Journal of Alzheimer's Disease - Volume 34, issue 2

Authors: Femminella, Grazia Daniela | Rengo, Giuseppe | Pagano, Gennaro | de Lucia, Claudio | Komici, Klara | Parisi, Valentina | Cannavo, Alessandro | Liccardo, Daniela | Vigorito, Carlo | Filardi, Pasquale Perrone | Ferrara, Nicola | Leosco, Dario

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is a devastating form of dementia that imposes a severe burden on health systems and society. Although several aspects of AD pathogenesis have been elucidated over the last few decades, many questions still need to be addressed. In fact, currently available medications only provide symptomatic improvement in patients with AD without affecting disease progression. The β-adrenergic receptor (β-AR) system can be considered a possible target that deserves further exploration in AD. The central noradrenergic system undergoes substantial changes in the course of AD and β-ARs have been implicated not only in amyloid formation in AD brain but …also in amyloid-induced neurotoxicity. Moreover, clinical evidence suggests a protective role of β-AR blockers on AD onset. In addition to that, post-receptor components of β-AR signaling seem to have a role in AD pathogenesis. In particular, the G protein coupled receptor kinase 2, responsible for β-AR desensitization and downregulation, mediates amyloid-induced β-AR dysfunction in neurons, and its levels in circulating lymphocytes of AD patients are increased and inversely correlated with patient's cognitive status. Therefore, there is an urgent need to gain further insight on the role of the adrenergic system components in AD pathogenesis in order to translate preclinical and clinical knowledge to more efficacious prognostic and therapeutic strategies. Show more

Keywords: Alzheimer's disease, amyloid, beta-adrenergic receptors, G-protein coupled receptor kinase-2

DOI: 10.3233/JAD-121813

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 341-347, 2013

Authors: Sillerud, Laurel O. | Solberg, Nathan O. | Chamberlain, Ryan | Orlando, Robert A. | Heidrich, John E. | Brown, David C. | Brady, Christina I. | Vander Jagt, Thomas A. | Garwood, Michael | Vander Jagt, David L.

Article Type: Research Article

Abstract: In our program to develop non-invasive magnetic resonance imaging (MRI) methods for the diagnosis of Alzheimer's disease (AD), we have synthesized antibody-conjugated, superparamagnetic iron oxide nanoparticles (SPIONs) for use as an in vivo agent for MRI detection of amyloid-β plaques in AD. Here we report studies in AβPP/PS1 transgenic mice, which demonstrate the ability of novel anti-AβPP conjugated SPIONs to penetrate the blood-brain barrier to act as a contrast agent for MR imaging of plaques. The conspicuity of the plaques increased from an average Z-score of 5.1 ± 0.5 to 8.3 ± 0.2 when the plaque contrast to noise ratio …was compared in control AD mice with AD mice treated with SPIONs. The number of MRI-visible plaques per brain increased from 347 ± 45 in the control AD mice, to 668 ± 86 in the SPION treated mice. These results indicated that our SPION enhanced amyloid-β detection method delivers an efficacious, non-invasive MRI detection method in transgenic mice. Show more

Keywords: Magnetic resonance imaging, transgenic mice, superparamagnetic iron oxide nanoparticles

DOI: 10.3233/JAD-121171

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 349-365, 2013

Authors: Laske, Christoph | Schmohl, Michael | Leyhe, Thomas | Stransky, Elke | Maetzler, Walter | Berg, Daniela | Fallgatter, Andreas J. | Joos, Thomas | Dietzsch, Janko

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) has been linked to a state of cerebral and systemic inflammation. The objective of the present study was to determine whether singular markers or a set of inflammatory biomarkers in peripheral blood allow discrimination between AD patients and healthy controls at the individual level. Methods: Using bead based multiplexed sandwich immunoassays, 25 inflammatory biomarkers were measured in 164 serum samples from individuals with early AD and age-matched cognitively healthy elderly controls. The data set was randomly split into a training set for feature selection and classification training and a test set for class prediction …of blinded samples (1 : 1 ratio) to evaluate the chosen predictors and parameters. Multivariate data analysis was performed with use of a support vector machine (SVM). Results: After selection of sTNF-R1 as most discriminative parameter in the training set, the application of SVM to the independent test dataset resulted in a 90.0% correct classification for individual AD and control subjects. Conclusions: We identified sTNF-R1 from a marker set consisting of 25 inflammatory biomarkers, which allowed SVM-based discrimination of AD patients from healthy controls on a single-subject classification level comparably well as biomarker panels with a clinically relevant accuracy and validity. Although larger sample populations will be needed to confirm this diagnostic accuracy, our study suggests that sTNF-R1 in serum—either as singular marker or incorporated into a biomarker panel—could be a powerful new biomarker for detection of AD. In addition, selective inhibition of TNF-R1 function may represent a new therapeutic approach in AD. Show more

