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

Authors: Nicolas, Gaël | Beherec, Laurène | Hannequin, Didier | Opolczynski, Gaëlle | Rothärmel, Maud | Wallon, David | Véra, Pierre | Martinaud, Olivier | Guillin, Olivier | Campion, Dominique

Article Type: Research Article

Abstract: Background: Although numerous studies have assessed cognitive dysfunction in patients with schizophrenia, very few have focused on the diagnosis of dementia. Objective: Our objectives were to accurately diagnose dementia in a cohort of middle-aged patients with schizophrenia and to assess the type of dementia. Methods: 96 patients with schizophrenia (46 inpatients and 50 outpatients), aged 50 to 70 years, underwent a psychiatric, neurological, and neuropsychological evaluation at baseline and after a 20-month follow-up. We established a 3-step procedure: 1) diagnose dementia according to the DSM-IV criteria, using the Mattis Dementia Rating and Activities of Daily Living …scales; 2) characterize dementia using brain imaging, perfusion by 99m Tc-ECD-SPECT and laboratory tests including Alzheimer’s disease cerebrospinal fluid biomarkers; and 3) search for genetic determinants. Results: Fourteen patients fulfilled the diagnostic criteria of dementia. Four were diagnosed with possible or probable behavioral-variant frontotemporal dementia (bvFTD), two with probable Alzheimer’s disease, two with probable vascular dementia (including one due to CADASIL), one with CNS inflammatory disease, and six could not be fully characterized. Conclusions: The diagnosis of dementia in middle-aged patients with schizophrenia is challenging but possible, using a multistep procedure. The most frequent condition, bvFTD, could reflect the presence of an evolutive neurodegenerative process in some patients. Show more

Keywords: Alzheimer's disease, dementia, frontotemporal lobar degeneration, Mattis Dementia Rating Scale, schizophrenia, vascular dementia

DOI: 10.3233/JAD-131688

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 809-822, 2014

Authors: Mitolo, Micaela | Salmon, David P. | Gardini, Simona | Galasko, Douglas | Grossi, Enzo | Caffarra, Paolo

Article Type: Research Article

Abstract: Visual-constructional apraxia is a prominent feature of dementia with Lewy bodies (DLB) that might help to clinically distinguish it from Alzheimer's disease (AD). The main goal of this study was to assess performance on the copy intersecting-pentagon item of the Mini-Mental State Examination with the new Qualitative Scoring method for the Pentagon copy Test (QSPT). In order to determine which aspects of the drawings might differentiate DLB from AD, pentagon drawings of autopsy-verified DLB (n = 16) and AD (n = 15) patients were assessed using the QSPT. The qualitative scoring encompasses the assessment of different parameters of the drawing, …such as number of angles, distance/intersection, closure/opening, rotation, and closing-in. The QSPT scores were compared between groups using linear analyses and artificial neural network analyses at four different time points. Linear analyses showed that during the first evaluation, number of angles was the only parameter that showed a significant difference between DLB and AD patients. A gradual decline in other parameters and total pentagon score occurred in both groups during subsequent years, with greater decline for the DLB group. The artificial neural network analyses using auto-contractive maps showed that, with disease progression, DLB became related to relatively lower qualitative pentagon scores, whereas AD became related to relatively higher qualitative scores. These findings suggest that the QSPT might be a sensitive measure of visuo-constructive abilities able to differentiate DLB from AD at disease onset and as the diseases progress, but further studies on larger population are necessary in order to establish its clinical relevance. Show more

Keywords: Alzheimer's disease, autopsy-confirmed, copy of pentagons, dementia with Lewy bodies

DOI: 10.3233/JAD-131403

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 823-832, 2014

Authors: Grande, Giulia | Vanacore, Nicola | Maggiore, Laura | Cucumo, Valentina | Ghiretti, Roberta | Galimberti, Daniela | Scarpini, Elio | Mariani, Claudio | Clerici, Francesca

Article Type: Research Article

Abstract: Background: Leisure activities, particularly exercise, play a protective role against dementia in healthy people, but it is unknown if this protective effect could be generalized to subjects with mild cognitive impairment (MCI). Objective: To investigate the influence of leisure activities on the risk of progression of MCI to dementia. Methods: 176 MCI subjects attending a memory clinic underwent a standardized lifestyle questionnaire between October 2007 and May 2010. Social, cognitive, and physical scores were derived based on the assiduity of interpersonal contacts and on the frequency of participation in individual leisure activities. Subjects were requested to …return every 12 months for dementia surveillance. The outcome measure was the risk of dementia associated with social, cognitive, and physical scores. Results: Over a median follow-up time of 2.59 year, 92 (52.2%) MCI subjects developed dementia. Subjects with physical scores in the highest third had a lower risk (HR 0.44; 95% CI 0.23–0.85) of dementia compared with those in the lowest third. No association was found between cognitive or social scores and the risk of dementia. Conclusion: To our knowledge, this is the first prospective clinical study which demonstrates that high levels of participation in physical leisure activities are associated with reduced risk of dementia in subjects with MCI. In line with findings coming from community-based studies on healthy elderly, our finding suggests that the protective role of exercise against the development of dementia can be generalized to MCI subjects seen in clinical practice. Clinicians should encourage MCI subjects to participate in physical leisure activities. Show more

