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Volume 56, Number 2, 2017

Pages 429-439
Ethics Review

Andrew M. Siegel, Marna S. Barrett, Mahendra T. Bhati (Handling Editor: Allyson Rosen)
Deep Brain Stimulation for Alzheimer’s Disease: Ethical Challenges for Clinical Research
Abstract: Deep brain stimulation (DBS) is an invasive neuromodulation modality that has shown early promise as a novel treatment of Alzheimer’s disease (AD). Further clinical research is warranted on the basis of positive results from animal and human studies, as well as the inadequacy of existing treatments in reducing the enormous medical and financial costs of untreated AD. Nevertheless, unique ethical challenges require particular attention to elements of subject enrollment and informed consent. Study protocols should specify robust assessment and regular monitoring of subject decision-making capacity to consent to trial participation. Investigators should also assess for and mitigate therapeutic misconception (the phenomenon whereby a research participant conflates the goals of research with those of clinical treatment) and ensure that all prospective trial participants have adequate post-trial access to treatment and DBS device maintenance. In the following discussion, each issue is summarized and followed by recommendations for proper ethical procedure. We conclude by assimilating relevant ethical considerations into a decision-making algorithm designed to aid future clinical investigators of DBS for AD with the task of ethical subject enrollment.

Pages 441-446
Short Communication

Marwan N. Sabbagh, Barbara Schäuble, Keshav Anand, Danielle Richards, Shigeo Murayama, Hiroyasu Akatsu, Masaki Takao, Christopher C. Rowe, Colin L. Masters, Henryk Barthel, Hermann-Josef Gertz, Oliver Peters, Natalie Rasgon, Aleksandar Jovalekic, Osama Sabri*, Walter J. Schulz-Schaeffer*, John Seibyl* *These authors contributed equally to this work.
Histopathology and Florbetaben PET in Patients Incorrectly Diagnosed with Alzheimer’s Disease
Abstract: Of 57 individuals diagnosed with Alzheimer’s disease (AD) in a phase III study, 13 (23%) had amyloid-β (Aβ) levels on postmortem histopathology that did not explain the dementia. Based on postmortem histopathology, a wide range of different non-AD conditions was identified, including frontotemporal dementia, hippocampal sclerosis, and dementia with Lewy bodies. Of the histopathologically Aβ negative scored cases ante-mortem Florbetaben PET scans were classified as negative for Aβ in 11 patients based on visual analysis and in all 12 quantifiable cases based on composite standardized uptake value ratios. Thus, florbetaben PET can assist physicians in the differential diagnosis of neurodegenerative disorders by reliably excluding Aβ pathology.

Pages 447-452
Short Communication

Megan A. Hird, Kristin A. Vesely, Corinne E. Fischer, Simon J. Graham, Gary Naglie, Tom A. Schweizer
Investigating Simulated Driving Errors in Amnestic Single- and Multiple-Domain Mild Cognitive Impairment
Abstract: The areas of driving impairment characteristic of mild cognitive impairment (MCI) remain unclear. This study compared the simulated driving performance of 24 individuals with MCI, including amnestic single-domain (sd-MCI, n = 11) and amnestic multiple-domain MCI (md-MCI, n = 13), and 20 age-matched controls. Individuals with MCI committed over twice as many driving errors (20.0 versus 9.9), demonstrated difficulty with lane maintenance, and committed more errors during left turns with traffic compared to healthy controls. Specifically, individuals with md-MCI demonstrated greater driving difficulty compared to healthy controls, relative to those with sd-MCI. Differentiating between different subtypes of MCI may be important when evaluating driving safety.

Pages 453-458
Short Communication

Bushra Imtiaz, Anna Maija Tolppanen, Alina Solomon, Hilkka Soininen, Miia Kivipelto
Estradiol and Cognition in the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) Cohort Study
Abstract: Cardiovascular Risk factors, Aging and Dementia (CAIDE) is a Finnish population-based study. 731 cognitively normal women had self-reported hormone therapy (HT) data in 1998 as: no use, use ≤5 years, and >5 years. Information on type of HT was only available from 1995-1998 (Prescription Register). Cognition was assessed in 1998 and 2005-2008. Long-term (>5 years) HT use, especially use of estradiol alone among women having hysterectomy with bilateral oophorectomy, was associated with better episodic memory in 1998, but not in 2005-2008. Although a strong evidence for protective effect of estradiol on cognition was not observed in our study, improved global cognition among long-term users suggests that long-term postmenopausal HT may be beneficial for some cognitive domains.

Pages 459-470
Eric Doran, David Keator, Elizabeth Head, Michael J. Phelan, Ron Kim, Minodora Totoiu, Jorge R. Barrio, Gary W. Small, Steven G. Potkin, Ira T. Lott (Handling Associate Editor: Juan Fortea)
Down Syndrome, Partial Trisomy 21, and Absence of Alzheimer’s Disease: The Role of APP
Abstract: Overexpression of the amyloid precursor protein (APP) gene on chromosome 21 in Down syndrome (DS) has been linked to increased brain amyloid levels and early-onset Alzheimer’s disease (AD). An elderly man with phenotypic DS and partial trisomy of chromosome 21 (PT21) lacked triplication of APP affording an opportunity to study the role of this gene in the pathogenesis of dementia. Multidisciplinary studies between ages 66-72 years comprised neuropsychological testing, independent neurological exams, amyloid PET imaging with 11C-Pittsburgh compound-B (PiB), plasma amyloid-β (Aβ) measurements, and a brain autopsy examination. The clinical phenotype was typical for DS and his intellectual disability was mild in severity. His serial neuropsychological test scores showed less than a 3% decline as compared to high functioning individuals with DS who developed dementia wherein the scores declined 17-28% per year. No dementia was detected on neurological examinations. On both PiB-PET scans, the patient with PT21 had lower PiB standard uptake values than controls with typical DS or sporadic AD. Plasma Aβ42 was lower than values for demented or non-demented adults with DS. Neuropathological findings showed only a single neuritic plaque and neurofibrillary degeneration consistent with normal aging but not AD. Taken together the findings in this rare patient with PT21 confirm the obligatory role of APP in the clinical, biochemical, and neuropathological findings of AD in DS.