Keywords: Alzheimer's disease, biomarkers, blood, inflammation, TNF-R1

DOI: 10.3233/JAD-121558

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 367-375, 2013

Authors: Cagnin, Annachiara | Leon, Alberta | Vianello, Daniela | Colavito, Davide | Favaretto, Silvia | Zarantonello, Giulia | Stecca, Anna | Ermani, Mario | Zambon, Alberto

Article Type: Research Article

Abstract: Cholesterol metabolism alteration is a hot topic in the field of Alzheimer's disease (AD). However, data on plasma lipoproteins cholesterol distribution and oxidation in AD and their possible genetic determinants are lacking. The paraoxonase-1 (PON1) gene -107C/T promoter polymorphisms have been found associated with AD. One of the fundamental functions of PON1 enzyme is the inhibition of low-density lipoproteins (LDL) oxidation. We therefore evaluated plasma lipoprotein profile and LDL density and oxidation in late-onset AD patients and healthy elderly subjects, without neuroimaging evidence of cerebrovascular lesions and not on lipid-lowering treatment, and their interaction with PON1 -107C/T and apolipoprotein E …(APOE) genotypes. Mean plasma total cholesterol and LDL levels were higher in AD than controls (p < 0.05). Lipoproteins cholesterol distribution shifted toward a greater prevalence of smaller, denser LDL (sd-LDL, p < 0.05) only in AD patients with PON1 -107TT genotype, who also showed increased plasma levels of oxidized LDL (ox-LDL, p = 0.02). A significant association was observed between sd-LDL and ox-LDL levels (p < 005) in AD patients. APOE genotype did not modulate lipoprotein distribution. Increased levels of sd-LDL and ox-LDL particles in the AD PON1 TT patients could be explained by the combined effect of an AD-related pro-oxidant milieu and an ineffective PON1 gene polymorphism-related antioxidant capacity. The functional correlate of the association between PON1 -107C/T polymorphism and AD may be the abnormal modulation of LDL oxidation. Ox-LDL may amplify the processes of endothelial injury promoted by vascular amyloid deposition, which represents one of the potential pathways explaining the cross-road between vascular and neurodegenerative pathomechanisms in AD. Show more

Keywords: Alzheimer's disease, cholesterol, lipoprotein profile, low-density-lipoproteins, oxidized LDL, paraoxonase, PON1 gene

DOI: 10.3233/JAD-121717

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 377-385, 2013

Authors: Dieks, Jana-Katharina | Gawinecka, Joanna | Asif, Abdul R. | Varges, Daniela | Gmitterova, Karin | Streich, Jan-Hendrik | Dihazi, Hassan | Heinemann, Uta | Zerr, Inga

Article Type: Research Article

Abstract: Dementia with Lewy bodies (DLB) is one of the most common neurodegenerative diseases and shares multiple clinical and neuropathological parallels with Alzheimer's (AD) and Parkinson's disease (PD). A variety of clinical signs are suggestive for the diagnosis, and imaging (βCIT SPECT) contributes substantially to the diagnosis. The study reported here was performed in search for a biomarker in the cerebrospinal fluid (CSF) of these patients. We applied 2D fluorescence difference gel electrophoresis and mass spectrometry to analyze the CSF proteome pattern of DLB patients after depleting twelve high-abundant proteins. The densitometric analysis of 2D gels showed the up- or down-regulation …of 44 protein spots. Subsequently, 23 different proteins were identified. The majority is involved in acute phase and immune response. Many of these proteins were previously reported before as being associated with AD or PD, which strongly suggests a molecular cross-talk and may explain clinical and pathological overlap of these disease entities. Among the identified proteins are two highly upregulated proteins—inter alpha trypsin inhibitor heavy chain (ITIH4) and calsyntenin 1—that may have the potential to serve as molecular biomarkers specific for DLB. The identification of DLB-associated proteome changes will help to further understand pathological processes occurring in DLB and may provide future prospects to diagnostic and therapeutic options. Show more

Keywords: Biomarker, cerebrospinal fluid, dementia with Lewy bodies, 2-D fluorescence difference gel electrophoresis

