Journal of Alzheimer's Disease - Volume 27, issue 4

Authors: Cerami, Chiara | Marcone, Alessandra | Galimberti, Daniela | Villa, Chiara | Scarpini, Elio | Cappa, Stefano F.

Article Type: Research Article

Abstract: Frontotemporal lobar degeneration (FTLD) is a common early-onset dementia, which shows highly heterogeneous phenotypic presentations. Although an autosomal dominant transmission can be found only in about 10% cases, familial aggregation is frequently observed in FTLD. Recently, the progranulin gene (GRN) was reported to be involved in the disease pathogenesis. We describe two clinically different, apparently sporadic FTLD cases, sharing the previously described GRN mutation g.11019_11022delCACT (relative to nt1, NCBI NG_007886.1), alias Thr272fs, with a premorbid psychiatric history. Both patients are males and were in their sixties when diagnosed clinically with, respectively, the behavioral variant of frontotemporal dementia (bvFTD) and progressive …nonfluent aphasia (PNFA). In both cases, the medical history revealed the presence of bipolar spectrum disorders. Mutations in GRN are considered to be a major cause of FTLD. However, the phenotypes associated with these mutations are highly variable. Our description of two novel FTLD genetic cases confirms the high frequency of the g.11019_11022delCACT mutation in Northern Italy. On this basis, we recommend to consider the presence of this mutation as a possible cause of the disease, particularly in patients with premorbid psychiatric symptoms. Show more

Keywords: Bipolar disorder, dementia, frontotemporal dementia, frontotemporal lobar degeneration, GRN mutation, primary progressive nonfluent aphasia

DOI: 10.3233/JAD-2011-110788

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 791-797, 2011

Authors: Guan, Jun-Wen | Huang, Chang-Quan | Li, Yong-Hong | Wan, Chao-Min | You, Chao | Wang, Zheng-Rong | Liu, Yan-You | Liu, Qing-Xiu

Article Type: Research Article

Abstract: This study examined the association between hypertension and AD by using a quantitative meta-analysis of longitudinal studies. EMBASE and MEDLINE were searched for articles published up to February 2011. All studies that examined the association of hypertension or antihypertensive medication use with the onset of AD were included. Pooled relative risks (RR) were calculated using fixed and random effects models. Twelve studies met our inclusion criteria for this meta-analysis. All subjects were without dementia at baseline. Among them, 9 studies compared the incidence of AD between subjects with (7,270) and without (8,022) hypertension. The quantitative meta-analysis showed that there was …no significant difference in incidence of AD (RR: 1.02, 95% confidence interval (CI): 0.91–1.14) between subjects with and without hypertension. Seven studies compared the incidence of AD between subjects with (8,703) and without (13,041) antihypertensive medication use. The quantitative meta-analysis showed that there was no significant difference in incidence of AD (RR: 0.90, 95% CI: 0.79–1.03) between subjects with and without antihypertensive medication use. The quantitative meta-analysis showed that neither hypertension nor antihypertensive medication use was associated with risk for incident AD. Show more

Keywords: Alzheimer's disease, hypertension, meta-analysis

DOI: 10.3233/JAD-2011-111160

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 799-807, 2011

Authors: Licastro, Federico | Carbone, Ilaria | Ianni, Manuela | Porcellini, Elisa

Article Type: Research Article

Abstract: Genome wide association investigations from large cohorts of patients with Alzheimer's disease (AD) and non demented controls (CTR) showed that a limited set of genes were associated (p > 10−5 ) with the disease. A very recent study from our group showed that an additional limited group of SNP in selected genes were associated with AD. In this report we argue that the association of these genes with AD is suggestive of a pivotal role of environmental factors in the pathogenesis of the disease and one of these factors is virus infection. In other words, the genetic signature revealed by …genome wide association (GWA) studies discloses a network of genes that might influence the ability of the central nervous system to cope with and fight against the invasion by virus of the herpes family. In fact, Nectin-2 (NC-2); apolipoprotein E (APOE); glycoprotein carcinoembryonic antigen related cell adhesion molecule-16 (CEACAM-16); B-cell lymphoma-3 (Bcl-3); translocase of outer mitochondrial membrane 40 homolog (T0MM-40); complement receptor-1 (CR-l); APOJ or clusterin and C-type lectin domain A family-16 member (CLEC-16A); Phosphatidyl inositol- binding clathrin assembly protein gene (PICALM); ATP-bonding cassette, sub family A, member 7 (ABCA7); membrane spanning A4 (MSA4); CD2 associated protein (CD2AP); cluster of differentiation 33 (CD33); and ephrin receptor A1 (EPHA1) result in a genetic signature that might affect individual brain susceptibility to infection by the herpes virus family during aging, leading to neuronal loss, inflammation, and amyloid deposition. Show more

