Journal of Alzheimer's Disease - Volume 43, issue 4

Authors: Jung, Cha-Gyun | Uhm, Kyung-Ok | Horike, Hirofumi | Kim, Mi-Jeong | Misumi, Sachiyo | Ishida, Akimasa | Ueda, Yoshimoto | Choi, Eun-Kyoung | Kim, Yong-Sun | Michikawa, Makoto | Hida, Hideki

Article Type: Research Article

Abstract: Amyloid-β (Aβ) peptide plays a major role in the pathogenesis of Alzheimer's disease (AD), and is generated by β- and γ-secretase-mediated proteolytic processing of amyloid-β protein precursor (AβPP). In the present study, we investigated the effect of 118 natural compounds on Aβ production in the medium of HEK293 cells stably expressing human AβPP695 (HEK293-AβPP) using Aβ42 sandwich ELISA to find natural compounds that can modulate Aβ production. We found that a coumarin derivative of citrus fruits, auraptene, increased Aβ production. Treatment of HEK293-AβPP cells and rat primary cortical neurons with auraptene significantly increased the secretion of Aβ40 , Aβ42 …, and the Aβ42/40 ratio. However, auraptene did not change the protein levels of the AβPP processing enzymes, a disintegrin and metalloproteinases 10 (ADAM10, α-secretase), β-site AβPP cleaving enzyme-1 (BACE-1, β-secretase), and presenilin 1 (PS1, γ-secretase component). Auraptene increased the activity of γ-secretase but not that of α- and β-secretase. Furthermore, auraptene enhanced γ-secretase-mediated production of Aβ from AβPP or AβPP-C99, but not through α- and β-secretase. Auraptene also phosphorylated c-Jun N-terminal kinase (JNK), and pretreatment with the JNK inhibitor, SP600125, reduced auraptene-induced γ-secretase activity. Overall, our results suggest that auraptene-mediated activation of JNK may contribute to the production of Aβ by promoting γ-secretase activity. Show more

Keywords: Alzheimer's disease, amyloid-β production, auraptene, c-Jun N-terminal kinase, γ-secretase

DOI: 10.3233/JAD-141692

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1215-1228, 2015

Authors: Schmidt, Christian | Gerlach, Nicole | Peter, Christoph | Gherib, Kerim | Lange, Katharina | Friede, Tim | Zerr, Inga

Article Type: Research Article

Abstract: Background/Objective: Apolipoprotein E plays a role in the pathogenesis of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) and plasma level alterations have been reported in AD patients. In search of a potential biomarker, which would be predictive of cognitive, functional, or motor decline, we analyzed CSF apolipoprotein E (ApoE) levels of AD patients in this regard. Methods: Subjects with newly diagnosed AD enrolled into an observational study were followed up longitudinally. Neuropsychological testing and physical examination were performed annually. In a sub-cohort of patients, where baseline CSF ApoE concentration values were available, multiple regression analyses were used to determine …possible associations of CSF ApoE concentration and speed of decline on different cognitive, functional, and motor scales (MMSE, iADL, bADL, GDS, UPDRSIII) adjusting for possible confounders. Results: No association of CSF ApoE levels and speed of decline on the various scales could be established (p = 0.09 to 0.88). Nevertheless, the use of neuroleptic drugs could be linked to higher velocity of global and extrapyramidal deterioration (p = 0.04 and 0.05 for GDS and UPDRSIII, respectively), but not to other outcomes (MMSE, bADL, and iADL). Conclusion: Herein, CSF ApoE at time of AD diagnosis could not be shown to be a viable biomarker for future cognitive, functional, or motor decline. Expectedly, the use of neuroleptic drugs was associated with detrimental effects. Show more

Keywords: Alzheimer's disease, apolipoprotein E, biomarker, cerebrospinal fluid, cognition

