Journal of Alzheimer's Disease - Volume 34, issue 1

Authors: Pontiki, Eleni | Kontogiorgis, Christos | Xu, Yanan | Hadjipavlou-Litina, Dimitra | Luo, Yuan

Article Type: Research Article

Abstract: Neuroinflammation and oxidative stress are contributing factors to neurodegeneration in physiological aging as well as in age-related neurological disorders. Neuroinflammation can be both a cause and a result of chronic oxidative stress. The role of the oxidative stress and free radicals in the development of Alzheimer's disease (AD) is currently the focus of many studies. Hydrogen peroxide (H2 O2 ) in AD is thought to be associated with amyloid-β (Aβ) damage in cells. Aryl acetic acid derivatives were previously reported to be potent anti-inflammatory and antioxidant agents. In the present study, aryl acetic acid derivatives were tested as H2 O2 …scavengers using the DCF assay on two types of neuronal cells: a) the wild type N2a neuroblastoma cells; and b) the AβPP/PS1 transgenic cell line expressing Aβ. The scavenging activity of these agents and their protective role against cell death was demonstrated in both cell types. Our results suggest that these compounds could be used as a template in the design of novel therapeutic agents for AD. Show more

Keywords: Amyloid-β peptide, aryl-acetic acid derivatives, Δ.9 mutant cells, hydrogen peroxide scavengers, N2a neuroblastoma cells

DOI: 10.3233/JAD-120940

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 215-230, 2013

Authors: Tagliapietra, Matteo | Zanusso, Gianluigi | Fiorini, Michele | Bonetto, Nicola | Zarantonello, Giulia | Zambon, Alberto | Ermani, Mario | Monaco, Salvatore | Manara, Renzo | Cagnin, Annachiara

Article Type: Research Article

Abstract: Rapidly progressive dementia (RPD) is a rare presentation of different neurological disorders characterized by cognitive impairment leading to loss of functional independence within 24 months or less. The increasing recognition of treatable non-prion causes of RPD has made the differential diagnosis with sporadic Creutzfeldt-Jakob disease (sCJD) of crucial importance. We therefore assessed the frequency of different etiologies of RPD and evaluated the accuracy of newly proposed diagnostic criteria for sCJD. Clinical records of patients with RPD referred to Memory Clinic between 2007 and 2012 were retrospectively analyzed. The accuracy of diagnostic criteria for sCJD was evaluated by: a) MRI images …in DWI and FLAIR sequences; and (b) CSF 14-3-3 protein. In addition, CSF total tau protein level was also assessed. Final diagnosis was obtained after a 1-year follow-up or after autopsy. Among 37 patients with RPD, the most frequent causes were non-prion diseases, either untreatable (38%) or potentially treatable (32%), thus leaving sCJD as a less frequent cause (30%). DWI images had a sensitivity of 73% and specificity of 96%, while FLAIR yielded a very low sensitivity (40%). CSF 14-3-3 protein had a sensitivity of 100%, but a very low specificity (43%). The strongest independent predictor of sCJD diagnosis was the CSF tau level (p = 0.002) (91% sensitivity, 83% specificity). Treatable causes of RPD are as frequent as sCJD and a rapid differential diagnosis is mandatory. We suggest that DWI images and CSF analysis combining 14-3-3 and total tau protein determination hold the best informative diagnostic values. Show more

Keywords: Creutzfeldt-Jakob disease, limbic encephalitis, rapidly progressive dementia, tau protein

DOI: 10.3233/JAD-121873

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 231-238, 2013

Authors: Minjarez, Benito | Rustarazo, Ma. Luz Valero | Sanchez del Pino, Manuel M. | González-Robles, Arturo | Sosa-Melgarejo, Jorge A. | Luna-Muñoz, Jose | Mena, Raul | Luna-Arias, Juan Pedro

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. AD brains are characterized by the presence of neurofibrillary tangles (NFTs) and neuritic plaques. NFTs are constituted of paired helical filaments, which are structurally composed by assembled hyperphosphorylated and truncated tau polypeptides. To date, the integral constituents of NFTs remain unknown mainly due to the high insolubility of NFTs. The aim of this study was to identify by tandem mass spectrometry, the polypeptides contained in both isolated NFTs by laser capture microdissection and total homogenates, using tissue sections from paraformaldehyde-fixed AD brains. In the first case, we …isolated 2,000 NFTs from tissue samples of hippocampus from each of the three Mexican AD brains used in our study. These were previously stained with anti-hyperphosphorylated tau AT-100 antibodies. After the removal of paraformaldehyde and delipidation with organic solvents, we tested three solubilization methods. We identified 102 polypeptides from total homogenates and 41 from isolated NFTs. We selected UCH-L1, transferrin, and GAPDH polypeptides to be studied by immunofluorescence and confocal microscopy. Only UCH-L1 and GAPDH colocalized with hyperphosphorylated tau in NFTs. Show more

