Journal of Alzheimer's Disease - Volume 56, issue 2

Authors: van Waalwijk van Doorn, Linda J.C. | Gispert, Juan D. | Kuiperij, H. Bea | Claassen, Jurgen A.H.R. | Arighi, Andrea | Baldeiras, Inês | Blennow, Kaj | Bozzali, Marco | Castelo-Branco, Miguel | Cavedo, Enrica | Emek-Savaş, Derya D. | Eren, Erden | Eusebi, Paolo | Farotti, Lucia | Fenoglio, Chiara | Ormaechea, Juan Fortea | Freund-Levi, Yvonne | Frisoni, Giovanni B. | Galimberti, Daniela | Genc, Sermin | Greco, Viviana | Hampel, Harald | Herukka, Sanna-Kaisa | Liu, Yawu | Lladó, Albert | Lleó, Alberto | Nobili, Flavio M. | Oguz, Kader K. | Parnetti, Lucilla | Pereira, João | Picco, Agnese | Pikkarainen, Maria | de Oliveira, Catarina Resende | Saka, Esen | Salvadori, Nicola | Sanchez-Valle, Raquel | Santana, Isabel | Scarpini, Elio | Scheltens, Philip | Soininen, Hilkka | Tarducci, Roberto | Teunissen, Charlotte | Tsolaki, Magda | Urbani, Andrea | Vilaplana, Eduard | Visser, Pieter Jelle | Wallin, Asa K. | Yener, Görsev | Molinuevo, José L. | Meulenbroek, Olga | Verbeek, Marcel M.

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer’s disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., Aβ42 , total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers …(and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF Aβ42 levels inversely correlated to VV/TIV in the whole study population (Aβ42 : r  = –0.28; p  < 0.0001). For CSF t-tau and p-tau, this association only reached statistical significance in the combined MCI and AD group (t-tau: r  = –0.15; p-tau: r  = –0.13; both p  < 0.01). Correction for differences in VV/TIV improved the differentiation of AD versus controls based on CSF Aβ42 alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF Aβ42 levels. Show more

Keywords: Alzheimer’s disease, amyloid biomarkers, cerebrospinal fluid, lateral ventricles, tau protein

DOI: 10.3233/JAD-160668

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 543-555, 2017

Authors: Gareri, Pietro | Castagna, Alberto | Cotroneo, Antonino Maria | Putignano, Daria | Conforti, Raffaele | Santamaria, Francesco | Marino, Saverio | Putignano, Salvatore

Article Type: Research Article

Abstract: Background: Citicoline can have beneficial effects both in degenerative and in vascular cognitive decline in a variety of ways (apoptosis inhibition, neuroplasticity potentiation, phospholipid, and acetylcholine (ACh) synthesis). Acetylcholinesterase inhibitors (AChEIs) have been used for treatment of Alzheimer’s disease (AD). When co-administered with cholinergic precursors, they are able to increase the intrasynaptic levels of ACh more than when the single drugs given alone. Objective: The aim of the present study was to show the effectiveness of oral citicoline plus AChEIs in patients affected with AD. Methods: This was a retrospective multi-centric case-control study, involving seven …Centers for Cognitive Impairment and Dementia in Italy, on 448 consecutive patients aged 65 years old or older affected with AD. 197 patients were treated with an AChEI while 251 were treated with an AchEI + citicoline 1000 mg/day given orally. Cognitive functions were assessed by MMSE, daily life functions by ADL and IADL, behavioral symptoms by NPI, comorbidities by CIRS, and mood by GDS-short form. Tests were administered at baseline (T0), after 3 (T1), and 9 months (T2). The primary outcomes were effects of combined administration versus AChEIs given alone on cognitive functions assessed by MMSE. The secondary outcomes were possible side effects or adverse events of combination therapy versus AChEIs alone. Results: Patients treated with citicoline plus an AChEI showed a statistically significant increase in MMSE between T0 and T1 (16.88±3.38 versus 17.62±3.64; p  = 0.000) and between T1 and T2 (17.62±3.64 versus 17.89±3.54; p  = 0.000). Conclusion: The present study encourages the role of combined administration in disease management by slowing disease progression. Show more

Keywords: Acetylcholinesterase inhibitors, Alzheimer’s disease, citicoline, donepezil, elderly, galantamine, rivastigmine

DOI: 10.3233/JAD-160808

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 557-565, 2017

Authors: Sugimoto, Taiki | Yoshida, Masaki | Ono, Rei | Murata, Shunsuke | Saji, Naoki | Niida, Shumpei | Toba, Kenji | Sakurai, Takashi

