Journal of Alzheimer's Disease - Volume 53, issue 1

Authors: van de Vorst, Irene E. | Koek, Huiberdina L. | Bots, Michiel L. | Vaartjes, Ilonca

Article Type: Research Article

Abstract: Background: Insight in causes of death in demented patients may help physicians in end-of-life care. Objectives: To investigate underlying causes of death (UCD) in demented patients stratified by age, sex, dementia subtype [Alzheimer’s disease (AD), vascular dementia (VaD)] and to compare them with UCD in the general population (GP). Methods: A nationwide cohort of 59,201 patients with dementia (admitted to a hospital or visiting a day clinic) was constructed [38.7% men, 81.4 years (SD 7.0)] from 2000 through 2010. UCDs were reported and compared to the GP by calculating relative risks (RRs). Results: …During follow up [median follow up time 1.3 years (IQR 0.3– 3.0)], 64.2% of women and 69.3% of men died. Leading UCDs were dementia (17.5% in men and 23.7% in women) and cardiovascular disease (CVD) (18.7% and 19.2%, respectively). When compared to the GP, dementia was a more common UCD (RR in men 4.65, 95% CI 4.43–4.88), while CVD (RR in men 0.67, 95% CI 0.65–0.68) and cancer (RR 0.40, 95% CI 0.39–0.41) were less common. These differences were more pronounced in patients aged between 60–69 as compared to those aged≥90 years. Patients with AD died less often of cerebrovascular diseases as compared to VaD (RR in men 0.53, 95% CI 0.47–0.59). Conclusion: UCDs in patients with dementia differs from that of the GP, as dementia is more often and cancer less often an UCD. Although less frequent compared to the GP, CVD also is one of the leading UCDs in patients with dementia. This information is valuable for targeted advance care planning. Show more

Keywords: Cardiovascular disease, cause of death, cohort, dementia, mortality

DOI: 10.3233/JAD-150925

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 117-125, 2016

Authors: Uekawa, Ken | Hasegawa, Yu | Senju, Satoru | Nakagata, Naomi | Ma, Mingjie | Nakagawa, Takashi | Koibuchi, Nobutaka | Kim-Mitsuyama, Shokei

Article Type: Research Article

Abstract: This work was performed to test our hypothesis that angiotensin-(1–7) can ameliorate cognitive impairment and cerebrovascular reactivity in 5XFAD mice, a useful model of Alzheimer’s disease. 5XFAD mice received intracerebroventricular infusion of (1) vehicle, (2) angiotensin-(1–7), or (3) angiotensin-(1–7)+A779, a specific Mas receptor antagonist, for 4 weeks. Angiotensin-(1–7), through Mas receptor, significantly ameliorated cognitive impairment in 5XFAD mice. As estimated by acetazolamide-induced increase in cerebral blood flow, angiotensin-(1–7), through Mas receptor, enhanced cerebrovascular reactivity in 5XFAD mice. In conclusion, angiotensin-(1–7)/Mas receptor axis improves cognitive function and cerebrovascular function in a mouse model of Alzheimer’s disease.

Keywords: Acetazolamide, angiotensin-(1–7), cognitive function, Mas receptor, vascular reactivity, water maze test

DOI: 10.3233/JAD-150642

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 127-133, 2016

Authors: Staekenborg, Salka S. | Pijnenburg, Yolande A.L. | Lemstra, Afina W. | Scheltens, Philip | vd Flier, Wiesje M.

Article Type: Research Article

Abstract: Background: Dementia is typically known for its insidious onset and slowly progressive course, but a subgroup deteriorates fast and dies within years or even months. Objective: The purpose of this study was to characterize dementia patients with a rapidly progressive course to death and evaluate their cause of death. Methods: We retrospectively included all patients from the Amsterdam Dementia Cohort who died within two years after diagnosis. We evaluated the characteristics of these rapid progressors and compared them to patients known to be alive two years after diagnosis (‘non-rapid mortality’). Results: We included …129 dementia patients (13% of our total cohort with known follow-up) with rapid mortality (age 72±10 y [29%  <65 y], 70[55%]M, MMSE 20±5). Mean(SD) survival was 12±7 months. Compared to non-rapid mortality patients (n  = 892; age 68±9, 503(56%)M, MMSE 22±5), patients with rapid mortality were slightly older at time of diagnosis, had lower MMSE scores, more depressive symptoms and higher prevalence of a cardiovascular history (all p  < 0.05). Alzheimer’s disease (AD, 43%) was most frequent in patients with rapid mortality, but the occurrence was much lower compared to non-rapid mortality patients (71%), while all other dementia diagnoses, especially Creutzfeldt-Jakob disease (CJD), vascular dementia (VaD), and frontotemporal dementia (FTD), were more frequent (p  < 0.001). There were no specific characteristics for AD patients with rapid versus non-rapid mortality, especially APOE genotypes and CSF-profiles were comparable (p  > 0.70). Cause of death was highly variable without a clear relation to dementia diagnosis, with exception of dementia itself in CJD, intracerebral hematoma in VaD, and motor neuron disease in FTD. Conclusions: Short survival is relatively common (∼13% in our cohort) and occurs in all different types of dementia, with overrepresentation of non-AD dementias like CJD, VaD, and FTD. Show more

