Increased Albumin Oxidation in Cerebrospinal Fluid and Plasma from Alzheimer’s Disease Patients
Authors: Costa, Montserrat | Horrillo, Raquel | Ortiz, Ana María | Pérez, Alba | Mestre, Anna | Ruiz, Agustín | Boada, Mercè | Grancha, Salvador
Article Type: Research Article
Abstract: Background: Oxidative stress in the brain and peripheral systems is considered a major player in Alzheimer’s disease (AD). Albumin is the main transporter and the main extracellular antioxidant in the human body. Objective: Here we explore for the first time the oxidation status of cerebrospinal fluid (CSF) and plasma albumin in AD in comparison to healthy subjects. Methods: Plasma and CSF samples were obtained from mild-moderate AD patients and control healthy age-matched donors. Albumin redox state forms (reduced: HMA; reversibly oxidized: HNA1; irreversibly oxidized: HNA2) were determined by HPLC. Albumin post-translational modifications (PTM) analysis was performed by mass spectrometry. Results: …HPLC showed less HMA in AD plasma than in controls (54.1% versus 65.2% ; p < 0.0001), mainly at expense of HNA1 (42.8% versus 32.5% ; p < 0.0001). In AD CSF, HMA was drastically decreased compared to controls (9.6% versus 77.4% ; p < 0.0001), while HNA2 was increased (52.8% versus 7.4% ; p < 0.0001). In AD patients but not in healthy controls, CSF albumin was much more irreversibly oxidized than in plasma (close to 20-fold increase in HNA2). PTM analysis showed that AD CSF albumin samples behave as a differentiated cluster, thus confirming the albumin oxidative pattern observed by HPLC. Conclusion: CSF albumin oxidation in AD patients was dramatically increased comparing to healthy controls, while in plasma this increase was smaller. CSF albumin in AD patients was much more oxidized than in plasma, but this effect was not observed in healthy controls. These results suggest that albumin oxidation, especially in CSF, and its role in AD deserves further investigation. Show more
Keywords: Albumin, Alzheimer’s disease, cerebrospinal fluid, oxidation status, plasma
DOI: 10.3233/JAD-180243
Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1395-1404, 2018
Aβ 1-17 is a Major Amyloid-β Fragment Isoform in Cerebrospinal Fluid and Blood with Possible Diagnostic Value in Alzheimer's Disease
Authors: Pérez-Grijalba, Virginia | Pesini, Pedro | Allué, José Antonio | Sarasa, Leticia | Montañés, María | Lacosta, Ana-María | Casabona, Diego | San-José, Itziar | Boada, Mercè | Tárraga, Lluis | Ruiz, Agustín | Sarasa, Manuel
Article Type: Research Article
Abstract: This work was prompted by the finding that Aβ1-17 (Aβ17 ) appeared to be the second-most abundant cerebrospinal fluid (CSF) Aβ fragment, after Aβ40 . We developed an ELISA to quantify levels of Aβ17 directly accessible in plasma (DA17), recovered from the proteomic plasma matrix (RP17) and associated with the cellular pellet (CP17) that remained after plasma collection. Then, we used a sample of 19 healthy control (HC), 27 mild cognitive impairment (MCI), and 17 mild Alzheimer's disease (AD) patients to explore the association of the diagnostic groups with those direct markers, their ratios or the ratios with their Aβ40 …or Aβ42 counterparts. After dichotomization (d) for the median of the sample population, logistic regression analysis showed that in the AD versus HC subgroup, subjects with a dDA/CP17 higher than the median had a significantly greater risk of being AD than those with marker levels equal to or below the median (odds ratio OR; 95% confidence interval; 17.21; 1.42–208.81). Subjects with dRP17/42 below the median had an increased likelihood of being MCI (20.00; 1.17–333.33) or AD (40.00; 1.87–1000) versus being HC, than those with dRP17/42 higher than the median. Although the confidence intervals are wide, these findings suggest that assessment of Aβ17 may increase the diagnostic performance of blood-based Aβ tests which might be developed into minimally invasive first-step screening tests for people with increased risk for AD. Show more
Keywords: Amyloid-β, biomarkers, cerebrospinal fluid, ELISA, mass spectrometry
DOI: 10.3233/JAD-140156
Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 47-56, 2015
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
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
Patient Engagement: The Fundació ACE Framework for Improving Recruitment and Retention in Alzheimer’s Disease Research
Authors: Boada, Mercè | Santos-Santos, Miguel A. | Rodríguez-Gómez, Octavio | Alegret, Montserrat | Cañabate, Pilar | Lafuente, Asunción | Abdelnour, Carla | Buendía, Mar | de Dios, Maria José | Morera, América | Sanabria, Ángela | Campo, Laura | Ruiz, Agustín | Tárraga, Lluís
Article Type: Review Article
Abstract: Alzheimer’s disease (AD) research is at a critical time. The global society is increasingly aware of the frightening rate of growth of the human and financial burden caused by this condition and of the urgent need to halt its progression. Consequently, the scientific community holds great responsibility to quickly put in place and optimize the machinery necessary for testing new treatments or interventions. In this context demand for participants for AD research is at an all-time high. In this review, we will focus on a methodological factor that is increasingly recognized as a key factor that shapes trial populations and …affects validity of results in clinical trials: patient engagement, recruitment, and retention. We outline specific problems relevant to patient engagement in AD including recruiting enough participants, difficulties in participant retention, ensuring the recruited sample is representative of the general AD population, the burden of screening failures, and new challenges related to recruiting in preclinical disease. To address the urgent need for more research studying the applicability and cost-effectiveness of different recruitment strategies across different settings and nationalities, we describe the Models of Patient Engagement for Alzheimer’s Disease (MOPEAD) project, a public-private partnership promoted by the Innovative Medicine Initiative (IMI), which will provide a large multinational quantitative analysis comparing different innovative recruitment models. We also discuss strategies that address each problem and draw on the experience of Fundació ACE to argue that focusing resources on comprehensive AD centers that offer coordinated clinical and social care and participate in basic and clinical research, is an effective and efficient way of implementing many of the discussed strategies. Show more
Keywords: Alzheimer’s disease, clinical trials, community outreach, Fundació ACE, MOPEAD, patient engagement, recruitment, retention
DOI: 10.3233/JAD-170866
Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1079-1090, 2018
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