Journal of Alzheimer's Disease - Volume 45, issue 2

Authors: Revel, Frédéric | Gilbert, Thomas | Roche, Sylvain | Drai, Jocelyne | Blond, Emilie | Ecochard, René | Bonnefoy, Marc

Article Type: Research Article

Abstract: Background: Abnormal oxidative stress is an established feature of Alzheimer’s disease (AD). Markers of lipoperoxidation and deficits in serum antioxidants could have a predictive value for identifying subjects at risk of dementia and to predict cognitive decline. Objective: Search for relationships between the levels of some oxidative stress biomarkers and cognitive function decline that would help predict this decline. Methods: The study solicited and included 97 patients aged 63 to 93 years with various suspected neurodegenerative diseases (35 with AD). They were followed up at six-month intervals over two years (2010–2012). The study: i) assessed the …blood levels of glutathione peroxidase, glutathione, and malondialdehyde; ii) performed the Mini-Mental Status Examination (MMSE), the Clock Drawing test, the free/cued recall task with 16-item lists, the cue percentage; and the Trail Making Test; and iii) acquired brain magnetic resonance imaging or tomodensitometry. The primary outcome measure was the MMSE score. Results: The MMSE score was correlated with the score of each neuropsychological test, the age at baseline, and the glutathione level. On average, the decline in the MMSE score was 1.63 points per six months. A 100 International Unit increase in glutathione peroxidase was associated with an average loss of 1.19 MMSE points per six months (p = 0.002). A 100 µmol/L increase in glutathione was associated with an average loss of 1.80 MMSE points per six months (p = 0.014). Conclusion: Oxidative stress biomarkers, especially glutathione peroxidase and glutathione, may predict the course of cognitive decline in patients with AD or other neurodegenerative disorders. Show more

Keywords: Alzheimer's disease, biological markers, glutathione, glutathione peroxidase, malondialdehyde, oxidative stress

DOI: 10.3233/JAD-141797

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 553-560, 2015

Authors: Zhang, Hua | Liu, Jie | Sun, Suya | Pchitskaya, Ekaterina | Popugaeva, Elena | Bezprozvanny, Ilya

Article Type: Research Article

Abstract: Alzheimer's disease (AD) and aging result in impaired ability to store memories, but the cellular mechanisms responsible for these defects are poorly understood. Presenilin 1 (PS1) mutations are responsible for many early-onset familial AD (FAD) cases. The phenomenon of hippocampal long-term potentiation (LTP) is widely used in studies of memory formation and storage. Recent data revealed long-term LTP maintenance (L-LTP) is impaired in PS1-M146V knock-in (KI) FAD mice. To understand the basis for this phenomenon, in the present study we analyzed structural synaptic plasticity in hippocampal cultures from wild type (WT) and KI mice. We discovered that exposure to picrotoxin …induces formation of mushroom spines in both WT and KI cultures, but the maintenance of mushroom spines is impaired in KI neurons. This maintenance defect can be explained by an abnormal firing pattern during the consolidation phase of structural plasticity in KI neurons. Reduced frequency of neuronal firing in KI neurons is caused by enhanced calcium-induced calcium release (CICR), enhanced activity of calcium-activated potassium channels, and increased afterhyperpolarization. As a result, “consolidation” pattern of neuronal activity converted to “depotentiation” pattern of neuronal activity in KI neurons. Consistent with this model, we demonstrated that pharmacological inhibitors of CICR (dantrolene), of calcium-activated potassium channels (apamin), and of calcium-dependent phosphatase calcineurin (FK506) are able to rescue structural plasticity defects in KI neurons. Furthermore, we demonstrate that incubation with dantrolene or apamin also rescued L-LTP defects in KI hippocampal slices, suggesting a role for a similar mechanism. This proposed mechanism may be responsible for memory defects in AD but also for age-related memory decline. Show more

Keywords: Alzheimer's disease, calcium signaling, excitability, synaptic plasticity

DOI: 10.3233/JAD-142427

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 561-580, 2015

Authors: Moreau, Noémie | Rauzy, Stéphane | Bonnefoi, Bernadette | Renié, Laurent | Martinez-Almoyna, Laurent | Viallet, François | Champagne-Lavau, Maud

