Journal of Alzheimer's Disease - Volume 26, issue 3

Authors: Zhang, Lu | Fang, Yu | Zeng, Zhaoshu | Lian, Yajun | Wei, Jianke | Zhu, Hongcan | Jia, Yanjie | Zhao, Xinyu | Xu, Yuming

Article Type: Research Article

Abstract: Brain-derived neurotrophic factor (BDNF) is needed to support neuronal survival and differentiation. It also promotes synaptic remodeling and modulates the function of many other neurotransmitters. The current study examined potential association between single nucleotide polymorphisms (SNPs) of the BDNF gene (G11757 C, C270T, G196A, G-712A) and Alzheimer's disease-related depression (AD-D). Participants included 336 patients with AD; 128 of these patients had AD-D. Response to 8-week paroxetine treatment was also assessed. The frequency of the 11757 C allele was significantly higher in AD-D than in the Alzheimer's disease without depression (AD-nD) patients (p = 0.003 after Bonferroni correction). The 196A allele …occurred with significantly higher frequency in AD-D patients (p = 0.001 after Bonferroni correction versus AD-nD). Carriers of the A allele of G196A responded better to paroxetine treatment. These findings support an important role of BDNF polymorphism in AD-D. Show more

Keywords: Alzheimer's disease-related depression, brain-derived neurotrophic factor, paroxetine, polymorphism

DOI: 10.3233/JAD-2011-110113

Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 523-530, 2011

Authors: Lachno, D. Richard | Romeo, Martin J. | Siemers, Eric R. | Vanderstichele, Hugo | Coart, Els | Konrad, Robert J. | Zajac, Joseph J. | Talbot, Jayne A. | Jensen, Hans F. | Sethuraman, Gopalan | DeMattos, Ronald B. | May, Patrick C. | Dean, Robert A.

Article Type: Research Article

Abstract: Tau measurements in cerebrospinal fluid (CSF) are gaining acceptance as aids to diagnosis of Alzheimer's disease (AD) and differentiation from other dementias. Two ELISA assays, the INNOTEST® hTAU Ag and the INNOTEST® PHOSPHO-TAU(181P) for quantification of t-tau and p-tau181 respectively, have been validated to regulatory standards. Validation parameters were determined by repeated testing of human CSF pools. Specimens from Phase 2 studies of the γ-secretase inhibitor semagacestat and the therapeutic antibody solanezumab at baseline and following 12–14 weeks of treatment were also tested. Estimated intra-assay CV for repeated testing of 3 CSF pools were ≤11.5% and …RE varied between −14.1% and +6.4%. Inter-assay CV for t-tau was <5% and RE was within ±8%. For p-tau181 , inter-assay CV was <9% and RE was within ±2.5%. Total CV (intra-assay plus inter-assay) were below 10% for both analytes. Up to 20-fold dilutional linearity was demonstrated for both analytes. Stability of t-tau and p-tau181 was demonstrated in CSF during five freeze-thaw cycles at ≤−20°C and ≤−70°C and at 18–22°C for up to 24 h. Neither semagacestat nor solanezumab interfered with either assay. Inter-individual t-tau and p-tau181 concentrations were highly variable but intra-individual variations were small. These assays are suitable for analysis of CSF t-tau and p-tau181 in a single laboratory supporting multi-center AD clinical trials. No effect of treatment with semagacestat or solanezumab was observed in response to three months of drug administration. Show more

Keywords: Alzheimer's disease, assay validation, biomarker, cerebrospinal fluid, p-tau181, t-tau

DOI: 10.3233/JAD-2011-110296

Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 531-541, 2011

Authors: Villarejo, Alberto | Benito-León, Julián | Trincado, Rocío | Posada, Ignacio J. | Puertas-Martín, Verónica | Boix, Raquel | Medrano, Ma José | Bermejo-Pareja, Félix

Article Type: Research Article

Abstract: To evaluate the mortality, thirteen years after the baseline wave (1994), of participants suffering dementia in the Neurological Disorders in Central Spain (NEDICES) Cohort Study, we conducted a population-based cohort study in the elderly (65 years and more) with 5,278 screened participants at baseline. Mortality has been evaluated by means of the National Death Registry of Spain at 1-5-2007, 13 years after enrolment. Cox's proportional hazards regression models were used to evaluate the hazard of death according to dementia severity and type, adjusting for potential covariates (gender, age, level of education, and co-morbidity). Survival was estimated using Kaplan-Meier method. Of …the 5,278 participants screened at baseline, 306 had dementia. Mortality at 13 years was: 275 deaths (89.9%) in dementia subjects; and 2,426 (49.0%) in subjects without dementia. Mortality was higher and statistically significant in dementia subjects. The degree of dementia (DSM-III-R) correlated with the risk of mortality, from mild (HR = 2.23; CI: 1.77–2.82) to moderate (HR =3.10; CI: 2.47–3.89) and severe dementia (HR = 4.98; CI: 3.85–6.44). Survival was similar in Alzheimer's disease and vascular dementia. Factors associated with higher mortality in Cox proportional hazard models were older age, male gender, and comorbidity. Using Population Attributable risk (PAR%), dementia was related to 11.3% of all deaths. Dementia intensity increases the mortality risk at ten years in the NEDICES Study as in other cohort studies. Age, gender, and co-morbidity are associated with higher mortality in dementia patients. Almost one third of deaths in persons over 85 years-old could be attributable to dementia. Show more

Keywords: Aging, cause of mortality, death, dementia, epidemiology, memory, mortality

