Journal of Alzheimer's Disease - Volume 54, issue 3

Authors: Shankle, William R. | Hara, Junko | Barrentine, Lori W. | Curole, Melanie V.

Article Type: Research Article

Abstract: We examined whether using a medical food therapy for hyperhomocysteinemia (HHcy) in patients with Alzheimer’s disease (AD) or cognitive impairment due to cerebrovascular disease (CVD) with Cerefolin® /CerefolinNAC® (CFLN: L-methylfolate, methylcobalamin, and N-acetyl-cysteine) slowed regional brain atrophy. Thirty HHcy patients with AD and related disorders (ADRD) received CFLN (HHcy+CFLN: duration [μ ±  σ ] = 18.6±16.1 months); a sub-sample of this group did not receive CFLN for varying periods of time (HHcy+NoCFLN: duration [μ ±  σ ] = 12.6±5.6 months). Thirty-seven NoHHcy patients with ADRD did not receive CFLN (NoHHcy+NoCFLN: duration [μ ±  σ ] = 13.3±17.7 months). No participant took supplemental B vitamins. Regional brain volumes were measured at baseline …and end of study, and covariate-adjusted rates of hippocampal, cortical, and forebrain parenchymal (includes white matter) atrophy were predicted. The HHcy+CFLN group’s hippocampal and cortical atrophy adjusted rates were 4.25 and 11.2 times slower than those of the NoHHcy+NoCFLN group (p  < 0.024). The HHcy+CFLN group’s forebrain parenchyma atrophy rate was significantly slower only for CVD; the rate of slowing was proportional to the degree of homocysteine lowering (p  < 0.0001). CFLN was associated with significantly slowed hippocampal and cortical atrophy rates in ADRD patients with HHcy, and forebrain parenchymal atrophy rates in CVD patients with HHcy. The present results should be further validated. Show more

Keywords: B12, brain atrophy, circadian rhythm, cognitive impairment, dementia, folate, hippocampus, vascular, volumetrics, white matter

DOI: 10.3233/JAD-160241

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1073-1084, 2016

Authors: Bengoetxea, Xabier | de Cerain, Adela López | Azqueta, Amaya | Ramirez, Maria J.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by the presence of aggregates of the amyloid-β peptide (Aβ) that are believed to be neurotoxic. One of the purposed damaging mechanisms of Aβ is oxidative insult, which eventually could damage the cellular genome. Stress and associated increases in glucocorticoids (GCs) have been described as a risk factor for the development of AD, although the purported genotoxic effects of GCs have not been fully characterized. Therefore, it is possible to speculate about purported synergistic effects of GCs on the Aβ-driven genotoxic damage. This in vitro study addresses the single and …combined cyto/genotoxic effects of Aβ and GCs in SH-SY5Y cells. Cytotoxicity was determined by the MTT assay, and the genotoxic effects were studied using the comet assay. A comet assay derivation allows for measuring the presence of the FPG-sensitive sites (mainly 8-oxoguanines) in the DNA, apart from the DNA strand breaks. Treatment with Aβ (10 μM, 72 h) induced cytotoxicity (35% decrease in cell viability) and DNA strand breaks, but had no significant effect on oxidative DNA damage (FPG sites). Corticosterone showed no effect on cell viability, genotoxicity, or reparation processes. Corticosterone was unable to neither reverse nor potentiate Aβ driven effects. The present results suggest the existence of alternative mechanisms for the Aβ driven damage, not involving oxidative damage of DNA. In addition, could be suggested that the interaction between Aβ and GCs in AD does not seem to involve DNA damage. Show more

Keywords: Comet assay, DNA breaks, DNA damage, DNA-formamidopyrimidine glycosylase, oxidative stress

DOI: 10.3233/JAD-160636

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1085-1094, 2016

Authors: Zhang, Han | Chen, Xiaobo | Shi, Feng | Li, Gang | Kim, Minjeong | Giannakopoulos, Panteleimon | Haller, Sven | Shen, Dinggang