Article Type: Research Article

Abstract: Theory of Mind refers to the ability to infer other's mental states, their beliefs, intentions, or knowledge. To date, only two studies have reported the presence of Theory of Mind impairment in mild cognitive impairment (MCI). In the present study, we evaluated 20 MCI patients and compared them with 25 healthy control participants using two Theory of Mind tasks. The first task was a false belief paradigm as frequently used in the literature, and the second one was a referential communication task, assessing Theory of Mind in a real situation of interaction and which had never been used before in …this population. The results showed that MCI patients presented difficulties inferring another person's beliefs about reality and attributing knowledge to them in a situation of real-life interaction. Two different patterns of Theory of Mind emerged among the patients. In comparison with the control group, some MCI patients demonstrated impairment only in the interaction task and presented isolated episodic memory impairment, while others were impaired in both Theory of Mind tasks and presented cognitive impairment impacting both episodic memory and executive functioning. Theory of Mind is thus altered in the very early stages of cognitive impairment even in real social interaction, which could impact precociously relationships in daily life. Show more

Keywords: Episodic memory, executive functions, mild cognitive impairment, social interaction, theory of mind

DOI: 10.3233/JAD-143021

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 581-597, 2015

Authors: Ye, Byoung Seok | Choi, Seong Hye | Han, Seol-Heui | Kim, SangYun | Yang, Dong-Won | Park, Kee Hyung | Han, Hyun Jeong | Youn, Young Chul | Choi, Byung-Ok | Kim, Seung H. | Woo, Sook-young | Na, Duk L. | Kim, Eun-Joo

Article Type: Research Article

Abstract: Background: Cognitive performance changes with chronological aging. Previous studies investigating clinical heterogeneity in frontotemporal dementia (FTD) according to the age of symptom onset did not consider the effect of chronological aging on cognition. Objective: We compared cognitive and behavioral symptoms in patients with early-onset (EO) and late-onset (LO) FTD with consideration of chronological aging effect. Methods: A total of 166 FTD patients were enrolled consecutively from multi-center memory clinics using a nationwide FTD register. To control for the effects of chronological aging on neuropsychological scores, seven hundred and two subjects with normal cognition were also enrolled …and regression models were set up. Neuropsychological scores that were detrended with the regression models and the behavioral symptoms of the EO-FTD and LO-FTD groups were compared. Subgroup analyses were performed for three main subtypes of FTD, behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA). Results: Among 166 FTD patients, there were 76 bvFTD, 57 SD, and 33 PNFA patients who met new diagnostic criteria for bvFTD or primary progressive aphasia, respectively. LO-FTD (48.2%) was more common than previously thought and the proportions of EO and LO groups differed across FTD subtypes. EO-FTD patients had lower memory and frontal/executive scores and more prominent frontal/behavioral symptoms than LO-FTD patients. Conclusion: Our study suggested that FTD could be heterogeneous with respect the age of symptom onset. After controlling for the effects of chronological aging, EO-FTD patients exhibited more profound memory and frontal/executive dysfunction and more behavioral symptoms than LO-FTD patients. Show more

Keywords: Age at symptom onset, behavior, frontotemporal dementia, neuropsychology

DOI: 10.3233/JAD-141044

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 599-608, 2015

Authors: Miranda, Luís F.J.R. | Gomes, Karina B. | Silveira, Josianne N. | Pianetti, Gerson A. | Byrro, Ricardo M.D. | Peles, Patrícia R.H. | Pereira, Fernando H. | Santos, Thiago R. | Assini, Arthur G. | Ribeiro, Valéria V. | Tito, Pedro A.L. | Matoso, Rafael O. | Lima, Thiago O.L. | Moraes, Edgar N. | Caramelli, Paulo