Pages 471-489
Jing Chen, Libin Zhan, Xiaoguang Lu, Chi Xiao, Nijing Sun (Handling Associate Editor: Zhanjun Zhang)
The Alteration of ZiBuPiYin Recipe on Proteomic Profiling of Forebrain Postsynaptic Density of db/db Mice with Diabetes-Associated Cognitive Decline
Abstract: Diabetes-associated cognitive decline (DACD) is a brain injury induced by diabetes mellitus, with cognitive impairment as the major symptom. Growing evidence has revealed that DACD is correlated with disruptions in synapses involved in cognition. Within synapses, more specifically in areas of postsynaptic density (PSD), there is a high concentration of proteins that receive and transduce synaptic information. In the present study, to identify the differentially expressed PSD proteins among DACD mice, ZiBuPiYin recipe (ZBPYR)-treated DACD mice and control mice, we applied isobaric tags for relative and absolute quantitation (iTRAQ) with LC-MS/MS technology, by which three biological replicates and three technical replicates were examined. A total of 24 and 23 differentially expressed proteins were observed in control versus DACD mice and in DACD versus ZBPYR-treated DACD mice, respectively. Notably, we found ‘Protein processing in endoplasmic reticulum’ and ‘PI3K-Akt signaling pathway’ might be impaired in DACD pathogenesis, while Growth factor receptor-bound protein 2 might be a crucial protein as a molecular target of the neuroprotective effects of ZBPYR. To our knowledge, this is the first study to provide a reference proteome map for DACD and ZBPYR-treated DACD mouse forebrain PSD to aid understanding the underlying mechanisms of DACD and ZBPYR.

Pages 491-507
Fan Su, Hao Shu, Qing Ye, Chunming Xie, Baoyu Yuan, Zhijun Zhang, Feng Bai (Handling Associate Editor: Irena Rektorová)
Integration of Multilocus Genetic Risk into the Default Mode Network Longitudinal Trajectory during the Alzheimer’s Disease Process
Abstract: The aim of the study was to investigate the cognitive significances of the changes in default mode network (DMN) during the process of Alzheimer’s disease (AD) and the genetic basis that drives the alteration. Eighty-seven subjects with mild cognitive impairment (MCI) and 131 healthy controls (HC) were employed at baseline, and they had the genetic risk scores (GRS) based on the GWAS-validated AD-related top loci. Eleven MCIs who converted to AD (c-MCIs), 32 subjects who remained stable (nc-MCIs), and 56 HCs participated in the follow-up analyses after an average of 35 months. Decreased functional connectivity (FC) within temporal cortex was identified for MCIs at baseline, which was partially determined by the GRS; moreover, compensations may occur within the frontal-parietal brain to maintain relatively intact cognition. During the follow-ups, c-MCIs exhibited more FC declines within the prefrontal-parietal lobes and parahippocampal gyrus/hippocampus than the HCs and nc-MCIs. The GRS did not significantly vary among the three groups, whereas associations were identified at risky alleles and FC declines in all AD spectra. Interestingly, the influence of APOE ε4 varied as the disease progressed; APOE ε4 was associated with longitudinal FC decreases only for HCs in the single variance-based analyses and deteriorated DMN integration in nc-MCIs by combining the effects of other loci. However, the GRS without APOE ε4 predicted FC decline for converters. It is suggested that the integration of multilocus genetic risk predicted the longitudinal trajectory of DMN and may be used as a clinical strategy to track AD progression.

Pages 509-517
Clément Pimouguet, Mélanie Le Goff, Jérôme Wittwer, Jean-François Dartigues, Catherine Helmer (Handling Associate Editor: René Thyrian)
Benefits of Occupational Therapy in Dementia Patients: Findings from a Real-World Observational Study
Abstract: Background: There is a growing interest in developing non-pharmacological approaches in dementia. Clinical efficacy occupational therapy (OT) under routine care conditions has not been investigated yet. Objective: To analyze the short-term effects of OT in patients with dementia; and to identify factors related to greater benefit. Methods: Patients referred to OT were evaluated before starting a 3-month intervention and at 3 and 6 months later. Measures included: Mini-Mental State Examination (MMSE), Disability Assessment in Dementia, Neuropsychiatric Inventory Questionnaire, patients’ quality of life (EQ 5D-VAS), caregivers’ burden (Zarit scale), and amount of informal care. Linear mixed models were used to analyze trajectories of outcomes. Logistic regressions with stepwise descending selection were used to study factors associated with benefits. Results: 421 dementia patients benefited from OT (mean MMSE = 17.3). Patients remained cognitively stable over time. Functional performances also remained stable at 3 months and significantly decreased at 6 months (crude reduction of 2.8 points, p<0.01). Behavioral troubles were significantly reduced over the intervention period and remained stable after (p<0.01). Patients’ quality of life increased over the 3-month intervention (p=0.16) and significantly decreased thereafter. Caregivers’ burden and informal care significantly decreased over the 3-month intervention and remained stable thereafter. Patients who benefited from OT with regard to function were less educated and had higher cognitive levels. Conclusion: OT may be an effective intervention to maintain cognition and functionality and to reduce psychiatric symptoms in dementia patients. Mild stages of dementia could gain more benefits from OT with regard to functional decline.