DOI: 10.3233/JAD-2011-110443

Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 543-551, 2011

Authors: Gabelle, Audrey | Roche, Stéphane | Gény, Christian | Bennys, Karim | Labauge, Pierre | Tholance, Yannick | Quadrio, Isabelle | Tiers, Laurent | Gor, Baptiste | Boulanghien, Justine | Chaulet, Chloé | Vighetto, Alain | Croisile, Bernard | Krolak-Salmon, Pierre | Perret-Liaudet, Armand | Touchon, Jacques | Lehmann, Sylvain

Article Type: Research Article

Abstract: To improve the etiological diagnosis of neurodegenerative dementias like Alzheimer's disease (AD) or frontotemporal dementia (FTD), we evaluated the value of individual and combined measurements of the following relevant cerebrospinal fluid (CSF) biomarkers: Tau, 181p-Tau, Aβ38 , Aβ40 , Aβ42 , sAβPPα, and sAβPPβ. This study conducted in two centers included patients with FTD (n = 34), AD (n = 52), as well as a control group of persons without dementia (CTRL, n = 42). Identical clinical criteria and pre-analytical conditions were used while CSF biomarkers were measured using commercial single and multiplex quantitative immunoassays. Thorough statistical analyses, including ROC …curves, logistic regressions, and decision trees, were performed. We validated in AD the specific increase of p-Tau levels and the decrease of Aβ42 levels, two biological hallmarks of this disease. Tau concentrations were highest in AD and intermediate in FTD when compared to CTRL. The most interesting results were obtained by focusing on amyloid biomarkers as we found out in FTD a significant decrease of sAβPPβ, Aβ38 , and Aβ40 levels. Aβ38 in particular was the most useful biomarker to differentiate FTD subjects from the CTRL population. Combining p-Tau and Aβ38 led us to correctly classifying FTD patients with sensitivity at 85% and specificity at 82%. Significant changes in amyloid biomarkers, particularly for Aβ38 , are therefore seen in FTD. This could be quite useful for diagnosis purposes and it might provide additional evidence on the interrelationship between Tau and AβPP biology which understanding is essential to progress towards optimal therapeutic and diagnostic approaches of dementia. Show more

Keywords: Alzheimer's disease, frontotemporal dementia, CSF biomarkers, CSF amyloid peptides, Aβ38

DOI: 10.3233/JAD-2011-110515

Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 553-563, 2011

Authors: Silva, Diana F.F. | Esteves, A. Raquel | Arduino, Daniela M. | Oliveira, Catarina R. | Cardoso, Sandra M.

Article Type: Research Article

Abstract: Mitochondrial dysfunction is observed in Alzheimer's disease (AD) brain and peripheral tissues. Amyloid-β (Aβ) peptides are known to interact with several proteins inside the mitochondria, leading to mitochondrial dysfunction. Recent studies have provided substantial evidence that mitochondria serve as direct targets for Aβ-mediated neuronal toxicity. The observations that Aβ progressively accumulates in cortical mitochondria from AD patients and transgenic AD type mouse models suggest the role of mitochondrial Aβ in the pathogenesis or development of AD. Herein, we studied the downstream signaling pathways induced by Aβ-mediated mitochondrial metabolism alterations and its consequences on cellular fate. We found that Aβ peptides …induced an increase in NAD+ levels and a decrease in ATP levels, which was related with decreases in acetylated tubulin levels and tau hyperphosphorylation. As a result of microtubule disruption, alterations in macroautophagy, like a decrease in autophagossome degradation and altered cellular distribution of LC3B, were found. Taxol, a microtubule stabilizer drug, was able to restore microtubule network and to prevent cell death induced by Aβ peptides. Our data shows for the first time that mitochondrial and cytosolic Aβ oligomers were significantly reduced upon microtubule dynamics re-establishment. These observations point out that an intervention at a microtubule level may be effective as a disease modifying therapy. Show more

Keywords: amyloid-β, autophagy, mitochondria, sirtuins, tau, tubulin

DOI: 10.3233/JAD-2011-110423

Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 565-581, 2011

Authors: Marcon, Gabriella | Rossi, Giacomina | Giaccone, Giorgio | Giovagnoli, Anna Rita | Piccoli, Elena | Zanini, Sergio | Geatti, Onelio | Toso, Vito | Grisoli, Marina | Tagliavini, Fabrizio

Article Type: Research Article

Abstract: Mutations in the progranulin gene (GRN) were recently identified as an important cause of familial frontotemporal dementia (FTD). More than 60 pathogenic mutations have been reported up to now and prominent phenotypic variability within and among affected kindreds has been described. We have studied an Italian family with clinical evidence of dementia, and here we report detailed clinical records, imaging, sequential neurological examinations, cognitive assessments, and genetic analysis of three affected members of the same generation. Genetic analysis revealed the presence of the null mutation IVS6 + 5_8delGTGA in GRN, leading to haploinsufficiency, as documented by mRNA analysis. The mutation …is associated with wide variation of the clinical phenotype, ranging from FTD to Alzheimer's disease and to a rapidly-progressive dementia. In summary, the patients of this kindred showed highly variable clinical features that do not have a close correspondence with the pattern of the cerebral atrophy. Our data extend the phenotypic spectrum and the complexity of neurodegenerative diseases linked to GRN mutations. Show more

Keywords: Alzheimer's disease, frontotemporal dementia, haploinsufficiency, mutation, phenotype, progranulin

DOI: 10.3233/JAD-2011-110332

Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 583-590, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-110333

Citation: Journal of Alzheimer's Disease, vol. 26, no. 3, pp. 591-592, 2011