Article Type: Research Article

Abstract: Background: Naturalistic studies evaluate individuals in their usual way of living, presenting more “real-life” data regarding patients and their diseases. Objective: To investigate demographic, clinical, and genetic factors that could be predictive of good response to cholinesterase inhibitors (ChEI) treatment in Alzheimer’s disease (AD) and AD + cerebrovascular disease (CVD). Patients and Methods: A total of 129 patients were diagnosed with AD or AD + CVD and with mild-to-moderate dementia. After a 12-month treatment, 97 patients completed the study. They were evaluated at baseline and after three, six, and 12 months of ChEI (donepezil or rivastigmine …or galantamine) use. APOE genotype and CYP2D6 polymorphisms were determined for all of the participants. In each visit, we used cognitive, functional, mood, and behavior scales. We classified patients according to their scores in the Mini-Mental State Examination (MMSE). Good responders were defined as those scoring ≥2 in the MMSE at 12 months. Results: The rate of good clinical response was 27.8%. In a longitudinal analysis, the patients with mild AD and also good responders at three months were considered to be good responders at 12 months. There was no correlation between ChEI dose, APOE and CYP2D6 polymorphisms, and the pattern of clinical response. Conclusion: A higher rate of good response was observed in this study compared to that in previous investigations. The pharmacogenetic aspects do not seem to have an influence in the response. Show more

Keywords: Alzheimer's disease, APOE and CYP2D6 polymorphisms, cholinesterase inhibitors, predictive factors, response

DOI: 10.3233/JAD-142148

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 609-620, 2015

Authors: Moreno-Grau, Sonia | Barneda, Bruna | Carriba, Paulina | Marín, Juan | Sotolongo-Grau, Oscar | Hernández, Isabel | Rosende-Roca, Maitée | Mauleón, Ana | Vargas, Liliana | Espinosa, Ana | Alegret, Montserrat | Rodriguez, Octavio | Ortega, Gemma | Fernández, Maria Victoria | López-Arrieta, Jesús | Tárraga, Lluís | Boada, Mercè | Antúnez, Carmen | López, Joaquin | Ruiz, Agustín | Comella, Joan Xavier

Article Type: Research Article

Abstract: The objective of this study was to identify genetic variation in genes encoding death receptors and signals that modulate their activity. After conducting a meta-analysis with five previous genome-wide association studies and aggregated data, the most significant signals, (TNF locus: rs2395488, rs2534672, and rs9267445; and FASLG locus: rs730278), were replicated in 1,046 cases and 372 controls. The rs2395488 and rs2534672 markers showed a modest protective effect (OR = 0.849, p = 0.49780; OR = 0.687, p = 0.11335), in contrast to rs730278 marker (OR = 1.146, p = 0.17212), which did not follow the previous effect direction; in any case …it reached the significance level. Final meta-analysis, adding the replication sample, confirmed these observations. We concluded that FASLG marker is not etiologically linked to Alzheimer's disease. However, single nucleotide polymorphisms around TNF locus require further analyses in order to explain the association between Alzheimer's disease and human leukocyte antigen. Show more

Keywords: Alzheimer's disease, apoptosis, death receptors, FASLG, genetics, genome-wide association study, meta-analysis, TNF

DOI: 10.3233/JAD-142721

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 621-629, 2015

Authors: Moyse, Evelyne | Bastin, Christine | Salmon, Eric | Brédart, Serge

Article Type: Research Article

Abstract: A prerequisite for any function in social cognition is the perception and processing of social cues. Age estimation is a skill that is used in everyday life and is fundamental in social interactions. This study evaluated whether facial age estimation is impaired in patients with mild to moderate Alzheimer's disease (AD). The current age of faces is known to have an impact on age estimation, and therefore stimuli belonging to different age groups (young, middle-aged, and older adults' faces) were used. As expected, an impairment of age estimation from faces was observed in mild to moderate AD patients. However, the …profile of impairment depended on the age of faces and stage of the disease. Mild AD patients presented difficulties mainly in assessing the age of middle-aged adults. In moderate disease stage, these difficulties also affected the age estimation of young adult faces. Interestingly, AD patients remained relatively good at estimating the age of older adults' faces, compared to healthy controls. Show more

Keywords: Age discrimination, Alzheimer's disease, face, social perception

DOI: 10.3233/JAD-142253

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 631-638, 2015

Authors: Zhang, Cheng | Kuo, Ching-Chang | Moghadam, Setareh H. | Monte, Louise | Rice, Kenner C. | Rissman, Robert A.