Article Type: Research Article

Abstract: Temporal synchronization-based functional connectivity (FC) has long been used by the neuroscience community. However, topographical FC information may provide additional information to characterize the advanced relationship between two brain regions. Accordingly, we proposed a novel method, namely high-order functional connectivity (HOFC), to capture this second-level relationship using inter-regional resemblance of the FC topographical profiles. Specifically, HOFC first calculates an FC profile for each brain region, notably between the given brain region and other brain regions. Based on these FC profiles, a second layer of correlations is computed between all pairs of brain regions (i.e., correlation’s correlation). On this basis, we …generated an HOFC network, where “high-order” network properties were computed. We found that HOFC was discordant with the traditional FC in several links, indicating additional information being revealed by the new metrics. We applied HOFC to identify biomarkers for early detection of Alzheimer’s disease by comparing 77 mild cognitive impairment patients with 89 healthy individuals (control group). Sensitivity in detection of group difference was consistently improved by ∼25% using HOFC compared to using FC. An HOFC network analysis also provided complementary information to an FC network analysis. For example, HOFC between olfactory and orbitofrontal cortices was found significantly reduced in patients, besides extensive alterations in HOFC network properties. In conclusion, our results showed promise in using HOFC to comprehensively map the human brain connectome. Show more

Keywords: Alzheimer’s disease, biomarker, early detection, functional connectivity, functional magnetic resonance imaging (fMRI), high-order connectivity, mild cognitive impairment, resting state fMRI

DOI: 10.3233/JAD-160092

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1095-1112, 2016

Authors: Lima, Sara | Gago, Miguel | Garrett, Carolina | Pereira, M. Graça

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a chronic degenerative disease leading to global cognitive and functional decline. Quality of Life (QOL) is an important variable in the effectiveness of intervention programs in dementia. Objective: This study analyzed the relationships between gender, psychological variables and QOL, the predictors of QOL, and the role of spirituality as a moderator between functionality and QOL. Method: A cross-sectional study was conducted with 128 patients with mild AD. Results: Being a male, good social support, and high functionality were significant predictors of better QOL. Spirituality was a moderator in …the relationship between functionality and QOL. Conclusion: These results reinforce the importance of gender, psychological morbidity, social support, and functionality, with special emphasis on the role of spirituality, regarding intervention programs that promote QOL, in patients with mild AD. Show more

Keywords: Alzheimer’s disease, quality of life, self-care, spirituality

DOI: 10.3233/JAD-160256

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1113-1121, 2016

Authors: Maresova, Petra | Klimova, Blanka | Novotny, Michal | Kuca, Kamil

Article Type: Research Article

Abstract: The purpose of this study is to analyze the economic burden of persons with Alzheimer’s disease (AD) and Parkinson’s disease (PD) in Europe. On the basis of available data about the number of persons with dementia, their prevalence, and treatment and care costs, a mean cost burden is estimated for the year of 2030 and for the year of 2050 in Europe. The method of retrospective analysis of available sources was used; furthermore, analysis of database data such as WHO and Eurostat, which provide information about the number of older people and people with dementia; and specification of direct and …indirect medical and nonmedical costs of patients with AD and PD from current studies was also used. The findings of this study confirm that the number of patients affected with AD and PD, as well as annual costs of the treatment and care of these patients, in the selected European countries are rapidly growing. The cost burden of both AD and PD in the selected European countries rises year by year, and by 2050, the cost burden of both diseases in fact will be almost two times higher in comparison with the year of 2010. In 2050, the overall mean cost burden is estimated to reach 357 billion Euros. The European Union calls for a joint initiative in the development of a uniformed strategic plan in the fight against dementia. Show more

Keywords: Alzheimer’s disease, costs, economic burden, Europe, Parkinson’s disease