Keywords: Dementia, exercise, leisure activities, lifestyle, mild cognitive impairment

DOI: 10.3233/JAD-131808

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 833-839, 2014

Authors: Wang, Hualong | Lian, Kaoqi | Han, Bing | Wang, Yanyong | Kuo, Sheng-Han | Geng, Yuan | Qiang, Jing | Sun, Meiyu | Wang, Mingwei

Article Type: Research Article

Abstract: Alzheimer's disease (AD), the most common age-dependent neurodegenerative disorder, produces a progressive decline in cognitive function. The metabolic mechanism of AD has emerged in recent years. In this study, we used multivariate analyses of gas chromatography-mass spectrometry measurements to determine that learning and retention-related metabolic profiles are altered during aging in the hippocampus of the senescence-accelerated mouse prone 8 (SAMP8). Alterations in 17 metabolites were detected in mature and aged mice compared to young mice (13 decreased and 4 increased metabolites), including metabolites related to dysfunctional lipid metabolism (significantly increased cholesterol, oleic acid, and phosphoglyceride levels), decreased amino acid (alanine, …serine, glycine, aspartic acid, glutamate, and gamma-aminobutyric acid), and energy-related metabolite levels (malic acid, butanedioic acid, fumaric acid, and citric acid), and other altered metabolites (increased N-acetyl-aspartic acid and decreased pyroglutamic acid, urea, and lactic acid) in the hippocampus. All of these alterations indicated that the metabolic mechanisms of age-related cognitive impairment in SAMP8 mice were related to multiple pathways and networks. Lipid metabolism, especially cholesterol metabolism, appears to play a distinct role in the hippocampus in AD. Show more

Keywords: Aging, Alzheimer's disease, cholesterol, gas chromatography-mass spectrometry, hippocampus, metabolic profiles

DOI: 10.3233/JAD-131463

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 841-848, 2014

Authors: Martin, Carolina | Aguila, Blanca | Araya, Paulina | Vio, Karin | Valdivia, Sharin | Zambrano, Angara | Concha, Margarita I. | Otth, Carola

Article Type: Research Article

Abstract: Background: Currently, it is unclear whether asymptomatic recurrent reactivations of herpes simplex virus type 1 (HSV-1) occur in the central nervous systems of infected people, and if these events could lead to a progressive deterioration of neuronal function. In this context, HSV-1 constitutes an important candidate to be included among the risk factors for the development of neuropathies associated with chronic neuroinflammation. Objective: The aim of this study was to assess in vivo inflammatory and neurodegenerative markers in the brain during productive and latent HSV-1 infection using a mouse model of herpes simplex encephalitis. Methods: Neuroinflammation …and neurodegeneration markers were evaluated in mice trigeminal ganglia and cerebral cortex during HSV-1 infection, by immunohistochemistry, western blot, and RT-PCR. Results: Neuronal ICP4 viral antigen expression indicative of a reactivation episode during asymptomatic latency of HSV-1 infection in mice was accompanied by upregulation of neuroinflammatory (toll-like receptor-4, interferon α/β, and p-IRF3) and early neurodegenerative markers (phospho-tau and TauC3). Conclusions: HSV-1 reactivation from latency induced neuroinflammatory and neurodegenerative markers in the brain of asymptomatic mice suggesting that recurrent reactivations could be associated with cumulative neuronal dysfunctions. Show more

Keywords: Herpes simplex encephalitis, herpes simplex virus type 1, neurodegeneration, neuroinflammation, TauC3, toll-like receptor 4, trigeminal ganglion