Pages 519-527
Fiammetta Monacelli, Alessio Signori, Laura Roffredo, Katiuscia Pace, Alessio Nencioni, Gisele Pickering, Macian Nicolas, Patrizio Odetti
Algoplus® Scale in Older Patients with Dementia: A Reliable Real-World Pain Assessment Tool
Abstract: Pain is still a neglected clinical issue in elderly people with dementia and/or communicative disorders, with an unacceptable higher rate of under diagnosis and under treatment. Cognitive deficit and emotional and psychological disturbances entangle pain symptoms, affecting patient self-report. So far, observational pain tools do not have fully adequate clinimetric properties and quality requirements for easy-to-use daily rating. Older patients with dementia represent a clinical challenge. The assessment of pain is important for improving clinical outcomes, such as functional status, frailty trajectories, comorbidity, and quality of life. The PAINAID scale appears to be the most accurate pain tool in people with dementia along with the Algoplus® scale, a recently developed tool to rapidly assess acute pain in hospitals settings. The present study aimed to assess the clinimetric properties of the Algoplus®, as compared to PAINAID, for detecting acute pain in a real-world cohort of hospitalized older patients with dementia.

Pages 529-542
Rina Kotani, Yasuomi Urano, Hachiro Sugimoto, Noriko Noguchi (Handling Associate Editor: Ikuo Tooyama)
Decrease of Amyloid-β Levels by Curcumin Derivative via Modulation of Amyloid-β Protein Precursor Trafficking
Abstract: The abnormal production and deposition of amyloid-β (Aβ) peptides is a pathologic hallmark of Alzheimer’s disease. Aβ is generated from amyloid-β protein precursor (AβPP) by two sequential proteolytic cleavage steps involving β- and γ-secretases in the trans-Golgi network and endosomes. Since direct inhibition of secretase could induce undesirable side-effects due to inadvertent inhibition of unrelated secretase substrates, it is important to establish methods for inhibiting Aβ production that do not affect secretase activity. It has been suggested that curcumin may have potent anti-amyloidogenic effect. In the present study, we evaluate the effect of curcumin derivatives on Aβ production in human neuroblastoma SH-SY5Y cells and in CHO cells which stably express human AβPP (CHO-AβPP). We found that the curcumin derivative CU6 was more effective than curcumin itself in reducing Aβ secretion. We further found that in SH-SY5Y cells CU6 inhibited neither β- nor γ-secretase activity, and that increased amounts of immature forms of AβPP accumulated in the endoplasmic reticulum (ER). We also found that CU6 induced expression of the ER chaperone glucose-regulated protein 78 (GRP78), and enhanced formation of the AβPP/GRP78 complex. These results suggest that CU6 downregulates intracellular AβPP trafficking, resulting in suppression of Aβ production independently of secretase activity.

Pages 543-555
Linda J.C. van Waalwijk van Doorn*, Juan D. Gispert*, H. Bea Kuiperij, Jurgen A.H.R. Claassen, Andrea Arighi, Inês Baldeiras, Kaj Blennow, Marco Bozzali, Miguel Castelo-Branco, Enrica Cavedo, Derya D. Emek-Savaş, Erden Eren, Paolo Eusebi, Lucia Farotti, Chiara Fenoglio, Juan Fortea Ormaechea, Yvonne Freund-Levi, Giovanni B. Frisoni, Daniela Galimberti, Sermin Genc, Viviana Greco, Harald Hampel, Sanna-Kaisa Herukka, Yawu Liu, Albert Lladó, Alberto Lleó, Flavio M. Nobili, Kader K. Oguz, Lucilla Parnetti, João Pereira, Agnese Picco, Maria Pikkarainen, Catarina Resende de Oliveira, Esen Saka, Nicola Salvadori, Raquel Sanchez-Valle, Isabel Santana, Elio Scarpini, Philip Scheltens, Hilkka Soininen, Roberto Tarducci, Charlotte Teunissen, Magda Tsolaki, Andrea Urbani, Eduard Vilaplana Martinez, Pieter Jelle Visser, Asa K. Wallin, Görsev Yener, José L. Molinuevo, Olga Meulenbroek, Marcel M. Verbeek (Handling Associate Editor: Fabrizio Piazza) *These authors contributed equally to this work.
Improved Cerebrospinal Fluid-Based Discrimination between Alzheimer’s Disease Patients and Controls after Correction for Ventricular Volumes
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.

Pages 557-565
Pietro Gareri, Alberto Castagna, Antonino Maria Cotroneo, Daria Putignano, Raffaele Conforti, Francesco Santamaria, Saverio Marino, Salvatore Putignano (Handling Associate Editor: Francesco Panza)
The Citicholinage Study: Citicoline Plus Cholinesterase Inhibitors in Aged Patients Affected with Alzheimer’s Disease Study
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.

Pages 567-574
Taiki Sugimoto, Masaki Yoshida, Rei Ono, Shunsuke Murata, Naoki Saji, Shumpei Niida, Kenji Toba, Takashi Sakurai
Frontal Lobe Function Correlates with One-Year Incidence of Urinary Incontinence in Elderly with Alzheimer Disease
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.

Pages 575-584
Anne Katrine Bergland, Ingvild Dalen, Alf Inge Larsen, Dag Aarsland, Hogne Soennesyn (Handling Associate Editor: Koji Abe)
Effect of Vascular Risk Factors on the Progression of Mild Alzheimer’s Disease and Lewy Body Dementia
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 ɛ4 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.

