Journal of Alzheimer's Disease - Volume 29, issue 4

Authors: Harrison, Fiona E.

Article Type: Review Article

Abstract: Antioxidants in the diet have long been thought to confer some level of protection against the oxidative damage that is involved in the pathology of Alzheimer's disease as well as general cognitive decline in normal aging. Nevertheless, support for this hypothesis in the literature is equivocal. In the case of vitamin C (ascorbic acid) in particular, lack of consideration of some of the specific features of vitamin C metabolism has led to studies in which classification of participants according to vitamin C status is inaccurate, and the absence of critical information precludes the drawing of appropriate conclusions. Vitamin C levels …in plasma are not always reported, and estimated daily intake from food diaries may not be accurate or reflect actual plasma values. The ability to transport ingested vitamin C from the intestines into blood is limited by the saturable sodium-dependent vitamin C transporter (SVCT1) and thus very high intakes and the use of supplements are often erroneously considered to be of greater benefit that they really are. The current review documents differences among the studies in terms of vitamin C status of participants. Overall, there is a large body of evidence that maintaining healthy vitamin C levels can have a protective function against age-related cognitive decline and Alzheimer's disease, but avoiding vitamin C deficiency is likely to be more beneficial than taking supplements on top of a normal, healthy diet. Show more

Keywords: Alzheimer's disease, ascorbic acid, cognition, vitamin C

DOI: 10.3233/JAD-2012-111853

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 711-726, 2012

Authors: Liu, Zan-Chao | Fu, Zheng-Qi | Song, Jie | Zhang, Jia-Yu | Wei, Yu-Ping | Chu, Jiang | Han, Li | Qu, Na | Wang, Jian-Zhi | Tian, Qing

Article Type: Research Article

Abstract: Hyperphosphorylated tau is the major component of intracellular neurofibrillary tangles, which is positively correlated with the cognitive decline in Alzheimer's disease (AD). The upstream factors leading to tau hyperphosphorylation are still not fully understood. Endoplasmic reticulum (ER) stress has been indicated in AD pathogenesis and the increased level of binding immunoglobulin protein (Bip), an important ER associated chaperon, is increased in AD brain. Here hyperphosphorylation of tau, activation of glycogen synthase kinase-3β (GSK-3β), and elevation of Bip were induced by ventricular infusion of ER stressors, tunicamycin (TM) and thapsigargin (TG), in rats. GSK-3β was found to be responsible for tau …hyperphosphorylation induced by ER stressors both in vivo and in vitro. In addition, inhibited Akt, protein tyrosine phosphatase 1B, and activated Fyn were detected in vivo. Down-regulating Bip by tranfecting its siRNA plasmid significantly revised tau hyperphosphorylation in TG treated HEK293/tau cells, but the activation of GSK-3β was still observed. By immunoprecipitation, we found that the binding levels of Bip to tau and GSK-3β were significantly increased with the elevation of Bip in TM-treated rats. Moreover, in Bip overexpressed HEK293/tau cells, the binding levels of Bip to tau (mainly phosphorylated tau) and GSK-3β were also significantly increased. However, β-catenin, another important substrate of GSK-3β, was not found bound to the increased Bip. All these data suggest an essential role of Bip in GSK-3β dependent tau hyperphosphorylation in ER stress by promoting the binding of GSK-3β to tau. Show more

Keywords: Alzheimer's disease, Bip, endoplasmic reticulum stress, GSK-3β, tau

DOI: 10.3233/JAD-2012-111898

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 727-740, 2012

Authors: Miralbell, Julia | Spulber, Gabriela | Hooshmand, Babak | Besga, Ariadna | Mataró, Maria | Cedazo-Minguez, Angel | Kivipelto, Miia | Wahlund, Lars-Olof

Article Type: Research Article

Abstract: The aim of this study was to investigate brain tissue volumes, grey matter (GM) distribution, and cognitive performance for cognitively impaired subjects using cerebrospinal fluid (CSF) biomarker cut-offs as grouping criteria. 41 subjects attending the Memory Clinic, Karolinska University Hospital, Huddinge, Sweden, were divided into groups based on normal or abnormal CSF levels of Aβ1-42 , t-tau, and p-tau181 . SIENAX algorithms were employed for brain tissue volumes estimation and voxel-based morphometry (VBM) for mapping the differences in GM patterns. VBM revealed significant lower GM volumes in temporo-parietal, occipital, and prefrontal cortices for those subjects belonging to abnormal CSF t-tau …and p-tau181 groups. No differences were found between groups according to CSF Aβ1-42 cut-offs. Patients with abnormal CSF p-tau181 showed lower cognitive performance compared to those with normal levels. Patients with abnormal levels of CSF tau (but not Aβ1-42 ) showed an Alzheimer's disease-like pattern for both GM distribution and cognitive profile, compared to those with normal levels. These results support the hypothesis that CSF t-tau or p-tau181 levels may be of direct value for the evaluation of disease severity. Show more