DOI: 10.3233/JAD-131706

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 849-859, 2014

Authors: Omori, Chiori | Kaneko, Madoka | Nakajima, Etsuko | Akatsu, Hiroyasu | Waragai, Masaaki | Maeda, Masahiro | Morishima-Kawashima, Maho | Saito, Yuhki | Nakaya, Tadashi | Taru, Hidenori | Yamamoto, Tohru | Asada, Takashi | Hata, Saori | Suzuki, Toshiharu | for the Japanese Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: p3-Alcα is a metabolic fragment of Alcadeinα (Alcα). Similar to the generation of the p3 fragment from amyloid-β protein precursor (AβPP) processing, Alcα is cleaved by α- and γ-secretases, leading to the secretion of p3-Alcα peptides into cerebrospinal fluid (CSF). p3-Alcα is also detected in the plasma, similar to amyloid-β (Aβ), which is a metabolic fragment of AβPP cleaved by amyloidogenic β- and γ-secretases. Because p3-Alcα is a non-aggregatable and stable peptide, unlike aggregatable Aβ and metabolically labile p3 of AβPP, the changes of p3-Alcα in quality and/or quantity in CSF and plasma are expected to be a marker for …assessing alteration of substrate cleavage by γ-secretase, such as Aβ generation from AβPP. The present study describes a sandwich enzyme-linked immunosorbent assay for quantifying levels of p3-Alcα35, the major form of the p3-Alcα species, and examines levels of p3-Alcα35 in the plasma of three independent Japanese cohorts. In two of the three cohorts, the p3-Alcα35 levels were significantly increased with a concomitant decrease in the Mini-Mental State Examination score, or in clinically diagnosed Alzheimer's disease (AD) patients, when compared with age-matched non-demented subjects. The values were significantly lower in AD subjects who were administered donepezil, when compared to AD subjects without donepezil treatment. The increase in plasma p3-Alcα35 levels may indicate an endophenotype in subjects in whom AD is due to a progressing cognitive impairment in subjects with a γ-secretase malfunction, or a disorder of the clearance of peptides. Show more

Keywords: Alzheimer's disease, alcadein, diagnosis, donepezil, γ-secretase, p3-Alc, plasma biomarker

DOI: 10.3233/JAD-131610

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 861-870, 2014

Authors: Reinert, Jochim | Martens, Henrik | Huettenrauch, Melanie | Kolbow, Tekla | Lannfelt, Lars | Ingelsson, Martin | Paetau, Anders | Verkkoniemi-Ahola, Auli | Bayer, Thomas A. | Wirths, Oliver

Article Type: Research Article

Abstract: The pathogenesis of Alzheimer's disease (AD) is believed to be closely dependent on deposits of neurotoxic amyloid-β peptides (Aβ), which become abundantly present throughout the central nervous system in advanced stages of the disease. The different Aβ peptides existing are generated by subsequent cleavage of the amyloid-β protein precursor (AβPP) and may vary in length and differ at their C-terminus. Despite extensive studies on the most prevalent species Aβ40 and Aβ42 , Aβ peptides with other C-termini such as Aβ38 have not received much attention. In the present study, we used a highly specific and sensitive antibody against …Aβ38 to analyze the distribution of this Aβ species in cases of sporadic and familial AD, as well as in the brains of a series of established transgenic AD mouse models. We found Aβ38 to be present as vascular deposits in the brains of the majority of sporadic AD cases, whereas it is largely absent in non-demented control cases. Aβ38 -positive extracellular plaques were virtually limited to familial cases. Interestingly we observed Aβ38 -positive plaques not only among familial cases due to AβPP mutations, but also in cases of familial AD caused by presenilin (PSEN) mutations. Furthermore we demonstrate that Aβ38 deposits in the form of extracellular plaques are common in several AD transgenic mouse models carrying either only AβPP, or combinations of AβPP, PSEN1, and tau transgenes. Show more

Keywords: Aβ38, AβPP, amyloid, mutations, presenilin, transgenic mice, vasculature, vessels

DOI: 10.3233/JAD-131373

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 871-881, 2014

Authors: Cheng, Qi | Sun, Hong-Xian | Ye, Fu-Lin | Wang, Gang | Ling, Hua-Wei | Chen, Sheng-Di | Jiang, Guo-Xin

Article Type: Research Article

Abstract: The number of elderly in the world is increasing rapidly, especially in China. The prevalence of dementia among elderly was investigated in a community of Sheshan town, located in the Southwest suburb of Shanghai, China. Face-to-face interviews were conducted to collect relevant information with prepared questionnaires. The Chinese version of the Mini-Mental Status Examination was used to screen subjects with cognitive impairment (CI). Physical examinations and neuropsychological assessments were carried out. Dementia and its major subtypes, Alzheimer's disease (AD) and vascular dementia (VaD), were diagnosed by senior neurologists according to relevant diagnostic criteria. In addition, magnetic resonance imaging and EEG …(with P300) were performed for a number of cases with AD or VaD. There were 1,472 participants (666 males and 806 females) aged 60 years and over in the study. A total of 167 subjects with CI were screened. Among them, dementia was recognized in 79 cases with a prevalence of 5.37% (95% confidence intervals: 4.22%–6.52%). The diagnosis of AD was made for 53 cases (16 males and 37 females) with a prevalence of 3.60% (95% confidence intervals: 2.65%–4.55%), and VaD for 21 cases (5 males and 16 females) with a prevalence of 1.43% (95% confidence intervals: 0.82%–2.03%); while the ratio of AD to VaD was 2.52. The prevalence rates of dementia among elderly from our study are higher than that previously reported from China, but in line with that reported from most world regions. A nationwide survey and surveillance system on the prevalence of dementia is recommended. Show more

