Journal of Alzheimer's Disease - Volume 66, issue 4

Authors: Zanco, Marcos | Plácido, Jessica | Marinho, Valeska | Ferreira, José Vinicius | de Oliveira, Felipe | Monteiro-Junior, Renato | Barca, Maria | Engedal, Knut | Laks, Jerson | Deslandes, Andrea

Article Type: Research Article

Abstract: Background: Spatial navigation is a fundamental cognitive ability that allows an individual to maintain independence by facilitating the safe movement from one place to another. It emerges as one of the first deficits in patients with Alzheimer’s disease (AD). Objective: To compare spatial navigation performance in the healthy elderly and AD patients through use of the Floor Maze Test (FMT)— an easy-to-apply two-dimensional (2D) maze— and determine which cognitive and functional capacities were associated with performance in this task. Methods: The FMT was administered to 24 AD patients and 36 healthy controls. Spatial navigation was evaluated …through the FMT. Functional capacity was evaluated through the Senior Fitness Test battery of tests. Cognitive functions were evaluated through the Mini-Mental State Examination (MMSE), verbal fluency, digit span test, and the Rey Auditory Verbal Learning Test (RAVLT). Results: The group with AD was significantly slower and presented more errors at all stages of the FMT. Planning Time (PT) performance was associated with cardiorespiratory resistance (Step test) and delayed memory according to the RAVLT (R2  = 0.395, p  < 0.001). Performance in the Immediate Maze Time (IMT) and Delayed Maze Time (DMT) was associated with global cognitive status (MMSE) (R2  = 0.509) and delayed memory (R2  = 0.540). Conclusion: Patients with AD present significant spatial navigation deficits. Their performance on the FMT is influenced by cardiorespiratory capacity, memory, and global cognitive function. As exercise helps to improve executive function and functional capacity, future intervention studies should be carried out to analyze the possible effects of physical exercise on spatial navigation. Show more

Keywords: Alzheimer’s disease, functional capacity, executive function, spatial navigation

DOI: 10.3233/JAD-180819

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1683-1694, 2018

Authors: Gu, Jianlan | Chen, Feng | Chu, Dandan | Lu, Ying | Iqbal, Khalid | Gong, Cheng-Xin | Liu, Fei

Article Type: Research Article

Abstract: Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule-binding repeats, 3R-tau or 4R-tau, which are under developmental regulation. Dysregulation of tau exon 10 splicing is sufficient to cause neurodegenerative disorders. The RNA-binding Fox3 (Rbfox3), identified as NeuN, regulates RNA processing. However, whether Rbfox3/NeuN regulates tau exon 10 splicing is unknown. In the present study, we found that the developmental expression of 4R-tau coincided with the expression of Rbfox3 in rat brains. Rbfox3 enhanced tau exon 10 inclusion. Tau intron 10 contains UGCAUG, the conservative binding sequence of Rbfox3. Intron 10 of tau pre-mRNA was co-immunoprecipitated …by Rbfox3/NeuN. Deletion mutants of the RNA recognition motif (RRM) or three RNA-binding sites of the RRM in Rbfox3/NeuN failed to enhance tau exon 10 inclusion. Rbfox3, specifically expressed in the fetal brain, did not affect tau exon 10 splicing. The level of Rbfox3/NeuN was reduced and was associated with the ratio of 4R-tau/3R-tau in the excitotoxic mouse brains induced by kainic acid. These findings suggest that Rbfox3/NeuN regulates the alternative splicing of tau exon 10 and that decreased Rbfox3/NeuN may lower the ratio of 4R-tau/3R-tau. Show more

Keywords: Alternative splicing, alzheimer’s disease, rbfox3/NeuN, tau

DOI: 10.3233/JAD-180882

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1695-1704, 2018

Authors: Goto, Seiko | Shen, Xuting | Sun, Minkai | Hamano, Yutaka | Herrup, Karl