Keywords: Dementia, mortality, rapid progression

DOI: 10.3233/JAD-151063

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 135-142, 2016

Authors: Tsai, Chia-Liang | Pai, Ming-Chyi | Ukropec, Jozef | Ukropcová, Barbara

Article Type: Research Article

Abstract: Although elderly people with amnestic mild cognitive impairment (aMCI) have been found to show impaired behavioral performance in task switching, no research has yet explored the electrophysiological mechanisms and the potential correlation between physical fitness and neurocognitive (i.e., behavioral and electrophysiological) performance in aMCI. The present study was thus aimed to examine whether there are differences in electrophysiological (i.e., event-related potential) performance between aMCI participants and controls when performing a task-switching paradigm, and to investigate the role of physical fitness in the relationship between neurocognitive performance and aMCI. Sixty participants were classified into aMCI (n  = 30) and control (n  = 30) …groups, and performed a task-switching paradigm with concomitant electrophysiological recording, as well as underwent senior functional physical fitness tests. The aMCI group showed comparable scores on most parts of the physical fitness tests, but reduced lower body flexibility and VO2max as compared to the control group. When performing the task-switching paradigm, the aMCI group showed slower reaction times in the heterogeneous condition and larger global switching costs, although no significant difference was observed in accuracy rates between the two groups. In addition, the aMCI group showed significantly prolonged P3 latencies in the homogeneous and heterogeneous conditions, and a smaller P3 amplitude only in the heterogeneous condition. The level of cardiorespiratory fitness was significantly correlated with P3 amplitude in the aMCI group, particularly in the heterogeneous condition of the task-switching paradigm. These results show that the aMCI group exhibited abnormalities in their neurocognitive performance when performing the task-switching paradigm and such a deficit was likely associated with reduced cardiorespiratory fitness, which was shown to be the important predictor of neurocognitive performance. Show more

Keywords: Alzheimer’s disease, executive control, mild cognitive impairment, physical fitness, task switching

DOI: 10.3233/JAD-151093

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 143-159, 2016

Authors: Vidoni, Eric D. | Watts, Amber S. | Burns, Jeffrey M. | Greer, Colby S. | Graves, Rasinio S. | Van Sciver, Angela | Black, Jessica R. | Cooper, Sarah K. | Nagely, Allison C. | Uphoff, Elaine | Volmer, Jennifer M. | Bieberle, Natalie A.

Article Type: Research Article

Abstract: Background: Effective programs for promoting physical activity are needed for those with cognitive impairment. Objective: To test the feasibility of mobile Health (mHealth) technology-supported physical activity prescription from a tertiary care memory clinic. Methods: This feasibility study was designed as a 16-week randomized, crossover trial of a physical activity prescription: 8 weeks of intervention, 8 weeks of baseline or maintenance phase data collection. We recruited 2 cohorts: 21 individuals with Alzheimer-related cognitive impairment (mean age 72.3 (5.2), 9 females), and 9 individuals with normal cognition (mean age 69.6 (5.8), 8 females). We gave each cohort …an mHealth accelerometer-based physical activity prescription to double number of steps taken. Our primary outcomes were feasibility and safety. Our secondary outcomes were change in weekly steps taken, Dementia Quality of Life Scale, Self-efficacy Scale, 6-minute Walk, and mini-Physical Performance Test. Results: Set-up and use of the device was not a barrier to participation. However, only 62% of participants with cognitive impairment completed the intervention. The cohort with cognitive impairment did not change their weekly step count above Week 1. All participants in the cohort with normal cognition were able to set up and use their device and increased their weekly step count above Week 1. There were no differences between Week 1 and Week 8 for any secondary measures in either cohort. Conclusions: Setup and daily use of mHealth technology appears to be feasible for a person with cognitive impairment with the help of a partner, but increasing daily step counts over 8 weeks was not achieved. Future work needs to assess alternative activity prescription goals or additional support for patients and their partners. Show more

