DOI: 10.3233/JAD-170826
Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 611-619, 2018
Brain Perfusion Correlates of Visuoperceptual Deficits in Mild Cognitive Impairment and Mild Alzheimer's Disease
Authors: Alegret, Montserrat | Vinyes-Junqué, Georgina | Boada, Mercè | Martínez-Lage, Pablo | Cuberas, Gemma | Espinosa, Ana | Roca, Isabel | Hernández, Isabel | Valero, Sergi | Rosende-Roca, Maitée | Mauleón, Ana | Becker and, James T. | Tárraga, Lluís
Article Type: Research Article
Abstract: Visuoperceptual processing is impaired early in the clinical course of Alzheimer's disease (AD). The 15-Objects Test (15-OT) detects such subtle performance deficits in mild cognitive impairment (MCI) and mild AD. Reduced brain perfusion in the temporal, parietal, and prefrontal regions have been found in early AD and MCI patients. The objectives of this study were to confirm the role of the 15-OT in the diagnosis of MCI and AD and to investigate the brain perfusion correlates of visuoperceptual dysfunction (15-OT) in subjects with MCI, AD, and normal aging. Forty-two AD, 42 MCI, and 42 healthy elderly control subjects underwent a …brain Single Photon Emission Tomography (SPECT) and separately completed the 15-OT. An analysis of variance compared 15-OT scores between groups. SPM5 was used to analyse the SPECT data. 15-OT performace was impaired in the MCI and AD patients. In terms of the SPECT scans, AD patients showed reduced perfusion in temporal-parietal regions, while the MCI subjects had decreased perfusion in the middle and posterior cingulate. When MCI and AD groups were compared, a significant brain perfusion reduction was found in temporo-parietal regions. In the whole sample, 15-OT performance was significantly correlated with the clinical dementia rating scores, and with the perfusion in the bilateral posterior cingulate and the right temporal pole, with no significant correlation in each separate group. Our findings suggest that the 15-OT performance provides a useful gradation of impairment from normal aging to AD, and it seems to be related to perfusion in the bilateral posterior cingulate and the right temporal pole. Show more
Keywords: Alzheimer's disease, brain SPECT, cerebral perfusion, mild cognitive impairment, visuoperception
DOI: 10.3233/JAD-2010-091069
Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 557-567, 2010
Cognitive, Genetic, and Brain Perfusion Factors Associated with Four Year Incidence of Alzheimer's Disease from Mild Cognitive Impairment
Authors: Alegret, Montserrat | Cuberas-Borrós, Gemma | Espinosa, Ana | Valero, Sergi | Hernández, Isabel | Ruíz, Agustín | Becker, James T. | Rosende-Roca, Maitée | Mauleón, Ana | Sotolongo, Oscar | Castell-Conesa, Joan | Roca, Isabel | Tárraga, Lluís | Boada, Mercè
Article Type: Research Article
Abstract: Background: There is a range of factors that predict the development of Alzheimer’s disease (AD) dementia among patients with amnestic mild cognitive impairment (MCI). Objectives: To identify the neuropsychological, genetic, and functional brain imaging data that best predict conversion to AD dementia in patients with amnestic MCI. Methods: From an initial group of 42 amnestic MCI patients assessed with neurological, neuropsychological, and brain SPECT, 39 (25 converters, 14 non-converters) were followed for 4 years, and 36 had APOE ε4 genotyping. Baseline neuropsychological data and brain SPECT data were used to predict which of the MCI patients would develop dementia by …the end of the 4 years of observation. Results: The MCI patients who had converted to AD dementia had poorer performance on long-term visual memory and Semantic Fluency tests. The MCI subjects who developed dementia were more likely to carry at least one copy of the APOE ε4 allele (Hazard Risk = 4.22). There was lower brain perfusion in converters than non-converters, mainly in postcentral gyrus. An additional analysis of the SPECT data found differences between the MCI subjects and controls in the posterior cingulate gyrus and the basal forebrain. When the brain imaging and neuropsychological test data were combined in the same Cox regression model, only the neuropsychological test data were significantly associated with time to dementia. Conclusion: Although the presence of reduced brain perfusion in postcentral gyrus and basal forebrain indicated an at-risk condition, it was the extent of memory impairment that was linked to the speed of decline from MCI to AD. Show more
Keywords: Alzheimer's disease, brain SPECT, cerebral perfusion, four-year follow-up, longitudinal, mild cognitive impairment, prospective, visual memory
DOI: 10.3233/JAD-132516
Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 739-748, 2014
GOLPH2 Gene Markers are Not Associated with Alzheimer's Disease in a Sample of the Spanish Population
Authors: Antúnez, Carmen | Boada, Mercé | López-Arrieta, Jesús | Ramirez-Lorca, Reposo | Hernández, Isabel | Marín, Juan | Martínez-Lage, Pablo | González-Pérez, Antonio | Jorge Galan, José | Gayán, Javier | Real, Luis M. | Ruiz, Agustín
Article Type: Short Communication
Abstract: GOLPH2 gene SNP variants Rs10868366 and Rs7019241 were reported to decrease the risk of Alzheimer's disease in a recent Whole Genome Association Study. We have investigated these genetic variants in 2470 individuals from Spain to conduct an independent replication study of the proposed SNP markers. We found no evidence of association between GOLPH2 markers and susceptibility to Alzheimer's disease in our series. We concluded that GOLPH2 gene does not contribute to risk of disease in this study sample.