Keywords: Alzheimer's disease, neurofibrillary tangles, proteomics, tandem mass spectrometry, tau protein

DOI: 10.3233/JAD-121480

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 239-262, 2013

Authors: Valenti, Maria Teresa | Bolognin, Silvia | Zanatta, Cristina | Donatelli, Luca | Innamorati, Giulio | Pampanin, Maria | Zanusso, Gianluigi | Zatta, Paolo | Carbonare, Luca Dalle

Article Type: Research Article

Abstract: N-truncated and N-modified forms of amyloid-β (Aβ) peptide are found in diffused and dense core plaques in Alzheimer's disease (AD) brain. Among them, the most abundant N-truncated peptide starts with pyroglutamyl at residue 3 (AβpE3 ). AβpE3 has increased aggregation potential and toxicity and its abundance has been reported to correlate with the severity of the clinical phenotype in AD patients. N-terminal glutamate conversion generating AβpE3 is catalyzed by glutaminyl cyclase. This enzyme was found to be upregulated in the cortex of patients with AD. In the present study, we investigated glutaminyl cyclase mRNA and protein expression in …peripheral blood from AD patients and age-matched controls. Higher levels of glutaminyl cyclase mRNA and protein were present in AD patients compared with controls. Interestingly, we observed a correlation between glutaminyl cyclase expression and the severity of dementia (value of Mini-Mental State Examination). Therefore, we propose glutaminyl cyclase dosage in peripheral blood as a potential biomarker of AD. Show more

Keywords: Alzheimer's disease, gene expression, mini-mental state examination, peripheral blood, QPCT

DOI: 10.3233/JAD-120517

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 263-271, 2013

Authors: Katsumata, Yuriko | Todoriki, Hidemi | Higashiuesato, Yasushi | Yasura, Shotoku | Ohya, Yusuke | Willcox, D. Craig | Dodge, Hiroko H.

Article Type: Research Article

Abstract: We cross-sectionally examined which lipid profiles are associated with better cognitive function among those aged 80 and older, free of dementia (Clinical Dementia Rating ≤0.5), functionally independent, and community-dwelling. Our cohort consisted of 193 participants from the “Keys to Optimal Cognitive Aging (KOCOA) Project”, a prospective cohort study in Okinawa, Japan. Higher low-density lipoprotein cholesterol levels and lower triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratios were associated with higher scores in memory performance after controlling for confounders. Further research is required to clarify the associations among LDL-C levels, TG/HDL-C ratios, and healthy cognitive aging.

Keywords: Aged 80 and over, lipoprotein cholesterol, memory disorders

DOI: 10.3233/JAD-121138

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 273-279, 2013

Authors: Sanchez, Alma | Tripathy, Debjani | Luo, Jinau | Yin, Xiangling | Martinez, Joseph | Grammas, Paula

Article Type: Research Article

Abstract: Bidirectional communication between neurons and vascular cells is important to the maintenance of the central nervous system (CNS) milieu. Vascular endothelial growth factor (VEGF), through its ability to affect both vascular and neuronal cells, is likely a key protein in this process. Despite considerable literature documenting a neuroprotective function for VEGF, overexpression of this protein has also been shown in a wide variety of CNS diseases, including Alzheimer's disease (AD). Increased oxidative stress and elevated thrombin levels have also been documented in AD, specifically in the microvasculature. The aim of the current study is to examine endothelial cells and neurons …in vitro to determine the effects of oxidative stress and thrombin on VEGF release as well as the effects of low and high dose VEGF on neuronal viability. The data show that microvessels isolated from AD patients secrete significantly higher levels of VEGF compared to control-derived vessels. Exposure of brain endothelial cells to oxidative stress (sodium nitroprusside, menadione, or hydrogen peroxide) or thrombin significantly increases VEGF expression. Exposure of cultured neurons to oxidative stress increases expression of thrombin. Treating rat cortical neurons with high dose VEGF (≥500 ng/ml) decreases neuronal survival and expression of the anti-apoptotic protein Bcl-2 while increasing proapoptic proteins caspase 3 and phosphorylated p38 MAPK. High dose VEGF also negates the decrease in amyloid-β evoked by low dose VEGF. These results suggest that despite literature supporting neuroprotective effects of this protein, caution is warranted prior to implementation of VEGF as a therapeutic in the brain. Show more

Keywords: Dosage response, neurovascular unit, oxidative stress, thrombin, VEGF

DOI: 10.3233/JAD-121636

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 281-291, 2013

Authors: Robert, Philippe

Article Type: Editorial

DOI: 10.3233/JAD-121637

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 295-296, 2013

Authors: Gabelle, Audrey | Dumurgier, Julien | Vercruysse, Olivier | Paquet, Claire | Bombois, Stéphanie | Laplanche, Jean-Louis | Peoc'h, Katell | Schraen, Susanna | Buée, Luc | Pasquier, Florence | Hugon, Jacques | Touchon, Jacques | Lehmann, Sylvain