Article Type: Research Article

Abstract: Dementia is highly prevalent among the worldwide elderly population. Only a small number of the currently marketed drugs are effective in controlling its symptoms, and none has any effect on its progression. Further, as the condition advances, even these pharmaceuticals lose their efficiency, and new research into interventions that might improve the life quality of patients at the end stage of dementia and their families is increasingly rare. In our previous studies, we explored the benefits of exposure to nature, in the form of a Japanese garden, for persons with advanced dementia. In the current work, we extended our observations …to two new locations and a new set of subjects with a different ethnic composition with the goal of identifying interventions that might improve their quality of life. We found that, even in these new settings, garden observation not only relieved physiological stress, it improved qualitative measures such as verbalization and memory retrieval. We present data that viewing the garden is a holistic experience rather a solely visual stimulus. Our new data further support the conclusion that garden observation is worth including in the care planning schedule of advanced dementia patients. Its low cost and easy availability make it an economical adjunct to current pharmacological methods that has the potential to improve the quality of life of people with dementia. Show more

Keywords: Dementia, heart rate, Japanese garden, memory retrieval, stress relief

DOI: 10.3233/JAD-170510

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1705-1720, 2018

Authors: Choi, Hojin | Yang, YoungSoon | Han, Hyun Jeong | Jeong, Jee Hyang | Park, Mee Young | Kim, Yong Bum | Jo, Kwang Deog | Choi, Jin-Yong | Kang, Kyung-Hun | Kang, Heeyoung | Kwon, Do-Young | Yoo, Bong-Goo | Lee, Hyun Jin | Shin, Byoung-Soo | Jeon, Sung-Man | Kwon, Oh Dae | Kim, Jin-Suk | Lee, Soo-Joo | Kim, Youngsoo | Park, Tai-Hwan | Kim, Young Jin | Yang, Hui-Jun | Park, Hyun-Young | Shin, Hae-Eun | Lee, Jung Seok | Jung, Yo Han | Lee, Ae Young | Shin, Dong-Ick | Shin, Kyong Jin | Park, Kee Hyung

Article Type: Research Article

Abstract: Background: Magnetic resonance imaging (MRI) is a useful tool to predict the diagnosis and progression of Alzheimer’s disease (AD), especially for primary physicians. However, the correlation between baseline MRI findings and AD progression has not been fully established. Objective: To investigate the correlation between hippocampal atrophy (HA) and white matter hyperintensities (WMH) on initial brain MRI images and the degree of cognitive decline and functional changes over 1 year. Methods: In this prospective, 12-month observational study, dementia outpatients were recruited from 29 centers across South Korea. Baseline assessments of HA and WMH on baseline brain MRI …were derived as well as cognitive function, dementia severity, activities of daily living, and acetylcholinesterase inhibitor (AChEI) use. Follow-up assessments were conducted at 6 and 12 months. Results: Among 899 enrolled dementia patients, 748 were diagnosed with AD of whom 654 (87%) were taking AChEIs. Baseline WMH showed significant correlations with age, current alcohol consumption, and Clinical Dementia Rating score; baseline HA was correlated with age, family history, physical exercise, and the results of cognitive assessments. Among the AChEI group, changes in the Korean version of the Instrumental Activities of Daily Living (K-IADL) were correlated with the severity of HA on baseline brain MRI, but not with the baseline severity of WMH. In the no AChEI group, changes in K-IADL were correlated with the severity of WMH and HA at baseline. Conclusion: Baseline MRI findings could be a useful tool for predicting future clinical outcomes by primary physicians, especially in relation to patients’ functional status. Show more

Keywords: Atrophy, brain imaging, cognitive function, hippocampus, white matter hyperintensities

DOI: 10.3233/JAD-180565

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1721-1730, 2018

Authors: Fan, ShuJuan | Xian, XiaoHui | Li, Li | Yao, XiaoGuang | Hu, YuYan | Zhang, Min | Li, WenBin