Keywords: Alzheimer's disease, genetic background, GWA studies, herpes-virus

DOI: 10.3233/JAD-2011-110755

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 809-817, 2011

Authors: Bihaqi, Syed Waseem | Huang, Hui | Wu, Jinfang | Zawia, Nasser H.

Article Type: Research Article

Abstract: The beginnings of late onset Alzheimer's disease (LOAD) are still unknown; however, the progressive and latent nature of neurodegeneration suggests that the triggering event occurs earlier in life. Aging primates exposed to lead (Pb) as infants exhibited an overexpression of the amyloid-β protein precursor (AβPP), amyloid-β (Aβ) and enhanced pathologic neurodegeneration. In this study, we measured the latent expression of a wide array of brain-specific genes and explored whether epigenetic pathways mediated such latent molecular and pathological changes. We analyzed the levels of proteins associated with DNA methylation, i.e., DNA methyltransferase 1 (Dnmt1), DNA methyltransferase3a (Dnmt3a), methyl-CpG binding protein-2 (MeCP2) …and those involved in histone modifications (acetylated and methylated histones). We monitored the expression profiles of these intermediates across the lifespan and analyzed their levels in 23-year-old primate brains exposed to Pb as infants. Developmental Pb exposure altered the gene expression of the arrayed genes, which were predominately repressed, with fewer upregulated genes. The latent induction and repression of genes was accompanied by a significant decrease in the protein levels of Dnmts, MeCP2, and proteins involved in histone modifications. The attenuation of DNA methylation enzymes is consistent with hypomethylating effects, which promote upregulation of the genes, while the alterations in the histone modifiers are associated with the repression of genes. Hence, we deduce that early life exposure to Pb can reprogram gene expression resulting in both upregulation and down-regulation of genes through alternate epigenetic pathways contributing to an enhancement in neurodegeneration in old age. Show more

Keywords: aging, Alzheimer's disease, DNA methylation, gene expression, histone modifications, Pb

DOI: 10.3233/JAD-2011-111013

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 819-833, 2011

Authors: Taghavi, Ali | Nasir, Samir | Pickhardt, Marcus | Hauβen, Roland Heyny-von | Mall, Gerhard | Mandelkow, Eckhard | Mandelkow, Eva-Maria | Schmidt, Boris

Article Type: Research Article

Abstract: The structure activity relationship of N′-benzylidene-benzohydrazide (NBB) binding to tau and paired helical filament (PHF) proteins as well as amyloid-β1-42 fibrils indicate differential selectivity for these protein aggregates. The ability of the compounds to stain neurofibrillary tangles and senile plaques isolated from human AD brain was investigated histochemically. These studies resulted in several tau-PHF and amyloid-β1-42 fibril selective ligands respectively. Supported by these results, we rationalized a model for the design of selective ligands for tau, PHF, and amyloid-β1-42 fibrils.

Keywords: Alzheimer's disease, amyloid-β, amphiphilicity, amphiphilic ligands, N′-benzylidene-benzohydrazide, neurofibrillary tangle, paired helical filament, selective tau ligands, tau, tau and PHF proteins

DOI: 10.3233/JAD-2011-111238

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 835-843, 2011

Authors: Dumurgier, Julien | Paquet, Claire | Peoc'h, Katell | Lapalus, Pauline | Mouton-Liger, François | Benisty, Sarah | Chasseigneaux, Stéphanie | Chabriat, Hughes | Hugon, Jacques

