Journal of Alzheimer's Disease - Volume 55, issue 1

Authors: Kennedy, Greg | Hardman, Roy J. | Macpherson, Helen | Scholey, Andrew B. | Pipingas, Andrew

Article Type: Review Article

Abstract: The rate of age-associated cognitive decline varies considerably between individuals. It is important, both on a societal and individual level, to investigate factors that underlie these differences in order to identify those which might realistically slow cognitive decline. Physical activity is one such factor with substantial support in the literature. Regular exercise can positively influence cognitive ability, reduce the rate of cognitive aging, and even reduce the risk of Alzheimer’s disease (AD) and other dementias. However, while there is substantial evidence in the extant literature for the effect of exercise on cognition, the processes that mediate this relationship are less …clear. This review examines cardiovascular health, production of brain derived neurotrophic factor (BDNF), insulin sensitivity, stress, and inflammation as potential pathways, via which exercise may maintain or improve cognitive functioning, and may be particularly pertinent in the context of the aging brain. A greater understanding of these mechanisms and their potential relationships with exercise and cognition will be invaluable in providing biomarkers for investigating the efficacy of differing exercise regimes on cognitive outcomes. Show more

Keywords: BDNF, cognition, cognitive aging, exercise, inflammation, insulin, stress, vascular

DOI: 10.3233/JAD-160665

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 1-18, 2017

Authors: Arnerić, Stephen P. | Batrla-Utermann, Richard | Beckett, Laurel | Bittner, Tobias | Blennow, Kaj | Carter, Leslie | Dean, Robert | Engelborghs, Sebastiaan | Genius, Just | Gordon, Mark Forrest | Hitchcock, Janice | Kaplow, June | Luthman, Johan | Meibach, Richard | Raunig, David | Romero, Klaus | Samtani, Mahesh N. | Savage, Mary | Shaw, Leslie | Stephenson, Diane | Umek, Robert M. | Vanderstichele, Hugo | Willis, Brian | Yule, Susan

Article Type: Review Article

Abstract: Abstract Alzheimer’s disease (AD) drug development is burdened with the current requirement to conduct large, lengthy, and costly trials to overcome uncertainty in patient progression and effect size on treatment outcome measures. There is an urgent need for the discovery, development, and implementation of novel, objectively measured biomarkers for AD that would aid selection of the appropriate subpopulation of patients in clinical trials, and presumably, improve the likelihood of successfully evaluating innovative treatment options. Amyloid deposition and tau in the brain, which are most commonly assessed either in cerebrospinal fluid (CSF) or by molecular imaging, are consistently and widely accepted. …Nonetheless, a clear gap still exists in the accurate identification of subjects that truly have the hallmarks of AD. The Coalition Against Major Diseases (CAMD), one of 12 consortia of the Critical Path Institute (C-Path), aims to streamline drug development for AD and related dementias by advancing regulatory approved drug development tools for clinical trials through precompetitive data sharing and adoption of consensus clinical data standards. This report focuses on the regulatory process for biomarker qualification, briefly comments on how it contrasts with approval or clearance of companion diagnostics, details the qualifications currently available to the field of AD, and highlights the current challenges facing the landscape of CSF biomarkers qualified as hallmarks of AD. Finally, it recommends actions to accelerate regulatory qualification of CSF biomarkers that would, in turn, improve the efficiency of AD therapeutic development. Show more

Keywords: Alzheimer’s disease, biomarker qualification, cerebrospinal fluid biomarkers, Coalition Against Major Diseases

DOI: 10.3233/JAD-160573

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 19-35, 2017

Authors: Cuccaro, Denis | De Marco, Elvira Valeria | Cittadella, Rita | Cavallaro, Sebastiano

