Journal of Alzheimer's Disease - Volume 21, issue 1

Authors: Borroni, Barbara | Del Bo, Roberto | Goldwurm, Stefano | Archetti, Silvana | Bonvicini, Cristian | Agosti, Chiara | Bigni, Barbara | Papetti, Alice | Ghezzi, Serena | Sacilotto, Giorgio | Pezzoli, Gianni | Gennarelli, Massimo | Bresolin, Nereo | Comi, Giacomo Pietro | Padovani, Alessandro

Article Type: Research Article

Abstract: Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are in the spectrum of tauopathies and recognized to have a strong genetic background. It has been widely reported that MAPT tau haplotype H1 is a genetic risk factor in both conditions, but no other genetic determinants have so far been proposed. Recently, vascular endothelial growth factor (VEGF) haplotypes were reported to confer risk to frontotemporal dementia (FTD). The aim of this study was to evaluate the role of VEGF genetic determinants in PSP and CBS susceptibility. We evaluated a cohort of 687 unrelated Italian subjects, including 117 PSP, 108 CBS, 199 …FTD, and 263 healthy controls. Genotype and allele frequencies of three well-known polymorphisms located within the VEGF promoter (-2578C/A, -1190G/A, and -1154G/A) were carried out. Genetic analysis revealed the presence of significant changes in terms of genotype and allele distributions in patients compared to healthy controls. A-G-G haplotype (-2578C/A, 1190G/A, -1154G/A) was overrepresented in both PSP (OR=6.64, 95% CI=2.3–19.6, P=0.0003, CGG=reference) and CBS (OR=5.20, 95% CI=1.70–15.9, P=0.003, CGG=reference) compared to healthy subjects. No differences between PSP and CBS and FTD were found, and the A-G-G haplotype was also overrepresented in FTD. Overall, these data suggest that VEGF gene variability represents a susceptibility factor for PSP and CBS. These data argue that additional genes may confer disease risk to PSP and CBS, and to FTD as well, beyond the MAPT tau haplotype. Further studies are warranted. Show more

Keywords: Corticobasal syndrome, frontotemporal dementia, haplotype, polymorphism, progressive supranuclear palsy, vascular endothelial growth factor

DOI: 10.3233/JAD-2010-091615

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 87-94, 2010

Authors: Benito-León, Juliín | Louis, Elan D. | Vega, Saturio | Bermejo-Pareja, Félix

Article Type: Research Article

Abstract: In a 2009 Cochrane review, the authors concluded that there is good evidence that statins, given in late life to people at risk of vascular disease, have no effect in preventing Alzheimer's disease or dementia. A related issue, which remains unclear, is whether statins improve cognitive function. While some studies have shown a beneficial effect of statins on cognitive function, others have observed mild detrimental effects on cognition. Our aim was to assess cognitive function in community-dwelling elderly participants treated with statins compared with their untreated counterparts (i.e., controls) living in the same population. 137 population-dwelling participants who were receiving …statins and 411 matched controls age ⩾ 65 years (median=72 years) in central Spain (the Neurological Disorders in Central Spain [NEDICES] study) underwent a neuropsychological assessment, including tests of global cognitive performance, frontal-executive function, verbal fluency, and memory. Median duration of statin treatment was 2 years. Of 137 participants receiving statins, 53 (38.7%) were taking pravastatin, 38 (27.7%) simvastatin, 37 (27.0%) lovastatin, 6 (4.4%) fluvastatin, and 3 (2.2%) atorvastatin. Although initial univariate analyses indicated some differences, after adjusting for age, gender, education, depressive symptoms, premorbid intelligence, medications that potentially affect cognitive function, and blood cholesterol levels, statin users and controls performed similarly on all neuropsychological tests. In this population-based sample, elderly participants treated with statins and untreated controls performed similarly in all tested cognitive areas. These results do not support a positive benefit of statins on cognition. Show more

