Journal of Alzheimer's Disease - Volume 22, issue 1

Authors: Lambert, Jean-Charles | Sleegers, Kristel | González-Pérez, Antonio | Ingelsson, Martin | Beecham, Gary W. | Hiltunen, Mikko | Combarros, Onofre | Bullido, Maria J. | Brouwers, Nathalie | Bettens, Karolien | Berr, Claudine | Pasquier, Florence | Richard, Florence | DeKosky, Steven T. | Hannequin, Didier | Haines, Jonathan L. | Tognoni, Gloria | Fiévet, Nathalie | Dartigues, Jean-François | Tzourio, Christophe | Engelborghs, Sebastiaan | Arosio, Beatrice | Coto, Elicer | De Deyn, Peter | Del Zompo, Maria | Mateo, Ignacio | Boada, Merce | Antunez, Carmen | Lopez-Arrieta, Jesus | Epelbaum, Jacques | Schjeide, Brit-Maren Michaud | Frank-Garcia, Ana | Giedraitis, Vilmentas | Helisalmi, Seppo | Porcellini, Elisa | Pilotto, Alberto | Forti, Paola | Ferri, Raffaele | Delepine, Marc | Zelenika, Diana | Lathrop, Mark | Scarpini, Elio | Siciliano, Gabriele | Solfrizzi, Vincenzo | Sorbi, Sandro | Spalletta, Gianfranco | Ravaglia, Giovanni | Valdivieso, Fernando | Vepsäläinen, Saila | Alvarez, Victoria | Bosco, Paolo | Mancuso, Michelangelo | Panza, Francesco | Nacmias, Benedetta | Bossù, Paola | Hanon, Olivier | Piccardi, Paola | Annoni, Giorgio | Mann, David | Marambaud, Philippe | Seripa, Davide | Galimberti, Daniela | Tanzi, Rudolph E | Bertram, Lars | Lendon, Corinne | Lannfelt, Lars | Licastro, Federico | Campion, Dominique | Pericak-Vance, Margaret A. | Soininen, Hilkka | Van Broeckhoven, Christine | Alpérovitch, Annick | Ruiz, Agustin | Kamboh, M. Ilyas | Amouyel, Philippe

Article Type: Research Article

Abstract: The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the ε4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant …of AD but may modulate age of onset by interacting with the effect of the ε4 allele of the APOE gene. Show more

Keywords: Age at onset, Alzheimer's disease, apolipoprotein E, CALHM1, polymorphism

DOI: 10.3233/JAD-2010-100933

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 247-255, 2010

Authors: Yu, Cun-Jing | Zheng, Mao-Fa | Kuang, Chun-Xiang | Huang, Wei-Da | Yang, Qing

Article Type: Research Article

Abstract: A well-known traditional Chinese medicinal prescription, Oren-gedoku-to (OGT), has been used in clinical therapies for many types of dementia in China and Japan. Additionally, it ameliorates the age-related deterioration of learning and memory in an Alzheimer's disease (AD) rat model. Indoleamine 2, 3-dioxygenase (IDO-1) is the first and rate-limiting enzyme in the kynurenine pathway of tryptophan catabolism, which ultimately leads to the production of the excitotoxin quinolinic acid (QUIN). IDO-1 has recently been established as one of the key players involved in the pathogenesis of AD. OGT is indicated to prevent cholinergic dysfunction and reduce oxidative stress; however, the exact …mechanism underlying its ability to improve cognitive ability remains elusive. Here we present a novel mechanism of OGT's therapeutic potential in AD. We demonstrated that OGT significantly inhibited recombinant human IDO-1 (rhIDO-1) activity in vitro, and its four main constituents (i.e., berberine, palmatine, jatrorrhizine, and baicalein) were potent IDO-1 inhibitors. IC50 values, obtained from a cell-based assay, of HEK 293 cells and an enzymatic assay were much lower than the most commonly used IDO-1 inhibitor, 1-methyl tryptophan (1-MT). Berberine was the best inhibitor and had IC50 values of 7 μM (cell-based assay) and 9.3 μM (enzymatic assay). Jatrorrhizine and palmatine exhibited irreversible inhibition of rhIDO-1, whereas berberine and baicalein behaved as uncompetitive, reversible inhibitors with Ki values of 8 μM and 215 μM, respectively. In conclusion, constituents of OGT show strong IDO-1 inhibitory activity and may have significant therapeutic potential for AD. Show more

Keywords: Alzheimer's disease, constituent, Indoleamine 2, 3-dioxygenase, Indoleamine 2, 3-dioxygenase inhibitor, Oren-gedoku-to

DOI: 10.3233/JAD-2010-100684

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 257-266, 2010

Authors: Saur, Ralf | Milian, Monika | Erb, Michael | Eschweiler, Gerhard W. | Grodd, Wolfgang | Leyhe, Thomas

