Journal of Alzheimer's Disease - Volume 38, issue 1

Authors: Kirste, Thomas | Hoffmeyer, André | Koldrack, Philipp | Bauer, Alexandra | Schubert, Susanne | Schröder, Stefan | Teipel, Stefan

Article Type: Research Article

Abstract: Background: Early detection of behavioral changes in Alzheimer’s disease (AD) would help the design and implementation of specific interventions. Objective: The target of our investigation was to establish a correlation between diagnosis and unconstrained motion behavior in subjects without major clinical behavior impairments. Method: We studied everyday motion behavior in 23 dyads with one partner suffering from AD dementia and one cognitively healthy partner in the subjects’ home, employing ankle-mounted three-axes accelerometric sensors. We determined frequency features obtained from the signal envelopes computed by an envelope detector for the carrier band 0.5 Hz to 5 Hz. …Based on these features, we employed quadratic discriminant analysis for building models discriminating between AD patients and healthy controls. Results: After leave-one-out cross-validation, the classification accuracy of motion features reached 91% and was superior to the classification accuracy based on the Cohen-Mansfield Agitation Inventory (CMAI). Motion features were significantly correlated with MMSE and CMAI scores. Conclusion: Our findings suggest that changes of everyday behavior are detectable in accelerometric behavior protocols even in the absence of major clinical behavioral impairments in AD. Show more

Keywords: Actigraphy, Alzheimer's disease, chronobiology phenomena, circadian rhythm disorders, Cohen-Mansfield Agitation Inventory, discriminant analysis, Fourier analysis, linear models, principal component analysis, psychomotor agitation

DOI: 10.3233/JAD-130272

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 121-132, 2014

Authors: Yu, Yang | Liu, Jin | Li, Shu-Qin | Peng, Lei | Ye, Richard D.

Article Type: Research Article

Abstract: Microglia and astrocytes in the brain play an important role in the development and progression of Alzheimer's disease (AD). Serum amyloid A (SAA) is a major acute-phase protein produced locally in the brain and colocalizes with senile plaques in AD patients. We investigated whether SAA plays a role in the development of AD. The viability of cultured primary microglia and astrocytes was measured by MTT; cell cycle and apoptosis analysis was also conducted. Cultured microglia and astrocytes were stimulated with 1 μM SAA for different periods of time (2, 4, 6, 12 h) or treated with 1 μM SAA with …or without 15 min pretreatment of MAPK or PI3K inhibitors. Total RNA was extracted for qPCR analysis. SAA induced morphological changes of primary microglia but not astrocytes. Interestingly, SAA increased the viability of microglia by inhibiting their apoptosis and reduced the viability of astrocytes by inducing G1 cell cycle arresting. SAA treatment increased the mRNA levels of IL-6, TNF-α, IL12p40, IL23p19, and IL-10, with higher potency in microglia than in astrocytes. However, SAA induced more iNOS mRNA in astrocytes than in microglia. SAA induced these cytokines and iNOS expression by activating the PI3K pathway in both glial cells, but selectively activated the JNK pathway in microglia and the NF-κB pathway in astrocytes. These results suggest that SAA can stimulate a different reactive phenotype in microglia and astrocytes, and SAA regulates cell viability differently in these two glial cells in part through the PI3K pathway. Show more

Keywords: Alzheimer's disease, astrocytes, glial cells, microglia, serum amyloid A