Keywords: Cognitive function, elderly, epidemiology, statins

DOI: 10.3233/JAD-2010-100180

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 95-102, 2010

Authors: Bokde, Arun L.W. | Karmann, Michaela | Born, Christine | Teipel, Stefan J. | Omerovic, Muamer | Ewers, Michael | Frodl, Thomas | Meisenzahl, Eva | Reiser, Maximilian | Möller, Hans-Jürgen | Hampel, Harald

Article Type: Research Article

Abstract: In subjects with mild cognitive impairment (MCI), memory disorders indicate a high risk for conversion to Alzheimer's disease (AD). The objective of this study was to delineate the differences in brain activation between amnestic MCI and age-matched healthy controls (HC) during a verbal working memory task. The verbal working memory task was a delay match to sample design. Brain activation was measured using functional magnetic resonance imaging. There were 8 subjects in each group and were matched for performance. The task was analyzed as an event-related design. Group differences were calculated using Analysis of Covariance (ANCOVA) with statistical significance at …p<0.05 corrected. Both groups activated a wide network in the posterior and frontal areas of the brain. There was higher activation in the parietal and frontal lobes in the MCI compared to the HC during the maintenance phase. There were no areas in the HC that activated higher than the MCI subjects. Response time in the task in the HC group was correlated to the left hippocampus during encoding phase and to the parietal and frontal areas during the recall phase. In the MCI group, there was strong correlation to the inferior and middle temporal gyrii during encoding, the middle frontal gyrus during the maintenance phase, and hippocampus during recall phase. The activation differences between groups may be compensatory mechanisms within the MCI group for the effects of the putative AD neuropathology. This has been the first study that has examined verbal working memory in MCI. Show more

Keywords: Face matching, functional magnetic resonance imaging, location matching, object matching, visual system

DOI: 10.3233/JAD-2010-091054

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 103-118, 2010

Authors: Baglietto-Vargas, David | Moreno-Gonzalez, Ines | Sanchez-Varo, Raquel | Jimenez, Sebastian | Trujillo-Estrada, Laura | Sanchez-Mejias, Elisabeth | Torres, Manuel | Romero-Acebal, Manuel | Ruano, Diego | Vizuete, Marisa | Vitorica, Javier | Gutierrez, Antonia

Article Type: Research Article

Abstract: Specific neuronal networks are preferentially affected in the early stages of Alzheimer's disease (AD). The distinct subpopulations of hippocampal inhibitory GABAergic system have been shown to display differential vulnerability to neurodegeneration in AD. We have previously reported a substantial loss of SOM/NPY interneurons, whereas those expressing parvalbumin were unaltered, in the hippocampus of 6 month-old PS1/AβPP transgenic mice. In the present study, we now investigated the pathological changes of hippocampal calretinin (CR) interneurons in this PS1/AβPP model from 2 to 12 months of age. The total number of CR-immunoreactive inhibitory cells was determined by stereology in CA1 and CA2/3 subfields. …Our findings show a substantial decrease (35%–45%) of CR-positive interneurons in both hippocampal subfields of PS1/AβPP mice at very early age (4 months) compared to age-matched control mice. This decrease was accompanied by a reduced CR mRNA content as determined by quantitative RT-PCR. However, the number of another hippocampal CR-positive population (belonging to Cajal-Retzius cells) was not affected. The selective early loss of CR-interneurons was parallel to the appearance of extracellular Aβ deposits, preferentially in CR-axonal fields, and the formation of dystrophic neurites. This specific GABAergic subpopulation plays a crucial role in the generation of synchronous rhythmic activity in hippocampus by controlling other interneurons. Therefore, early alterations of hippocampal inhibitory functionality in AD, caused by select CR-cells neurodegeneration, could result in cognitive impairments seen in initial stages of the disease. Show more

Keywords: Alzheimer's disease, amyloid, hippocampal formation, inhibitory neurons, neurodegeneration, neuropathology, transgenic

