Journal of Alzheimer's Disease - Volume 39, issue 4

Authors: Ma, Tao

Article Type: Review Article

Abstract: Understanding the molecular signaling pathways that go awry in Alzheimer's disease (AD) would provide insights into developing novel therapies for this devastating neurodegenerative disease. Previous work has established that hyperactive glycogen synthase kinase-3 (GSK3) is linked to both “sporadic” and “genetic” forms of AD, suggesting a crucial role of GSK3 in AD pathogenesis. Therefore, inhibition of GSK3 activity has been intensely investigated as a potential therapeutic intervention for AD. GSK3 exists in two isoforms: GSK3α and GSK3β. Markedly, recent studies indicate specific contributions of each of the α and β isoforms of GSK3 to AD pathogenesis, suggesting a role of …both isoforms in the disease. Here I review recent relevant work investigating isoform-specific roles of GSK3 in AD pathophysiology, highlighting the emerging role of GSK3α, which has been largely overlooked in favor of the more extensive studies of GSK3β. Show more

Keywords: Alzheimer's disease, amyloid-β, GSK3α, GSK3β, memory, signal transduction

DOI: 10.3233/JAD-131661

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 707-710, 2014

Authors: Dietrich, Marcelo | Antequera, Desiree | Pascual, Consuelo | Castro, Nerea | Bolos, Marta | Carro, Eva

Article Type: Short Communication

Abstract: Megalin has been suggested to be involved in Alzheimer's disease (AD), mediating blood-brain barrier (BBB) transport of multiple ligands, including amyloid-β peptide (Aβ), but also neuroprotective factors. Because no transgenic model is currently available to study this concept, we have obtained transgenic mice blocking megalin expression at the BBB. These endothelial megalin deficient (EMD) mice developed increased anxiety behavior and impaired learning ability and recognition memory, similar to symptoms described in AD. Degenerating neurons were also observed in the cerebral cortex of EMD mice. In view of our findings we suggest that, in mice, megalin deficiency at the BBB leads …to neurodegeneration. Show more

Keywords: Alzheimer's disease, cognitive impairment, memory, neurodegeneration, transgenic mice

DOI: 10.3233/JAD-131604

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 711-717, 2014

Authors: Alcolea, Daniel | Martínez-Lage, Pablo | Izagirre, Andrea | Clerigué, Montserrat | Carmona-Iragui, María | Alvarez, Rosa María | Fortea, Juan | Balasa, Mircea | Morenas-Rodríguez, Estrella | Lladó, Albert | Grau, Oriol | Blennow, Kaj | Lleó, Alberto | Molinuevo, José L.

Article Type: Research Article

Abstract: Background: Lumbar puncture (LP) is increasingly performed in memory units due to the usefulness of cerebrospinal fluid (CSF) biomarkers in the diagnosis of Alzheimer’s disease. The feasibility of this procedure in this context, however, is controversial. Objective: Our aim was to analyze the incidence of complications and their associated factors so as to determine the impact of LP in the study of CSF biomarkers of Alzheimer’s disease. Methods: In the context of a larger international initiative, we prospectively collected data from 689 participants who underwent LP in three memory units in Spain. Data included demographic factors, …headache history, subjective attitude toward the procedure, patient positioning, needle characteristics, volume of CSF extracted, attempts needed, and resting time after CSF acquisition. Five to seven days after the procedure, we asked participants about complications through a semi-structured telephone interview. Results: No adverse events were reported in 441 (64.0%) participants. The most frequent complication was headache, reported by 171 (24.8%) subjects. It was severe in only 17 (2.5%). Headache was more frequent in younger participants and when a cutting-edge needle was used. Back pain was present in 111 (16.1%) cases, and it was associated with female gender, cutting-edge needles, increased number of attempts, and longer resting time after LP. No major complications were reported. The use of pen-point needles showed a trend toward a higher frequency of hematic CSF. Conclusion: LP can be safely performed to study CSF biomarkers. The main complication is headache, associated with younger age and use of cutting-edge needles. Show more

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, dementia, lumbar puncture, post-lumbar puncture headache

DOI: 10.3233/JAD-131334

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 719-726, 2014

Authors: Palavicini, Juan Pablo | Wang, Hongjie | Minond, Dmitriy | Bianchi, Elisabetta | Xu, Shaohua | Lakshmana, Madepalli K.