DOI: 10.3233/JAD-130818

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 133-144, 2014

Authors: Koran, Mary Ellen I. | Hohman, Timothy J. | Meda, Shashwath A. | Thornton-Wells, Tricia A. | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The genetic etiology of late-onset Alzheimer's disease (LOAD) has proven complex, involving clinical and genetic heterogeneity and gene-gene interactions. Recent genome wide association studies in LOAD have led to the discovery of novel genetic risk factors; however, the investigation of gene-gene interactions has been limited. Conventional genetic studies often use binary disease status as the primary phenotype, but for complex brain-based diseases, neuroimaging data can serve as quantitative endophenotypes that correlate with disease status and closely reflect pathological changes. In the Alzheimer's Disease Neuroimaging Initiative cohort, we tested for association of genetic interactions with longitudinal MRI measurements of the inferior …lateral ventricles (ILVs), which have repeatedly shown a relationship to LOAD status and progression. We performed linear regression to evaluate the ability of pathway-derived SNP-SNP pairs to predict the slope of change in volume of the ILVs. After Bonferroni correction, we identified four significant interactions in the right ILV (RILV) corresponding to gene-gene pairs SYNJ2-PI4KA, PARD3-MYH2, PDE3A-ABHD12B, and OR2L13-PRKG1 and one significant interaction in the left ILV (LILV) corresponding to SYNJ2-PI4KA. The SNP-SNP interaction corresponding to SYNJ2-PI4KA was identical in the RILV and LILV and was the most significant interaction in each (RILV: p = 9.13 × 10−12 ; LILV: p = 8.17 × 10−13 ). Both genes belong to the inositol phosphate signaling pathway which has been previously associated with neurodegeneration in AD and we discuss the possibility that perturbation of this pathway results in a down-regulation of the Akt cell survival pathway and, thereby, decreased neuronal survival, as reflected by increased volume of the ventricles. Show more

Keywords: Alzheimer's disease, Alzheimer's disease neuroimaging initiative, atrophy, epistasis, inositol, magnetic resonance imaging, neuroimaging

DOI: 10.3233/JAD-130989

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 145-154, 2014

Authors: Cano-Cuenca, Nieves | Solís-García del Pozo, Julián E. | Jordán, Joaquín

Article Type: Research Article

Abstract: Over the last few years, latrepirdine, a démodé antihistamine drug, has been proposed to be useful for treating neurodegenerative disorders such as Alzheimer's and Huntington's diseases, and more recently schizophrenia. The mechanisms and pharmacological targets that are responsible for the beneficial effects on neurodegenerative diseases remain unknown. But it has been proposed that latrepirdine may modulate several targets including voltage-gate Ca+2 channels, mitochondrial permeability pore transition, or several neurotransmitter receptors. Herein, we present a meta-analysis of randomized controlled trials to ascertain the efficacy and safety of latrepirdine on cognitive function. By doing a search in electronic databases, we found …five clinical trials in which the effect of latrepirdine on cognition function has been studied, and this was evaluated using MMSE, ADAS-cog, ADCS-ADL, and NPI scores. Latrepirdine generally presented a good safety profile; it was well tolerated when given alone or in combination with a variety of other drugs. We observed heterogeneous results between trials; latrepirdine failed to exert a significant beneficial effect although it tended to improve cognitive scores. The only significant benefit that we found was for the NPI score in Alzheimer's disease patients. Show more

Keywords: Alzheimer's disease, clinical trials, cognition function, dimebon, Huntington's disease, schizophrenia

DOI: 10.3233/JAD-130872

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 155-164, 2014

Authors: Silva, Patricia Natalia | Furuya, Tatiane Katsue | Braga, Ianna Lacerda | Rasmussen, Lucas Trevizani | Labio, Roger Willian | Bertolucci, Paulo Henrique | Chen, Elizabeth Suchi | Turecki, Gustavo | Mechawar, Naguib | Payão, Spencer Luiz | Mill, Jonathan | Smith, Marília Cardoso

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common form of dementia in elderly. Chaperones may have a crucial role in AD due to their involvement in protein quality control, folding, and degradation. In this study, we investigated the mRNA and promoter DNA methylation levels of two chaperones, HSPA8 and HSPA9, in postmortem brain tissue (entorhinal and auditory cortices and hippocampus) from healthy elderly and AD subjects as well as in peripheral blood of healthy elderly and AD patients. mRNA quantification was performed by qRT-PCR and DNA methylation by mass spectrometry. In the peripheral blood, we did not observe a significant difference …in HSPA8 and HSPA9 expression between elderly controls and AD. A significant downregulation of HSPA8 and HSPA9 was observed in AD across the three brain regions compared to the controls, suggesting their participation in AD pathogenesis. However, no important DNA methylation differences were observed, suggesting that other mechanism may be involved in controlling these genes expression. Show more