Pages 585-599
Clara Theunis*, Oskar Adolfsson*, Natalia Crespo-Biel, Kasia Piorkowska, Maria Pihlgren, David T. Hickman, Valérie Gafner, Peter Borghgraef, Herman Devijver, Andrea Pfeifer, Fred Van Leuven, Andreas Muhs (Handling Associate Editor: Khalid Iqbal) *These authors contributed equally to this work.
Novel Phospho-Tau Monoclonal Antibody Generated Using a Liposomal Vaccine, with Enhanced Recognition of a Conformational Tauopathy Epitope
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.

Pages 601-617
Torbjörn Persson, Francesca Lattanzio, Javier Calvo-Garrido, Roberto Rimondini, Marta Rubio-Rodrigo, Erik Sundström, Silvia Maioli, Anna Sandebring-Matton, Ángel Cedazo-Mínguez (Handling Associate Editor: Maria Ramirez)
Apolipoprotein E4 Elicits Lysosomal Cathepsin D Release, Decreased Thioredoxin-1 Levels, and Apoptosis
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.

Pages 619-627
Stelios Zygouris, Konstantinos Ntovas, Dimitrios Giakoumis, Konstantinos Votis, Stefanos Doumpoulakis, Sofia Segkouli, Charalampos Karagiannidis, Dimitrios Tzovaras, Magda Tsolaki (Handling Associate Editor: Celeste de Jager)
A Preliminary Study on the Feasibility of Using a Virtual Reality Cognitive Training Application for Remote Detection of Mild Cognitive Impairment
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.

Pages 629-640
Long Tan*, Hongpeng Yang*, Wei Pang, Haiqiang Li, Wei Liu, Shoudan Sun, Nan Song, Wanqi Zhang, Yugang Jiang (Handling Associate Editor: Rudi D'Hooge) *These authors contributed to equally to this work.
Investigation on the Role of BDNF in the Benefits of Blueberry Extracts for the Improvement of Learning and Memory in Alzheimer’s Disease Mouse Model
Abstract: Background: Blueberry (BB) can provide a wide range of antioxidant benefits for AD. There have amounts of evidences shown 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 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.

Pages 641-653
Yuji Kamikubo, Nobumasa Takasugi, Kazue Niisato, Yoshie Hashimoto, Takashi Sakurai
Consecutive Analysis of BACE1 Function on Developing and Developed Neuronal Cells
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.

Pages 655-675
Glyn Chidlow, John P.M. Wood, Jim Manavis, John Finnie, Robert J. Casson (Handling Associate Editor: Carol Yim-lui Cheung)
Investigations into Retinal Pathology in the Early Stages of a Mouse Model of Alzheimer’s Disease
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/PS1E9). 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/PS1E9 mice.

Pages 667-686
Mohammad Asif Emran Khan Emon, Alpha Tom Kodamullil, Reagon Karki, Erfan Younesi, Martin Hofmann-Apitius
Using Drugs as Molecular Probes: A Computational Chemical Biology Approach in Neurodegenerative Diseases
Abstract: Neurodegenerative diseases including Alzheimer’s disease are complex to tackle because of the complexity of the brain, both in structure and function. Such complexity is reflected by the involvement of various brain regions and multiple pathways in the etiology of neurodegenerative diseases that render single drug target approaches ineffective. Particularly in the area of neurodegeneration, attention has been drawn to repurposing existing drugs with proven efficacy and safety profiles. However, there is a lack of systematic analysis of the brain chemical space to predict the feasibility of repurposing strategies. Using a mechanism-based, drug-target interaction modeling approach, we have identified promising drug candidates for repositioning. Mechanistic cause-and-effect models consolidate relevant prior knowledge on drugs, targets, and pathways from the scientific literature and integrate insights derived from experimental data. We demonstrate the power of this approach by predicting two repositioning candidates for Alzheimer’s disease and one for amyotrophic lateral sclerosis.

Pages 687-697
Rosalinde E.R. Slot, Argonde C. Van Harten, Maartje I. Kester, Wesley Jongbloed, Femke H. Bouwman, Charlotte E. Teunissen, Philip Scheltens, Robert Veerhuis, Wiesje M. van der Flier (Handling Associate Editor: Taher Darreh-Shori)
Apolipoprotein A1 in Cerebrospinal Fluid and Plasma and Progression to Alzheimer’s Disease in Non-Demented Elderly
Abstract: Background: HDL-cholesterol transporter Apolipoprotein A1 (ApoA1) holds neuroprotective properties, such as inhibition of amyloid-β aggregation. Low plasma ApoA1 concentrations are associated with Alzheimer’s disease (AD). Little is known about ApoA1 levels in the pre-dementia stages of AD. Objective: To investigate associations between cerebrospinal fluid (CSF) and plasma ApoA1 levels and clinical progression toward AD in non-demented elderly. Methods: From the Amsterdam Dementia Cohort, we included 429 non-demented elderly with subjective cognitive decline (SCD; n=206, 61±9 years, Mini-Mental State Exam (MMSE) 28±2) and mild cognitive impairment (MCI; n=223, 67±8 years, MMSE 27±2), with a mean follow-up of 2.5±1.6 years. We used Cox proportional hazard models to investigate relations between CSF and plasma ApoA1 concentrations and clinical progression, defined as progression to MCI or AD for SCD, and progression to AD for MCI. Analyses were adjusted for age, gender, MMSE, and plasma cholesterol levels. Analyses were stratified for diagnosis and APOE ε4 carriership. Results: 117 patients (27%) showed clinical progression. One standard deviation increase of CSF ApoA1 was associated with a 30% increased risk of clinical progression (hazard ratio (HR) (95% CI)=1.3(1.0-1.6)). The effect appeared to be attributable to the APOE ε4 carriers with SCD (HR 3.3(1.0-10.9)). Lower plasma ApoA1 levels were associated with an increased risk of clinical progression in APOE ε4 carriers with SCD (HR 5.0(1.3-18.9)). Conclusion: Higher CSF and lower plasma ApoA1 levels were associated with an increased risk of clinical progression in APOE ε4 carriers with SCD; suggesting that ApoA1 may be involved in the earliest stages of AD.