DOI: 10.3233/JAD-141581

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1229-1236, 2015

Authors: Zhu, Mingqin | Wang, Xiuzhe | Schultzberg, Marianne | Hjorth, Erik

Article Type: Research Article

Abstract: Resolution of inflammation terminates the inflammatory response in physiological conditions and promotes restoration and healing of the tissue; however, failure in resolution results in chronic inflammation that may lead to disease. Chronic inflammation mediated by microglia is a feature of Alzheimer's disease (AD) and can be a pathogenic factor in which both treatment targets and diagnostic markers may be found. In addition, there is evidence that the resolution pathway is altered in AD. It is therefore relevant to investigate whether amyloid-β (Aβ) peptide, the major component of senile plaque in AD brain, may have a negative influence on components of …the resolution cascade. In this pursuit, we exposed microglia to Aβ42 , and with bacterial lipopolysaccharides (LPS) for comparison with a general infectious stimulus. Differential effects were observed: LPS upregulated components of the resolution pathway including the LXA4 receptor/formyl peptide receptor 2 (ALX/FPR2) and phosphorylated 5-lipoxygenase (p-5-LOX), as well as cholinergic alpha 7 nicotinic receptor (α7nAChR) and peroxisome proliferator-activated receptor (PPAR)-δ whereas Aβ42 had an opposite or insignificant effect. Our results indicate that LPS-induced changes in the microglia were conducive for resolution of inflammation, whereas these responses were absent or suppressed in microglia treated with Aβ42 . Further studies may prove if Aβ42 -induced dysfunction of resolution in microglia contributes to the impaired resolution in the AD brain, and if stimulation of microglial resolution constitutes a treatment strategy for AD. Show more

Keywords: α7nAChR, ALX/FPR2, Alzheimer's disease, amyloid, lipopolysaccharide, microglia, specialized pro-resolving mediators

DOI: 10.3233/JAD-141233

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1237-1250, 2015

Authors: Bajic, Vladan | Mandusic, Vesna | Stefanova, Elka | Bozovic, Ana | Davidovic, Radoslav | Zivkovic, Lada | Cabarkapa, Andrea | Spremo-Potparevic, Biljana

Article Type: Research Article

Abstract: X-chromosome instability has been a long established feature in Alzheimer's disease (AD). Premature centromere division and aneuploidy of the X-chromosome has been found in peripheral blood lymphocytes and neuronal tissue in female AD patients. Interestingly, only one chromosome of the X pair has been affected. These results raised a question, “Is the X-chromosome inactivation pattern altered in peripheral blood lymphocytes of women affected by AD?” To address this question, we analyzed the methylation status of androgen receptor promoter which may show us any deviation from the 50 : 50% X inactivation status in peripheral blood lymphocytes of women with AD. …Our results showed skewed inactivation patterns (>90%). These findings suggest that an epigenetic alteration on the inactivation centers of the X-chromosome (or skewing) relates not only to aging, by might be a novel property that could account for the higher incidence of AD in women. Show more

Keywords: Alzheimer's disease, aneuploidy, methylation specific qPCR, X-chromosome, X-chromosome skewing

DOI: 10.3233/JAD-141674

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1251-1259, 2015

Authors: Haghighi, Mona | Smith, Amanda | Morgan, Dave | Small, Brent | Huang, Shuai | for the Alzheimer's Disease Neuroimaging Initiative (ADNI)

Article Type: Research Article

Abstract: Background: Detecting participants who are positive for amyloid-β (Aβ) pathology is germane in designing prevention trials by enriching for those cases that are more likely to be amyloid positive. Existing brain amyloid measurement techniques, such as the Pittsburgh Compound B-positron emission tomography and cerebrospinal fluid, are not reasonable first-line approaches limited by either feasibility or cost. Objective: We aimed to identify simple and cost-effective rules that can predict brain Aβ level by integrating both neuropsychological measurements and blood-based markers. Method: Several decision tree models were built for extracting the predictive rules based on the Alzheimer's Disease …Neuroimaging Initiative cohort. Results: We successfully extracted predictive rules of Aβ level. For cognitive function variables, cases above the 45th percentile in total cognitive score (TOTALMOD), above the 52nd percentile of delayed word recall, and above the 70th percentile in orientation resulted in a group that was highly enriched for amyloid negative cases. Conversely scoring below the 15th percentile of TOTALMOD resulted in a group highly enriched for amyloid positive cases. For blood protein markers, scoring below the 57th percentile for apolipoprotein E (ApoE) levels (irrespective of genotype) enriched two fold for the risk of being amyloid positive. In the high ApoE cases, scoring above the 60th percentile for transthyretin resulted in a group that was >90% amyloid negative. A third decision tree using both cognitive and blood-marker data slightly improved the classification of cases. Conclusion: Our study demonstrated that the integration of the neuropsychological measurements and blood-based markers significantly improved prediction accuracy. The prediction model has led to several simple rules, which have a great potential of being naturally translated into clinical settings such as enrichment screening for AD prevention trials of anti-amyloid treatments. Show more

Keywords: Amyloid, decision rules, neuropsychological tests, plasma markers, prediction

DOI: 10.3233/JAD-140705

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1261-1270, 2015

Authors: Takizawa, Claire | Thompson, Paula L. | van Walsem, Anneloes | Faure, Céline | Maier, William C.

