Journal of Alzheimer's Disease - Volume 59, issue 3

Authors: Shi, Yachen | Gu, Lihua | Alsharif, Abdul Azeez | Zhang, Zhijun

Article Type: Research Article

Abstract: To systematically assess the clinical significance of platelet amyloid-β protein precursor (AβPP) ratio between Alzheimer’s disease (AD) patients and controls. 14 articles were selected in this analysis by search of databases including PubMed and Web of Science up to December 2016. Random effects models were used to calculate the standardized mean difference (SMD). Subgroup analyses were used to detect the cause of heterogeneity. The result showed a significant drop in platelet AβPP ratio in AD patients compared to controls [SMD: –1.871; 95% CI: (–2.33, –1.41); p  < 0.001; I2  = 88.0% ]. Subgroup analysis revealed races or the quality of studies may …be the cause of high heterogeneity. This meta-analysis concluded that there is a close association between platelet AβPP ratio and AD. It is necessary to design a sizable sample study to further support that platelet AβPP ratio can be a biomarker of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β precursor protein, biomarker, meta-analysis, platelet

DOI: 10.3233/JAD-170253

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1037-1044, 2017

Authors: Kodamullil, Alpha Tom | Iyappan, Anandhi | Karki, Reagon | Madan, Sumit | Younesi, Erfan | Hofmann-Apitius, Martin

Article Type: Research Article

Abstract: Perturbance in inflammatory pathways have been identified as one of the major factors which leads to neurodegenerative diseases (NDD). Owing to the limited access of human brain tissues and the immense complexity of the brain, animal models, specifically mouse models, play a key role in advancing the NDD field. However, many of these mouse models fail to reproduce the clinical manifestations and end points of the disease. NDD drugs, which passed the efficacy test in mice, were repeatedly not successful in clinical trials. There are numerous studies which are supporting and opposing the applicability of mouse models in neuroinflammation and …NDD. In this paper, we assessed to what extend a mouse can mimic the cellular and molecular interactions in humans at a mechanism level. Based on our mechanistic modeling approach, we investigate the failure of a neuroinflammation targeted drug in the late phases of clinical trials based on the comparative analyses between the two species. Show more

Keywords: Alzheimer’s disease, human, mice, neuroinflammation

DOI: 10.3233/JAD-170255

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1045-1055, 2017

Authors: Santos, Cláudia Y. | Machan, Jason T. | Wu, Wen-Chih | Snyder, Peter J.

Article Type: Research Article

Abstract: To explore early autonomic cardiac changes in pre-clinical Alzheimer’s disease (AD), we have evaluated electrocardiologic measures of vagal tone for 63 adults (ages 55–75) at rest, during cognitive testing, and then again at rest. All subjects had multiple risk factors for AD, and all completed amyloid PET scans (18 F-Florbetapir) to determine amyloid positivity (Aβ+). No change in electrocardiographic measures were observed for Aβ+ participants under each testing condition, whereas Aβ–subjects showed an expected increase in vagal tone during the cognitive stress condition. These findings suggest an early relationship between cortical Aβ accumulation, a precursor to AD development, and autonomic …cardiac function. Show more

Keywords: Aging, Alzheimer’s disease, cardiac, heart rate variability, resting sinus arrhythmia, vagal tone

DOI: 10.3233/JAD-170217

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1057-1065, 2017

Authors: Wu, Meina | Shi, Hui | He, Yexin | Yuan, Li | Qu, Xuesong | Zhang, Jun | Wang, Zhaojun | Cai, Hongyan | Qi, Jinshun

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia, and effective therapeutics are lacking. Colivelin (CLN), a novel, strong humanin derivative, is effective in vitro in preventing cell death induced by AD-causative genes and amyloid-β protein (Aβ) even at a low concentration. We recently demonstrated that intrahippocampal injection of CLN prevents Aβ25–35 -induced deficits in spatial memory and synaptic plasticity in normal rats. Here, we further observed the effects of chronically intranasally (i.n.) administered CLN on cognitive behaviors and pathological hallmarks in 9-month-old APPswe/PS1dE9 (APP/PS1) AD mice using multiple behavioral tests and immunochemistry. The electrophysiological mechanism of CLN …neuroprotection was also investigated by recording in vivo hippocampal long-term potentiation (LTP). CLN pretreatment effectively prevented impairments in new object recognition, working memory, and long-term spatial memory and reversed the depression of in vivo hippocampal LTP in APP/PS1 mice. Additionally, chronic application of CLN obviously reduced Aβ deposition in the hippocampus in APP/PS1 mice. These results indicate that CLN has strong neuroprotective effects on learning and memory behaviors in APP/PS1 mice and that this behavioral improvement is closely associated with the reduction of Aβ deposition and alleviation of LTP suppression in the hippocampus, supporting the potential of CLN for the prevention and treatment of AD. Show more