Keywords: Alzheimer's disease, complex diseases, genetic susceptibility, Genome Wide Association Studies (GWAS), GOLPH2, human molecular genetics, neurodegeneration
DOI: 10.3233/JAD-2009-1200
Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 751-754, 2009
CALHM1 P86L Polymorphism is Associated with Late-Onset Alzheimer's Disease in a Recessive Model
Authors: Boada, Mercè | Antúnez, Carmen | López-Arrieta, Jesús | Galán, José Jorge | Morón, Francisco J. | Hernández, Isabel | Marín, Juan | Martínez-Lage, Pablo | Alegret, Montserrat | Carrasco, Jose M. | Moreno, Concha | Real, Luis M. | González-Pérez, Antonio | Tárraga, Lluís | Ruiz, Agustín
Article Type: Research Article
Abstract: CALHM1 gene coding non-synonymous SNP P86L (rs2986017) was reported to increase the risk of Alzheimer's disease (AD) in a recent study. We have investigated this genetic variant in 2470 individuals from Spain to conduct an independent replication study of the proposed SNP marker. By applying a recessive model, we observed weak evidence of an association between P86L mutation and late-onset AD (LOAD) susceptibility in our case-control study (OR = 1.38 C.I. = [1.01–1.89]). Meta-analysis of available studies also supports a recessive model for CALHM1 P86L variant and provides evidence of between study heterogeneity. Importantly, we found that adjusted mean age …at AD onset in P86L homozygous LOAD patients was significantly earlier that in the rest of patients (77.01 ± 6.1 for P86L homozygous carriers versus 79.0 ± 6.0 for the rest of patients, p = 0.002). We concluded that the CALMH1 gene may contribute to AD risk in our study population. The observed genetic model (recessive) and the estimated magnitude of the effect both imply that virtually all studies performed to date were markedly underpowered to detect this effect and underscore the importance of follow up, replication, and meta-analyses of promising genetic signals. Show more
Keywords: Alzheimer's disease, association, CALHM1, genotype, meta-analysis, molecular genetics, polymorphism
DOI: 10.3233/JAD-2010-1357
Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 247-251, 2010
The MTHFD1L Gene rs11754661 Marker is Not Associated with Alzheimer's Disease in a Sample of the Spanish Population
Authors: Ramírez-Lorca, Reposo | Boada, Mercé | Antúnez, Carmen | López-Arrieta, Jesús | Moreno-Rey, Concha | Hernández, Isabel | Marín, Juan | Gayán, Javier | González-Pérez, Antonio | Alegret, Montserrat | Tárraga, Lluis | Real, Luis M. | Ruiz, Agustín
Article Type: Short Communication
Abstract: The MTHFD1L gene SNP variant rs11754661 was found to increase the risk of Alzheimer's disease in a recent Whole Genome Association Study [1]. We have carried out an independent study of this genetic variant in 2467 individuals from Spain. We found no evidence of association between the MTHFD1L marker and susceptibility to Alzheimer's disease in our sample.
Keywords: Folate, GWAS, homocysteine, MTHFD1L, population genetics, susceptibility, SNP
DOI: 10.3233/JAD-2011-101983
Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 47-50, 2011