DOI: 10.3233/JAD-121810

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 387-397, 2013

Authors: Chong, Mei Sian | Goh, Liang Kee | Lim, Wee Shiong | Chan, Mark | Tay, Laura | Chen, Gengbo | Feng, Lei | Ng, Tze Pin | Tan, Chay Hoon | Lee, Tih Shih

Article Type: Research Article

Abstract: We previously reported TOMM40 was significantly down-regulated in whole blood of Alzheimer's disease (AD) subjects. In this study, we examined whole blood gene profiling differences over a one-year period comparing early AD subjects based on disease progression. 6-monthly assessments and blood sampling on 29 probable AD subjects compared with age- and gender-matched controls were performed. AD subjects with change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score of ≥2 points/year were classified as fast-progressors and those with CDR-SB change of <2 points/year were classified as slow-progressors. We found statistically significant upregulation in KIR2DL5A, SLC2A8, and PLOD1 for fast- (n = …8) compared with slow-progressors (n = 21) across the time-points. TOMM40 gene expression remained significantly lower in AD patients at all time-points compared to controls, supporting our previous findings. Our novel findings of specific gene expression differences between fast- and slow-progressors in combination with consistently lower TOMM40 expression, suggest their potential role as prognostic blood biomarkers to predict progression in early AD. Show more

Keywords: Alzheimer's disease, gene expression, progression, TOMM40

DOI: 10.3233/JAD-121621

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 399-405, 2013

Authors: Chatzistavraki, Maria | Kyratzi, Elli | Fotinopoulou, Angeliki | Papazafiri, Panagiota | Efthimiopoulos, Spiros

Article Type: Research Article

Abstract: The amyloid-β protein precursor (AβPP) is a type-1 transmembrane protein involved in Alzheimer's disease (AD). It has become increasingly evident that AβPP, its protein-protein interactions, and its proteolytical fragments may affect calcium homeostasis and vice versa. In addition, there is evidence that calcium dysregulation contributes to AD. To study the role of AβPP in calcium homeostasis, we downregulated its expression in SH-SY5Y cells using shRNA (SH-SY5Y/AβPP-) or increased expression of AβPP695 by transfection (SH-SY5Y/AβPP+). The levels of cytosolic Ca2+ after treatment with thapsigargin, monensin, activation of capacitative calcium entry (CCE), and treatment with SKF, a store operated channel (SOCs) …inhibitor, were measured by fura-2AM fluorimetry. SH-SY5Y/AβPP+ cells show reduced response to thapsigargin and reduced CCE, although this reduction is not statistically significant. On the other hand, we found that, relative to SH-SY5Y, SH-SY5Y/AβPP- cells show a significant increase in the response to thapsigargin but not in CCE and their SOCs were more susceptible to SKF inhibition. Additionally, downregulation of AβPP resulted in increased response to monensin that induces calcium release from acidic stores. The increase of calcium release from the endoplasmic reticulum and the acidic stores, when AβPP is downregulated, could be attributed to elevated Ca2+ content or to a dysregulation of Ca2+ transfer through their membranes. These data, along with already existing evidence regarding the role of AβPP in calcium homeostasis and the early occurring structural and functional abnormalities of endosomes, further substantiate the role of AβPP in calcium homeostasis and in AD. Show more

Keywords: Alzheimer's disease, calcium signaling, capacitative calcium entry, endosomes

DOI: 10.3233/JAD-121768

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 407-415, 2013

Authors: Zhao, Wei | Ho, Lap | Varghese, Merina | Yemul, Shrishailam | Dams-O'Connor, Kristen | Gordon, Wayne | Knable, Lindsay | Freire, Daniel | Haroutunian, Vahram | Pasinetti, Giulio Maria