Article Type: Research Article

Abstract: Loss of synaptic proteins and functional synapses in the brains of patients with Alzheimer's disease (AD) as well as transgenic mouse models expressing amyloid-β protein precursor is now well established. However, the earliest age at which such loss of synapses occurs, and whether known markers of AD progression accelerate functional deficits is completely unknown. We previously showed that RanBP9 overexpression leads to enhanced amyloid plaque burden in a mouse model of AD. In this study, we found significant reductions in the levels of synaptophysin and spinophilin, compared with wild-type controls, in both the cortex and the hippocampus of 5- and …6-month old but not 3- or 4-month old APΔE9/RanBP9 triple transgenic mice, and not in APΔE9 double transgenic mice, nor in RanBP9 single transgenic mice. Interestingly, amyloid plaque burden was also increased in the APΔE9/RanBP9 mice at 5–6 months. Consistent with these results, we found significant deficits in learning and memory in the APΔE9/RanBP9 mice at 5 and 6 month. These data suggest that increased amyloid plaques and accelerated learning and memory deficits and loss of synaptic proteins induced by RanBP9 are correlated. Most importantly, APΔE9/RanBP9 mice also showed significantly reduced levels of the phosphorylated form of cofilin in the hippocampus. Taken together these data suggest that RanBP9 overexpression down-regulates cofilin, causes early synaptic deficits and impaired learning, and accelerates accumulation of amyloid plaques in the mouse brain. Show more

Keywords: Amyloid plaques, cofilin, learning and memory, RanBP9, spinophilin, synaptophysin

DOI: 10.3233/JAD-131550

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 727-740, 2014

Authors: Romero, Juan Pablo | Benito-León, Julián | Mitchell, Alex J. | Trincado, Rocío | Bermejo-Pareja, Félix

Article Type: Research Article

Abstract: Previous studies have shown that dementia is frequently omitted as a cause of death from the death certificate in patients with long-standing dementia. However, most studies exclude those undiagnosed dementia sufferers in the population. In order to overcome this problem, it is necessary to examine all the participants or to screen the population for symptoms of dementia and confirm the diagnosis with a clinical examination (two-phase approach). We used this latter methodology to estimate the proportion of reporting of dementia on death certificates in a prospective population-based study (NEDICES), involving 4,197 elderly people. Community-dwelling subjects with and without dementia were …identified and followed during a median of 12.5 years, after which the death certificates of those who deceased were examined. A total of 1,976 (47.1%) died (403 subjects with dementia). Dementia was rarely reported as the primary cause of death, even in known cases of dementia (20.8%). Indeed it was reported in only 13.3% of those with mild dementia and 24.3% of those with moderate or severe dementia; in 24.9% of those with possible or probable Alzheimer's disease; and in 11.9% of those with non-Alzheimer dementia. In a stepwise multiple logistic regression analysis with the dependent variable being presence or absence of dementia on the death certificate, the significant associated independent variables were age at death, severity of dementia, and etiology of dementia. We conclude that reporting of dementia on death certificates remains poor. This suggests a lack of awareness of the importance of dementia as a cause of death. Show more

Keywords: Death certificates, dementia, elderly, epidemiology, population-based study, underreporting

DOI: 10.3233/JAD-131622

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 741-748, 2014

Authors: Patocskai, Anna Tünde | Pákáski, Magdolna | Vincze, Gábor | Fullajtár, Máté | Szimjanovszki, Irma | Drótos, Gergely | Boda, Krisztina | Janka, Zoltán | Kálmán, János