Pages 699-706
Mark Yarchoan, Bryan D. James, Raj C. Shah, Zoe Arvanitakis, Robert S. Wilson, Julie Schneider, David A. Bennett, Steven E. Arnold
Association of Cancer History with Alzheimer’s Disease Dementia and Neuropathology
Abstract: Background: Cancer and Alzheimer’s disease (AD) are common diseases of aging and share many risk factors. Surprisingly, however, epidemiologic data from several recent independent cohort studies suggest that there may be an inverse association between these diseases. Objective: To determine the relationship between history of cancer and odds of dementia proximate to death and neuropathological indices of AD. Methods: Using data from two separate clinical-pathologic cohort studies of aging and AD, the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP), we compared odds of AD dementia proximate to death among participants with and without a history of cancer. We then examined the relation of history of cancer with measures of AD pathology at autopsy, i.e., paired helical filament tau (PHFtau) neurofibrillary tangles and amyloid-β load. Results: Participants reporting a history of cancer had significantly lower odds of AD (OR 0.70 [0.55-0.89], p=0.0040) proximate to death as compared to participants reporting no prior history of cancer. The results remained significant after adjusting for multiple risk factors including age, sex, race, education, and presence of an APOE ε4 allele. At autopsy, participants with a history of cancer had significantly fewer PHFtau tangles (p<0.001) than participants without a history of cancer, but similar levels of amyloid-β. Conclusions: Cancer survivors have reduced odds of developing AD and a lower burden of neurofibrillary tangle deposition.

Pages 707-716
Ane Nørgaard, Christina Jensen-Dahm, Christiane Gasse, Elsebet Steno Hansen, Gunhild Waldemar (Handling Associate Editor: Corinne Fischer)
Psychotropic Polypharmacy in Patients with Dementia: Prevalence and Predictors
Abstract: Background: Antipsychotics and other psychotropics are frequently used to treat neuropsychiatric symptoms in patients with dementia, even though the evidence for effect is limited. Concerns have been raised about the safety of antipsychotics, but concomitant use of multiple psychotropic drug classes (psychotropic polypharmacy) may also pose a risk for patients. Objective: To investigate the prevalence and predictors associated with use of psychotropic polypharmacy in patients with dementia. Methods: A population-based study using nationwide registers. Patients with dementia were identified among all Danish residents ≥65 years on January 1, 2012. Data on prescriptions and comorbidity was included in the analysis. Overlapping prescriptions for different psychotropic drug classes were used to determine psychotropic polypharmacy. A multivariable logistic regression analysis was conducted to evaluate factors independently associated with the prescription of other psychotropic drug classes among patients already using antipsychotics. Results: Among all patients registered with dementia (34,553), 25.3% (8,728) used ≥2 psychotropic drugs. Among patients treated with antipsychotics 75.8% (5,403) used at least one other psychotropic drug during the antipsychotic treatment period. Nursing home residency, number of non-psychotropic medications used in 2011, and prior psychiatric diagnosis were associated with psychotropic polypharmacy among antipsychotic drug users. The most frequent combination of psychotropic drugs was antipsychotics and antidepressants. Conclusion: Concomitant use of psychotropic drugs was frequent in dementia patients. Patients living in nursing homes had the highest risk of receiving a combination of antipsychotics and other psychotropic drugs. Concomitant use of psychotropics may cause adverse events, and potential consequences for patients’ safety call for further investigation.

Pages 717-731
Malo Gaubert, Nicolas Villain, Brigitte Landeau, Florence Mézenge, Stéphanie Egret, Audrey Perrotin, Serge Belliard, Vincent de La Sayette, Francis Eustache, Béatrice Desgranges, Gaël Chételat*, Géraldine Rauchs* *These authors contributed equally to this work.
Neural Correlates of Self-Reference Effect in Early Alzheimer’s Disease
Abstract: Information that is processed with reference to the self (i.e., self-referential processing, SRP) is generally associated with better remembering than information processed in a semantic condition. This benefit of self on memory performance is called self-reference effect (SRE). In the present study, we assessed changes in the SRE and SRP-related brain activity in patients diagnosed with mild cognitive impairment or early Alzheimer’s disease (MCI/AD). Fifteen patients with confirmed amyloid-β deposits (positive florbetapir-PET scan) and 28 healthy controls (negative florbetapir-PET scan) were included. Participants either had to judge personality trait adjectives with reference to themselves (self condition) or to a celebrity (other condition), or determine whether these adjectives were positive or not (semantic condition). These adjectives were then presented with distractors in a surprise recognition task. Functional MRI data were acquired during both the judgment and recognition tasks. The SRE was observed in controls, but reduced in patients. Both controls and patients activated cortical midline structures when judging items with reference to themselves, but patients exhibited reduced activity in the angular gyrus. In patients, activity at encoding in the angular gyrus positively correlated with subsequent recognition accuracy in the self condition (self accuracy). This region also exhibited significant hypometabolism and Aβ burden, both related to self accuracy. By contrast, there were no differences in brain activity during recognition, either between the self and semantic conditions, or between groups. These results highlight SRE impairment in patients with MCI/AD, despite intact activity in cortical midline structures, and suggest that dysfunction of the angular gyrus is related to this impairment.