DOI: 10.3233/JAD-2010-100066

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 119-132, 2010

Authors: Zhuo, Jia-Min | Praticò, Domenico

Article Type: Research Article

Abstract: Since hyper-homocysteinemia (HHcy) was recognized as a risk factor for Alzheimer's disease (AD), many studies tried to induce HHcy in animal models to investigate its effect on amyloid-β protein precursor (AβPP) metabolism. Previous reports found that HHcy induced in AD transgenic mouse models, by either feedina a methionine-enriched diet or vitamin Bs deficient diet, is associated with elevation of amyloid-β (Aβ) levels. However, there is no data available on the effect of dietary intervention which combines both excessive methionine and low levels of vitamin Bs on amyloidogenesis in any of these models. In the current study, we investigated the effect …of a combination diet, which was both enriched in methionine and deficient in folate, vitamin B6 and B12 , in an AD mouse model, the Tg2576. We found that 7 months treatment of this diet induced severe HHcy in these mice with plasma homocysteine level higher than 150 μM. However, no difference was detected in brain Aβ levels or deposition between the diet-treated and control group. As shown by western blot, severe HHcy did not alter the steady state levels of proteins involved in AβPP metabolism, either. These results demonstrate that this combination diet-induced severe HHcy does not influence amyloidogenesis in vivo. Show more

Keywords: Alzheimer's disease, folate, methionine, plasma homocysteine, vitamin B

DOI: 10.3233/JAD-2010-100171

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 133-140, 2010

Authors: Lu, Jianghua | Wang, Kaixuan | Rodova, Mariana | Esteves, Raquel | Berry, Diana | E, Lezi | Crafter, Adam | Barrett, Matthew | Cardoso, Sandra M. | Onyango, Isaac | Parker, W. Davis | Fontes, Joseph | Burns, Jeffrey M. | Swerdlow, Russell H.

Article Type: Research Article

Abstract: Cytochrome oxidase (COX) activity varies between individuals and low activities associate with Alzheimer's disease. Whether genetic heterogeneity influences function of this multimeric enzyme is unknown. To explore this we sequenced three mitochondrial DNA (mtDNA) and ten nuclear COX subunit genes from at least 50 individuals. 20% had non-synonymous mtDNA COX gene polymorphisms, 12% had a COX4I1 non-synonymous G to A transition, and other genes rarely contained non-synonymous polymorphisms. Frequent untranslated region (UTR) polymorphisms were seen in COX6A1, COX6B1, COX6C, and COX7A1; heterogeneity in a COX7A1 5' UTR Sp1 site was extensive. Synonymous polymorphisms were common and less frequent in the …more conserved COX1 than the less conserved COX3, suggesting at least in mtDNA synonymous polymorphisms experience selection pressure and are not functionally silent. Compound gene variations occurred within individuals. To test whether variations could have functional consequences, we studied the COX4I1 G to A transition and an AGCCCC deletion in the COX7A1 5' UTR Sp1 site. Cells expressing the COX4I1 polymorphism had reduced COX Vmax activity. In reporter construct-transduced cells where green fluorescent protein expression depended on the COX7A1 Sp1 site, AGCCCC deletion reduced fluorescence. Our findings indicate COX subunit gene heterogeneity is pervasive and may mediate COX functional variation. Show more

Keywords: Alzheimer's disease, cytochrome oxidase, mitochondria, mitochondrial DNA, polymorphisms

DOI: 10.3233/JAD-2010-100123

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 141-154, 2010

Authors: Hausner, Lucrezia | Frölich, Lutz | Gardette, Virginie | Reynish, Emma | Ousset, Pierre-Jean | Andrieu, Sandrine | Vellas, Bruno | on behalf of the ICTUS-EADC study group