DOI: 10.3233/JAD-160484

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1123-1133, 2016

Authors: Wolfsgruber, Steffen | Kleineidam, Luca | Wagner, Michael | Mösch, Edelgard | Bickel, Horst | Lϋhmann, Dagmar | Ernst, Annette | Wiese, Birgitt | Steinmann, Susanne | König, Hans-Helmut | Brettschneider, Christian | Luck, Tobias | Stein, Janine | Weyerer, Siegfried | Werle, Jochen | Pentzek, Michael | Fuchs, Angela | Maier, Wolfgang | Scherer, Martin | Riedel-Heller, Steffi G. | Jessen, Frank | for the AgeCoDe Study Group

Article Type: Research Article

Abstract: Background: It is unknown whether longitudinal stability versus instability in subjective cognitive decline (SCD) is a modifying factor of the association between SCD and risk of incident Alzheimer’s disease (AD) dementia. Objective: We tested the modifying role of temporal stability of the SCD report on AD dementia risk in cognitively normal elderly individuals. Methods: We analyzed data of 1,990 cognitively normal participants from the longitudinal AgeCoDe Study. We assessed SCD with/without associated worries both at baseline and first follow-up 18 months later. Participants were then classified either as (a) Controls (CO, with no SCD at …both baseline and follow-up 1, n  = 613), (b) inconsistent SCD (with SCD reported only at baseline or at follow-up 1, n  = 637), (c) consistent SCD but without/or with inconsistent worries (n  = 610) or (d) consistent SCD with worries (n  = 130). We estimated incident AD dementia risk over up to 6 years for each group with Cox-Proportional Hazard Regression analyses adjusted for age, gender, education, ApoE4 status, and depression. Results: Compared to CO, inconsistent SCD was not associated with increased risk of incident AD dementia. In contrast, risk was doubled in the group of consistent SCD without/ with inconsistent worries, and almost 4-fold in the group of consistent SCD with worries. These results could be replicated when using follow-up 1 to follow-up 2 response patterns for group definition. Conclusion: These findings suggest that longitudinal stability versus instability is an important modifying factor of the association between SCD and AD dementia risk. Worrisome SCD that is also consistently reported over time is associated with greatly increased risk of AD dementia. Show more

Keywords: Alzheimer’s disease, dementia, prognosis, subjective cognitive decline

DOI: 10.3233/JAD-160407

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1135-1146, 2016

Authors: Rai, Nitish | Kumar, Rahul | Desai, Gaurav Rajesh | Venugopalan, G. | Shekhar, Shashank | Chatterjee, Prasun | Tripathi, Manjari | Upadhyay, Ashish Datt | Dwivedi, Sadanand | Dey, Aparajit B. | Dey, Sharmistha

Article Type: Research Article

Abstract: Sestrins (sesn) are highly conserved proteins that play an important neuroprotective role, in part as a consequence of their antioxidative capacity, which prevents reactive oxygen species formation. In this study, we evaluated the concentrations of sesn1 and sesn2 in the serum of 41 Alzheimer’s disease (AD) patients, 27 mild cognitive impairment (MCI), and 60 elderly controls, by surface plasmon resonance, which was validated by using western blot. Moreover, the mRNA level of sestrins in all the study groups was determined by real time polymerase chain reaction. The results showed significant overexpression of serum sesn2 protein and mRNA levels in the …AD group compared to MCI and elderly control groups. A difference in serum sesn2 concentration between MCI and the control group was also evident. ROC analysis showed highly sensitive, selective cutoff values for sens2 in the differentiation of AD, MCI, and controls. No significant difference in sesn1 level was observed among the study groups. This study highlights the important role of sesn2 in the progression of the AD, indicating its potential utility as a protein marker in this devastating disease. Show more

Keywords: Alzheimer’s disease, marker, mild cognitive impairment, serum, sestrins

DOI: 10.3233/JAD-160479

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1147-1155, 2016

Authors: Guo, Ling | Rezvanian, Aras | Kukreja, Lokesh | Hoveydai, Ramez | Bigio, Eileen H. | Mesulam, M.-Marsel | El Khoury, Joseph | Geula, Changiz