Pages 733-742
Jordi A. Matías-Guiu, Rosie E. Curiel, Teresa Rognoni, María Valles-Salgado, Marta Fernández-Matarrubia, Roshan Hariramani, Alejandro Fernández-Castro, Teresa Moreno-Ramos, David A. Loewenstein, Jorge Matías-Guiu
Validation of the Spanish Version of the LASSI-L for Diagnosing Mild Cognitive Impairment and Alzheimer’s Disease
Abstract: Background. The Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L) is a novel cognitive test that measures recovery from proactive semantic interference, which may be an early cognitive marker of Alzheimer’s disease (AD). Objective. To generate normative data for a Spaniard population and to validate the LASSI-L for the diagnosis of amnestic mild cognitive impairment (aMCI) and mild AD. Methods. We performed a cross-sectional study in which 97 healthy participants, 34 with aMCI, and 33 with mild AD were studied with LASSI-L and a comprehensive neuropsychological protocol. The overlapping strategy analysis was used to maximize the sample size and to provide age- and education-adjusted normative data using a logistic regression analysis. Results. Internal consistency was 0.932. Convergent validity with the Free and Cued Selective Reminding Test was moderate. LASSI-L raw scores were correlated with age and years of education, but not gender. The area under the curve for discriminating between healthy controls and aMCI was 0.909, and between healthy controls and mild AD was 0.986. LASSI-L sub-scores representing maximum storage capacity, recovery from proactive interference, and delayed recall yielded the highest diagnostic accuracy. Conclusions. The LASSI-L is a reliable and valid test for the diagnosis of aMCI and mild AD. The age and education influences on the performance of the test and normative data are provided. LASSI-L merits further studies to evaluate its ability to detect preclinical AD and predict progression to aMCI and early dementia.

Pages 743-761
Peng Liu, John H. Reichl, Eshaan R. Rao, Brittany M. McNellis, Eric S. Huang, Laura S. Hemmy, Colleen L. Forster, Michael A. Kuskowski, David R. Borchelt, Robert Vassar, Karen H. Ashe, Kathleen R. Zahs
Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice
Abstract: There exist several dozen lines of transgenic mice that express human amyloid-β protein precursor (AβPP) with Alzheimer’s disease (AD)-linked mutations. AβPP transgenic mouse lines differ in the types and amounts of Aβ that they generate and in their spatiotemporal patterns of expression of Aβ assemblies, providing a toolkit to study Aβ amyloidosis and the influence of Aβ aggregation on brain function. More complete quantitative descriptions of the types of Aβ assemblies present in transgenic mice and in humans during disease progression should add to our understanding of how Aβ toxicity in mice relates to the pathogenesis of AD. Here, we provide a direct quantitative comparison of amyloid plaque burdens and plaque sizes in four lines of AβPP transgenic mice. We measured the fraction of cortex and hippocampus occupied by dense-core plaques, visualized by staining with Thioflavin S, in mice from young adulthood through advanced age. We found that the plaque burdens among the transgenic lines varied by an order of magnitude: at 15 months of age, the oldest age studied, the median cortical plaque burden in 5XFAD mice was already ~4.5 times that of 21-month-old Tg2576 mice and ~15 times that of 21-24-month-old rTg9191 mice. Plaque-size distributions changed across the lifespan in a line- and region-dependent manner. We also compared the dense-core plaque burdens in the mice to those measured in a set of pathologically-confirmed AD cases from the Nun Study. Cortical plaque burdens in Tg2576, APPSwePS1E9, and 5XFAD mice eventually far exceeded those measured in the human cohort.

Pages 763-774
Herman Borghys, Bianca Van Broeck, Deborah Dhuyvetter, Tom Jacobs, Katja de Waepenaert, Tim Erkens, Melissa Brooks, Sandy Thevarkunnel, Joseph A. Araujo (Handling Associate Editor: Elizabeth Head)
Young to Middle-Aged Dogs with High Amyloid-β Levels in Cerebrospinal Fluid are Impaired on Learning in Standard Cognition tests
Abstract: Understanding differences in Alzheimer’s disease biomarkers before the pathology becomes evident can contribute to an improved understanding of disease pathogenesis and treatment. A decrease in amyloid- (A)42 in cerebrospinal fluid (CSF) is suggested to be a biomarker for A deposition in brain. However, the relevance of CSF A levels prior to deposition is not entirely known. Dogs are similar to man with respect to amyloid- protein precursor (APP)-processing, age-related amyloid plaque deposition, and cognitive dysfunction. In the current study, we evaluated the relation between CSF Aβ42 levels and cognitive performance in young to middle-aged dogs (1.5-7 years old). Additionally, CSF sAβPPα and sAβPPβ were measured to evaluate AβPP processing, and CSF cytokines were measured to determine the immune status of the brain. We identified two groups of dogs showing consistently low or high CSF Aβ42 levels. Based on prior studies, it was assumed that at this age no cerebral amyloid plaques were likely to be present. The cognitive performance was evaluated in standard cognition tests. Low or high Aβ concentrations coincided with low or high sAβPPα, sAβPPβ, and CXCL-1 levels, respectively. Dogs with high Aβ concentrations showed significant learning impairments on delayed non-match to position (DNMP), object discrimination, and reversal learning compared to dogs with low Aβ concentrations. Our data support the hypothesis that high levels of CSF Aβ in dogs coincide with lower cognitive performance prior to amyloid deposition. Further experiments are needed to investigate this link, as well as the relevance with respect to Alzheimer’s disease pathology progression.