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by progressive impairment of learning, memory, and cognitive deficits. Glutamate is the major excitatory neurotransmitter in the central nervous system and plays an important role in learning, memory, and cognition. The homeostasis and reutilization of glutamate are dependent on astrocytic uptake by glutamate transporter-1 (GLT-1) and the subsequent glutamate-glutamine cycle. Increasing evidence showed impairments in GLT-1 expression and uptake activity and glutamate-glutamine cycle in AD. Ceftriaxone (Cef) has been reported to upregulate the expression and uptake of GLT-1. Therefore, the present study was undertaken to explore whether Cef can improve cognitive deficits of APP/PS1 mice …in early stage of AD by upregulating GLT-1 expression, and then promoting the glutamate-glutamine cycle. It was shown that Cef treatment significantly alleviated the cognitive deficits measured by Morris water maze test and upregulated GLT-1 protein expression in the hippocampus of APP/PS1 mice. Particularly, the activity of glutamine synthetase (GS) and the protein expression of system N glutamine transporter 1 (SN1), which are the key factors involved in the glutamate-glutamine cycle, were significantly upregulated as well after the Cef treatment. Furthermore, inhibition of GLT-1 uptake activity by dihydrokainic acid, an inhibitor of GLT-1, blocked the Cef-induced improvement on the cognitive deficits, GS activity, and SN1 expression. The above results suggested that Cef could improve cognitive deficits of APP/PS1 mice in early stage of AD by upregulating the GLT-1 expression, GS activity, and SN1 expression, which would lead to stimulating the glutamate-glutamine cycle. Show more

Keywords: APP/PS1 mice, ceftriaxone, DHK, GLT-1, glutamate-glutamine cycle

DOI: 10.3233/JAD-180708

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1731-1743, 2018

Authors: Lahme, Larissa | Esser, Eliane Luisa | Mihailovic, Natasa | Schubert, Friederike | Lauermann, Jost | Johnen, Andreas | Eter, Nicole | Duning, Thomas | Alnawaiseh, Maged

Article Type: Research Article

Abstract: Background: There is increasing evidence for the involvement of cerebrovascular factors in Alzheimer’s disease (AD). Objective: To evaluate retinal and optic nerve head perfusion in patients with AD using optical coherence tomography angiography (OCTA), and to analyze the correlations of quantitative OCTA metrics with AD pathology and vascular cerebral lesions in AD patients. Methods: 36 eyes of 36 patients with AD (study group) and 38 eyes of 38 healthy subjects (control group) were prospectively included in this study. OCTA was performed using RTVue XR Avanti with AngioVue. In addition, patients underwent a detailed ophthalmological and neurological …examination including Mini-Mental State Examination, cerebral magnetic resonance imaging, and amyloid-β (Aβ) and tau levels in the cerebrospinal fluid (CSF). Results: The flow density in the superficial retinal OCT angiogram of the macula in the study group was significantly lower compared to the control group (p  = 0.001). There was a significant correlation between the flow density in the superficial retinal OCT angiogram of the macula, as measured using OCTA, and the Fazekas scale (Spearman’s correlation coefficient = –0.520; p  = 0.003). There was no significant correlation between the Aβ or tau levels in the CSF and the flow density data. Conclusion: Patients with AD showed a reduced flow density in the radial peripapillary capillaries layer and in the superficial retinal OCT angiogram when compared with healthy controls. The reduced retinal flow density measured using OCTA is not specifically associated with AD pathology but is associated with the vascular cerebral lesions in AD. Show more

Keywords: Alzheimer’s disease, flow density, optical coherence tomography angiography, retinal and optic nerve head perfusion

DOI: 10.3233/JAD-180738

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1745-1752, 2018

Authors: Javanshiri, Keivan | Waldö, Maria Landqvist | Friberg, Niklas | Sjövall, Fredrik | Wickerström, Karin | Haglund, Mattias | Englund, Elisabet

Article Type: Correction

DOI: 10.3233/JAD-189011

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1753-1753, 2018

Article Type: Other

DOI: 10.3233/JAD-189012

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1755-1768, 2018