Article Type: Research Article

Abstract: In patients with Alzheimer's disease (AD), neuroimaging studies have demonstrated decreased brain activation, while increased activation was detected in patients with mild cognitive impairment (MCI). It can be hypothesized that increased cerebral activity seen in patients with MCI reflects neural compensation at the beginning of neurodegenerative processes. Later, as patients develop AD, neural integrity is increasingly impaired. This is accompanied by decreased neural activation. In this study we examined cognitive performance and functional magnetic resonance imaging activation on a Clock Reading task (CRT) and a Spatial Control task (SCT) in healthy controls, patients with MCI, and patients with early AD. …Correlations between neural-functional activation and cognitive state, measured by the Mini Mental Status Examination, were determined using rank, linear and quadratic correlation models. It could be shown that CRT, in comparison to SCT, specifically activates brain regions in the ventral visual stream and precuneus known to be involved in conceptual processing and spatial imagery. The correlation between brain activity and cognitive state followed a quadratic rather than a linear pattern in several brain regions, including the lingual gyrus, cuneus, and precuneus. The strongest brain activity was found in patients with MCI and less severely impaired early AD subjects. These findings support the hypothesis that patients in early stages of dementia compensate for neuronal loss by the recruitment of additional neural resources reflected by increased neural activation, as measured by the blood oxygen level-dependent signal. Show more

Keywords: Alzheimer's disease, clock test, correlation analysis, functional magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-2010-091390

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 267-284, 2010

Authors: Sarazin, Marie | Chauviré, Valérie | Gerardin, Emilie | Colliot, Olivier | Kinkingnéhun, Serge | de Souza, Leonardo Cruz | Hugonot-Diener, Laurence | Garnero, Line | Lehéricy, Stéphane | Chupin, Marie | Dubois, Bruno

Article Type: Research Article

Abstract: The Free and Cued Selective Reminding Test (FCSRT) is a verbal episodic memory test used to identify patients with mild Alzheimer's disease (AD). The present study investigates the relationships between performance on FCSRT and grey matter atrophy assessed with structural MRI in patients with AD. Three complementary MRI-based analyses (VBM analysis, ROI-based analysis, and three-dimensional hippocampal surface-based shape analysis) were performed in 35 patients with AD to analyze correlations between regional atrophy and their scores for episodic memory using the FCSRT. With VBM analysis, the total score on the FCSRT was correlated with left medial temporal lobe atrophy including the …left hippocampus but also the thalami. In addition, using ROI-based analysis, the total recall score on the FCSRT was correlated with the left hippocampal volume. With three-dimensional hippocampal surface-based shape analysis, both free recall and total recall scores were correlated with regions corresponding approximately to the CA1 field. No correlation was found with short term memory scores using any of these methods of analysis. In AD, the FCSRT may be considered as a useful clinical marker of memory disorders due to medial temporal damage, specially the CA1 field of the hippocampus. Show more

Keywords: Alzheimer's disease, assessment of cognitive disorders/dementia, cognitive neuropsychology in dementia, memory, MRI

DOI: 10.3233/JAD-2010-091150

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 285-294, 2010

Authors: Yoshiyama, Yasumasa | Kojima, Ayako | Ishikawa, Chieko | Arai, Kimihito

Article Type: Research Article

Abstract: Acetylcholinesterase inhibitors (AChEIs) are widely used to compensate for acetylcholine (ACh) depletion in the Alzheimer's disease (AD) brain. Some clinical and experimental studies, however, have suggested that AChEIs also provide neuroprotection. To assess the effect of AChEIs on neurodegeneration, donepezil (DZ), an AChEI, was administered to FTDP-17 model mice with a P301S tau mutation (line PS19). Eight months of DZ treatment resulted in amelioration of neuroinflammation, tau pathology, synaptic loss, and neuronal loss, as well as decreased tau insolubility and phosphorylation. Tau kinase activity analysis demonstrated significantly suppressed c-Jun N-terminal kinase (JNK) in the brains of DZ-treated PS19 mice. Recently, …ACh has been shown to suppress inflammation, which plays a role in neurodegeneration. To confirm the anti-inflammatory effect of DZ, PS19 mice were injected with lipopolysaccharide, in combination with or without DZ, for one month. Results demonstrated that DZ suppressed IL-1β and COX-2 expression in the brain, as well as the spleen, suggesting that DZ directly prevents systemic inflammation. These data indicated that ACh did not act just as a cognition-linking neurotransmitter, but might suppress pathological mechanisms of neurodegeneration via anti-inflammatory action. Show more

Keywords: Acetylcholine, donepezil, neurodegeneration, neuroinflammation, tau

DOI: 10.3233/JAD-2010-100681

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 295-306, 2010

Authors: Valla, Jon | Yaari, Roy | Wolf, Andrew B. | Kusne, Yael | Beach, Thomas G. | Roher, Alex E. | Corneveaux, Jason J. | Huentelman, Matthew J. | Caselli, Richard J. | Reiman, Eric M.