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a devastating disease mainly afflicting elderly people, characterized by decreased cognition, loss of memory, and eventually death. Although risk and deterministic genes are known, major genetics research programs are underway to gain further insights into the inheritance of AD. In the last years, in particular, new developments in genome-wide scanning methodologies have enabled the association of a number of previously uncharacterized copy number variants (CNVs, gain or loss of DNA) in AD. Because of the exceedingly large number of studies performed, it has become difficult for geneticists as well as clinicians to systematically follow, evaluate, and interpret the …growing number of (sometime conflicting) CNVs implicated in AD. In this review, after a brief introduction of this type of structural variation, and a description of available databases, computational analyses, and technologies involved, we provide a systematic review of all published data showing statistical and scientific significance of pathogenic CNVs and discuss the role they might play in AD. Show more

Keywords: Alzheimer’s disease, comparative genomic hybridization, copy number variations, gene expression, genome, genome wide association studies, mutation

DOI: 10.3233/JAD-160469

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 37-52, 2017

Authors: Goossens, Joery | Laton, Jorne | Van Schependom, Jeroen | Gielen, Jeroen | Struyfs, Hanne | Van Mossevelde, Sara | Van den Bossche, Tobi | Goeman, Johan | De Deyn, Peter Paul | Sieben, Anne | Martin, Jean-Jacques | Van Broeckhoven, Christine | van der Zee, Julie | Engelborghs, Sebastiaan | Nagels, Guy

Article Type: Research Article

Abstract: We investigated the power of EEG as biomarker in differential diagnosis of Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD). EEG was recorded from 106 patients with AD or FTLD, of which 37 had a definite diagnosis, and 40 controls. Dominant frequency peaks were extracted for all 19 channels, for each subject. The average frequency of the largest dominant frequency peaks (maxpeak) was significantly lower in AD than FTLD patients and controls. Based on ROC analysis, classification could be made with diagnostic accuracy of 78.9%. Our findings show that quantitative analysis of EEG maxpeak frequency is an easy and useful …measure for differential dementia diagnosis. Show more

Keywords: Alzheimer’s disease, biomarkers, differential diagnosis, electroencephalography, frontotemporal lobardegeneration

DOI: 10.3233/JAD-160188

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 53-58, 2017

Authors: Sainaghi, Pier Paolo | Bellan, Mattia | Lombino, Franco | Alciato, Federica | Carecchio, Miryam | Galimberti, Daniela | Fenoglio, Chiara | Scarpini, Elio | Cantello, Roberto | Pirisi, Mario | Comi, Cristoforo

Article Type: Short Communication

Abstract: Growth arrest specific 6 (Gas6) has neurotrophic and neuroinflammatory functions, and may play a role in Alzheimer’s disease (AD). In keeping with this hypothesis, we observed that cerebrospinal fluid (CSF) Gas6 is increased in AD patients compared to controls (63 versus 67 subjects; median value 13.3 versus 9.1 ng/ml; p  < 0.0001). Thereafter, we assessed whether CSF Gas6 concentration was correlated to the following parameters: disease duration, MMSE score two years after clinical diagnosis, AD CSF biomarkers, and years of formal schooling. We detected an inverse correlation between CSF Gas6 levels at diagnosis and both disease duration (p  < 0.0001) and decrease in …the MMSE score two years later (p  < 0.0001). Conversely, we found no correlation between CSF Gas6 and both AD biomarkers and years of formal schooling. In conclusion, our results suggest that upregulation of CSF Gas6 may be part of a defensive response aimed at counteracting AD progression. Show more

Keywords: Dementia, disease progression, inflammation, neuroprotection

DOI: 10.3233/JAD-160599

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 59-65, 2017

Authors: Kitamura, Yoshihisa | Inden, Masatoshi | Kimoto, Yasuto | Takata, Kazuyuki | Yanagisawa, Daijiro | Hijioka, Masanori | Ashihara, Eishi | Tooyama, Ikuo | Shimohama, Shun | Ariga, Hiroyoshi

Article Type: Short Communication

Abstract: Previously, DJ-1 modulator UCP0054278/comp-B was identified by virtual screening, where comp-B interacts with DJ-1 to produce antioxidant and neuroprotective responses in Parkinson’s disease models. However, the effect of comp-B in an in vivo Alzheimer’s disease (AD) model is yet undetermined. Thus, we examined the effect of comp-B on spatial learning, memory, and amyloid-β (Aβ) clearance in a transgenic mouse model of AD. We found that comp-B resolved the cognitive deficits, reduced insoluble Aβ42 levels, and prevented the degeneration of synaptic functions, thereby suggesting that comp-B may become a major compound for AD treatment.