Article Type: Research Article

Abstract: Microglia are immune cells of the brain that display a range of functions. Most of our knowledge about microglia biology and function is based on cells from the rodent brain. Species variation in the complexity of the brain and differences in microglia response in the primate when compared with the rodent, require use of adult human microglia in studies of microglia biology. While methods exist for isolation of microglia from postmortem human brains, none allow culturing cells to high passage. Thus cells from the same case could not be used in parallel studies and multiple conditions. Here we report a …method, which includes use of growth factors such as granulocyte macrophage colony stimulating factor, for successful culturing of adult human microglia from postmortem human brains up to 28 passages without significant loss of proliferation. Such cultures maintained their phenotype, including uptake of the scavenger receptor ligand acetylated low density lipoprotein and response to the amyloid-β peptide, and were used to extend in vivo studies in the primate brain demonstrating that inhibition of microglia activation protects neurons from amyloid-β toxicity. Significantly, microglia cultured from brains with pathologically confirmed Alzheimer’s disease displayed the same characteristics as microglia cultured from normal aged brains. The method described here provides the scientific community with a new and reliable tool for mechanistic studies of human microglia function in health from childhood to old age, and in disease, enhancing the relevance of the findings to the human brain and neurodegenerative conditions. Show more

Keywords: Phenotype, primary human microglia cultures, reactive oxygen species, scavenger receptor ligand

DOI: 10.3233/JAD-160394

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1157-1167, 2016

Authors: Jenkins, Amy | Lindsay, Stephen | Eslambolchilar, Parisa | Thornton, Ian M. | Tales, Andrea

Article Type: Research Article

Abstract: Mobile technologies, such as tablet devices, open up new possibilities for health-related diagnosis, monitoring, and intervention for older adults and healthcare practitioners. Current evaluations of cognitive integrity typically occur within clinical settings, such as memory clinics, using pen and paper or computer-based tests. In the present study, we investigate the challenges associated with transferring such tests to touch-based, mobile technology platforms from an older adult perspective. Problems may include individual variability in technical familiarity and acceptance; various factors influencing usability; acceptability; response characteristics and thus validity per se of a given test. For the results of mobile technology-based tests …of reaction time to be valid and related to disease status rather than extraneous variables, it is imperative the whole test process is investigated in order to determine potential effects before the test is fully developed. Researchers have emphasized the importance of including the ‘user’ in the evaluation of such devices; thus we performed a focus group-based qualitative assessment of the processes involved in the administration and performance of a tablet-based version of a typical test of attention and information processing speed (a multi-item localization task), to younger and older adults. We report that although the test was regarded positively, indicating that using a tablet for the delivery of such tests is feasible, it is important for developers to consider factors surrounding user expectations, performance feedback, and physical response requirements and to use this information to inform further research into such applications. Show more

Keywords: Aging, attention, cognition, focus groups, qualitative research, tablet computers

DOI: 10.3233/JAD-160545

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1169-1182, 2016

Authors: Zakarias, Johanne Købstrup | Jensen-Dahm, Christina | Nørgaard, Ane | Stevnsborg, Lea | Gasse, Christiane | Andersen, Bodil Gramkow | Søren, Jakobsen | Waldorff, Frans Boch | Moos, Torben | Waldemar, Gunhild

Article Type: Research Article

Abstract: Background: Use of antipsychotics in elderly patients with dementia has decreased in the past decade due to safety regulations; however use is still high. Geographical variation may indicate discrepancies in clinical practice and lack of adherence to evidence-based guidelines for the management of behavioral symptoms. Objective: To investigate potential geographical variances in use of antipsychotic drugs in dementia care. Methods: A registry-based cross-sectional study in the entire elderly population of Denmark (≥65 years) conducted in 2012. Data included place of residence, prescriptions filled, and hospital discharge diagnoses. Antipsychotic drug use among elderly with (n  = 34,536) …and without (n  = 931,203) a dementia diagnosis was compared across the five regions and 98 municipalities in Denmark, adjusted for age and sex. Results: In 2012, the national prevalence of antipsychotic drug use was 20.7% for elderly patients with dementia, with a national incidence of 3.9%. The prevalence ranged from 17.0% to 23.3% in the five regions and from 7.5% to 33.1% in the 98 municipalities, demonstrating an over four-fold difference. Conclusion: The observed geographical variation was more pronounced at municipal level as compared to regional level, suggesting that the variation may be related to variances in clinical practice in primary care. This study highlights an urgent need for further educating professional carers and physicians to guide non-pharmacological as well as pharmacological management of neuropsychiatric symptoms in elderly patients with dementia. Show more