Keywords: Alzheimer's disease, dementia, prevalence, vascular dementia

DOI: 10.3233/JAD-131601

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 883-889, 2014

Authors: Wang, Gang | Tang, Hui-Dong | Zhuang, Jun-Peng | Xu, Xu-Hua | Liu, Li-Hua | Li, Bo | Wang, Li-Ling | Xu, Zhi-Min | Cheng, Qi | Chen, Sheng-Di

Article Type: Research Article

Abstract: Background: The prevalence of cognitive impairment (CI) and its associated risk factors among elderly peoples in China has been investigated. However, dynamic studies revealing the risk factors associated with cognitive decline from follow-up observations in China are rarely performed. Objective: The present study aimed to identify factors predicting late-life cognitive decline in China. Methods: Participants were 223 community-dwelling residents (⩾65 years old) from the urban community of Shanghai with no CI upon comprehensive assessments at baseline. Cognitive decline at 2-year follow-up was defined as a drop of two or more points from baseline score in the …Mini-Mental State Examination (MMSE). Associations with baseline demographic, lifestyle, health, and medical factors were then determined within the population. Results: After 2 years, cognitive decline and incident CI developed in 75 (33.6%) and 25 (11.2%) participants, respectively. Across all participants, risk factors for cognitive decline included low education, high body mass index, and diabetes mellitus. Among participants with cognitive decline, points were predominantly lost in items relating to time orientation and complex commands in the MMSE. Conclusion: This study confirms the differences in risk factors between cross-sectional and longitudinal studies for cognitive decline among the elderly population in urban Shanghai. Interventions tailored to potential risk factors associated with cognitive decline may offer further benefits. Show more

Keywords: Alzheimer's disease, body mass index, cognitive impairment, diabetes mellitus

DOI: 10.3233/JAD-131514

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 891-897, 2014

Authors: BK, Binukumar | Zheng, Ya-Li | Shukla, Varsha | Amin, Niranjana D. | Grant, Philip | Pant, Harish C.

Article Type: Research Article

Abstract: Multiple lines of evidence link the incidence of diabetes to the development of Alzheimer's disease (AD). Patients with diabetes have a 50 to 75% increased risk of developing AD. Cyclin dependent kinase 5 (Cdk5) is a serine/threonine protein kinase, which forms active complexes with p35 or p39, found principally in neurons and in pancreatic β cells. Recent studies suggest that Cdk5 hyperactivity is a possible link between neuropathology seen in AD and diabetes. Previously, we identified P5, a truncated 24-aa peptide derived from the Cdk5 activator p35, later modified as TFP5, so as to penetrate the blood-brain barrier after intraperitoneal …injections in AD model mice. This treatment inhibited abnormal Cdk5 hyperactivity and significantly rescued AD pathology in these mice. The present study explores the potential of TFP5 peptide to rescue high glucose (HG)-mediated toxicity in rat embryonic cortical neurons. HG exposure leads to Cdk5-p25 hyperactivity and oxidative stress marked by increased reactive oxygen species production, and decreased glutathione levels and superoxide dismutase activity. It also induces hyperphosphorylation of tau, neuroinflammation as evident from the increased expression of inflammatory cytokines like TNF-α, IL-1β, and IL-6, and apoptosis. Pretreatment of cortical neurons with TFP5 before HG exposure inhibited Cdk5-p25 hyperactivity and significantly attenuated oxidative stress by decreasing reactive oxygen species levels, while increasing superoxide dismutase activity and glutathione. Tau hyperphosphorylation, inflammation, and apoptosis induced by HG were also considerably reduced by pretreatment with TFP5. These results suggest that TFP5 peptide may be a novel candidate for type 2 diabetes therapy. Show more

Keywords: Alzheimer's disease, cyclin dependent kinase 5, diabetes, neuroinflammation, oxidative stress

DOI: 10.3233/JAD-131784

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 899-909, 2014

Article Type: Other

DOI: 10.3233/JAD-131785

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 911-914, 2014

Article Type: Other

DOI: 10.3233/JAD-131785

Citation: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 915-924, 2014