Article Type: Research Article

Abstract: Background: Urinary incontinence (UI) is frequently observed in patients with Alzheimer’s disease (AD). Although previous works highlight the association between frontal lobe-related function and UI, causal relationship is unclear. Objects: To clarify the longitudinal association between frontal lobe function and the incidence of UI at 1 year in patients with AD. Methods: The subjects were 215 continent AD patients who attended the Memory Clinic of the National Center for Geriatrics and Gerontology of Japan during the period from March 2011 to December 2014. The absence or presence of UI was operationally assigned by the dementia …behavior disturbance scale subscale, which was completed by the patients’ caregivers. Frontal lobe function was assessed using the Frontal Assessment Battery (FAB). Other confounding factors including demographic data, cognitive status, vitality, mood, physical performance, and use of medication (cholinesterase inhibitors, calcium channel blockers [CCBs], diuretics, alpha blockers and anticholinergic drugs) were assessed. Results: During 1-year follow up (mean: 377.4±83.7 days), the incidence of UI was 12.1% (n  = 26). Patients with UI had significantly lower FAB performance at baseline (no UI versus UI = 9.3±2.8 versus 7.8±2.7). In multivariate analysis, stepwise logistic regression analysis demonstrated that FAB (odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.66–0.94) and the use of CCB (OR = 2.72, 95% CI = 1.09–6.77) were significantly associated with UI at 1 year. Conclusion: The results of study indicate that frontal lobe dysfunction is predictor for UI in patients with AD. Show more

Keywords: Alzheimer’s disease, calcium channel blocker, cholinesterase inhibitors, frontal lobe function, urinaryincontinence

DOI: 10.3233/JAD-160923

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 567-574, 2017

Authors: Bergland, Anne Katrine | Dalen, Ingvild | Larsen, Alf Inge | Aarsland, Dag | Soennesyn, Hogne

Article Type: Research Article

Abstract: Background: Vascular risk factors (VRF) are associated with an increased risk of neurodegenerative disease. Objective: To examine the association between VRF and cognitive decline in patients with Alzheimer’s disease (AD) and Lewy body dementia (LBD). Methods: We included consecutive referrals with mild AD or LBD to dementia clinics in western Norway from 2005 to 2013. The Mini-Mental Status Exam (MMSE) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) were administered at baseline and then annually for up to five years. The VRF include diabetes mellitus, hypertension, hypercholesterolemia, overweight and smoking. Generalized Estimating Equations (GEE) …were used to examine the potential association between VRF scores and the change in MMSE and CDR-SB scores, adjusting for age, sex, and the apolipoprotein ɛ 4 allele (APOE4). Results: A total of 200 patients were included (113 AD, 87 LBD) (mean age 76 years, mean baseline MMSE 24.0, mean follow-up time 3.5 years). Smoking was the only VRF significantly associated with a more rapid cognitive decline, however only in the AD group. Being overweight at baseline was associated with a slower cognitive decline. Moreover, hypertension at baseline predicted a slower decline in MMSE scores. In the LBD group diabetes mellitus was found to be associated with a slower increase in CDR-SB scores. Conclusion: With the exception of smoking, VRF at time of dementia diagnosis were not associated with a more rapid cognitive decline. Show more

Keywords: Alzheimer’s disease, dementia, Lewy body dementia, progression, vascular risk factors

DOI: 10.3233/JAD-160847

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 575-584, 2017

Authors: Theunis, Clara | Adolfsson, Oskar | Crespo-Biel, Natalia | Piorkowska, Kasia | Pihlgren, Maria | Hickman, David T. | Gafner, Valérie | Borghgraef, Peter | Devijver, Herman | Pfeifer, Andrea | Van Leuven, Fred | Muhs, Andreas

Article Type: Research Article

Abstract: The microtubule-associated protein Tau is an intrinsically unfolded, very soluble neuronal protein. Under still unknown circumstances, Tau protein forms soluble oligomers and insoluble aggregates that are closely linked to the cause and progression of various brain pathologies, including Alzheimer’s disease. Previously we reported the development of liposome-based vaccines and their efficacy and safety in preclinical mouse models for tauopathy. Here we report the use of a liposomal vaccine for the generation of a monoclonal antibody with particular characteristics that makes it a valuable tool for fundamental studies as well as a candidate antibody for diagnostic and therapeutic applications. The specificity …and affinity of antibody ACI-5400 were characterized by a panel of methods: (i) measuring the selectivity for a specific phospho-Tau epitope known to be associated with tauopathy, (ii) performing a combination of peptide and protein binding assays, (iii) staining of brain sections from mouse preclinical tauopathy models and from human subjects representing six different tauopathies, and (iv) evaluating the selective binding to pathological epitopes on extracts from tauopathy brains in non-denaturing sandwich assays. We conclude that the ACI-5400 antibody binds to protein Tau phosphorylated at S396 and favors a conformation that is typically present in the brain of tauopathy patients, including Alzheimer’s disease. Show more

