Journal of Alzheimer's Disease - Volume 47, issue 2

Authors: Aso, Ester | Serrano, Antonio L. | Muñoz-Cánoves, Pura | Ferrer, Isidro

Article Type: Research Article

Abstract: Fibrinogen has emerged as a promising therapeutic target against Alzheimer’s disease because of its dual role in altered vascular function and amyloid-β aggregation. Here we provide evidence regarding cognitive improvement and reduction of brain parenchyma amyloid-β deposition in AβPP/PS1 mice after treatment for one month with the fibrinogen-blocking peptide Fibγ 377–395 . No alteration in glial response or other neuroinflammatory markers was observed in the cortex of treated animals. Considering these results and the fact that Fibγ 377–395 does not affect coagulation function, this peptide could be considered as a promising and safe candidate for chronic treatment of Alzheimer’s …disease. Show more

Keywords: AβPP/PS1 mice, Alzheimer’s disease, amyloid, fibrinogen, inflammation

DOI: 10.3233/JAD-142928

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 403-412, 2015

Authors: Jouvent, Eric | Reyes, Sonia | De Guio, François | Chabriat, Hugues

Article Type: Research Article

Abstract: Background: The assessment of early and subtle cognitive and behavioral effects of cerebral small vessel disease (SVD) requires specific and long-lasting evaluations performed by experienced neuropsychologists. Simpler tools would be helpful for daily clinical practice. Objective: To determine whether a simple reaction time task that lasts 5 minutes and can be performed without external supervision on any tablet or laptop can be used as a proxy of early cognitive and behavioral alterations in CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), a monogenic form of pure SVD related to NOTCH3 mutations. …Methods: Twenty-two genetically confirmed patients with CADASIL having preserved global cognitive abilities and without disability (MMSE >24 and modified Rankin’s scale ≤1) were compared to 29 age-and-gender matched controls to determine group differences according to: 1) conventional neuropsychological and behavioral testing; 2) a computerized battery evaluating reaction time, processing speed, and executive functions. In a second step, correlations between reaction time and cognitive and behavioral alterations detected using both conventional and computerized testing were tested in patients. Results: Reaction time was significantly higher in patients than in controls (mean in patients: 283 ms – in controls: 254 ms, p  = 0.03). In patients, reaction time was significantly associated with conventional and chronometric tests of executive functions, working memory, and apathy. Conclusion: Reaction time obtained using a very simple task may serve as a proxy of early cognitive and behavioral alterations in SVD and could be easily used in daily clinical practice. Show more

Keywords: Apathy, CADASIL, cerebral small vessel disease, cognitive impairment, processing speed, reaction time

DOI: 10.3233/JAD-150083

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 413-419, 2015

Authors: Guercio, Brendan J. | Donovan, Nancy J. | Munro, Catherine E. | Aghjayan, Sarah L. | Wigman, Sarah E. | Locascio, Joseph J. | Amariglio, Rebecca E. | Rentz, Dorene M. | Johnson, Keith A. | Sperling, Reisa A. | Marshall, Gad A.

Article Type: Research Article

Abstract: Background: Apathy is a common neuropsychiatric symptom in Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI). Detecting apathy accurately may facilitate earlier diagnosis of AD. The Apathy Evaluation Scale (AES) is a promising tool for measurement of apathy in prodromal and possibly preclinical AD. Objective: To compare the three AES sub-scales— subject-reported (AES-S), informant-reported (AES-I), and clinician-reported (AES-C)— over time in individuals at risk for AD due to MCI and advanced age (cognitively normal [CN] elderly). Methods: Mixed effects longitudinal models were used to assess predictors of score for each AES …sub-scale. Cox proportional hazards models were used to assess which AES sub-scales predict progression from MCI to AD dementia. Results: Fifty-seven MCI and 18 CN subjects (ages 53–86) were followed for 1.4 ± 1.2 years and 0.7 ± 0.7 years, respectively. Across the three mixed effects longitudinal models, the common findings were associations between greater apathy and greater years in study, a baseline diagnosis of MCI (compared to CN), and male gender. CN elderly self-reported greater apathy compared to that reported by informants and clinicians, while individuals with MCI under-reported their apathy compared to informants and clinicians. Of the three sub-scales, the AES-C best predicted transition from MCI to AD dementia. Conclusion: In a sample of CN elderly and elderly with MCI, apathy increased over time, particularly in men and those with MCI. AES-S scores may be more sensitive than AES-I and AES-C scores in CN elderly, but less reliable if subjects have MCI. Moreover, the AES-C sub-scale predicted progression from MCI to AD dementia. Show more