Keywords: Alzheimer’s disease, clinic activities, exercise, mobile health

DOI: 10.3233/JAD-160158

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 161-170, 2016

Authors: Happich, Michael | Kirson, Noam Y. | Desai, Urvi | King, Sarah | Birnbaum, Howard G. | Reed, Catherine | Belger, Mark | Lenox-Smith, Alan | Price, David

Article Type: Research Article

Abstract: Background: Prior diagnosis of Alzheimer’s disease (AD) among patients later diagnosed with vascular dementia (VaD) has been associated with excess costs, suggesting potential benefits of earlier rule-out of AD diagnosis. Objective: To investigate whether prior diagnosis with AD among patients with VaD is associated with excess costs in the UK. Methods: Patients with a final VaD diagnosis, continuous data visibility for≥6 months prior to index date, and linkage to Hospital Episode Statistics data were retrospectively selected from de-identified Clinical Practice Research Datalink data. Patients with AD diagnosis before a final VaD diagnosis were matched to …similar patients with no prior AD diagnosis using propensity score methods. Annual excess healthcare costs were calculated for 5 years post-index, stratified by time to final diagnosis. Results: Of 9,311 patients with VaD, 508 (6%) had prior AD diagnosis with a median time to VaD diagnosis exceeding 2 years from index date. Over the entire follow-up period, patients with prior AD diagnosis had accumulated healthcare costs that were approximately GBP2,000 higher than those for matched counterparts (mostly due to higher hospitalization costs). Cost differentials peaked particularly in the period including the final VaD diagnosis, with excess costs quickly declining thereafter. Conclusion : Potential misdiagnosis of AD among UK patients with VaD resulted in substantial excess costs. The decline in excess costs following a final VaD diagnosis suggests potential benefits from earlier rule-out of AD. Show more

Keywords: Alzheimer’s disease, cost and cost analysis, diagnosis, health resources, vascular dementia

DOI: 10.3233/JAD-150685

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 171-183, 2016

Authors: Zhang, Junying | Liu, Zhen | Li, Zixiao | Wang, Yunxia | Chen, Yaojing | Li, Xin | Chen, Kewei | Shu, Ni | Zhang, Zhanjun

Article Type: Research Article

Abstract: Type 2 diabetes mellitus is accompanied by cognitive impairment and is associated with an increased risk of dementia. Damage to brain structures such as white matter network disruption may underlie this cognitive disturbance. In the present study, 886 non-diabetic and 163 type 2 diabetic participants completed a battery of neuropsychological tests. Among them, 38 diabetic patients and 34 non-diabetic participants that matched the patients for age/sex/education received a magnetic resonance imaging-based diffusion tensor imaging. Then we calculated the topological properties of the white matter network using a graph theoretical method to investigate network efficiency differences between groups. We found that …type 2 diabetic patients had inferior performances compared to the non-diabetic controls, in several cognitive domains involving executive function, spatial processing, memory, and attention. We also found that diabetic patients exhibited a disrupted topological organization of the white matter network (including the global network properties, i.e., network strength, global efficiency, local efficiency and shortest path length, and the nodal efficiency of the right rolandic operculum) in the brain. Moreover, those global network properties and the nodal efficiency of the right rolandic operculum both had positive correlations with executive function in the patient group. The results suggest that type 2 diabetes mellitus leads to an alteration in the topological organization of the cortical white matter network and this alteration may account for the observed cognitive decline. Show more

Keywords: Alzheimer’s disease, diffusion tensor imaging, graph theory, type 2 diabetes mellitus, white matter network

DOI: 10.3233/JAD-160111

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 185-195, 2016

Authors: Peters, Christian | Sepúlveda, Fernando J. | Fernández-Pérez, Eduardo J. | Peoples, Robert W. | Aguayo, Luis G.