Keywords: Alzheimer’s disease, amyloid-β, DJ-1, Parkinson’s disease

DOI: 10.3233/JAD-160574

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 67-72, 2017

Authors: Nunomura, Akihiko | Zhu, Xiongwei | Perry, George

Article Type: Article Commentary

Abstract: DJ-1, a causative gene product of an autosomal recessive familial form of Parkinson’s disease (PD), plays roles in reducing oxidative stress and transcriptional regulation. Loss of its function is thought to result in the onset of PD. DJ-1 has been demonstrated to show general cytoprotective function mainly through antioxidant properties and possibly regulates the extent of stroke-induced damage and neurodegeneration in Alzheimer’s disease (AD). The paper, “Effects of a DJ-1-Binding Compound on Spatial Learning and Memory Impairment in a Mouse Model of Alzheimer’s Disease”, by Kitamura et al. in this issue of Journal of Alzheimer’s Disease reports that a …DJ-1 modulator UCP0054278/compound B (comp-B), which has been previously shown to exhibit antioxidant and neuroprotective properties in PD models, can prevent neurodegenerative changes and cognitive dysfunction in an animal model of AD. Indeed, comp-B reduces not only α-synuclein but also insoluble Aβ42 levels, prevents the reductions in synaptophysin and drebrin, and rescues cognitive deficits in transgenic APdE9 mice model of AD. It is noteworthy that pharmacological modulation of a familial PD gene product is sufficient to modify biochemical phenotypes and cognitive performance in amyloid-based genetically driven mouse models of AD. Together with mixed pathology in the vast majority of the patients with late-onset dementia, these findings strongly suggest the existence of common pathogenesis of diverse neurodegenerative disorders. Anti-oxidative strategy such as DJ-1 modulation is one of the major candidates to address the common pathogenesis and should be assembled among multimodal or combinatory interventions against neurodegenerative disorders. Show more

Keywords: α-synuclein, Alzheimer’s disease, amyloid-β, DJ-1, oxidative stress, Parkinson’s disease

DOI: 10.3233/JAD-160878

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 73-75, 2017

Authors: Chang, Peifen | Li, Xin | Ma, Chao | Zhang, Sisi | Liu, Zhen | Chen, Kewei | Ai, Lin | Chang, Jingling | Zhang, Zhanjun

Article Type: Research Article

Abstract: Polymorphisms of the apolipoprotein E (APOE) promoter rs405509 are related to Alzheimer’s disease (AD). The T/T allele of rs405509 decreases the transcription of the APOE gene and leads to impairments in a specific brain structural network in aged individuals; thus, it is an important risk factor for AD. However, it remains unknown whether rs405509 affects white matter networks during aging. Here, we investigated the effect of the rs405509 genotype (T/T versus G-allele) on age-related brain white matter structural networks via construction of the graph theory-based structural connectome using diffusion MRI data in a large cohort. Network communication efficiency was quantified, …along with the network’s betweenness centrality (Bc), global efficiency, local efficiency, and shortest path length. Regarding cognition, TT carriers had significant negative correlations between age and memory performance and between age and executive functions. A network analysis showed that TT carriers had an accelerated age-related loss of Bc and that regional Bc decreased in the left inferior frontal gyrus pars opercularis, the left posterior cingulate cortex, the right inferior occipital gyrus (IOG.R), and the left angular gyrus (ANG.L). Additional brain-behavior relationship analyses showed that polymorphism of rs405509 and age have strong interaction effects on the association of nodal Bc and cognition, mainly in the IOG.R and ANG.L. These results demonstrate that the rs405509 T/T allele of APOE causes an age-related cognitive decline in non-demented elderly people, possibly by modulating brain network communication efficiency, which may be beneficial for understanding the neural mechanisms of rs405509-related cognitive aging and AD pathogenesis. Show more

Keywords: APOE promoter, brain connectome, cognitive aging, diffusion MRI, graph theory