Article Type: Research Article

Abstract: Background: The Clock Drawing Test (CDT) is a widely-used, rapid assessment tool for the screening of cognitive decline though its evaluation and interpretation are still not uniform. The aim of present study was to investigate the difference in sensitivity and specificity of two types of CDTs and to compare the clinical benefits of quantitative and semiquantitative scoring systems. Objective: To investigate the difference in sensitivity and specificity of two types of CDTs and to compare the clinical benefits of quantitative and semiquantitative scoring systems. Methods: Six hundred and ninety-two participants with or without dementia completed 10-item …CDTs in nursing homes in two counties in southern Hungary. The dementia was not further subclassified. The results of the two tests, CDT1 (representing five minutes to a quarter to four) and CDT2 (representing ten past five), were evaluated quantitatively and semiquantitatively. Results: In the quantitative evaluation, the sensitivity and the specificity for the diagnosis of dementia at cut-off scores of 7 points were determined: 87.1% and 51.9%, respectively, for CDT1, and 81.7% and 57% for CDT2, respectively. The semiquantitative analysis revealed a sensitivity of 67.3% and a specificity of 65.3% for CDT1, and of 64.6% and 66.6% for CDT2, respectively. Conclusion: The results of CDT tests do not appear to depend on the positions of the clock hands and additionally suggest that the quantitative evaluation method is more sensitive than the semiquantitative method. Show more

Keywords: Clock drawing test, cognitive disorders, dementia, early diagnosis, sensitivity, specificity

DOI: 10.3233/JAD-131313

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 749-757, 2014

Authors: Murray, Patrick S. | Kirkwood, Caitlin M. | Gray, Megan C. | Fish, Kenneth N. | Ikonomovic, Milos D. | Hamilton, Ronald L. | Kofler, Julia K. | Klunk, William E. | Lopez, Oscar L. | Sweet, Robert A.

Article Type: Research Article

Abstract: Psychosis occurs in 40–60% of Alzheimer's disease (AD) subjects, is heritable, and indicates a more rapidly progressive disease phenotype. Neuroimaging and postmortem evidence support an exaggerated prefrontal cortical synaptic deficit in AD with psychosis. Microtubule-associated protein tau is a key mediator of amyloid-β-induced synaptotoxicity in AD, and differential mechanisms of progressive intraneuronal phospho-tau accumulation and interneuronal spread of tau aggregates have recently been described. We hypothesized that psychosis in AD would be associated with greater intraneuronal concentration of phospho-tau and greater spread of tau aggregates in prefrontal cortex. We therefore evaluated prefrontal cortex phospho-tau in a cohort of 45 AD …cases with and without psychosis. Intraneuronal phospho-tau concentration was higher in subjects with psychosis, while a measure of phospho-tau spread, volume fraction, was not. Across groups both measures were associated with lower scores on the Mini-Mental State Examination and Digit Span Backwards test. These novel findings indicate that tau phosphorylation may be accelerated in AD with psychosis, indicating a more dynamic, exaggerated pathology in AD with psychosis. Show more

Keywords: Alzheimer's disease, Braak stage, Mini-Mental State Examination, psychosis, tau

DOI: 10.3233/JAD-131166

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 759-773, 2014

Authors: Salcedo-Tello, Pamela | Hernández-Ortega, Karina | Arias, Clorinda

Article Type: Research Article

Abstract: The abnormal phosphorylation of the microtubule-associated protein tau is a prominent aspect of Alzheimer's disease (AD). Considerable evidence suggests that glycogen synthase kinase 3β (GSK3β) and the protein phosphatase 2A (PP2A) are involved in normal and pathological tau phosphorylation. However, the mechanisms underlying a shift of the phosphorylation/dephosphorylation balance that leads to abnormal tau phosphorylation remains unknown. The canonical Wnt pathway negatively regulates GSK3β activity, and this signaling pathway has also been found to be dysregulated in the AD brain. Here, we report that the Wnt antagonist Dkk-1 selectively increases tau phosphorylation in the hippocampus of aged rats at Ser199/202, …Ser396/404, and Ser214 sites. In the aged hippocampus, the inhibition of Wnt signaling is also accompanied by reduced PP2A activity. This study suggests that aging promotes tau hyperphosphorylation after Wnt inhibition, due to an imbalance between GSK3β and PP2A activities. Show more

Keywords: Aging, GSK3β, hippocampal slices, PP2A, tau phosphorylation, Wnt signaling

DOI: 10.3233/JAD-130749

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 775-785, 2014

Authors: Arodin, Lisa | Lamparter, Heidrun | Karlsson, Håkan | Nennesmo, Inger | Björnstedt, Mikael | Schröder, Johannes | Fernandes, Aristi P.