Article Type: Research Article

Abstract: The French Alzheimer's Disease Plan aims, in an unprecedented national effort, to develop research, promote optimal diagnosis, and take better care of patients. In order to evaluate the clinical interest and use of cerebrospinal fluid (CSF) biomarkers, a data-sharing project, the PLM (Paris-North, Lille and Montpellier) study has emerged through collaboration between these memory centers, already involved in this field. The revised Alzheimer's disease (AD) diagnosis criteria include CSF biomarkers, but little is known about their use in routine clinical practice. To evaluate their interest and diagnostic accuracy in routine AD diagnosis, a cohort of 677 patients from Montpellier was …first analyzed. The results were then validated through the analysis of a second cohort of 638 patients from Lille and Paris-Nord. Diagnoses of AD and other dementias were established by multidisciplinary expert teams, based on neuropsychological exams and structural brain imaging, blinded from CSF results. CSF amyloid-β, tau, and p-tau concentrations were measured for all patients. Receiver-operating characteristic curves were used to define cut-offs and evaluate the ability of each biomarker to discriminate AD from other diagnoses. We showed that p-tau outperformed other biomarkers for discriminating AD from non-AD patients and presents a clear clinical interest. The other biomarkers also showed relevant variations especially when the differential AD diagnoses were taken into account. Altogether we could demonstrate in both mono-centric and multi-centric cohorts from memory clinics the capacity of CSF biomarkers to discriminate AD from non-AD patients in clinical routine with a high sensitivity and specificity. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, cerebrospinal fluid biomarkers, cohort studies, dementia, p-tau

DOI: 10.3233/JAD-121549

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 297-305, 2013

Authors: Pimouguet, Clément | Bassi, Valérie | Somme, Dominique | Lavallart, Benoit | Helmer, Catherine | Dartigues, Jean François

Article Type: Review Article

Abstract: The 2008–2012 French Alzheimer plan has proposed measures to improve care for dementia patients in a more personalized and graduate approach owing to patients and caregivers needs. A key measure of the plan is the nationwide implementation of the MAIA (French acronym for Maison pour l'Autonomie et l'Intégration des malades d'Alzheimer). The main goal is to implement a process of integration through a network of partners involved in elderly care, assistance, or support. The MAIA model comprises tools and mechanisms necessary to improve the integrated care process; in particular, case management for elderly in complex situations. The purpose of this …paper is to describe the main measures from the national plan that aim to improve care for dementia patients with an emphasis on the MAIA measure. We summarize initial results of case management activity in one MAIA in the South West of France and we present two vignettes of cases benefiting from case management in order to demonstrate the nature of intervention. The French Alzheimer plan has promoted several non-pharmacological strategies for dementia patients. Implementation of both integrated care and case management represent a challenging perspective for the elderly and health professionals. Show more

Keywords: Alzheimer's disease, case management, dementia, integrated care, public health

DOI: 10.3233/JAD-121648

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 307-314, 2013

Authors: Fontaine, Denys | Deudon, Audrey | Lemaire, Jean Jacques | Razzouk, Micheline | Viau, Philippe | Darcourt, Jacques | Robert, Philippe

Article Type: Research Article

Abstract: Recent studies have suggested that memory circuits can be modulated by deep brain stimulation (DBS). This propriety might be used to slow down cognitive decline in patients suffering from Alzheimer's disease (AD). We conducted a prospective study to evaluate the feasibility and safety of DBS in AD patients with mild cognitive decline. Inclusion criteria were: patients (<70 years old) with AD diagnosed for less than 2 years, predominant impairment of episodic memory, and Mini-Mental Status Exam (MMSE) score between 20 and 24. The fornix was stimulated bilaterally by electrodes implanted stereotactically in the hypothalamus. Clinical, biological, neuropsychological, and imaging evaluations …were conducted 3 months before surgery and 3, 6, and 12 months thereafter. During the one year-period of inclusion, 110 patients with recently diagnosed AD and predominant impairment of episodic memory were screened. Only 9 patients (8.2%) fulfilled all the inclusion criteria. Finally, just one patient accepted to be operated (acceptance rate 11.1%) and completed the study. No complications occurred and the stimulation was perfectly tolerated. After one year of stimulation, the memory scores (MMSE, ADAS-Cog, Free and Cued Selective Reminding Test) were stabilized compared to baseline, and mesial temporal lobes metabolism increased. This pilot study provides new data about the safety of fornix DBS in the hypothalamus. However, it suggests that only a small proportion of AD patients might be interested in this approach and that the acceptance of DBS by AD patients was low, raising questions about the relevance of this approach to meet the expectations of these patients. Show more

Keywords: Alzheimer's disease, deep brain stimulation, dementia, fornix, hypothalamus

DOI: 10.3233/JAD-121579

Citation: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 315-323, 2013