Article Type: Research Article

Abstract: Glucose dysmetabolism has been consistently associated with an increased risk of cognitive disorders, and brain insulin resistance could play a role in Alzheimer's disease (AD) pathogenesis. Recent evidence suggests that cerebrospinal fluid (CSF) biomarkers may reflect the brain pathology in AD. We have investigated the relationship between CSF concentrations of amyloid-β peptide 1-42 (Aβ1-42 ), total tau, and phosphorylated tau (ptau-181) and plasma and CSF glucose levels in a cohort of 94 newly diagnosed non-diabetics AD patients. We report that CSF Aβ1-42 level was inversely associated with CSF to plasma glucose ratio (Spearman's coefficient = −0.27, p = 0.008). …This relationship remained after adjustment for age, gender, body mass index, hypertension, and MMSE score (β [SE] of linear regression = −0.93 [0.37], p = 0.01). In stratified analysis, this relationship was observed only in patients who did not carry the apolipoprotein E4 allele. No significant relationship was found between glucose levels and total tau or phosphorylated tau 181. These results support the idea that a link between glucose dysmetabolism and the amyloid pathway may exist in the pathogenesis of AD. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, biomarkers, CSF, glucose

DOI: 10.3233/JAD-2011-111007

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 845-851, 2011

Authors: Lebbadi, Meryem | Julien, Carl | Phivilay, Alix | Tremblay, Cyntia | Emond, Vincent | Kang, Jing X. | Calon, Frédéric

Article Type: Research Article

Abstract: Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) reduces amyloid-β (Aβ) and tau pathology and improves cognitive performance in animal models of Alzheimer's disease (AD). To exclude confounding variables associated with the diet, we crossed 3 × Tg-AD mice (modeling AD neuropathology) with transgenic Fat-1 mice that express the fat-1 gene encoding a PUFA desaturase, which endogenously produces n-3 PUFA from n-6 PUFA. The expression of fat-1 shifted the n-3:n-6 PUFA ratio upward in the brain (+11%, p < 0.001), including docosahexaenoic acid (DHA; +5%, p < 0.001) in 20 month-old mice. The expression of fat-1 decreased the levels …of soluble Aβ42 (−41%, p < 0.01) at 20 months without reducing the level of insoluble forms of Aβ40 and Aβ42 in the brain of 3 × Tg-AD mice. The 3 × Tg-AD/Fat-1 mice exhibited lower cortical levels of both soluble (−25%, p < 0.05) and insoluble phosphorylated tau (−55%, p < 0.05) compared to 3 × Tg-AD mice, but only in 20 month-old animals. Whereas a decrease of calcium/calmodulin-dependent protein kinase II was observed in 3 × Tg-AD/Fat-1 mice (−039%, p < 0.05), altered tau phosphorylation could not be related to changes in glycogen synthase kinase 3β, cyclin-dependent kinase 5, or protein phosphatase type 2A enzymatic activity. In addition, the expression of the fat-1 transgene prevented the increase of glial fibrillary acidic protein (−37%, p < 0.01) observed in 20 month-old 3 × Tg-AD mice. In conclusion, the expression of fat-1 in 3 × Tg-AD mice increases brain DHA and induces biomarker changes that are consistent with a beneficial effect against an AD-like neuropathology. Show more

Keywords: Alzheimer disease, docosahexaenoic acids, n-3 fatty acid desaturase, n-3 polyunsaturated fatty acid, transgenic mice

DOI: 10.3233/JAD-2011-111010

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 853-869, 2011

Authors: Guglielmotto, Michela | Monteleone, Debora | Giliberto, Luca | Fornaro, Michele | Borghi, Roberta | Tamagno, Elena | Tabaton, Massimo

Article Type: Research Article

Abstract: The sequential endoproteolytic cleavages operated by the γ-secretase and the β-secretase (BACE1) on the amyloid-β protein precursor (AβPP) result in the production of the amyloid-β (Aβ) species, with two C-terminal variants, at residue 40 or at residue 42. Accumulation in brain tissue of small, soluble aggregates of Aβ42 is the major pathogenic event of Alzheimer's disease (AD). However, the physiologic activity of Aβ peptides is still elusive. Here, we show that expression of BACE1 is regulated by Aβ42 , which augments BACE1 gene transcription through the JNK/c-jun signaling pathway. Of note, Aβ40 has much less effect on BACE1 …expression. These findings unveil a positive feedback loop in which γ-secretase cleavage of AβPP releases a functionally-active peptide, Aβ42 , that promotes BACE1 transcription. Thus, gene expression induced by Aβ42 may have implications in the neuronal dysfunction and degeneration that occurs in AD. Show more

Keywords: Alzheimer's disease, amyloid-β42, BACE1, γ-secretase, JNK/c-jun pathway

DOI: 10.3233/JAD-2011-110884

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 871-883, 2011

Authors: Ashford, J. Wesson | Gere, Emily | Bayley, Peter J.

