Journal of Alzheimer's Disease - Volume 47, issue 4

Authors: Fu, Yongyao | Zhao, Deming | Pan, Bo | Wang, Jihong | Cui, Yongyong | Shi, Fushan | Wang, Chunyu | Yin, Xiaoming | Zhou, Xiangmei | Yang, Lifeng

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia. Mice in the transgenic Aβ PPswe/PS1dE9 mouse line express a chimeric mouse/human amyloid-β protein precursor (Mo/HuAβ PP695swe) and mutant human presenilin 1 (PS1-dE9) associated with early-onset AD. Knowing the protein expression in these mice may offer better understanding of the pathological changes in AD. In this study, we used two-dimensional gel electrophoresis combined with mass spectrometry techniques to compare protein expression in Aβ PPswe/PS1dE9 mice with age-matched wild-type mice throughout the disease progression. We identified 15 proteins that were significantly different between the Aβ PPswe/PS1dE9 mice and age-matched controls …and also changed with disease development. Among those, the expression levels of the following proteins in Aβ PPswe/PS1dE9 mice were at least 1.5 times higher than those in normal mice: DCC-interacting protein 13-beta, serum albumin, creatine kinase B-type, heat shock 70 kDa protein 1A, T-complex protein 1 subunit beta, adenylate kinase isoenzyme 1, pyruvate dehydrogenase E1 component subunit beta mitochondrial, and V-type proton ATPase catalytic subunit A. Levels of the following proteins in Aβ PPswe/PS1dE9 mice were at least 1.5 times lower than those in normal mice: dihydropyrimidinase-related protein 2, actin cytoplasmic 2, isoform 1 of V-type proton ATPase catalytic subunit, tubulin alpha-1C chain, F-actin-capping protein subunit alpha-2, ubiquitin carboxyl-terminal hydrolase isozyme L1, and actin cytoplasmic 1. These proteins are involved in regulating various cellular functions, including cytoskeletal structure, energy metabolism, synaptic components, and protein degradation. These findings indicate altered protein expression in the pathogenesis of AD and illuminate novel therapeutic avenues for treatment in AD. Show more

Keywords: Alzheimer’s disease, DRP-2, HSP-70, proteomics, UCH-L1

DOI: 10.3233/JAD-150312

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 915-926, 2015

Authors: Wang, Xin | Cui, Jin | Li, Wei | Zeng, Xianglu | Zhao, Jian | Pei, Gang

Article Type: Research Article

Abstract: Elucidation of γ-secretase structure and dynamic conformational changes is of importance to drug discovery targeting this enzyme. Electron microscopy analyses provided important structural information, but the dynamic changes of γ-secretase in cells need to be explored further. We found that PS1 internal fluorescence resonance energy transfer (FRET) probes can incorporate into γ-secretase complex and possess secretase activity. Our results from fluorescence lifetime image microscopy (FLIM) and acceptor photobleaching FRET show different PS1 internal FRET when PS1 fluorescent probes expressed alone or with other secretase subunits Aph1aL, Nicastrin, and Pen2, indicating that PS1 internal FRET could be applied for probing conformational …change of γ-secretase complex. Further, we accessed whether γ-secretase activity interfering compounds induced different conformational changes of PS1. Our results show that both γ-secretase modulators and inhibitors affect PS1 internal FRET but in different manners. These results demonstrate that FLIM and acceptor photobleaching FRET could be applied to monitor different PS1 conformational changes in γ-secretase. Show more

Keywords: Förster resonance energy transfer, gamma-secretase, gamma-secretase inhibitors, gamma-secretase modulators, molecular conformation, presenilin