Article Type: Research Article

Abstract: In vivo PET imaging studies of young-adult carriers of the apolipoprotein E ε4 allele (APOEε4), the major Alzheimer's disease (AD) susceptibility gene, have demonstrated declines in glucose metabolism in brain areas later vulnerable to AD, such as posterior cingulate cortex, decades before the possible onset of symptoms. We have previously shown in postmortem studies that such metabolic declines in AD are associated with brain regional mitochondrial dysfunction. To determine whether young adult at-risk individuals demonstrate similar mitochondrial functional decline, we histochemically assessed postmortem tissues from the posterior cingulate cortex of young-adult carriers and noncarriers of APOEε4. At-risk ε4 carriers had …lower mitochondrial cytochrome oxidase activity than noncarriers in posterior cingulate cortex, particularly within the superficial cortical lamina, a pattern similar to that seen in AD patients. Except for one 34 year-old ε4 homozygote, the ε4 carriers did not have increased soluble amyloid-β, histologic amyloid-β, or tau pathology in this same region. This functional biomarker may prove useful in early detection and tracking of AD and indicates that mitochondrial mechanisms may contribute to the predisposition to AD before any evidence of amyloid or tau pathology. Show more

Keywords: Alzheimer's etiology, bioenergetics, biomarkers, cytochrome c oxidase, differential vulnerability, neocortex

DOI: 10.3233/JAD-2010-100129

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 307-313, 2010

Authors: Haller, Sven | Nguyen, Duy | Rodriguez, Cristelle | Emch, Joan | Gold, Gabriel | Bartsch, Andreas | Lovblad, Karl O. | Giannakopoulos, Panteleimon

Article Type: Research Article

Abstract: Although cross-sectional diffusion tensor imaging (DTI) studies revealed significant white matter changes in mild cognitive impairment (MCI), the utility of this technique in predicting further cognitive decline is debated. Thirty-five healthy controls (HC) and 67 MCI subjects with DTI baseline data were neuropsychologically assessed at one year. Among them, there were 40 stable (sMCI; 9 single domain amnestic, 7 single domain frontal, 24 multiple domain) and 27 were progressive (pMCI; 7 single domain amnestic, 4 single domain frontal, 16 multiple domain). Fractional anisotropy (FA) and longitudinal, radial, and mean diffusivity were measured using Tract-Based Spatial Statistics. Statistics included group comparisons …and individual classification of MCI cases using support vector machines (SVM). FA was significantly higher in HC compared to MCI in a distributed network including the ventral part of the corpus callosum, right temporal and frontal pathways. There were no significant group-level differences between sMCI versus pMCI or between MCI subtypes after correction for multiple comparisons. However, SVM analysis allowed for an individual classification with accuracies up to 91.4% (HC versus MCI) and 98.4% (sMCI versus pMCI). When considering the MCI subgroups separately, the minimum SVM classification accuracy for stable versus progressive cognitive decline was 97.5% in the multiple domain MCI group. SVM analysis of DTI data provided highly accurate individual classification of stable versus progressive MCI regardless of MCI subtype, indicating that this method may become an easily applicable tool for early individual detection of MCI subjects evolving to dementia. Show more

Keywords: Diffusion tensor imaging, fractional anisotrophy, mild cognitive impairment, support vector machines, Tract-Based Spatial Statistics

DOI: 10.3233/JAD-2010-100840

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 315-327, 2010

Authors: Cao, Ying | Xiao, Yan | Ravid, Rivka | Guan, Zhi-Zhong

Article Type: Research Article

Abstract: In the study, the expression of clathrin regulatory proteins dynamin I, AP180, and synaptic vesicle protein synaptophysin in multiple brain regions of the patients with Alzheimer's disease (AD), the transgenic mice carrying the Swedish mutation of amyloid-β protein precursor (AβPP) 670/671 (AβPPSWE ), and the rats injected by bilateral hippocampus with amyloid-β peptide (Aβ)1-42 were examined by immunohistochemistry and Nissl staining, Western blotting, and Real-time PCR, respectively. Spatial learning and memory of the rats were evaluated by Morris Water Maze test, and the ability of endocytosis in the cultured rat hippocampal neurons was detected by FM1-43 fluorescence imaging. Significant …decreases in protein levels of dynamin I, AP180, and synaptophysin were observed in both AD patients and mice with AβPPSWE as compared to controls. Obvious declines of dynamin I and synaptophysin at protein and mRNA levels and impaired learning and spatial memory ability were found in the rats injected with Aβ1-42 as compared to controls. In addition, deposits of Aβ localized in the hippocampus around the sites of Aβ1-42 injection and the decreased numbers of Nissl bodies in neurons were found. Moreover, the disrupted synaptic vesicle endocytosis and decreased dynamin I protein were detected in stimulated hippocampal neurons treated with Aβ1-42 . These findings imply a malfunctioning clathrin-mediated endocytosis during AD pathological processes, which might be relevant to the mechanism underlying the cognitive deficit associated with AD. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, AP180, clathrin regulatory proteins, dynamin I, synaptophysin

DOI: 10.3233/JAD-2010-100162

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 329-342, 2010

Article Type: Announcement

DOI: 10.3233/JAD-2010-101468

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 343-344, 2010