Article Type: Research Article

Abstract: Reports from Alzheimer's disease (AD) biomarker work have shown a strong link between oxidative stress and AD neuropathology. The nonenzymatic antioxidant, glutathione (GSH), plays a crucial role in defense against reactive oxygen species and maintenance of GSH redox homeostasis. In particular, our previous studies on GSH redox imbalance have implicated oxidative stress induced by excessive reactive oxygen species as a major mediator of AD-like events, with the presence of S-glutathionylated proteins (Pr-SSG) appearing prior to overt AD neuropathology. Furthermore, evidence suggests that oxidative stress may be associated with dysfunction of the hypothalamic-pituitary-adrenal axis, leading to activation of inflammatory pathways and …increased production of corticotropin-releasing factor (CRF). Therefore, to investigate whether oxidative insults can be attenuated by reduction of central CRF signaling, we administered the type-1 CRF receptor (CRFR1) selective antagonist, R121919, to AD-transgenic mice beginning in the preclinical/prepathologic period (30-day-old) for 150 days, a timepoint where behavioral impairments and pathologic progression should be measureable. Our results indicate that R121919 treatment can significantly reduce Pr-SSG levels and increase glutathione peroxide activity, suggesting that interference of CRFR1 signaling may be useful as a preventative therapy for combating oxidative stress in AD. Show more

Keywords: Alzheimer's disease, corticotropin-releasing factor-1 receptor (CRFR1), glutathione, glutathione peroxide, glutathione reductase, oxidative stress, oxidized glutathione, R121919, S-glutathionylated protein

DOI: 10.3233/JAD-141722

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 639-650, 2015

Authors: Wang, Xingbin | Lopez, Oscar | Sweet, Robert A. | Becker, James T. | DeKosky, Steven T. | Barmada, Mahmud M. | Feingold, Eleanor | Demirci, F. Yesim | Kamboh, M. Ilyas

Article Type: Research Article

Abstract: There is a strong genetic basis for late-onset of Alzheimer's disease (LOAD), and thus far >20 genes/loci have been identified that affect the risk of LOAD. In addition to disease risk, genetic variation at these loci may also affect components of the natural history of AD, such as survival in AD. In this study, we first examined the role of known LOAD genes with survival time in 983 AD patients. We then performed genome-wide single-nucleotide polymorphism (SNP) and gene-based association analyses to identify novel loci that may influence survival of AD. Survival analysis was conducted using Cox proportional hazards regression …under an additive genetics model. We found multiple nominally significant associations (p < 0.01) either within or adjacent to known LOAD genes. Genome-wide SNP analysis identified multiple suggestive novel loci and two of them were also significant in gene-based analysis (CCDC85C and NARS2) that survived after controlling for false-discovery rate at 0.05. In summary, we have identified two novel genes for survival in AD that need to be replicated in independent samples. Our findings highlight the importance of focusing on AD-related phenotypes that may help to identify additional genes relevant to AD. Show more

Keywords: Gene-based analysis, genome-wide association studies, late-onset Alzheimer's disease, survival

DOI: 10.3233/JAD-142442

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 651-658, 2015

Authors: Zheng, Nan | Yuan, Peng | Li, Changhao | Wu, Jun | Huang, Jian

Article Type: Research Article

Abstract: Beta-secretase (BACE1) controls an essential step for the generation of amyloid-β peptide (Aβ). As Aβ forms the principle pathologies in Alzheimer's disease, lowering Aβ production by inhibiting BACE1 is a plausible therapeutic approach. In the present study, we identified a natural polyphenol, luteolin, as a potent inhibitor of BACE1 transcription in human embryonic kidney 293 (HEK293) and human neuroblastoma (SH-SY5Y) cell lines. Luteolin is capable of suppressing the activation of BACE1 promoter by NF-κB signaling. We further characterized that luteolin interferes with NF-κB signaling by both directly and indirectly disrupting p65 complex formation. In addition, we discovered that estrogen receptor …mediates luteolin's effect in inhibiting NF-κB signaling and BACE1 transcription. Interestingly, the beneficial effects of luteolin may be attributed to selective activation profiles of luteolin to different estrogen receptor subtypes. Our study reports luteolin as a potent BACE1-inhibiting compound, providing useful information in understanding estrogen receptor- and NF-κB-mediated signaling in regulating BACE1 expression. Show more

Keywords: Alzheimer's disease, amyloid-β protein, beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1), estrogen receptor, luteolin, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)

DOI: 10.3233/JAD-142517

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 659-671, 2015