Keywords: Aged, Alzheimer’s disease, apathy, mild cognitive impairment, symptom assessment

DOI: 10.3233/JAD-150146

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 421-432, 2015

Authors: Weimar, Christian | Winkler, Angela | Dlugaj, Martha | Lehmann, Nils | Hennig, Frauke | Bauer, Marcus | Kröger, Knut | Kälsch, Hagen | Mahabadi, Amir-Abass | Dragano, Nico | Moebus, Susanne | Hoffmann, Barbara | Jöckel, Karl-Heinz | Erbel, Raimund | on behalf the Heinz Nixdorf Recall Study Investigative Group

Article Type: Research Article

Abstract: Background: Several studies have reported an association of atherosclerosis with mild cognitive impairment (MCI) and dementia independent of cardiovascular risk factors. Objective: To compare the cross-sectional association of the ankle-brachial index (ABI), intima media thickness (IMT), and coronary artery calcification (CAC) with MCI and its subtypes, amnestic MCI (aMCI) and non-amnestic MCI (naMCI) in the population-based Heinz Nixdorf Recall cohort study. Methods: 4,086 participants performed a validated brief cognitive assessment at the first follow-up examination (2006–2008). MCI was diagnosed according to previously published criteria. Prevalence ratio (PR) regression models adjusted for age, gender, education, cardiovascular …risk factors, and APOE genotype were used to compare the association of the ABI, the CAC-Agatston score and the IMT with MCI and its subtypes. Results: We identified 490 participants with MCI (mean age 66.1 ± 7.8, 46.9 % male, aMCI n  = 249, naMCI n  = 241) and 1,242 cognitively normal participants. A decreasing ABI (per 0.1) was significantly associated with a higher MCI prevalence in fully adjusted models (PR 1.06; 95% confidence interval (CI) 1.01–1.11), whereas an increasing CAC (log(CAC+1)) or IMT (per 0.1 mm) were not associated after adjustment. A decreasing ABI was also significantly associated with naMCI in fully adjusted models (PR 1.12; CI 1.03–1.21) but not with aMCI. Conclusions: Our data show that the degree of generalized atherosclerosis as measured by the ABI is associated with MCI and with naMCI in a population-based cohort. Show more

Keywords: Aging, ankle-brachial index, atherosclerosis, cognition, coronary artery calcification, intima media thickness, mild cognitive impairment, peripheral arterial disease, population-based studies

DOI: 10.3233/JAD-150218

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 433-442, 2015

Authors: Fink, Anne | Doblhammer, Gabriele

Article Type: Research Article

Abstract: As the population ages, the numbers of people developing care- and cost-intensive forms of dementia are raising. We investigated the pathways of incident dementia patients to long-term care (LTC) dependence and death, and examined the effects of: (1) the type of the main treating physician, differentiated by neurologists/psychiatrists (NPs) and non-NPs; (2) the prescription of antidementive drugs on the risk of needing LTC, differentiated by the degree of care need. Longitudinal claims data of the largest German public sickness fund of 10,043 incident dementia cases aged 60 years and above were analyzed for the years 2006 to 2010. Cox proportional …hazard models were performed to investigate the risk of LTC and death based on what type of physician was treating the patient, and whether the patient was prescribed antidementive drugs; adjusted for age, gender, cardiovascular comorbidities, and the previous LTC level. The patients who were primarily treated by NPs had a significantly lower risk of LTC than patients who were mainly treated by non-NPs (considerable LTC: RR = 0.72, p  = 0.000, severe LTC: RR = 0.78, p  = 0.000, extreme LTC: RR = 0.67, p  = 0.001). They generally had a lower risk of death. Antidementive drug treatment was correlated with an increased risk of LTC (considerable LTC: RR = 1.66, p  = 0.000, severe LTC: RR = 1.50, p  = 0.000, extreme LTC: RR = 1.48, p  = 0.000) but with a decreased risk of death. A higher rate of involvement of specialists in the treatment of dementia patients is associated with a reduced LTC dependence and increased survival of dementia patients. Antidementive drug treatments appear to extend live years with dementia. Show more