Article Type: Research Article

Abstract: Oxidative stress has an important role in the pathological process of most neurodegenerative disorders, including Alzheimer's disease (AD). The glutaredoxin (Grx) and thioredoxin (Trx) systems are central in maintaining a reduced environment in the cell and thus render protection against oxidative stress. Here, we show that Trx1 and Grx1 were released to the cerebrospinal fluid in 120 cases examined, and that the levels of these proteins increased significantly in the early stages of AD in comparison to mild cognitive impairment (MCI). Trx1 and Grx1 levels correlated with the established AD biomarkers tau and phospho-tau (p-tau). Moreover, by determining the levels …of Trx1 and Grx1, discrimination between MCI converters and patients with stable MCI were possible. By applying the protein levels of Trx1 together with conventional diagnostic markers (Mini-Mental State Examination, tau, and p-tau) to a stepwise regression model, MCI stable, MCI converter, mild AD, and moderate AD was correctly diagnosed in 32 out of 33 cases. In order to further evaluate the involvement of these systems in AD, the immunoreactivity of Trx1, Trx2, Grx1, and Grx2 were investigated and the expression pattern was shown to be altered in hippocampus tissue sections from AD patients compared to controls. In conclusion, we introduce members of the thioredoxin super family of proteins as promising early biomarkers in the diagnosis of AD, suggesting their potential involvement in the pathogenesis of the disease. Show more

Keywords: Alzheimer's disease, glutaredoxin, mild cognitive impairment, thioredoxin

DOI: 10.3233/JAD-131814

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 787-797, 2014

Authors: Cotelli, Maria | Manenti, Rosa | Petesi, Michela | Brambilla, Michela | Cosseddu, Maura | Zanetti, Orazio | Miniussi, Carlo | Padovani, Alessandro | Borroni, Barbara

Article Type: Research Article

Abstract: Background: Primary progressive aphasia (PPA) is an untreatable neurodegenerative disorder that disrupts language functions. Previous studies have demonstrated transcranial direct current stimulation (tDCS) may improve language symptoms in patients with post stroke aphasia or neurodegenerative diseases. Objective: The present study investigated whether the application of anodal tDCS (AtDCS) to the scalp overlying the left dorsolateral prefrontal cortex (DLPFC), which may increase cortical excitability, in combination with individualized speech therapy would improve naming accuracy in the agrammatic variant of PPA (avPPA). Methods: Sixteen avPPA patients were randomly allocated into two subgroups: AtDCS (n = 8) or placebo …tDCS (PtDCS). tDCS was applied over the left DLPFC (BA 8/9) 25 minutes per day for two weeks (10 days). Each patient underwent 25 minutes of individualized speech therapy with either AtDCS or PtDCS during each treatment session. Neuropsychological assessment, experimental naming, and linguistic abilities in daily living were assessed at baseline (T0), after two weeks of intervention (T1) and at a 12-week follow-up (T2). Results: Significant improvement in experimental naming was observed in both groups at T1 and T2, but this effect was significantly greater in AtDCS than PtDCS patients. Naming correctness, as assessed using the Aachener Aphasie Test, increased selectively in the AtDCS group from T0 to T1, and this effect remained significant at T2. The analysis of daily living language abilities improved selectively in AtDCS group. Conclusion: Our results support the beneficial effect of targeted language training in combination with brain stimulation in avPPA patients. tDCS should be considered a useful tool for the improvement of language functions in patients with neurodegenerative diseases in future trials. Show more

Keywords: Aphasia, frontotemporal dementia, non-invasive brain stimulation, rehabilitation

DOI: 10.3233/JAD-131427

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 799-808, 2014