Keywords: epigenetics, gene expression, HSPA8, HSPA9, mRNA

DOI: 10.3233/JAD-130428

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 165-170, 2014

Authors: Chien, David T. | Szardenings, A. Katrin | Bahri, Shadfar | Walsh, Joseph C. | Mu, Fanrong | Xia, Chunfang | Shankle, William R. | Lerner, Alan J. | Su, Min-Ying | Elizarov, Arkadij | Kolb, Hartmuth C.

Article Type: Research Article

Abstract: Aggregates of hyperphosphorylated tau (PHF-tau), such as neurofibrillary tangles, are linked to the degree of cognitive impairment in Alzheimer's disease. We have recently reported early clinical results of a novel PHF-tau targeting PET imaging agent, [F18]-T807. Since then, we have investigated a second novel PHF-tau targeting PET imaging agent, [F18]-T808, with different pharmacokinetic characteristics, which may be favorable for imaging Alzheimer's disease and other tauopathies. Here, we describe the first human brain images with [F18]-T808.

Keywords: Alzheimer's disease, amyloid-β, brain imaging, mild cognitive impairment, molecular imaging, neurofibrillary tangles, PHF-tau, tau, tau aggregates, tauopathy

DOI: 10.3233/JAD-130098

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 171-184, 2014

Authors: Ito, Shingo | Ohtsuki, Sumio | Murata, Sho | Katsukura, Yuki | Suzuki, Hiroya | Funaki, Miho | Tachikawa, Masanori | Terasaki, Tetsuya

Article Type: Research Article

Abstract: Cerebral clearance of amyloid-β peptide (Aβ), which is implicated in Alzheimer's disease, involves elimination across the blood-brain barrier (BBB), and we previously showed that an insulin-sensitive process is involved in the case of Aβ1-40 . The purpose of this study was to clarify the molecular mechanism of the insulin-sensitive Aβ1-40 elimination across mouse BBB. An in vivo cerebral microinjection study demonstrated that [125 I]hAβ1-40 elimination from mouse brain was inhibited by human natriuretic peptide (hANP), and [125 I]hANP elimination was inhibited by hAβ1-40 , suggesting that hAβ1-40 and hANP share a common elimination process. Internalization of [125 …I]hAβ1-40 into cultured mouse brain capillary endothelial cells (TM-BBB4) was significantly inhibited by either insulin, hANP, other natriuretic peptides or insulin-degrading enzyme (IDE) inhibitors, but was not inhibited by phosphoramidon or thiorphan. Although we have reported the involvement of natriuretic peptide receptor C (Npr-C) in hANP internalization, cells stably expressing Npr-C internalized [125 I]hANP but not [125 I]hAβ1-40 , suggesting that there is no direct interaction between Npr-C and hAβ1-40 . IDE was detected in plasma membrane of TM-BBB4 cells, and internalization of [125 I]hAβ1-40 by TM-BBB4 cells was reduced by IDE-targeted siRNAs. We conclude that elimination of hAβ1-40 from mouse brain across the BBB involves an insulin- and ANP-sensitive process, mediated by IDE expressed in brain capillary endothelial cells. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, atrial natriuretic peptide, blood-brain barrier, brain capillary endothelial cells, insulin-degrading enzyme

DOI: 10.3233/JAD-122077

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 185-200, 2014

Authors: Tolppanen, Anna-Maija | Ngandu, Tiia | Kåreholt, Ingemar | Laatikainen, Tiina | Rusanen, Minna | Soininen, Hilkka | Kivipelto, Miia