Keywords: Antidementive medication, cox proportional hazards models, dementia, long-term care, neurologist, psychiatrist

DOI: 10.3233/JAD-142082

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 443-452, 2015

Authors: Gilson, Virginie | Mbebi-Liegeois, Corinne | Sellal, François | de Barry, Jean

Article Type: Research Article

Abstract: Numerous studies have shown that amyloid-β (Aβ) modulate intracellular metabolic cascades and an intracellular Ca2+ homeostasis and a cell surface NMDA receptor expression alteration in Alzheimer’s disease (AD). However most of these findings have been obtained by using non-physiological Aβ concentrations. The present study deals with the effect of low Aβ concentrations on cellular homeostasis. We used nerve growth factor-differentiated PC12 cells and murine cortical neurons sequentially treated with low chronic monomeric or small oligomeric Aβ concentrations and high acute oligomeric Aβ concentrations to bring out a priming effect of chronic treatment on subsequently high Aβ concentrations-elicited cellular response. …Both cell types indeed displayed an enhanced capacity to bind oligomeric Aβ after monomeric or small oligomeric Aβ application. Furthermore, the results show that monomeric Aβ1–42 application to the cells induces an increase of the Ca2+ -response and of the membrane expression of the extrasynaptic subunit of the NMDA receptor GluN2B in PC12 cells, while the opposite effects were observed in cultured neurons. This suggests a sequential interaction of Aβ with the cellular plasma membrane involving monomers or small Aβ oligomers which would facilitate the binding of the deleterious high molecular Aβ oligomers. This mechanism would explain the slow progression of AD in the human nervous system and the deep gradient of neuronal death observed around the amyloid plaques in the nervous tissue. Show more

Keywords: Alzheimer’s disease, amyloid-β, cortical neurons, homeostasis, in vitro model, intracellular calcium, NMDA receptor, oligomers, pathogenesis, PC12 cells

DOI: 10.3233/JAD-142529

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 453-466, 2015

Authors: Léon, Christophe | Pin, Stéphanie | Kreft-Jaïs, Carmen | Arwidson, Pierre

Article Type: Research Article

Abstract: Background: The negative image surrounding AD has a substantial impact on caregiving and on those affected by the disease. Opinion surveys were created as part of the 2008–2012 Alzheimer Plan in France, which included two surveys of the general population, at the beginning and at the end. Objective: To evaluate changes of the French population in perceptions, knowledge and beliefs over 5 years and to analyze dimensions with sociodemographics criteria and proximity with AD. Methods: After selection by quota sampling, 2013 French people aged 18 years and over were interviewed by phone …in 2008 and 2509 in 2013. Chi-squared tests were carried out to measure the changes between two periods and multivariate logistics regressions were used to assess perceptions. Results: People who cited AD as one of the three most serious diseases increased in 2013 (33.6% versus 26.7% in 2008; p  <  0.001). There was no significant change as regards the fear, the sense of being informed and the feeling of embarrassment. Opinions “there are treatments available to improve the wellbeing of patients” and “it is normal to suffer memory loss as you get older” decreased in 2013. Close family carers had a greater sense of the seriousness, a higher risk perception, a better sense of being informed and a greater ease in the presence of a person with AD. Conclusions: The results serve as indicators of the effects of the Alzheimer Plan on French society and testify to the rather weak impact of the Plan on public opinion. Show more

Keywords: Alzheimer’s disease, perceptions, opinions, survey, general public

DOI: 10.3233/JAD-142922

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 467-478, 2015

Authors: Pusswald, Gisela | Tropper, Elisa | Kryspin-Exner, Ilse | Moser, Doris | Klug, Stefanie | Auff, Eduard | Dal-Bianco, Peter | Lehrner, Johann

