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

Authors: Emon, Mohammad Asif Emran Khan | Kodamullil, Alpha Tom | Karki, Reagon | Younesi, Erfan | Hofmann-Apitius, Martin

Article Type: Research Article

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. Show more

Keywords: Alzheimer disease, amyotrophic lateral sclerosis, biological expression language, disease-drug modeling, drug repositioning, neurodegenerative diseases

DOI: 10.3233/JAD-160222

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 677-686, 2017

Authors: Slot, Rosalinde E.R. | Van Harten, Argonde C. | Kester, Maartje I. | Jongbloed, Wesley | Bouwman, Femke H. | Teunissen, Charlotte E. | Scheltens, Philip | Veerhuis, Robert | van der Flier, Wiesje M.

Article Type: Research Article

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 ɛ 4 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 ɛ 4 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 ɛ 4 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 ɛ 4 carriers with SCD; suggesting that ApoA1 may be involved in the earliest stages of AD. Show more

Keywords: Alzheimer’s disease, Apolipoprotein-A1, Apolipoprotein E, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-151068

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 687-697, 2017

Authors: Yarchoan, Mark | James, Bryan D. | Shah, Raj C. | Arvanitakis, Zoe | Wilson, Robert S. | Schneider, Julie | Bennett, David A. | Arnold, Steven E.

Article Type: Research Article

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 ɛ 4 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. Show more

Keywords: Alzheimer’s disease, amyloid-β, cancer, cohort study, dementia, malignancy, neurofibrillary tangles, PHFtau

DOI: 10.3233/JAD-160977

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 699-706, 2017

Authors: Nørgaard, Ane | Jensen-Dahm, Christina | Gasse, Christiane | Hansen, Elsebet Steno | Waldemar, Gunhild

Article Type: Research Article

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. Show more

Keywords: Antidepressant drugs, antipsychotic drugs, dementia, pharmacoepidemiology, polypharmacy, psychotropic drugs

DOI: 10.3233/JAD-160828

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 707-716, 2017

Authors: Gaubert, Malo | Villain, Nicolas | Landeau, Brigitte | Mézenge, Florence | Egret, Stéphanie | Perrotin, Audrey | Belliard, Serge | de La Sayette, Vincent | Eustache, Francis | Desgranges, Béatrice | Chételat, Gaël | Rauchs, Géraldine

Article Type: Research Article

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. Show more

Keywords: Alzheimer’s disease, functional magnetic resonance imaging, memory, psychology, self

DOI: 10.3233/JAD-160561

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 717-731, 2017

Authors: Matías-Guiu, Jordi A. | Curiel, Rosie E. | Rognoni, Teresa | Valles-Salgado, María | Fernández-Matarrubia, Marta | Hariramani, Roshan | Fernández-Castro, Alejandro | Moreno-Ramos, Teresa | Loewenstein, David A. | Matías-Guiu, Jorge

Article Type: Research Article

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. Show more

Keywords: Alzheimer’s disease, LASSI-L, memory, mild cognitive impairment, neuropsychological assessment, proactive interference, validation

DOI: 10.3233/JAD-160866

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 733-742, 2017

Authors: Liu, Peng | Reichl, John H. | Rao, Eshaan R. | McNellis, Brittany M. | Huang, Eric S. | Hemmy, Laura S. | Forster, Colleen L. | Kuskowski, Michael A. | Borchelt, David R. | Vassar, Robert | Ashe, Karen H. | Zahs, Kathleen R.

Article Type: Research Article

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, APPSwe PS1Δ E9, and 5XFAD mice eventually far exceeded those measured in the human cohort. Show more

Keywords: Alzheimer’s disease, amyloid plaque, amyloid-β protein precursor, plaque burden, plaque size, Thioflavin S, transgenic mouse

DOI: 10.3233/JAD-161027

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 743-761, 2017

Authors: Borghys, Herman | Van Broeck, Bianca | Dhuyvetter, Deborah | Jacobs, Tom | de Waepenaert, Katja | Erkens, Tim | Brooks, Melissa | Thevarkunnel, Sandy | Araujo, Joseph A.

Article Type: Research Article

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-β (Aβ)42 in cerebrospinal fluid (CSF) is suggested to be a biomarker for Aβ deposition in brain. However, the relevance of CSF Aβ levels prior to deposition is not entirely known. Dogs are similar to man with respect to amyloid-β protein precursor (AβPP)-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. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, biomarker, cognition, dog

DOI: 10.3233/JAD-160434

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 763-774, 2017

Authors: Brandscheid, Carolin | Schuck, Florian | Reinhardt, Sven | Schäfer, Karl-Herbert | Pietrzik, Claus U. | Grimm, Marcus | Hartmann, Tobias | Schwiertz, Andreas | Endres, Kristina

Article Type: Research Article

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. Show more

Keywords: Alzheimer’s disease, gut, microbiome, trypsin

DOI: 10.3233/JAD-160926

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 775-788, 2017

Authors: Meijboom, Rozanna | Steketee, Rebecca M.E. | Ham, Leontine S. | van der Lugt, Aad | van Swieten, John C. | Smits, Marion

Article Type: Research Article

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. Show more

Keywords: Behavioral variant frontotemporal dementia, diffusion tensor imaging, functional connectivity, lateralization, resting state functional MRI, semantic dementia, white matter microstructure

DOI: 10.3233/JAD-160564

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 789-804, 2017

Authors: Carotenuto, Anna | Rea, Raffaele | Traini, Enea | Fasanaro, Angiola Maria | Ricci, Giovanna | Manzo, Valentino | Amenta, Francesco

Article Type: Research Article

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. Show more

Keywords: Alzheimer’s disease, behavioral and psychological symptoms of dementia, choline alphoscerate, donepezil, neuropsychiatric symptoms

DOI: 10.3233/JAD-160675

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 805-815, 2017

Authors: Nakanishi, Miharu | Niimura, Junko | Yamasaki, Syudo | Nishida, Atsushi

Article Type: Research Article

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. Show more

Keywords: Behavioral symptoms, community mental health services, dementia, health services research, psychiatric hospitals

DOI: 10.3233/JAD-160935

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 817-824, 2017

Authors: Benussi, Luisa | Ghidoni, Roberta | Dal Piaz, Fabrizio | Binetti, Giuliano | Di Iorio, Giuseppe | Abrescia, Paolo

Article Type: Research Article

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. Show more

Keywords: Alzheimer’s disease, biomarker, case control studies, cholesterol esterification, cohort studies, mild cognitive impairment

DOI: 10.3233/JAD-160930

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 825-833, 2017

Authors: Dashinimaev, Erdem B. | Artyuhov, Alexander S. | Bolshakov, Alexey P. | Vorotelyak, Ekaterina A. | Vasiliev, Andrey V.

Article Type: Research Article

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 . Show more

Keywords: Alzheimer’s disease, amyloid-β, Aβ42, APP, BACE2, Down syndrome, ETS2, IPSC, RCAN1, TMED10

DOI: 10.3233/JAD-160945

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 835-847, 2017

Authors: Betrie, Ashenafi H. | Ayton, Scott | Bush, Ashley I. | Angus, James A. | Lei, Peng | Wright, Christine E.

Article Type: Research Article

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. Show more

Keywords: Alzheimer’s disease, cardiovascular, heart, mesenteric arteries, pharmacology, tau protein

DOI: 10.3233/JAD-161093

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 849-860, 2017