Keywords: Alzheimer's disease, CSF biomarkers, grey matter, MRI, voxel based morphometry

DOI: 10.3233/JAD-2012-111553

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 741-749, 2012

Authors: Di Bona, Danilo | Rizzo, Claudia | Bonaventura, Giuseppe | Candore, Giuseppina | Caruso, Calogero

Article Type: Research Article

Abstract: It has been hypothesized that polymorphisms of interleukin (IL)-10 genes affect the risk of developing late onset Alzheimer's disease (AD). However, results of different studies are often inconsistent. Our aim was to investigate by meta-analysis the association of the common polymorphisms comprehensively defining the genetic variability of the IL-10 gene with AD risk. Fifteen studies investigating the association between IL-10 polymorphisms (-1082, -819, -592) and AD were found and analyzed. The model-free approach was applied to meta-analyze these case-control genetic association studies. Available data suggested an association between -1082 polymorphism and AD risk with a marginal statistical significance (GG versus …AG/AA: pooled odds ratio [OR]: 0.82, 95% confidence interval CI: 0.65–1.02) and evidence of a moderate degree of between-study heterogeneity (χ2 = 27.13, d.f. = 13, p = 0.01, I2 = 52%). For the -819 and -592 polymorphisms, we did not find an association with AD, but significant between-study heterogeneity made genotype data pooling unacceptable. Analysis by IL-10 haplotype showed that the -1082G/-819C/-592C haplotype is associated with a lower risk of AD, although with a marginal statistical significance, probably due to the low number of studies included (GCC versus other genotypes: OR: 0.61, 95% CI: 0.32–1.15; I2 : 85%). Current findings suggest a possible association between -1082 A > G polymorphism and the risk of developing AD; this effect is more evident in the oldest patients. The high degree of between-study heterogeneity, due to several underpowered studies and to other methodological problems of individual studies underlies the need for further methodologically adequate studies. Show more

Keywords: Alzheimer's disease, IL-10, meta-analysis, polymorphisms

DOI: 10.3233/JAD-2012-111838

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 751-759, 2012

Authors: Spalletta, Gianfranco | Girardi, Paolo | Caltagirone, Carlo | Orfei, Maria Donata

Article Type: Research Article

Abstract: Anosognosia is a multidimensional phenomenon that negatively affects course of illness. This study aimed to explore the association between anosognosia and neuropsychiatric phenomena in mild Alzheimer's disease (AD) and in mild cognitive impairment (MCI). The Anosognosia Questionnaire for Dementia to assess anosognosia, and the Neuropsychiatric Inventory to assess neuropsychiatric symptoms were administered to 209 patients (103 mild AD, 52 amnestic-MCI, and 54 amnestic multidomain-MCI). Categorical diagnoses of apathy, depression, and psychosis were made using specific criteria for dementia. With regard to continuous scores, in mild AD, we found positive correlation between symptoms of anosognosia and apathy, agitation and aberrant motor …behaviors, while in MCI, we did not find significant association. At a categorical level, the diagnosis of anosognosia in mild AD was associated with the diagnosis of apathy. In mild AD, the frequent co-occurrence of frontally mediated behavioral disorders and anosognosia, particularly apathy, supports the hypothesis of a shared neuropsychogenic process due to the disruption of frontal brain networks. Show more

Keywords: Alzheimer's disease, apathy, awareness, behavioral symptoms, depression

DOI: 10.3233/JAD-2012-111886

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 761-772, 2012

Authors: Valls-Pedret, Cinta | Lamuela-Raventós, Rosa Maria | Medina-Remón, Alexander | Quintana, Melibea | Corella, Dolores | Pintó, Xavier | Martínez-González, Miguel Ángel | Estruch, Ramon | Ros, Emilio