Article Type: Research Article

Abstract: Memory function generally deteriorates with age, and memory impairments are a common symptom of serious illness such as dementia. Although screening tests are widely used throughout Medicine, they are not yet commonly used to detect memory impairments. The objective of this study was to characterize an audience-based memory test suitable for administration to a large number of individuals simultaneously. A continuous recognition test was developed to assess memory function in audiences using a slide-show in which 50 images were presented, of which 25 were repeated. Audience members responded by recording if an image was a repetition. The test was administered …to a total of 1018 participants at 25 sites with an average audience size of 41 individuals (range = 9–142). A total of 868 individuals aged 40–97 y completed the test appropriately and provided their age, education level, and gender. Recognition memory as measured by discriminability (d′) showed a significant decline with age (40–49 y old, d′ = 3.51; 90–99 y old, d′ = 1.95, p < 0.001) together with a greater than three-fold increase in variability. Individuals with less than 13 y of education had lower scores than those with more education (d′ = 2.13 vs. 2.88, respectively, p < 0.001). These results are consistent with the known effects of age and education on memory. There were no significant effects of gender on test performance. Such memory tests represent a practical and novel approach to screen for the signs of early dementia. Show more

Keywords: Alzheimer's disease, episodic memory, memory screening, object recognition, recognition memory, visual memory

DOI: 10.3233/JAD-2011-110950

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 885-895, 2011

Authors: Greenwood, Tiffany A. | Beeri, Michal S. | Schmeidler, James | Valerio, Daniel | Raventós, Henriette | Mora-Villalobos, Lara | Camacho, Karla | Carrión-Baralt, José R. | Angelo, Gary | Almasy, Laura | Sano, Mary | Silverman, Jeremy M.

Article Type: Research Article

Abstract: We sought to identify cognitive phenotypes for family/genetic studies of successful cognitive aging (SCA; maintaining intact cognitive functioning while living to late old age). We administered a battery of neuropsychological tests to nondemented nonagenarians (n = 65; mean age = 93.4 ± 3.0) and their offspring (n = 188; mean age = 66.4 ± 5.0) from the Central Valley of Costa Rica. After covarying for age, gender, and years of education, as necessary, heritability was calculated for cognitive functions at three pre-defined levels of complexity: specific neuropsychological functions (e.g., delayed recall, sequencing), three higher level cognitive domains (memory, executive functions, …attention), and an overall neuropsychological summary. The highest heritability was for delayed recall (h2 = 0.74, se = 0.14, p < 0.0001) but significant heritabilities involving memory were also observed for immediate recall (h2 = 0.50), memory as a cognitive domain (h2 = 0.53), and the overall neuropsychological summary (h2 = 0.42). Heritabilities for sequencing (h2 = 0.42), fluency (h2 = 0.39), abstraction (h2 = 0.36), and the executive functions cognitive domain (h2 = 0.35) were also significant. In contrast, the attention domain and memory recognition were not significantly heritable in these families. Among the heritable specific cognitive functions, a strong pleiotropic effect (i.e., evidence that these may be influenced by the same gene or set of genes) for delayed and immediate recall was identified (bivariate statistic = 0.934, p < 0.0001) and more modest but significant effects were found for four additional bivariate relationships. The results support the heritability of good cognitive function in old age and the utilization of several levels of phenotypes, and they suggest that several measures involving memory may be especially useful for family/genetic studies of SCA. Show more

Keywords: Family studies, hispanic population, neuropsychological phenotype, oldest-old, successful cognitive aging

DOI: 10.3233/JAD-2011-110782

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 897-907, 2011