Article Type: Research Article

Abstract: Alzheimer’s disease is a neurodegenerative disorder that affects mostly the elderly. The main histopathological markers are the senile plaques formed by amyloid-β peptide (Aβ) aggregates that can perforate the plasma membrane of cells, increasing the intracellular calcium levels and releasing synaptic vesicles that finally lead to a delayed synaptic failure. Several membrane proteins and lipids interact with Aβ affecting its toxicity in neurons. Here, we focus on NMDA receptors (NMDARs) as proteins that could be modulating the association and neurotoxic perforation induced by Aβ on the plasma membrane. In fact, our results showed that decreasing NMDARs, using enzymatic or siRNA …approaches, increased the association of Aβ to the neurons. Furthermore, overexpression of NMDARs also resulted in an enhanced association between NMDA and Aβ. Functionally, the reduction in membrane NMDARs augmented the process of membrane perforation. On the other hand, overexpressing NMDARs had a protective effect because Aβ was now unable to cause membrane perforation, suggesting a complex relationship between Aβ and NMDARs. Because previous studies have recognized that Aβ oligomers are able to increase membrane permeability and produce amyloid pores, the present study supports the conclusion that NMDARs play a critical protective role on Aβ actions in hippocampal neurons. These results could explain the lack of correlation between brain Aβ burden and clinically observed dementia. Show more

Keywords: Alzheimer’s disease, amyloid-beta, glutamate, glycine receptor, hippocampal neurons, membrane damage, membrane pore, NMDA receptor

DOI: 10.3233/JAD-160170

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 197-207, 2016

Authors: Farnsworth, Bryn | Peuckert, Christiane | Zimmermann, Bettina | Jazin, Elena | Kettunen, Petronella | Emilsson, Lina Sors

Article Type: Research Article

Abstract: Quaking (QKI ) is a gene exclusively expressed within glial cells. QKI has previously been implicated in various neurological disorders and diseases, including Alzheimer’s disease (AD), a condition for which increasing evidence suggests a central role of glia cells. The objective of the present study was to investigate the expression levels of QKI and three QKI isoforms (QKI5 , QKI6 , and QKI7 ) in AD. Genes that have previously been related to the ontogeny and progression of AD, specifically APP , PSEN1 , PSEN2 , and MAPT , were also investigated. A real-time PCR assay of …123 samples from human postmortem sporadic AD patients and control brains was performed. The expression values were analyzed with an analysis of covariance model and subsequent multiple regressions to explore the possibility of related expression values between QKI , QKI isoforms, and AD-related genes. Further, the sequences of AD-related genes were analyzed for the presence of QKI binding domains. QKI and all measured QKI isoforms were found to be significantly upregulated in AD samples, relative to control samples. However, APP , PSEN1 , PSEN2 , and MAPT were not found to be significantly different. QKI and QKI isoforms were found to be predictive for the variance of APP , PSEN1 , PSEN2 , and MAPT , and putative QKI binding sites suggests an interaction with QKI. Overall, these results implicate a possible role of QKI in AD, although the exact mechanism by which this occurs remains to be uncovered. Show more

Keywords: Amyloid-β, APP, gene expression, glia, MAPT, neurodegenerative diseases, real-time polymerase chain reaction, PSEN1, PSEN2

DOI: 10.3233/JAD-160160

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 209-219, 2016

Authors: Tang, Wei | Cheng, Juan | Wang, Zheng-Yu | Chen, Ke-Yang | Han, Zhen-Min | Wang, Qi-Hong | Yao, Yu-You

Article Type: Research Article

Abstract: In Alzheimer’s disease (AD), extensive experimental studies have demonstrated a negative impact of chronic stress during various stages of life (including prenatal phase) on some aspects of AD pathology. Nevertheless, presently, few studies have been involved in the learning and memory impairments, as well as neuropathology elicited by the chronic prenatal stress (CPS) and the chronic offspring stress (COS) exposures simultaneously, particularly for the adult male APPswe/PS1dE9 murine offspring. Therefore, the aim of the present study was to investigate the influence of CPS on learning and memory impairments induced by COS in 6-month-old male APPswe/PS1dE9 offspring mice and the related …mechanism. Our study firstly demonstrates that 14-day exposure to CPS could exacerbate the learning and memory impairments, as well as neuropathological damages in the CA3 regions of the hippocampus and cortex neurons, which is induced by the 28-day exposure to COS in 6-month-old male APPswe/PS1dE9 offspring mice. In addition, CPS could potentiate the production of AβPP, Aβ42, and corticosterone in 6-month-old male APPswe/PS1dE9 offspring that also suffer COS. In conclusion, our novel findings strongly implicate the synergistic roles of the CPS and COS exposures in impairing offspring learning and memory. Moreover, CPS potentiating the production of Aβ42 might be mediated by glucocorticoids through increasing the expression of APP and BACE1 gene. Show more

Keywords: Alzheimer’s disease, amyloid-β, chronic offspring stress, chronic prenatal stress, glucocorticoid, learning and memory impairments

DOI: 10.3233/JAD-160011

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 221-236, 2016