DOI: 10.3233/JAD-150313

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 927-937, 2015

Authors: Klöppel, Stefan | Peter, Jessica | Ludl, Anna | Pilatus, Anne | Maier, Sabrina | Mader, Irina | Heimbach, Bernhard | Frings, Lars | Egger, Karl | Dukart, Juergen | Schroeter, Matthias L. | Perneczky, Robert | Häussermann, Peter | Vach, Werner | Urbach, Horst | Teipel, Stefan | Hüll, Michael | Abdulkadir, Ahmed | and for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Several studies have demonstrated that fully automated pattern recognition methods applied to structural magnetic resonance imaging (MRI) aid in the diagnosis of dementia, but these conclusions are based on highly preselected samples that significantly differ from that seen in a dementia clinic. At a single dementia clinic, we evaluated the ability of a linear support vector machine trained with completely unrelated data to differentiate between Alzheimer’s disease (AD), frontotemporal dementia (FTD), Lewy body dementia, and healthy aging based on 3D-T1 weighted MRI data sets. Furthermore, we predicted progression to AD in subjects with mild cognitive impairment (MCI) at baseline and …automatically quantified white matter hyperintensities from FLAIR-images. Separating additionally recruited healthy elderly from those with dementia was accurate with an area under the curve (AUC) of 0.97 (according to Fig. 4 ). Multi-class separation of patients with either AD or FTD from other included groups was good on the training set (AUC >  0.9) but substantially less accurate (AUC = 0.76 for AD, AUC = 0.78 for FTD) on 134 cases from the local clinic. Longitudinal data from 28 cases with MCI at baseline and appropriate follow-up data were available. The computer tool discriminated progressive from stable MCI with AUC = 0.73, compared to AUC = 0.80 for the training set. A relatively low accuracy by clinicians (AUC = 0.81) illustrates the difficulties of predicting conversion in this heterogeneous cohort. This first application of a MRI-based pattern recognition method to a routine sample demonstrates feasibility, but also illustrates that automated multi-class differential diagnoses have to be the focus of future methodological developments and application studies Show more

Keywords: Dementia diagnostics, machine learning, magnetic resonance imaging, prognosis, support vector machine

DOI: 10.3233/JAD-150334

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 939-954, 2015

Authors: Quiroz, Yakeel T. | Willment, Kim Celone | Castrillon, Gabriel | Muniz, Martha | Lopera, Francisco | Budson, Andrew | Stern, Chantal E.

Article Type: Research Article

Abstract: Background: Brain regions critical to episodic memory are altered during the preclinical stages of Alzheimer’s disease (AD). However, reliable means of identifying cognitively-normal individuals at higher risk to develop AD have not been established. Objective: To examine whether functional MRI can detect early functional changes associated with scene encoding in a group of presymptomatic presenilin-1 (PSEN1 ) E280A mutation carriers. Methods: Participants were 39 young, cognitively-normal individuals from an autosomal dominant early-onset AD kindred, located in Antioquia, Colombia. Participants performed a functional MRI scene encoding task and a post-scan subsequent memory test. …Results: PSEN1 mutation carriers exhibited hyperactivation within medial temporal lobe regions (hippocampus,parahippocampal formation) during successful scene encoding compared to age-matched non-carriers. Conclusion: Hyperactivation in medial temporal lobe regions during scene encoding is seen in individuals genetically-determined to develop AD years before their clinical onset. Our findings will guide future research with the ultimate goal of using functional neuroimaging in the early detection of preclinical AD. Show more

Keywords: Alzheimer’s disease, autosomal-dominant, functional MRI, memory encoding, presenilin-1