Article Type: Research Article

Abstract: Background: Alzheimer's disease (AD) weighs heavily on health expenditure and is strongly associated with increasing age. Due to population aging, increasing global prevalence of AD will pose huge challenges to public health and elderly care systems in all countries across the world. Objectives: This study aimed to better understand the burden of AD from a healthcare perspective. Methods: A systematic literature review of journal articles published between January 2002 and December 2012 was performed for studies conducted in France, Germany, Italy, The Netherlands, Spain, the United Kingdom (UK), and the United States of America (USA), using …Medline, Embase, and the NHS Economic Evaluation Database. Results: 3,288 references were initially retrieved, and 39 epidemiological and 66 economic publications were selected for data extraction. AD incidence rates greatly varied between countries; however, prevalence was more consistent across all included countries, ranging between 3–7%. Overall, medical costs were lower in France compared to other included countries and increased with AD severity, e.g., direct medical costs per year for mild AD ranged from 5,476 int$ in France to 27,380 int$ in Spain. Limitations, such as heterogeneous methodology and missing data, prevented the comparison of results across studies between countries or the conclusion of any trend over time. Conclusion: This review corroborates previous understanding that AD burden is high for both society and healthcare providers. Limitations regarding study heterogeneity restricted conclusions; further research is required. Stakeholders could benefit from new healthcare strategies addressing both epidemiological and economic aspects of AD. Show more

Keywords: Alzheimer's disease, direct costs, economic, epidemiology, incidence, indirect costs, medical costs, mortality, non-medical costs, prevalence

DOI: 10.3233/JAD-141134

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1271-1284, 2015

Authors: Bonoti, Fotini | Tzouvaleka, Evanthia | Bonotis, Konstantinos | Vlachos, Filippos

Article Type: Research Article

Abstract: Background: Previous studies have shown that AD patients present a stepwise regression to their cognitive functioning from a mature adult to that of an infant. Objectives: The present study aimed to compare Alzheimer's disease (AD) patients' and 4–10 year old children's drawing performance, taking into account that drawing is currently considered as a cognitive process and that AD manifests a severe cognitive impairment. Methods: The sample consisted of 10 AD patients and 10 adult controls, as well as of 40 children, divided into 4 age groups (4-, 6-, 8-, and 10-years old). Participants were asked to …draw from memory (a) six simple objects, (b) a man, and (c) a tree behind a house. Results: Analysis showed an improvement with age in children's drawing performance, while controls' drawing scores were similar to those obtained by older children. On the contrary, drawing performance of AD patients significantly decreased into levels under that of the 4-year old children in drawing errors, or under that of the 8-year old children in drawing a man task and partial occlusion task. Conclusions: The observed regression in AD patients' drawing performance is discussed in relation to the cognitive deficits accompanying the disease. Show more

Keywords: Alzheimer's disease, children, drawing, drawing development, impairment

DOI: 10.3233/JAD-140528

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1285-1292, 2015

Authors: Peña-Longobardo, Luz María | Oliva-Moreno, Juan

Article Type: Research Article

Abstract: Background: Alzheimer's disease constitutes one of the leading causes of burden of disease, and it is the third leading disease in terms of economic and social costs. Objective: To analyze the burden and problems borne by informal caregivers of patients who suffer from Alzheimer's disease in Spain. Data and Methods: We used the Survey on Disabilities, Autonomy and Dependency to obtain information on the characteristics of disabled people with Alzheimer's disease and the individuals who provide them with personal care. Additionally, statistical multivariate analyses using probit models were performed to analyze the burden placed on caregivers …in terms of health, professional, and leisure/social aspects. Results: 46% of informal caregivers suffered from health-related problems as a result of providing care, 90% had leisure-related problems, and 75% of caregivers under 65 years old admitted to suffering from problems related to their professional lives. The probability of a problem arising for an informal caregiver was positively associated with the degree of dependency of the person cared for. In the case of caring for a greatly dependent person, the probability of suffering from health-related problems was 22% higher, the probability of professional problems was 18% higher, and there was a 10% greater probability of suffering from leisure-related problems compared to non-dependents. Conclusions: The results show a part of the large hidden cost for society in terms of problems related to the burden lessened by the caregivers. This information should be a useful tool for designing policies focused toward supporting caregivers and improving their welfare. Show more