Pages 775-788
Carolin Brandscheid, Florian Schuck, Sven Reinhardt, Karl-Herbert Schäfer, Claus U. Pietrzik, Marcus Grimm, Tobias Hartmann, Andreas Schwiertz, Kristina Endres
Altered Gut Microbiome Composition and Tryptic Activity of the 5xFAD Alzheimer’s Mouse Model
Abstract: The regulation of physiological gut functions such as peristalsis or secretion of digestive enzymes by the central nervous system via the Nervus vagus is well known. Recent investigations highlight that pathological conditions of neurological or psychiatric disorders might directly interfere with the autonomous neuronal network of the gut – the enteric nervous system, or even derive from there. By using a murine Alzheimer’s disease model, we investigated a potential influence of disease-associated changes on gastrointestinal properties. 5xFAD mice at three different ages were compared to wild type littermates in regard to metabolic parameters and enzymes of the gut by fluorimetric enzyme assay and western blotting. Overexpression of human amyloid-β protein precursor (AβPP) within the gut was assessed by qPCR and IHC; fecal microbiome analysis was conducted by 16SrRNA quantitation of selected phyla and species. While general composition of fecal samples, locomotion, and food consumption of male 5xFAD animals were not changed, we observed a reduced body weight occurring at early pathological stages. Human AβPP was not only expressed within the brain of these mice but also in gut tissue. Analysis of fecal proteins revealed a reduced trypsin amount in the 5xFAD model mice as compared to the wild type. In addition, we observed changes in fecal microbiota composition along with age. We therefore suggest that the presence of the mutated transgenes (AβPP and PS1), which are per se the basis for the genetic form of Alzheimer’s disease in humans, directly interferes with gut function as shown here for the disease model mice.

Pages 789-804
Rozanna Meijboom, Rebecca M.E. Steketee, Leontine S. Ham, Aad van der Lugt, John C. van Swieten, Marion Smits (Handling Associate Editor: Jennifer Whitwell)
Differential Hemispheric Predilection of Microstructural White Matter and Functional Connectivity Abnormalities between Respectively Semantic and Behavioral Variant Frontotemporal Dementia
Abstract: Semantic dementia (SD) and behavioral variant frontotemporal dementia (bvFTD), subtypes of frontotemporal dementia, are characterized by distinct clinical symptoms and neuroimaging features, with predominant left temporal grey matter (GM) atrophy in SD and bilateral or right frontal GM atrophy in bvFTD. Such differential hemispheric predilection may also be reflected by other neuroimaging features, such as brain connectivity. This study investigated white matter (WM) microstructure and functional connectivity differences between SD and bvFTD, focusing on the hemispheric predilection of these differences. Eight SD and 12 bvFTD patients, and 17 controls underwent diffusion tensor imaging and resting state functional MRI at 3T. Whole-brain WM microstructure was assessed to determine distinct WM tracts affected in SD and bvFTD. For these tracts, diffusivity measures and lateralization indices were calculated. Functional connectivity was established for GM regions affected in early stage SD or bvFTD. Results of a direct comparison between SD and bvFTD are reported. Whole-brain WM microstructure abnormalities were more pronounced in the left hemisphere in SD and bilaterally—with a slight predilection for the right—in bvFTD. Lateralization of tract-specific abnormalities was seen in SD only, toward the left hemisphere. Functional connectivity of disease-specific regions was mainly decreased bilaterally in SD and in the right hemisphere in bvFTD. SD and bvFTD show WM microstructure and functional connectivity abnormalities in different regions, that are respectively more pronounced in the left hemisphere in SD and in the right hemisphere in bvFTD. This indicates differential hemispheric predilection of brain connectivity abnormalities between SD and bvFTD.

Pages 805-815
Anna Carotenuto, Raffaele Rea, Enea Traini, Angiola Maria Fasanaro, Giovanna Ricci, Valentino Manzo, Francesco Amenta
The Effect of the Association between Donepezil and Choline Alphoscerate on Behavioral Disturbances in Alzheimer’s Disease: Interim Results of the ASCOMALVA Trial
Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) are a group of psychological reactions, psychiatric symptoms, and behaviors commonly found in Alzheimer’s disease (AD). Four clusters of BPSD have been described: mood disorders (depression, anxiety, and apathy), psychotic symptoms (delusions and hallucinations), aberrant motor behaviors (pacing, wandering, and other purposeless behaviors), and inappropriate behaviors (agitation, disinhibition, and euphoria). Most of them are attributed to acetylcholine deficiency. Objective: To evaluate if a higher amount of acetylcholine obtained by associating donepezil and choline alphoscerate might have a favorable effect on BPSD. Methods: BPSD were measured at baseline and after 24 months in 113 mild/moderate AD patients, included in the double-blind randomized trial ASCOMALVA, by the Neuropsychiatric Inventory (NPI). Two matched groups were compared: group A treated with donepezil (10 mg/day) plus choline alphoscerate (1200 mg/day), and group B treated with donepezil (10 mg/day) plus placebo. Results: Data of NPI revealed a significant decrease of BPSD severity and distress of the caregiver in patients of group A compared with group B. Mood disorders (depression, anxiety and apathy) were significantly decreased in subjects treated with donepezil and choline alphoscerate, while their severity and frequency was increased in the other group. Conclusions: Patients treated with donepezil plus choline alphoscerate showed a lower level of behavioral disturbances than subjects treated with donepezil only, suggesting that the association can have beneficial effects.