DOI: 10.3233/JAD-150214

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 955-964, 2015

Authors: Malpas, Charles B. | Saling, Michael M. | Velakoulis, Dennis | Desmond, Patricia | O’Brien, Terence J. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by two primary pathologies: tau-related neurofibrillary tangles and the extracellular accumulation of amyloid-β (Aβ). The development of these pathologies is topologically distinct early in the disease, with Aβ beginning to accumulate as a diffuse, neocortical pathology, while tau-related pathology begins to form in mesial temporal regions. This study investigated the hypothesis that, by virtue of this distinction, there exist preferential associations between the primary pathologies and aspects of the cognitive phenotype. We investigated the relationship between cerebrospinal fluid (CSF) biomarkers for tau and Aβ pathologies with neurocognitive measures in 191 patients with mild cognitive impairment …(MCI). Participants completed cognitive tests of new learning, information processing speed, and working memory. Separate regression models were computed and then followed up with mediation analyses to examine the predictive status of CSF biomarkers. The effect of Aβ on learning was mediated by phospho-tau (p  = 0.008). In contrast, Aβ had a direct effect on information processing speed that was not mediated by phospho-tau (p  = 0.59). No predictors were significant for working memory. This study provided evidence for a differential relationship of Aβ and phospho-tau pathologies on the neurocognitive phenotype of MCI. This supports the proposition that these primary AD pathologies maximally affect different aspects of cognition, and has potential implications for cognitive assessments and the use of biomarkers in disease-modifyingtherapeutic trials. Show more

Keywords: Amyloid-β, cerebrospinal fluid, cognition, mild cognitive impairment, tau

DOI: 10.3233/JAD-142643

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 965-975, 2015

Authors: Dell’Acqua, Flavio | Khan, Wasim | Gottlieb, Natalie | Giampietro, Vincent | Ginestet, Cedric | Bouls, David | Newhouse, Steven | Dobson, Richard | Banaschewski, Tobias | Barker, Gareth J. | Bokde, Arun L.W. | Büchel, Christian | Conrod, Patricia | Flor, Herta | Frouin, Vincent | Garavan, Hugh | Gowland, Penny | Heinz, Anreas | Lemaítre, Hervé | Nees, Frauke | Paus, Tomas | Pausova, Zdenka | Rietschel, Marcella | Smolka, Michael N. | Ströhle, Andreas | Gallinat, Jean | Westman, Eric | Schumann, Gunther | Lovestone, Simon | Simmons, Andrew | the IMAGEN consortium ()

Article Type: Research Article

Abstract: The apolipoprotein E (APOE) ɛ 4 allele is the best established genetic risk factor for Alzheimer’s disease (AD) and has been previously associated with alterations in structural gray matter and changes in functional brain activity in healthy middle-aged individuals and older non-demented subjects. In order to determine the neural mechanism by which APOE polymorphisms affect white matter (WM) structure, we investigated the diffusion characteristics of WM tracts in carriers and non-carriers of the APOE ɛ 4 and ɛ 2 alleles using an unbiased whole brain analysis technique (Tract Based Spatial Statistics) in a healthy young adolescent (14 years) cohort. A …large sample of healthy young adolescents (n  = 575) were selected from the European neuroimaging-genetics IMAGEN study with available APOE status and accompanying diffusion imaging data. MR Diffusion data was acquired on 3T systems using 32 diffusion-weighted (DW) directions and 4 non-DW volumes (b-value = 1,300 s/mm2 and isotropic resolution of 2.4×2.4×2.4 mm). No significant differences in WM structure were found in diffusion indices between carriers and non-carriers of the APOE ɛ 4 and ɛ 2 alleles, and dose-dependent effects of these variants were not established, suggesting that differences in WM structure are not modulated by the APOE polymorphism. In conclusion, our results suggest that microstructural properties of WM structure are not associated with the APOE ɛ 4 and ɛ 2 alleles in young adolescence, suggesting that the neural effects of these variants are not evident in 14-year-olds and may only develop later in life. Show more

Keywords: Apolipoprotein E, diffusion tensor imaging, magnetic resonance imaging, tract based spatial statistics, young healthy adolescents

DOI: 10.3233/JAD-140519

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 977-984, 2015

Authors: Mendez, Mario F. | Paholpak, Pongsatorn | Lin, Andrew | Zhang, Jeannie Y. | Teng, Edmond