Article Type: Research Article

Abstract: Background: Health related quality of life (HRQOL) is an important issue in the context of dementia care. Objectives: The purpose of this study was to investigate HRQOL in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI) and its relation to Activity of Daily Living (ADL). Methods: In this cross sectional study, four experimental groups (each n  = 98), controls, SCD, naMCI and aMCI, were compared. For data collection, neuropsychological methods (NTBV) and psychological questionnaires (SF-36 and B-ADL) were used. Multivariate analysis of variance was calculated to detect differences in HRQOL …between groups. Correlations between HRQOL and ADL were explored. Results: The dimensions of HRQOL showed mainly consistent differences between the control and the SCD group and MCI subgroups. In almost every dimension of HRQOL, the control group scored higher than subjects with SCD, naMCI, or aMCI. The controls showed low to moderate negative correlations between HQROL and B-ADL in some dimensions of the HRQOL. In the SCD group, low negative correlations with ADL were observed in some HRQOL scales. Low to moderate correlations were found between each scale of the SF-36 and the B-ADL in both MCI subtypes. We found gender differences in HRQOL. Conclusion: In conclusion, we could demonstrate that patients with SCD report reduced quality of life. This knowledge is important to get a better understanding of the individuals with SCD and may pave the way for the development of early intervention. Show more

Keywords: Activities of daily living, health related quality of life, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-150284

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 479-486, 2015

Authors: Matsuzono, Kosuke | Yamashita, Toru | Ohta, Yasuyuki | Hishikawa, Nozomi | Koike, Makoto | Sato, Kota | Kono, Syoichiro | Deguchi, Kentaro | Nakano, Yumiko | Abe, Koji

Article Type: Research Article

Abstract: The clinical benefits of memantine, depending on the baseline cognitive and affective conditions in real world dementia clinics, have not been completely examined. We performed the “Okayama Memantine Study II (OMS II)” to retrospectively evaluate the clinical effects of memantine monotherapy (n  = 38) in Alzheimer’s disease (AD) patients using seven batteries to assess dementia at the baseline, at 3, 6, and 12 months. Additionally, we divided 163 AD patients treated with memantine into two subgroups depending on the baseline cognitive score of the Mini-Mental State Examination (MMSE): the MMSE <15 group (n  = 36) and the baseline MMSE ≥15 group (n … = 127). We also analyzed 71 AD patients based on the baseline behavioral and psychological symptoms of dementia (BPSD) severity using Abe’s BPSD score (ABS). Memantine monotherapy maintained cognitive functions until 6 months of treatment, but showed a decrease at 12 months ( * p  <  0.05 versus baseline). However, memantine monotherapy greatly improved BPSD symptoms until 12 months ( * p  <  0.05,  ** p  <  0.01) and maintained other affective functions as well as the activity of daily living. Memantine treatment showed similar effects, regardless of the baseline cognitive functions, but showed better effects on ABS for higher baseline cognitive functions. Memantine treatment greatly improved ABS depending on baseline BPSD severity. Our present OMS II showed that memantine monotherapy improved BPSD until 12 months. The higher baseline cognitive subgroup (MMSE ≥15) and the worse baseline BPSD subgroup were expected to show better effects with memantine. Show more

Keywords: Alzheimer’s disease, behavioral and psychological symptoms of dementia, memantine, Mini-Mental State Examination, monotherapy

DOI: 10.3233/JAD-150094

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 487-493, 2015

Authors: Yin, Rui-Hua | Tan, Lan | Liu, Yong | Wang, Wen-Ying | Wang, Hui-Fu | Jiang, Teng | Joaquim Radua, | Zhang, Yu | Gao, Junling | Canu, Elisa | Migliaccio, Raffaella | Filippi, Massimo | Gorno-Tempini, Maria Luisa | Yu, Jin-Tai

Article Type: Research Article

Abstract: An increasing number of MRI investigations suggest that patients with Alzheimer’s disease (AD) show not only gray matter decreases but also white matter (WM) abnormalities, including WM volume (WMV) deficits and integrity disruption of WM pathways. In this study, we applied multimodal voxel-wise meta-analytical methods to study WMV and fractional anisotropy in AD. Fourteen studies including 723 participants (340 with AD and 383 controls) were involved. The meta-analysis was performed using effect size signed differential mapping. Significant WMV reductions were observed in bilateral inferior temporal gyrus, splenium of corpus callosum, right parahippocampal gyrus, and hippocampus. Decreased fractional anisotropy was identified …mainly in left posterior limb of internal capsule, left anterior corona radiata, left thalamus, and left caudate nucleus. Significant decreases of both WMV and fractional anisotropy were found in left caudate nucleus, left superior corona radiata, and right inferior temporal gyrus. Most findings showed to be highly replicable in the jackknife sensitivity analyses. In conclusion, AD patients show widespread WM abnormalities mainly in bilateral structures related to advanced mental and nervous activities. Show more