DOI: 10.3233/JAD-160447

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 77-87, 2017

Authors: Fried, Peter J. | Schilberg, Lukas | Brem, Anna-Katharine | Saxena, Sadhvi | Wong, Bonnie | Cypess, Aaron M. | Horton, Edward S. | Pascual-Leone, Alvaro

Article Type: Research Article

Abstract: Background: Type-2 diabetes mellitus (T2DM) accelerates cognitive aging and increases risk of Alzheimer’s disease. Rodent models of T2DM show altered synaptic plasticity associated with reduced learning and memory. Humans with T2DM also show cognitive deficits, including reduced learning and memory, but the relationship of these impairments to the efficacy of neuroplastic mechanisms has never been assessed. Objective: Our primary objective was to compare mechanisms of cortical plasticity in humans with and without T2DM. Our secondary objective was to relate plasticity measures to standard measures of cognition. Methods: A prospective cross-sectional cohort study was conducted on …21 adults with T2DM and 15 demographically-similar non-diabetic controls. Long-term potentiation-like plasticity was assessed in primary motor cortex by comparing the amplitude of motor evoked potentials (MEPs) from single-pulse transcranial magnetic stimulation before and after intermittent theta-burst stimulation (iTBS). Plasticity measures were compared between groups and related to neuropsychological scores. Results: In T2DM, iTBS-induced modulation of MEPs was significantly less than controls, even after controlling for potential confounds. Furthermore, in T2DM, modulation of MEPs 10-min post-iTBS was significantly correlated with Rey Auditory Verbal Learning Task (RAVLT) performance. Conclusion: Humans with T2DM show abnormal cortico-motor plasticity that is correlated with reduced verbal learning. Since iTBS after-effects and the RAVLT are both NMDA receptor-dependent measures, their relationship in T2DM may reflect brain-wide alterations in the efficacy of NMDA receptors. These findings offer novel mechanistic insights into the brain consequences of T2DM and provide a reliable means to monitor brain health and evaluate the efficacy of clinical interventions. Show more

Keywords: Cognitive aging, neuroplasticity, transcranial magnetic stimulation, type 2 diabetes mellitus, verbal learning

DOI: 10.3233/JAD-160505

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 89-100, 2017

Authors: Philippens, Ingrid H. | Ormel, Paul R. | Baarends, Guus | Johansson, Maja | Remarque, Ed J. | Doverskog, Magnus

Article Type: Research Article

Abstract: Background: The immune system is increasingly mentioned as a potential target for Alzheimer’s disease (AD) treatment. Objective: In the present pilot study, the effect of (neuro)inflammation on amyloidopathy was investigated in the marmoset monkey, which has potential as an AD animal model due to its natural cerebral amyloidosis similar to humans. Methods: Six adult/aged marmosets (Callithrix jacchus ) were intracranial injected with amyloid-beta (Aβ) fibrils at three cortical locations in the right hemisphere. Additionally, in half of the monkeys, lipopolysaccharide (LPS) was co-injected with the Aβ fibrils and injected in the other hemisphere without Aβ …fibrils. The other three monkeys received phosphate buffered saline instead of LPS, as a control for the inflammatory state. The effect of inflammation on amyloidopathy was also investigated in an additional monkey that suffered from chronic inflammatory wasting syndrome. Mirror histology sections were analyzed to assess amyloidopathy and immune reaction, and peripheral blood for AD biomarker expression. Results: All LPS-injected monkeys showed an early AD immune blood cell expression profile on CD95 and CD45RA. Two out of three monkeys injected with Aβ and LPS and the additional monkey, suffering from chronic inflammation, developed plaques. None of the controls, injected with Aβ only, developed any plaques. Conclusion: This study shows the importance of immune modulation on the susceptibility for amyloidosis, a hallmark of AD, which offers new perspectives for disease modifying approaches in AD. Show more

Keywords: Alzheimer’s disease, amyloid, amyloidosis, inflammation, marmoset, microglia, non-human primates, pathology, plaque progression, pro-inflammatory cytokines

DOI: 10.3233/JAD-160673

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 101-113, 2017