Article Type: Research Article

Abstract: Background: Traumatic brain injury (TBI) is the most established environmental risk factor for Alzheimer’s disease (AD), but it is unclear if TBI is specifically associated with early-onset AD (EOAD). Objective: To evaluate the relationship between TBI and EOAD (<65 years). Methods: We identified 1,449 EOAD, 4,337 late-onset AD (LOAD), and corresponding EOAD-matched and LOAD-matched normal controls (NC) in the National Alzheimer’s Coordinating Center Uniform (NACC) database and compared the prevalence of any history of TBI as well as measures of cognition, function, behavior, and neuropathology. For validation, we determined TBI prevalence among …115 well-characterized clinic patients with EOAD. Results: Part A: The prevalence of any TBI in the NACC-database EOAD participants (13.3%) was comparable to that observed in the clinic EOAD patients (13.9%) but significantly higher than in the NACC-database LOAD participants (7.7% ; p  <  0.0001) and trended to higher compared to EOAD-matched NC (11.1% ; logistic regression p  = 0.053). Part B: When we compared EOAD patients with documented non-acute and non-residually impairing TBI to EOAD without a documented history of prior TBI, those with TBI had significantly more disinhibition. Part C: Autopsies did not reveal differences in AD neuropathology based on a history of TBI. Conclusions: These findings suggest, but do not establish, that TBI is a specific risk factor for EOAD and may lead to disinhibition, a feature that often results from the frontal effects of head injury. This study recommends further research on the effects of TBI in EOAD in larger numbers of participants. Show more

Keywords: Aging, Alzheimer’s disease, concussion, dementia, epidemiology, head injury, memory loss, neurodegeneration, risk factors, traumatic brain injury

DOI: 10.3233/JAD-143207

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 985-993, 2015

Authors: Weiler, Marina | Agosta, Federica | Canu, Elisa | Copetti, Massimiliano | Magnani, Giuseppe | Marcone, Alessandra | Pagani, Elisabetta | Balthazar, Marcio Luiz Figueredo | Comi, Giancarlo | Falini, Andrea | Filippi, Massimo

Article Type: Research Article

Abstract: Background: Longitudinal MRI studies in Alzheimer’s disease (AD) are one of the most reliable way to track brain changes along the course of the disease. Objective: To investigate the evolution of grey matter (GM) atrophy and white matter (WM) damage in AD patients, and to assess the relationships of MRI changes with baseline clinical and cognitive variables and their evolution over time. Methods: Clinical, neuropsychological, and MRI assessments (T1-weighted and diffusion tensor [DT]-MRI) were obtained from 14 patients with AD at baseline and after a 16 ± 3 month period. Lumbar puncture …was obtained at study entry. At baseline, AD patients were compared to 37 controls. GM atrophy progression was assessed with tensor-based morphometry and GM volumes of interest, and WM damage progression using tract-based spatial statistics and tractography. Results: At baseline, patients showed cortical atrophy in the medial temporal and parietal regions and a widespread pattern of WM damage involving the corpus callosum, cingulum, and temporo-occipital, parietal, and frontal WM tracts. During follow up, AD patients showed total GM atrophy, while total WM volume did not change. GM tissue loss was found in frontal, temporal, and parietal regions. In addition, AD patients showed a progression of WM microstructural damage to the corpus callosum, cingulum, fronto-parietal and temporo-occipital connections bilaterally. Patients with higher baseline cerebrospinal fluid total tau showed greater WM integrity loss at follow up. GM and WM changes over time did not correlate with each other nor with cognitive evolution. Conclusion: In AD, GM atrophy and WM tract damage are likely to progress, at least partially, independently. This study suggests that a multimodal imaging approach, which includes both T1-weighted and DT MR imaging, may provide additional markers to monitor disease progression. Show more

Keywords: Alzheimer’s disease, grey matter atrophy, longitudinal MRI, progression, tau pathology, white matter tract damage