Article Type: Research Article

Abstract: Brain oxidative processes play a major role in age-related cognitive decline, thus consumption of antioxidant-rich foods might help preserve cognition. Our aim was to assess whether consumption of antioxidant-rich foods in the Mediterranean diet relates to cognitive function in the elderly. In asymptomatic subjects at high cardiovascular risk (n = 447; 52% women; age 55–80 y) enrolled in the PREDIMED study, a primary prevention dietary-intervention trial, we assessed food intake and cardiovascular risk profile, determined apolipoprotein E genotype, and used neuropsychological tests to evaluate cognitive function. We also measured urinary polyphenols as an objective biomarker of intake. Associations between energy-adjusted …food consumption, urinary polyphenols, and cognitive scores were assessed by multiple linear regression models adjusted for potential confounders. Consumption of some foods was independently related to better cognitive function. The specific associations [regression coefficients (95% confidence intervals)] were: total olive oil with immediate verbal memory [0.755 (0.151–1.358)]; virgin olive oil and coffee with delayed verbal memory [0.163 (0.010–0.316) and 0.294 (0.055–0.534), respectively]; walnuts with working memory [1.191 (0.061–2.322)]; and wine with Mini-Mental State Examination scores [0.252 (0.006–0.496)]. Urinary polyphenols were associated with better scores in immediate verbal memory [1.208 (0.236–2.180)]. Increased consumption of antioxidant-rich foods in general and of polyphenols in particular is associated with better cognitive performance in elderly subjects at high cardiovascular risk. The results reinforce the notion that Mediterranean diet components might counteract age-related cognitive decline. Show more

Keywords: Aging, coffee, cognition, Mediterranean diet, nutrition, polyphenols, olive oil, walnuts, wine

DOI: 10.3233/JAD-2012-111799

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 773-782, 2012

Authors: Chua, Li-Min | Lim, Mei-Li | Chong, Pey-Rou | Hu, Ze Ping | Cheung, Nam Sang | Wong, Boon-Seng

Article Type: Research Article

Abstract: Reduced glucose utilization is likely to precede the onset of cognitive deficits in Alzheimer's disease (AD). Similar aberrant glucose metabolism can also be detected in the brain of several AD mouse models. Although the cause of this metabolic defect is not well understood, it could be related to impaired insulin signaling that is increasingly being reported in AD brain. However, the temporal relationship between insulin impairment and amyloid-β (Aβ) biogenesis is unclear. In this study using female AβPPsw/PS1ΔE9 mice, we found that the level of Aβ40 was fairly constant in 6- to 15-month-old brains, whereas Aβ42 was only …significantly increased in the 15-month-old brain. In contrast, increased levels of IRβ, IGF-1R, IRS1, and IRS-2, along with reduced glucose and insulin content, were detected earlier in the 12-month-old brains of AβPPsw/PS1ΔE9 mice. The reduction in brain glucose content was accompanied by increased GLUT3 and GLUT4 levels. Importantly, these changes precede the significant upregulation of Aβ42 level in the 15-month-old brain. Interestingly, reduction in the p85 subunit of PI3K was only apparent in the 15-month-old AβPPsw/PS1ΔE9 mouse brain. Furthermore, the expression profile of IRβ, IRS-2, and p85/PI3K in AβPPsw/PS1ΔE9 was distinct in wild-type mice of a similar age. Although the exact mechanisms underlining this connection remain unclear, our results suggest a possible early role for insulin signaling impairment leading to amyloid accumulation in AβPPsw/PS1ΔE9 mice. Show more

Keywords: Alzheimer's disease, amyloid, glucose transporter, insulin signaling, neurodegeneration

DOI: 10.3233/JAD-2012-111880

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 783-791, 2012

Authors: Kim, Kyung Hwa | Moon, Minho | Yu, Saet-Byeol | Mook-Jung, Inhee | Kim, Jong-Il

Article Type: Research Article

Abstract: The pathogenesis of Alzheimer's disease (AD), especially the early events of AD pathology, remains unknown because of the complexity of AD and limitation of analysis methods. Transcriptome analysis has provided comprehensive insights to investigate the complex cellular activity in brain, but the transcriptome profiles from AD patients with microarray have generated discordant results. Here, for the first time, we performed transcriptome analysis of frontal cortex and cerebellum in 7-week-old 5XFAD transgenic mice (before extracellular amyloid plaque deposits) using high-throughput RNA-Seq analysis. Specific functional annotations were identified with differentially expressed genes (DEGs) of frontal cortex (a typically vulnerable region of AD …pathology) and cerebellum (a typically non-vulnerable region of AD pathology). Cardiovascular disease-related genes were significantly found in down-regulated DEGs of frontal cortex, and mitochondrial dysfunction-related genes were evident in down-regulated DEGs of cerebellum. Additionally, we found RNA variants at the nucleotide level in transgenic mice compared with non-transgenic mice. Our results indicate that both frontal cortex and cerebellum in 5XFAD transgenic mice show specific pathological processes in the early pathophysiology of AD. Show more