Keywords: Antipsychotic drugs, clinical practice variation, dementia, geography, small area variation

DOI: 10.3233/JAD-160485

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1183-1192, 2016

Authors: Estrada, Lisbell D. | Chamorro, David | Yañez, María José | Gonzalez, Marcelo | Leal, Nancy | von Bernhardi, Rommy | Dulcey, Andrés E. | Marugan, Juan | Ferrer, Marc | Soto, Claudio | Zanlungo, Silvana | Inestrosa, Nibaldo C. | Alvarez, Alejandra R.

Article Type: Research Article

Abstract: One of the pathological hallmarks of Alzheimer’s disease (AD) is the presence of amyloid plaques, which are deposits of misfolded and aggregated amyloid-beta peptide (Aβ). The role of the c-Abl tyrosine kinase in Aβ-mediated neurodegeneration has been previously reported. Here, we investigated the therapeutic potential of inhibiting c-Abl using imatinib. We developed a novel method, based on a technique used to detect prions (PMCA), to measure minute amounts of misfolded-Aβ in the blood of AD transgenic mice. We found that imatinib reduces Aβ-oligomers in plasma, which correlates with a reduction of AD brain features such as plaques and oligomers accumulation, …neuroinflammation, and cognitive deficits. Cells exposed to imatinib and c-Abl KO mice display decreased levels of β-CTF fragments, suggesting that an altered processing of the amyloid-beta protein precursor is the most probable mechanism behind imatinib effects. Our findings support the role of c-Abl in Aβ accumulation and AD, and propose AD-PMCA as a new tool to evaluate AD progression and screening for drug candidates. Show more

Keywords: Alzheimer’s disease, amyloid-beta peptide, amyloid-beta protein precursor, c-Abl tyrosine kinase, imatinib, oligomers, PMCA

DOI: 10.3233/JAD-151087

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1193-1205, 2016

Authors: Baker, Siân | Polanco, Juan Carlos | Götz, Jϋrgen

Article Type: Research Article

Abstract: In Alzheimer’s disease, the distribution of neurofibrillary tangles, a histological hallmark comprised of phosphorylated forms of the protein tau, follows a distinct pattern through anatomically connected brain regions. The well-documented correlation between the severity of tau pathology and disease progression implies a prion-like seeding and spreading mechanism for tau. Experimentally, this has been addressed in transgenic mice by the injection of protein lysates isolated from brains of transgenic mice or patients with tauopathies, including AD, that were shown to behave like seeds, accelerating tau pathology and tangle formation in predisposed mice. More specifically, in vivo data suggest that brain …lysates from mice harboring the P301S mutation of tau can seed protein aggregation when injected into the hippocampi of human wild-type tau transgenic ALZ17 mice. Here, we compared the seeding potential of lysates and extracellular vesicles enriched for exosomes (EVs) from wild-type and human P301L tau transgenic rTg4510 mouse brains. We show that transgenic EVs cause increased tau phosphorylation and soluble oligomer formation in a manner comparable to that of freely available proteins in brain lysates, a prerequisite for the formation of mature protein aggregates. Show more

Keywords: Alzheimer’s disease, extracellular vesicles, phosphorylation, seeding, tau

DOI: 10.3233/JAD-160371

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1207-1217, 2016

Authors: Boehm-Cagan, Anat | Bar, Roni | Liraz, Ori | Bielicki, John K. | Johansson, Jan O. | Michaelson, Daniel M.