Article Type: Research Article

Abstract: This study set out to describe the variations within Europe for Alzheimer's disease (AD) patients with regards to clinical and socio-demographic features, co-morbidities, drug treatment, and psychosocial care. 1,379 mild to moderate AD subjects from the ICTUS study were clustered into four geographic regions according to WHO-classification of European countries. Northern patients showed the mildest severity of dementia (MMSE: 21.6 ± 3.7, p< 0.001), received the lowest rate of concomitant psychotropic drug treatment (24.3%, p< 0.001), and appeared to be healthier than patients in the rest of Europe. Western subjects were diagnosed earliest (0.5 ± 0.9 month, p< 0.001), received …the highest rate of formal care (45.0%, p< 0.001), and had the highest rates of antidementia drug treatment (60.4%, p< 0.001). Southern subjects had the shortest education period (5.6 ± 4.0, p< 0.001), the most severe cognitive decline in MMSE: 19.8 ± 4.0, $p<$ 0.001 and ADAScog: 24.2 9.6, p< 0.001 and received less antidementia drug treatment (37.6%; p< 0.001), lived more often with their caregivers (74.4%, p< 0.001), and had the highest caregiver burden (22.6 ± 15.2, p=0.049). Eastern AD subjects received more concomitant psychopharmacological drugs (68.6%, p< 0.001), caregivers were more often different (18.6%, p< 0.001) from spouse or offspring, caregiver burden was lowest (18.7 ± 12.4, p=0.049), nearly all subjects received only informal care (95.7%, p< 0.001) and were affected more by co-morbidities. Overall, these data show differences in socio-demographic and clinical characteristics between AD patients from four European geographical regions. The presentation and management of AD in Europe appears to differ according to European regions and likely reflects differences in cultural factors and health politics. Show more

Keywords: Alzheimer's disease, clinical course, cross-sectional data, dementia, drug usage, Europe, multi-centre study, observational study

DOI: 10.3233/JAD-2010-091489

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 155-165, 2010

Authors: Wang, Hai-Hong | Li, Hong-Lian | Liu, Rong | Zhang, Yao | Liao, Kai | Wang, Qun | Wang, Jian-Zhi | Liu, Shi-Jie

Article Type: Research Article

Abstract: The formation of neurofibrillary tangles, mainly composed of hyperphosphorylated tau protein, is a hallmark in the brain of human tauopathies, including Alzheimer's disease (AD). Although neurons bearing neurofibrillary tangles are constantly exposed to various apoptotic stimuli, they do not appear to preferentially die by apoptosis. The underlying mechanism for such resistance to apoptosis remains elusive. Previously, we studied the role of tau phosphorylation in apoptosis and found that tau hyperphosphorylation by glycogen synthase kinase-3 (GSK-3) rendered cells more resistant to apoptosis. In this study, we show that the overexpression of tau without any exogenous activation of kinases also confers increased …resistance to apoptosis in both N2a cells and in a tau transgenic mouse model. Mechanistically, the overexpression of tau was associated with a reduced p53 level, decreased release of cytochrome C from mitochondria, and inhibition of caspases-9/-3. Additionally, a decreased phosphorylation and increased nuclear translocation of β-catenin were also detected in N2a/tau cells, and knockdown of β-catenin eliminated the anti-apoptotic effect of tau. Furthermore, tau was spontaneously hyperphosphorylated upon overexpression and by staurosporine treatment. The phosphorylation level of p53 decreased upon tau overexpression, and a more profound reduction of the phosphorylated p53 was detected when the cells were treated with lithium and roscovitine, inhibitors of GSK-3 and cyclin-dependent kinase-5 (Cdk-5). These results suggest that the overexpression of tau, which may be hyperphosphorylated by endogenous GSK-3 and Cdk-5, is anti-apoptotic by mechanisms involving modulation of multiple anti-apoptotic factors, including β-catenin and p53-mitochondria-caspase-mediated apoptotic pathways. Show more