Keywords: 5XFAD, Alzheimer's disease, differentially expressed genes, RNA-Seq, RNA variants

DOI: 10.3233/JAD-2012-111793

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 793-808, 2012

Authors: Bibl, Mirko | Gallus, Marion | Welge, Volker | Esselmann, Hermann | Wiltfang, Jens

Article Type: Research Article

Abstract: Carboxyterminally elongated and aminoterminally truncated amyloid-β (Aβ) peptides and their oxidized derivates are major constituents of human amyloid plaques. The objective of the present study was to clarify the diagnostic impact of the Aβ peptides 1-38ox , 2-40, and 2-42 peptides on the neurochemical cerebrospinal fluid (CSF) diagnosis of Alzheimer's disease (AD). For this purpose, 22 patients with AD and 20 non-demented disease controls (NDC) were comparatively analyzed for their cerebrospinal fluid pattern of Aβ1-38 ox , Aβ2-40 , and Aβ2-42 along with Aβ1-37 , Aβ1-38 , Aβ1-39 , Aβ1-40 , Aβ1-40 ox , and Aβ1-42 using a …novel sequential aminoterminally and carboxyterminally specific immunoprecipitation protocol and subsequent analysis in the Aβ-SDS-PAGE/immunoblot. The Aβ peptides 1-38ox , 2-40, and 2-42 could not be consistently detected in the investigated CSF samples, which applied to samples from AD and NDC patients alike. Otherwise, our approach revealed a striking decrease of Aβ1-42 and Aβ2-42 , but not of Aβ1-38 ox and Aβ2-40 in AD. Both Aβ1-42 and Aβ2-42 reached reasonable accuracies for diagnosing AD alone as well as in relation to Aβ1-40 , Aβ1-38 , or the sum of all measured Aβ peptides. Aβ1-38 ox was negatively correlated to the Mini-Mental Status Examination score of AD patients, indicating that this peptide to linked to disease severity. We conclude that an exact analysis of CSF Aβ peptides regarding their carboxy- and aminoterminus as well as posttranslational modification may be a promising approach for diagnosing and tracking AD. Show more

Keywords: Alzheimer's disease, aminoterminally truncated, cerebrospinal fluid, dementia, oxidized amyloid-β peptides

DOI: 10.3233/JAD-2012-111796

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 809-816, 2012

Authors: Perrin, Margaux | Henaff, Marie-Anne | Padovan, Catherine | Faillenot, Isabelle | Merville, Adrien | Krolak-Salmon, Pierre

Article Type: Research Article

Abstract: Healthy subjects remember emotional stimuli better than neutral, as well as stimuli embedded in an emotional context. This better memory of emotional messages is linked to an amygdalo-hippocampal cooperation taking place in a larger fronto-temporal network particularly sensitive to pathological aging. Amygdala is mainly involved in gist memory of emotional messages. Whether emotional content or context enhances memory in mild Alzheimer's disease (AD) patients is still debated. The aim of the present study is to examine the influence of emotional content and emotional context on the memory in mild AD, and whether this influence is linked to amygdala volume. Fifteen …patients affected by mild AD and 15 age-matched controls were submitted to series of negative, positive, and neutral pictures. Each series was embedded in an emotional or neutral sound context. At the end of each series, participants had to freely recall pictures, and answer questions about each picture. Amygdala volumes were measured on patient 3D-MRI scans. In the present study, emotional content significantly favored memory of gist but not of details in healthy elderly and in AD patients. Patients' amygdala volume was positively correlated to emotional content memory effect, implying a reduced memory benefit from emotional content when amygdala was atrophied. A positive context enhanced memory of pictures in healthy elderly, but not in AD, corroborating early fronto-temporal dysfunction and early working memory limitation in this disease. Show more

Keywords: Alzheimer's disease, amygdala, emotions, memory

DOI: 10.3233/JAD-2012-111490

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 817-826, 2012