DOI: 10.3233/JAD-150196

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 995-1007, 2015

Authors: Gleason, Carey E. | Fischer, Barbara L. | Dowling, N. Maritza | Setchell, Kenneth D.R. | Atwood, Craig S. | Carlsson, Cynthia M. | Asthana, Sanjay

Article Type: Research Article

Abstract: Background: In a previous trial, treatment with soy isoflavones was associated with improved nonverbal memory, construction abilities, verbal fluency, and speeded dexterity compared to treatment with placebo in cognitively healthy older adults. Objective: The current trial aimed to examine the potential cognitive benefits of soy isoflavones in patients with Alzheimer’s disease. Methods: Sixty-five men and women over the age of 60 were treated with 100 mg/day soy isoflavones, or matching placebo capsules for six months. APOE genotype was determined for all participants. Cognitive outcomes and plasma isoflavone levels were measured at baseline, …and at two additional time points: three and six months after baseline. Results: Of the sixty-five participants enrolled, thirty-four (52.3% ) were women, and 31 (47.7% ) were APOE ɛ 4 positive. Average age was 76.3 (SD = 7.2) years. Fifty-nine (90.8% ) subjects completed all study visits. Plasma isoflavone levels increased in subjects treated with soy isoflavones compared to baseline and to placebo, although intersubject variability in plasma levels was large. No significant differences in treatment effects for cognition emerged between treatment groups or genders. Exploratory analyses of associations between changes in cognition and plasma isoflavone levels revealed an association between equol levels, and speeded dexterity and verbal fluency. Conclusions: Six months of 100 mg/day treatment with soy isoflavones did not benefit cognition in older men and women with Alzheimer’s disease. However, our results suggest the need to examine the role of isoflavone metabolism, i.e., the ability to effectively metabolize soy isoflavones by converting daidzen to equol when attempting to fully clarify the cognitive effects of isoflavones. Show more

Keywords: Alzheimer’s disease, clinical trial, cognition, daidzein, equol, genistein, phytoestrogens, soy isoflavones

DOI: 10.3233/JAD-142958

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 1009-1019, 2015

Authors: Liu, Kai | Chojnacki, Jeremy E. | Wade, Emily E. | Saathoff, John M. | Lesnefsky, Edward J. | Chen, Qun | Zhang, Shijun

Article Type: Research Article

Abstract: Multiple pathogenic factors have been suggested to play a role in the development of Alzheimer’s disease (AD). The multifactorial nature of AD also suggests the potential use of compounds with polypharmacology as effective disease-modifying agents. Recently, we have developed a bivalent strategy to include cell membrane anchorage into the molecular design. Our results demonstrated that the bivalent compounds exhibited multifunctional properties and potent neuroprotection in a cellular AD model. Herein, we report the mechanistic exploration of one of the representative bivalent compounds, 17MN, in MC65 cells. Our results established that MC65 cells die through a necroptotic mechanism upon the removal …of tetracycline (TC). Furthermore, we have shown that mitochondrial membrane potential and cytosolic Ca2+ levels are increased upon removal of TC. Our bivalent compound 17MN can reverse such changes and protect MC65 cells from TC removal induced cytotoxicity. The results also suggest that 17MN may function between the Aβ species and RIPK1 in producing its neuroprotection. Colocalization studies employing a fluorescent analog of 17MN and confocal microscopy demonstrated the interactions of 17MN with both mitochondria and endoplasmic reticulum, thus suggesting that 17MN exerts its neuroprotection via a multiple-site mechanism in MC65 cells. Collectively, these results strongly support our original design rationale of bivalent compounds and encourage further optimization of this bivalent strategy to develop more potent analogs as novel disease-modifying agents for AD. Show more

Keywords: Alzheimer’s disease, bivalent compound, calcium, mitochondria, multifunctional, neuroprotection

DOI: 10.3233/JAD-150242

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 1021-1033, 2015