Keywords: Alzheimer’s disease, diffusion tension imaging, fractional anisotropy, magnetic resonance imaging, voxel-based morphometry, white matter

DOI: 10.3233/JAD-150139

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 495-507, 2015

Authors: Xie, Yunyan | Cui, Zaixu | Zhang, Zhongmin | Sun, Yu | Sheng, Can | Li, Kuncheng | Gong, Gaolang | Han, Ying | Jia, Jianping

Article Type: Research Article

Abstract: Identifying amnestic mild cognitive impairment (aMCI) is of great clinical importance because aMCI is a putative prodromal stage of Alzheimer’s disease. The present study aimed to explore the feasibility of accurately identifying aMCI with a magnetic resonance imaging (MRI) biomarker. We integrated measures of both gray matter (GM) abnormalities derived from structural MRI and white matter (WM) alterations acquired from diffusion tensor imaging at the voxel level across the entire brain. In particular, multi-modal brain features, including GM volume, WM fractional anisotropy, and mean diffusivity, were extracted from a relatively large sample of 64 Han Chinese aMCI patients and 64 …matched controls. Then, support vector machine classifiers for GM volume, FA, and MD were fused to distinguish the aMCI patients from the controls. The fused classifier was evaluated with the leave-one-out and the 10-fold cross-validations, and the classifier had an accuracy of 83.59% and an area under the curve of 0.862. The most discriminative regions of GM were mainly located in the medial temporal lobe, temporal lobe, precuneus, cingulate gyrus, parietal lobe, and frontal lobe, whereas the most discriminative regions of WM were mainly located in the corpus callosum, cingulum, corona radiata, frontal lobe, and parietal lobe. Our findings suggest that aMCI is characterized by a distributed pattern of GM abnormalities and WM alterations that represent discriminative power and reflect relevant pathological changes in the brain, and these changes further highlight the advantage of multi-modal feature integration for identifying aMCI. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, classification, diffusion tensor imaging, structural magnetic resonance imaging, support vector machine

DOI: 10.3233/JAD-150184

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 509-522, 2015

Authors: Giil, Lasse M. | Kristoffersen, Einar K. | Vedeler, Christian A. | Aarsland, Dag | Nordrehaug, Jan Erik | Winblad, Bengt | Cedazo-Minguez, Angel | Lund, Anders | Reksten, Tove Ragna

Article Type: Research Article

Abstract: Background: Autoantibodies with agonist function are described in cardiovascular disorders. Since vascular risk factors are associated with an increased risk for Alzheimer’s disease (AD), we investigated a potential association between antibodies to the angiotensin 2 type 1 receptor (anti-AT1R) and AD. Objective: The primary objective of this study was to investigate the association between anti-AT1R and AD. The secondary objective was to investigate the association between clinical or biomarker features of AD and anti-AT1R. Methods: Samples from patients with mild AD participating in a longitudinal study in Western Norway (n  = 92, 65 …[71%] females, mean age 74.8 [range 50–89]) and age- and gender-matched healthy controls (n  = 102) were included. Cerebrospinal fluid (CSF) AD biomarkers were assessed in a subgroup of patients. Patients were examined annually, including Mini-Mental State Examination. ELISA was used to measure anti-AT1R in serum. Non-parametric tests were used for statistical calculations and a p  <  0.05 was considered significant. Results: AD patients had significantly higher levels of anti-AT1R compared with healthy controls (10.2 U/mL versus 8.1 U/mL, p  = 0.04). This difference was found only in patients without hypertension and diabetes. Anti-AT1R levels correlated with CSF total tau (p  = 0.03) and phosphorylated tau (p  = 0.03) levels, and inversely with blood pressure in AD (Spearman R −0.277, p  = 0.008). Discussion: AD is associated with increased levels of anti-AT1R, and the antibodies correlated with CSF total, and phosphorylated tau levels. Further research is needed to understand the blood pressure response in AD without hypertension and a potential link between tau and anti-AT1R in AD. Show more

Keywords: AT1R, autoimmunity, dementia, neurodegeneration

DOI: 10.3233/JAD-150053

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 523-529, 2015

Article Type: Meeting Report

DOI: 10.3233/JAD-150425

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 531-534, 2015