Keywords: Alzheimer's disease, burden, caregivers, informal care, social costs

DOI: 10.3233/JAD-141374

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1293-1302, 2015

Authors: Eichler, Tilly | Wucherer, Diana | Thyrian, Jochen René | Kilimann, Ingo | Hertel, Johannes | Michalowsky, Bernhard | Teipel, Stefan | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: The present study is the first to analyze primary data about the use of antipsychotic drugs among community dwelling people with dementia in German primary care. Objectives: To determine (1) prevalence of antipsychotic drug treatment in German primary care patients who screened positive for dementia and (2) factors associated with antipsychotic drug treatment. Methods: DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg-Western Pomerania) is an ongoing general practitioner-based, randomized, controlled intervention trial. A total of 4,064 community dwelling patients (≥70 years) recruited from 108 participating practices were screened for dementia (DemTect <9). Of 692 eligible …patients (17%), a total of 406 patients provided informed consent (59%). Present analyses are based on data of 243 patients who completed baseline assessment before January 2014 (preliminary data). Results: Of the 243 patients who screened positive for dementia, a total of 25 patients (10%) received at least one antipsychotic drug. Atypical antipsychotic drugs (64%) were prescribed more often than typical antipsychotic drugs (36%). The results of the multivariate analysis showed that treatment by a specialist (neurologist/psychiatrist) was the only factor significantly associated with antipsychotic drug treatment (odds ratio, 12.86; p < 0.05; 95% confidence interval, 1.04–158.71). Conclusions: Compared to the antipsychotic drug treatment rate among people with dementia living in nursing homes (>50%), the rate we found for community dwelling primary care patients who screened positive for dementia was low. Further research is needed to evaluate if these patients are adequately treated or if the antipsychotic drug treatment should and could be further reduced. Show more

Keywords: Ambulatory care, antipsychotic drugs, dementia, general practitioner, primary health care

DOI: 10.3233/JAD-141554

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1303-1311, 2015

Authors: Salvadori, Emilia | Poggesi, Anna | Pracucci, Giovanni | Inzitari, Domenico | Pantoni, Leonardo | on behalf of the VMCI-Tuscany Study Group

Article Type: Research Article

Abstract: Background and Objective: Vascular cognitive impairment may have a selective neuropsychological profile. We developed a battery for assessing mild cognitive impairment (MCI) in patients with small vessel disease (SVD), its applicability, and psychometric properties. Methods: Among those proposed by the 2006 NINDS-CSN Consensus Conference, we selected tests for which norms based on healthy Italians and equivalent scores methodology were available. Confirmatory factor analysis was applied to ascertain the fit of the theoretically assumed dimensions to empirical data and to derive each cognitive dimension compound measures. Results: The entire battery was applied to 146 out of a …cohort of 201 patients with MCI and SVD. Most tests showed good applicability. Fifty-five patients, who were older and cognitively more impaired, proved unable to complete the Trail Making Test part B, the Rey-Osterrieth Complex Figure, and the Stroop test, and were excluded from the analysis. Among the remaining patients, Mini-Mental State Examination proved largely normal, while Rey-Osterrieth Complex Figure, Symbol digit modalities test, and Trail Making Test part B were most frequently abnormal. Confirmatory factor analysis showed a good fit of the 4-factor theoretical model to empirical data. Praxis domain resulted in the highest percentage of abnormal performance (65%), followed by Memory and Attention/EF domains (19% and 15%), and Language (8%). Conclusions: Our battery proved to be comprehensive, robust, and applicable. Attention-executive dysfunction and impaired memory and visuo-constructional abilities, were the prominent features. The assessment of the Consensus Conference, that included Trial Making Test, looks poorly applicable to older and cognitively impaired patients. Show more

Keywords: Cognitive assessment, confirmatory factor analysis, psychometric properties, small vessel disease, neuropsychology, subcortical ischemic vascular disease

DOI: 10.3233/JAD-141449

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1313-1323, 2015