Keywords: Antibody binding sites, Alzheimer’s disease, monoclonal antibody, protein conformation, tauopathies

DOI: 10.3233/JAD-160695

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 585-599, 2017

Authors: Persson, Torbjörn | Lattanzio, Francesca | Calvo-Garrido, Javier | Rimondini, Roberto | Rubio-Rodrigo, Marta | Sundström, Erik | Maioli, Silvia | Sandebring-Matton, Anna | Cedazo-Mínguez, Ángel

Article Type: Research Article

Abstract: The major genetic risk factor for Alzheimer’s disease (AD), apolipoprotein E4 (ApoE4), has been suggested to have detrimental effects on neurons, including direct toxicity via apoptosis. Thioredoxin-1 (Trx1) is an endogenous antioxidant protein important for redox regulation and participates in the regulation of apoptosis through the inhibition of apoptosis signal-regulating kinase-1 (Ask-1). In this study, we have investigated the effects of ApoE on Trx1 in the brain. Our results showed that the protein levels of Trx1 were reduced in the hippocampus of ApoE4 targeted replacement (TR) mice compared to ApoE3 TR mice. The reduction was also seen in vitro …after treatment of both human primary cortical neurons and neuroblastoma cells with human recombinant ApoE4 (rApoE4). Furthermore, ApoE4 caused a disruption of lysosomal integrity and a shift in the localization of Cathepsin D, an enzyme known to degrade Trx1. ApoE4 treatment induced in addition apoptosis through translocation of Death-domain associated protein-6 (Daxx) from the nucleus to the cytosol, suggesting an activation of the Ask-1 pathway. This toxicity was prevented by overexpression of Trx1 and other endogenous Ask-1 inhibitors. Our data suggests that down-regulation of Trx1 is involved in the toxicity caused by ApoE4. An activated ASK-1 pathway might indeed make cells more vulnerable to other insults such as amyloid-β, which could partially explain the mechanism behind the strongest genetic risk factor for AD. Show more

Keywords: Alzheimer’s disease, apolipoprotein E4, apoptosis, cathepsin D, lysosomes, thioredoxins

DOI: 10.3233/JAD-150738

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 601-617, 2017

Authors: Zygouris, Stelios | Ntovas, Konstantinos | Giakoumis, Dimitrios | Votis, Konstantinos | Doumpoulakis, Stefanos | Segkouli, Sofia | Karagiannidis, Charalampos | Tzovaras, Dimitrios | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: It has been demonstrated that virtual reality (VR) applications can be used for the detection of mild cognitive impairment (MCI). Objective: The aim of this study is to provide a preliminary investigation on whether a VR cognitive training application can be used to detect MCI in persons using the application at home without the help of an examiner. Methods: Two groups, one of healthy older adults (n  = 6) and one of MCI patients (n  = 6) were recruited from Thessaloniki day centers for cognitive disorders and provided with a tablet PC with custom software enabling …the self-administration of the Virtual Super Market (VSM) cognitive training exercise. The average performance (from 20 administrations of the exercise) of the two groups was compared and was also correlated with performance in established neuropsychological tests. Results: Average performance in terms of duration to complete the given exercise differed significantly between healthy(μ  = 247.41 s/ sd = 89.006) and MCI (μ= 454.52 s/ sd = 177.604) groups, yielding a correct classification rate of 91.8% with a sensitivity and specificity of 94% and 89% respectively for MCI detection. Average performance also correlated significantly with performance in Functional Cognitive Assessment Scale (FUCAS), Test of Everyday Attention (TEA), and Rey Osterrieth Complex Figure test (ROCFT). Discussion: The VR application exhibited very high accuracy in detecting MCI while all participants were able to operate the tablet and application on their own. Diagnostic accuracy was improved compared to a previous study using data from only one administration of the exercise. The results of the present study suggest that remote MCI detection through VR applications can be feasible. Show more

Keywords: Aging, Alzheimer’s disease, computers, dementia, diagnosis, memory disorders, mild cognitive impairment, new technologies, practice effect, tablet PC

DOI: 10.3233/JAD-160518

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 619-627, 2017

Authors: Tan, Long | Yang, Hongpeng | Pang, Wei | Li, Haiqiang | Liu, Wei | Sun, Shoudan | Song, Nan | Zhang, Wanqi | Jiang, Yugang