Article Type: Research Article

Abstract: Background: Obesity has been consistently associated with dementia. The role of certain risk factors of dementia may change during life, and the importance of having a life-course perspective has been acknowledged. Objective: The aim of this study was to investigate the association of midlife and late-life body mass index (BMI) with late-life dementia/Alzheimer’s disease (AD) and whether the association was independent of other obesity-related co-morbidities. Methods: The association between midlife BMI (mean age 50.2, SD 6.0) and late-life BMI (mean age 71.2, SD 4.0) and incident dementia later in life (mean age 75.7, SD 5.0) were …investigated among 1,304 participants of the longitudinal population-based Cardiovascular risk factors, Aging and Dementia (CAIDE) study, conducted in Eastern Finland. The duration of follow-up was 26 years. The diagnosis of dementia was based on DSM-IV criteria and the probable and possible AD on the NINCDS-ADRDA criteria. Results: Higher midlife BMI was associated with higher risk of incident dementia (adjusted HR, 95% CI 1.07, 1.00–1.14). However, decrease in BMI from midlife to late-life was associated with higher risk of dementia (1.14, 1.03–1.25 for one-unit decrease) and AD (1.20, 1.09–1.33). High late-life BMI was associated with lower risk of AD (0.89, 0.81–0.98) but the association with dementia was less evident (0.94, 0.86–1.03). Conclusion: Higher midlife BMI is related to higher risk of dementia and AD, independently of obesity-related risk factors and co-morbidities. Steeper decrease of BMI and low late-life BMI are associated with higher risk of dementia and AD. These findings highlight the importance of life-course perspective when assessing the association between BMI and cognition. Show more

Keywords: Alzheimer's disease, body mass index, dementia, obesity

DOI: 10.3233/JAD-130698

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 201-209, 2014

Authors: Heringa, Sophie M. | Reijmer, Yael D. | Leemans, Alexander | Koek, Huiberdina L. | Kappelle, L. Jaap | Biessels, Geert Jan | on behalf of the Utrecht Vascular Cognitive Impairment (VCI) Study Group

Article Type: Research Article

Abstract: Background: Cerebral microbleeds are a manifestation of small vessel disease and are common in patients with Alzheimer’s disease (AD). However, their clinical significance in this condition is uncertain. We hypothesized that microbleeds contribute to disturbances of the cerebral network in AD and as such may affect cognition. Objective: The goal of this study was to examine the relationship between microbleeds and brain networks in patients with amnestic mild cognitive impairment (aMCI) or early AD. Methods: Sixty-seven patients (77.9 ± 7.5 years) with aMCI (n = 29) or early AD (n = 38) underwent cognitive testing and …3Tesla MRI. Microbleeds were rated visually. Diffusion tensor imaging and graph theoretical analysis were used to reconstruct brain networks and to quantify network efficiency for each patient. Network measures were compared between patients without and with ⩾1 microbleeds and between patients without or with ≥3 microbleeds. In secondary analyses, cognitive functioning was compared between groups. Analyses were adjusted for age and gender, and additionally for other markers of small vessel disease and atrophy. Results: Network measures did not differ between patients with ≥1 microbleed (n = 26) and patients without microbleeds (n = 41). However, patients with ≥3 microbleeds (n = 11) showed significant white matter disruptions, longer path length, and less global efficiency than patients without microbleeds, independent of other markers of small vessel disease and atrophy. Cognitive functioning did not differ between patients without microbleeds and patients with ≥1 or ≥3 microbleeds. Conclusion: Multiple microbleeds are related to structural network disruption in patients with early AD, but their direct impact on cognitive functioning appears to be limited. Show more

Keywords: Alzheimer's disease, cerebral amyloid angiopathy, cerebral small vessel disease, cognition, diffusion tensor imaging, magnetic resonance imaging, microbleeds, mild cognitive impairment, network

DOI: 10.3233/JAD-130542

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 211-221, 2014

Article Type: Other

DOI: 10.3233/JAD-130543

Citation: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 223-225, 2014