Article Type: Research Article

Abstract: The allele ɛ4 of apolipoprotein E (apoE4) is the most prevalent genetic risk factor for Alzheimer’s disease (AD) and is therefore a promising therapeutic target. Human and animal model studies suggest that apoE4 is hypolipidated; accordingly, we have previously shown that the retinoid X receptor (RXR) agonist bexarotene upregulates ABCA1, the main apoE-lipidating protein, resulting in increased lipidation of apoE4, and the subsequent reversal of the pathological effects of apoE4, namely: accumulation of Aβ42 and hyperphosphorylated tau, as well as reduction in the levels of synaptic markers and cognitive deficits. Since the RXR system has numerous other targets, it …is important to devise the means of activating ABCA1 selectively. We presently utilized CS-6253, a peptide shown to directly activate ABCA1 in vitro , and examined the extent to which it can affect the degree of lipidation of apoE4 in vivo and counteract the associated brain and behavioral pathologies. This revealed that treatment of young apoE4-targeted replacement mice with CS-6253 increases the lipidation of apoE4. This was associated with a reversal of the apoE4-driven Aβ42 accumulation and tau hyperphosphorylation in hippocampal neurons, as well as of the synaptic impairments and cognitive deficits. These findings suggest that the pathological effects of apoE4 in vivo are associated with decreased activation of ABCA1 and impaired lipidation of apoE4 and that the downstream brain-related pathology and cognitive deficits can be counteracted by treatment with the ABCA1 agonist CS-6253. These findings have important clinical ramifications and put forward ABCA1 as a promising target for apoE4-related treatment of AD. Show more

Keywords: ABCA1, Alzheimer’s disease, apoE, CS-6253, lipidation, lipids

DOI: 10.3233/JAD-160467

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1219-1233, 2016

Authors: Sepe-Monti, Micaela | Vanacore, Nicola | Bartorelli, Luisa | Tognetti, Alessandra | Giubilei, Franco | Caregiver Study Group Savvy

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a major cause of disability in the elderly, leading to a considerable burden on caregivers and high costs to society. Psycho-education programs such as the Savvy Caregiver Program (SCP) are reported to be a successful means of reducing caregivers’ distress through various intervention strategies. The aim of the present study was to assess the efficacy of the SCP in reducing the burden and psychological symptoms in caregivers of AD patients and to analyze the coping strategies adopted by the caregivers. The study was designed as a multicenter, randomized, controlled, pilot clinical trial. One hundred and sixty-four …caregivers of patients with probable AD were randomized. The SCP was structured in six, weekly, two-hour sessions. All the clinical scales were administered before treatment, two weeks and six months after treatment. Caregivers in the SCP group displayed better coping strategies adopted to positive attitudes, and they tended to be less anxious and less depressed than those in the control group. However, caregiver burden levels were not reduced in SCP caregivers. The patients of SCP caregivers received a lower number of new prescriptions of neuroleptics during the 6 months of follow-up than the patients of control caregivers and apathy was the neuropsychiatric symptom that improved most as a result of the SCP. The results of this study suggest that the SCP may improve coping strategies of caregivers of people affected by AD, influencing their psychological symptoms and those of their patients. Show more

Keywords: Alzheimer’s disease, caregivers, coping skills, dementia

DOI: 10.3233/JAD-160235

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1235-1246, 2016

Article Type: Book Review

DOI: 10.3233/JAD-160816

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1247-1248, 2016

Authors: Dugger, Brittany N. | Whiteside, Charisse M. | Maarouf, Chera L. | Walker, Douglas G. | Beach, Thomas G. | Sue, Lucia I. | Garcia, Angelica | Dunckley, Travis | Meechoovet, Bessie | Reiman, Eric M. | Roher, Alex E.

Article Type: Correction

DOI: 10.3233/JAD-169007

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1249-1249, 2016

Authors: Tanifum, Eric A. | Ghaghada, Ketan | Vollert, Craig | Head, Elizabeth | Eriksen, Jason L.

Article Type: Correction

DOI: 10.3233/JAD-169008

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1251-1251, 2016

Article Type: Other

DOI: 10.3233/JAD-160749

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1253-1257, 2016