Keywords: Alzheimer's disease, apoptosis, β-catenin, GSK-3, tau

DOI: 10.3233/JAD-2010-091279

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 167-179, 2010

Authors: Pellicanò, Mariavaleria | Bulati, Matteo | Buffa, Silvio | Barbagallo, Mario | Di Prima, Anna | Misiano, Gabriella | Picone, Pasquale | Di Carlo, Marta | Nuzzo, Domenico | Candore, Giuseppina | Vasto, Sonya | Lio, Domenico | Caruso, Calogero | Colonna-Romano, Giuseppina

Article Type: Research Article

Abstract: To investigate the systemic signs of immune-inflammatory responses in Alzheimer's disease (AD), in the present study we have analyzed blood lymphocyte subsets and the expression of activation markers on peripheral blood mononuclear cells (PBMCs) from AD patients and age-matched healthy controls (HC) activated in vitro by recombinant amyloid-β peptide (rAβ42 ). Our study of AD lymphocyte subpopulations confirms the already described decrease of the absolute number and percentage of B cells when compared to HC lymphocytes, whereas the other subsets are not significantly different in patients and controls. We report the increased expression of the activation marker CD69 and of …the chemokine receptors CCR2 and CCR5 on T cells but no changes of CD25 after activation. B cells are also activated by rAβ42 as demonstrated by the enhanced expression of CCR5. Moreover, rAβ42 induces an increased expression of the scavenger receptor CD36 on monocytes. Some activation markers and chemokine receptors are overexpressed in unstimulated AD cells when compared to controls. This is evidence of the pro-inflammatory status of AD. Stimulation by rAβ42 also induces the production of the pro-inflammatory cytokines IL-1β, IL-6, IFN-γ, and TNF-α, and of the anti-inflammatory cytokines IL-10 and IL-1Ra. The chemokines RANTES, MIP-1β, and eotaxin as well as some growth factors (GM-CSF, G-CSF) are also overproduced by AD-derived PBMC activated by rAβ42 . These results support the involvement of systemic immunity in AD patients. However, our study is an observational one so we cannot draw a conclusion about its contribution to the pathophysiology of the disease. Show more

Keywords: Alzheimer's disease, chemokine, cytokine, PBMC, rAβ42

DOI: 10.3233/JAD-2010-091714

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 181-192, 2010

Authors: Kim, Woojin Scott | Bhatia, Surabhi | Elliott, David A. | Agholme, Lotta | Kågedal, Katarina | McCann, Heather | Halliday, Glenda M. | Barnham, Kevin J. | Garner, Brett

Article Type: Research Article

Abstract: ATP-binding cassette transporter A1 (ABCA1) reduces amyloid-β burden in transgenic mouse models of Alzheimer's disease (AD). Associations between ABCA1 polymorphisms and AD risk are also established. Little is known regarding the regulation of ABCA1 expression in the brain and how this may be affected by AD. In the present study we assessed ABCA1 mRNA and protein expression in the hippocampus of AD cases compared to controls. ABCA1 was clearly expressed in hippocampal neurons and expression was increased two- to three-fold in AD cases. The increased hippocampal ABCA1 expression was associated with increased APOE and PUMA gene expression, implying an association …with neuronal stress. Consistent with this, treatment of SK-N-SH neurons with amyloid-β peptide resulted in a 48% loss in survival and a significant upregulation of ABCA1, APOE, and PUMA gene expression. Studies in young (2 month) and old (12 month) transgenic mice expressing a familial AD form of human amyloid-β protein precursor and presenilin-1 revealed a significant age-dependent upregulation of hippocampal Abca1 compared to wild-type control mice. However, hippocampal Apoe and Puma gene expression were not correlated with increased Abca1 expression in mice. Our data indicate that ABCA1 is upregulated in AD hippocampal neurons potentially via an amyloid-β-mediated pathway. Show more

Keywords: ABCA1, Alzheimer's disease, amyloid-β peptide, ATP-binding cassette transporter A1, hippocampus, neurodegeneration

DOI: 10.3233/JAD-2010-100324

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 193-205, 2010