Article Type: Research Article

Abstract: Background: Blueberry (BB) can provide a wide range of antioxidant benefits for AD. There is evidence that BB extracts could improve brain functions. However, the details are still unknown. Objective: In the present study, we aimed to investigate the possible mechanism involved in the improvement of learning and memory capacity from BB extracts in AD. Methods: APP/PS1 transgenic mice were fed BB extracts for 16 weeks. The capacity of learning and memory was assessed by Morris water maze (MWM) test, and long-term potentiation (LTP) was determined to evaluate hippocampal neuronal plasticity at the end of …administration. Pathological changes in the brain were observed, and the expressions of brain-derived neurotrophic factor (BDNF) and extracellular signal-related kinase (ERK1/2) were determined to explore the mechanism of BB extract-induced benefits. Results: AD mice exhibited more difficulties to learn and remember the exact position of the platform in the MWM test. The data showed that AD mice lacked effective learning in the platform search. In contrast, AD mice exhibited better performance both in the training phase and probe test of MWM after the BB treatment. Moreover, LTP was enhanced and the neuron loss was alleviated with BB treatment, while we did not find any obvious effect on the elimination of amyloid-β. In the AD mice, the expression of ERK1/2 was significantly increased (p  < 0.05), while the level of BDNF was decreased (p  < 0.05). Conclusions: BB treatment was beneficial for the improvement of learning and memory of AD, and these effects might be related to the regulation of BDNF. Show more

Keywords: Alzheimer’s disease, APP/PS1, brain-derived neurotrophic factor, blueberry, transgenic mice

DOI: 10.3233/JAD-151108

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 629-640, 2017

Authors: Kamikubo, Yuji | Takasugi, Nobumasa | Niisato, Kazue | Hashimoto, Yoshie | Sakurai, Takashi

Article Type: Research Article

Abstract: The amyloid-β protein precursor (AβPP) is cleaved by a transmembrane protease termed β-site AβPP cleavage enzyme (BACE1), which is being explored as a target for therapy and prevention of Alzheimer’s disease (AD). Although genetic deletion of BACE1 results in abolished amyloid pathology in AD model mice, it also results in neurodevelopmental phenotypes such as hypomyelination and synaptic loss, observed in schizophrenia and autism-like phenotype. These lines of evidence indicate that the inhibition of BACE1 causes adverse side effects during the neurodevelopmental stage. However, the effects of the inhibition of BACE1 activity on already developed neurons remain unclear. Here, we utilized …hippocampal slice cultures as an ex vivo model that enabled continuous and long-term analysis for the effect of BACE1 inhibition on neuronal circuits and synapses. Temporal changes in synaptic proteins in hippocampal slices indicated acute synaptic loss, followed by synapse formation and maintenance phases. Long-term BACE1 inhibition in the neurodevelopmental stage caused the loss of synaptic proteins but failed to alter synaptic proteins in the already developed maintenance stage. These data indicate that BACE1 function on synapses is dependent on synaptic developmental stages, and our study provides a useful model to observe the long-term effect of BACE1 activity in the brain, and to evaluate adverse effects of BACE inhibitors. Show more

Keywords: Alzheimer’s disease, amyloid β, β-secretase, hippocampus, slice culture, synapse

DOI: 10.3233/JAD-160806

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 641-653, 2017

Authors: Chidlow, Glyn | Wood, John P.M. | Manavis, Jim | Finnie, John | Casson, Robert J.

Article Type: Research Article

Abstract: There is increasing recognition that visual performance is impaired in early stages of Alzheimer’s disease (AD); however, no consensus exists as to the mechanisms underlying this visual dysfunction, in particular regarding the timing, nature, and extent of retinal versus cortical pathology. If retinal pathology presents sufficiently early, it offers great potential as a source of novel biomarkers for disease diagnosis. The current project utilized an array of immunochemical and molecular tools to perform a characterization of retinal pathology in the early stages of disease progression using a well-validated mouse model of AD (APPSWE /PS1ΔE 9 ). Analytical endpoints included examination …of aberrant amyloid and tau in the retina, quantification of any neuronal degeneration, delineation of cellular stress responses of neurons and particularly glial cells, and investigation of oxidative stress. Brain, eyes, and optic nerves were taken from transgenic and wild-type mice of 3 to 12 months of age and processed for immunohistochemistry, qPCR, or western immunoblotting. The results revealed robust expression of the human APP transgene in the retinas of transgenic mice, but a lack of identifiable retinal pathology during the period when amyloid deposits were dramatically escalating in the brain. We were unable to demonstrate the presence of amyloid plaques, dystrophic neurites, neuronal loss, macro- or micro-gliosis, aberrant cell cycle re-entry, oxidative stress, tau hyperphosphorylation, or upregulations of proinflammatory cytokines or stress signaling molecules in the retina. The overall results do not support the hypothesis that detectable retinal pathology occurs concurrently with escalating amyloid deposition in the brains of APPSWE /PS1ΔE 9 mice. Show more

Keywords: Alzheimer’s disease, early biomarker, microglia, müller cell, retina, retinal ganglion cell

DOI: 10.3233/JAD-160823

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 655-675, 2017