Article Type: Research Article

Abstract: Traumatic brain injury (TBI) is a leading cause of death and disability among children and young adults in the United States. In this study, we explored whether changes in the gene expression profile of peripheral blood mononuclear cells (PBMC) may provide a clinically assessable “window” into the brain, reflecting molecular alterations following TBI that might contribute to the onset and progression of TBI clinical complications. We identified three olfactory receptor (OR) TBI biomarkers that are aberrantly down-regulated in PBMC specimens from TBI subjects. Down-regulation of these OR biomarkers in PBMC was correlated with the severity of brain injury and TBI-specific …symptoms. A two- biomarker panel comprised of OR11H1 and OR4M1 provided the best criterion for segregating the TBI and control cases with 90% accuracy, 83.3% sensitivity, and 100% specificity. We found that the OR biomarkers are ectopically expressed in multiple brain regions, including the entorhinal-hippocampus system known to play an important role in memory formation and consolidation. Activation of OR4M1 led to attenuation of abnormal tau phosphorylation, possibly through JNK signaling pathway. Our results suggested that addition of the two-OR biomarker model to current diagnostic criteria may lead to improved TBI detection for clinical trials, and decreased expression of OR TBI biomarkers might be associated with TBI-induced tauopathy. Future studies exploring the physiological relevance of OR TBI biomarkers in the normal brain and in the brain following TBI will provide a better understanding of the biological mechanisms underlying TBI and insights into novel therapeutic targets for TBI. Show more

Keywords: Biomarker, olfactory receptor, peripheral blood mononuclear cell, tauopathy, traumatic brain injury

DOI: 10.3233/JAD-121894

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 417-429, 2013

Authors: Barnes, Josephine | Bartlett, Jonathan W. | Fox, Nick C. | Schott, Jonathan M. | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: There is interest in using cerebrospinal fluid (CSF) biomarkers to enrich mild cognitive impairment (MCI) clinical trials; however, there are conflicting views on their utility. We identified MCI subjects with CSF from the Alzheimer's Disease Neuroimaging Initiative. We measured brain and hippocampal atrophy rates, ventricular expansion rates, and decline in ADAS-Cog 13 and MMSE over one year. We examined proportionate and absolute reductions in mean outcome measures. Using a CSF Aβ1-42 cut-off (192 pg/ml), we estimated sample size ratios for clinical trials based on these outcomes for targeted (i.e., low-Aβ-MCI subjects only) compared with unrestricted recruitment. We further examined …sample size ratios assuming only low-Aβ-MCIs would benefit from treatment. We found that for proportionate reductions in mean outcomes targeted recruitment led to significantly smaller sample sizes for all outcomes apart from ADAS-Cog. No sample size reduction was demonstrated for outcomes based on absolute reductions. Excluding subjects who would not benefit from treatment always reduces sample sizes. Using CSF biomarkers as inclusion criteria for AD trials increases the number of subjects needing to be screened but may reduce required sample sizes and reduce the risk of exposing patients without amyloid pathology to treatment side-effects. Whether targeted recruitment reduces required sample sizes depends critically on assumptions regarding treatment effects. Show more

Keywords: Alzheimer's disease, amyloid, clinical trial, magnetic resonance imaging, mild cognitive impairment, patient recruitment

DOI: 10.3233/JAD-121936

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 431-437, 2013

Authors: Porcellini, Elisa | Carbone, Ilaria | Martelli, Pier Luigi | Ianni, Manuela | Casadio, Rita | Pession, Annalisa | Licastro, Federico

Article Type: Research Article

Abstract: Our previous works showed that single nucleotide polymorphisms (SNPs) in genes with regulatory function upon inflammatory response and cholesterol metabolism were associated with Alzheimer's disease (AD) risk. The list comprises SNPs located on the promoters of alpha 1 antichymotrypsin (rs1884082), hydroxy methyl glutaryl coenzime A reductase (rs376140), tumor necrosis factor alpha (rs1800629), and interleukin 10 (rs1800869). Here we investigated the effect of these SNPs on the binding for transcription factors. We computationally detected putative binding sites for transcription factors located in the SNP regions. To this aim, the TESS program for scanning the promoter sequences against the binding-site models available …at TRANSFACT and JASPAR databases was adopted. All the analyzed SNPs appeared to affect the binding of myeloid zinc finger protein 1 (MZF-1) to the promoter sequence of the above reported genes. Therefore 16 SNPs in MZF-1 gene were tested in 120 AD cases and 88 controls to asses a possible association between MZF-1 and AD. 14 SNPs showed no variability in AD and control populations, while two SNPs rs4756 and rs2228162 showed the three genotypes. Genotype distributions and allele frequencies of these two SNPs were comparable between AD and controls. On the other hand, the haplotype distribution of rs4756 and rs2228162 was different between AD and controls; being the AG haplotype associated with a decreased AD risk. In conclusion, selected SNPs in MZF-1 gene exert a minor effect on AD risk. Show more

Keywords: Alzheimer's disease, gene polymorphisms, MZF-1, transcription factors binding

DOI: 10.3233/JAD-121546

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 439-447, 2013