Pages 817-824
Miharu Nakanishi, Junko Niimura, Syudo Yamasaki, Atsushi Nishida (Handling Associate Editor: Edimansyah Abdin)
Death of Dementia Patients in Psychiatric Hospitals and Regional Supply of Psychiatric Services: Study of the National Data from 1996 to 2014 in Japan
Abstract: Background: Japan designates psychiatric inpatient care for behavior management of individuals with dementia and for helping dementia patients discharge to home. However, there has been no examination of the effectiveness of this strategy. Objective: The present study investigated the association between dementia and the discharge destination of patients in psychiatric hospitals. Methods: Data from the National Patient Survey, which is a nationally representative cross-sectional survey of inpatient care, were used. The 96,420 patients with dementia or other mental illness who were discharged from psychiatric hospitals in September of every 3 years from 1996 to 2014 were included in analyses. Results: Of the 96,420 discharged patients, 13,823 had dementia as the primary disease. Of the 13,823 dementia patients, 3,865 (28.0%) were discharged to home, 3,870 (28.0%) were admitted to a facility or other care settings, 3,574 (25.9%) were admitted to another hospital, and 2,514 (18.2%) died. Patients were more likely to die in psychiatric hospital if their primary disease was dementia, and they had resided in a region that provided fewer home visits for psychiatric nursing care or had available a larger number of psychiatric hospital beds per capita. Conclusion: Psychiatric inpatient care may be ineffective as a treatment for the challenging behaviors of dementia. A community mental health system for behavior management should be constructed in parallel with a reduction in the number of hospital beds allotted for psychiatric care.

Pages 825-833
Luisa Benussi, Roberta Ghidoni, Fabrizio Dal Piaz, Giuliano Binetti, Giuseppe Di Iorio, Paolo Abrescia (Handling Associate Editor: Simone Lista)
The Level of 24-Hydroxycholesteryl Esters is an Early Marker of Alzheimer’s Disease
Abstract: Cholesterol (C) brain accumulation seems to play a role in the Alzheimer’s disease (AD) pathogenesis. 24(S)-hydroxycholesterol (24OH-C) is the predominant metabolite of brain C and its synthesis is believed to represent a way to remove excess C from neurons. Previous studies showed that 24OH-C level is altered in patients with neurodegenerative diseases, including AD. Only one study demonstrated that 24OH-C esterification is altered in neurodegenerative diseases, i.e., amyotrophic lateral sclerosis. Herein we analyzed the level of 24OH-C esters (%24OH-CE) in i) cerebrospinal fluid (CSF) and homologous serum of AD (n=13) and controls (n=8); ii) plasma from AD (n=30), controls (n=30), mild cognitive impairment (MCI) converting to AD (n=34), and stable MCI (n=40). The %24OH-CE in CSF positively correlated with that in homologous serum and was lower in both CSF and blood from AD patients as compared to controls; moreover, the plasma value of %24OH-CE was lower in MCI conv-AD than in non-converters. Kaplan Meier Survival curves revealed a significant anticipation of the disease onset in AD and MCI conv-AD subjects with the lowest %24OH-CE values. In conclusion, the reduction of %24OH-CE in AD and MCI conv-AD, as well as the anticipation of the disease in patients with the lowest %24OH-CE, support a role of the cholesterol/lecithin-cholesterol acyltransferase axis in AD onset/progression. Thus, targeting brain cholesterol metabolism could be a valuable strategy to prevent AD associated cognitive decline.

Pages 835-847
Erdem B. Dashinimaev, Alexander S. Artyuhov, Alexey P. Bolshakov, Ekaterina A. Vorotelyak, Andrey V. Vasiliev
Neurons Derived from Induced Pluripotent Stem Cells of Patients with Down Syndrome Reproduce Early Stages of Alzheimer’s Disease Type Pathology in vitro
Abstract: People with Down syndrome (DS) are at high risk of developing pathology similar to Alzheimer's disease (AD). Modeling of this pathology in vitro may be useful for studying this phenomenon. In this study, we analyzed three different cultures of neural cells carrying trisomy of chromosome 21, which were generated by directed differentiation from induced pluripotent stem cells (iPS cells). We report here that in vitro generated DS neural cells have abnormal metabolism of amyloid-β (Aβ) manifested by increased secretion and accumulation of Aβ granules of Aβ42 pathological isoform with upregulated expression of the APP gene. Additionally, we found increased expression levels of genes that are considered to be associated with AD (BACE2, RCAN1, ETS2, TMED10), as compared to healthy controls. Thus, the neural cells generated from induced pluripotent stem cells with DS reproduce initial cellular signs of AD-type pathology and can be useful tools for modeling and studying this variant of AD in vitro.

Pages 849-860
Ashenafi H. Betrie*, Scott Ayton*, Ashley I. Bush, James A. Angus, Peng Lei, Christine E. Wright *These authors contributed equally to this work.
Evidence of a Cardiovascular Function for Microtubule-Associated Protein Tau
Abstract: Aggregation of tau protein into intracellular deposits is a pathognomonic feature of tauopathies such as Alzheimer’s disease (AD) and lowering tau is a prominent therapeutic strategy under development. However, the physiological function of tau protein is not well known, particularly in the periphery. Lowering tau protein risks disrupting its physiological role leading to unwanted effects. In this study, the presence of tau protein in cardiac tissue is confirmed and the functional role in the cardiovascular system and the consequences of its loss were explored. Isolated right and left atria and small mesenteric arteries from wild type and tau deficient (KO) mice of two age groups (13 and 23 months old) were used to assess cardiovascular phenotypes. Tau KO mice showed an increased systolic blood pressure and cardiac hypertrophy at 13 months, which was accompanied by a significantly lower right atrial rate and a subtle decrease in the maximum contractility to calcium, isoprenaline, and electrical sympathetic nerve stimulation. Aging tau KO mice to 23 months resulted in cardiac hypertrophy with significantly attenuated left atrial contractility, increased blood pressure, and sensitivity of isolated mesenteric arteries to angiotensin II contraction and isoprenaline relaxation compared to their younger counterparts. This study supports a functional role of tau in the heart and loss of this protein leads to a deterioration in cardiovascular performance which worsens with age. Taken together, these results provide insight into the peripheral function of tau protein, and give caution to the therapeutic strategy of lowering tau protein.