Keywords: Amyloid-β protein, APP/PS1 transgenic mice, colivelin, learning and memory, long-term potentiation

DOI: 10.3233/JAD-170307

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1067-1078, 2017

Authors: Esquerda-Canals, Gisela | Martí-Clúa, Joaquim | Roda, Alejandro R. | Villegas, Sandra

Article Type: Research Article

Abstract: The main histopathological hallmarks of Alzheimer’s disease (AD) are the extracellular deposition of neuritic amyloid plaques, composed of amyloid-β (Aβ) peptide, and the intracellular accumulation of neurofibrillary tangles, composed of hyperphosphorylated tau. Both traits are emulated in the 3xTg-AD mouse model. Because the relevance of this model in the bibliography and the main role of Aβ in neuronal impairment, here we have detailed the brain Aβ/AβPP distribution to subsequently quantify cellular density and intracellular burden for specific neuronal populations in the early stages of the disease. 6E10 immunoreactivity was evident in the deep layers of the cerebral cortex, in the …pyramidal cell layer of the hippocampus, in the basolateral amygdala nucleus, and in the deep cerebellar nuclei macroneurons; whereas the specific neuronal populations with decreased cellular density were the large pyramidal neurons from the layers V-VI in the cerebral cortex, the pyramidal neurons from the CA2-3 region in the hippocampus, and the large neurons from the basolateral nucleus in the amygdala, apart from the already reported deep cerebellar nuclei. Interestingly, we found a strong correlation between intracellular Aβ/AβPP burden and cellular density in all these populations. In addition, behavioral testing showed the functional consequences of such a neuronal depletion. Concretely, anxious-like behavior is manifested in the corner and open-field tests, as well as cognitive functions shown to be impaired in the novel object recognition test and Morris water maze paradigm. To our knowledge, this is the first deep characterization of the specific neuronal populations affected in the 3xTg-AD mouse model. Show more

Keywords: 3xTg-AD, Alzheimer’s disease, amyloid-β, AβPP, behavioral alterations, 6E10 immunoreactivity, neuronal loss

DOI: 10.3233/JAD-170218

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1079-1096, 2017

Authors: Küster, Olivia C. | Laptinskaya, Daria | Fissler, Patrick | Schnack, Cathrin | Zügel, Martina | Nold, Verena | Thurm, Franka | Pleiner, Sina | Karabatsiakis, Alexander | von Einem, Björn | Weydt, Patrick | Liesener, André | Borta, Andreas | Woll, Alexander | Hengerer, Bastian | Kolassa, Iris-Tatjana | von Arnim, Christine A.F.

Article Type: Research Article

Abstract:  Psychosocial stress and physical, cognitive, and social activity predict the risk of cognitive decline and dementia. The aim of this study was to elucidate brain-derived neurotrophic factor (BDNF), irisin, and the kynurenine pathway (KP) as potential underlying biological correlates. We evaluated associations of irisin and the KP with BDNF in serum and with cognition, stress, and activities. Furthermore, changes in serum concentrations of BDNF, irisin, and KP metabolites were investigated after physical or cognitive training. Forty-seven older adults at risk of dementia were assigned to 10 weeks of physical training, cognitive training, or a wait-list control condition. Previous physical, cognitive, and …social activities and stressful life events were recorded; global cognition, episodic memory, and executive functions were assessed. Serum levels of L-kynurenine, kynurenic acid, 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN) were determined by validated assays based on liquid chromatography coupled to tandem mass spectrometry. BDNF and irisin serum levels were determined with enzyme-linked immunosorbent assays. BDNF and irisin correlated positively with global cognition and episodic memory, while the neurotoxic metabolite QUIN correlated negatively with executive functions. Stressful life events were associated with reduced BDNF and increased 3-HK. 3-HK decreased after cognitive training, while BDNF tended to increase after physical training. This suggests that psychosocial stress as well as cognitive and physical training may impact BDNF serum levels and the KP. Irisin and QUIN may constitute novel serum biomarkers of cognitive impairment, in addition to BDNF. Larger scale trials are needed to replicate and extend these novel findings. Show more

Keywords: Brain-derived neurotrophic factor, cognitive function, dementia, exercise training, kynurenine, lifestyle∥

DOI: 10.3233/JAD-170447

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1097-1111, 2017

Authors: Edwards, Jodi D. | Ramirez, Joel | Callahan, Brandy L. | Tobe, Sheldon W. | Oh, Paul | Berezuk, Courtney | Lanctôt, Krista | Swardfager, Walter | Nestor, Sean | Kiss, Alexander | Strother, Stephen | Black, Sandra E. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Hypertension is an important risk factor for Alzheimer’s disease (AD) and cerebral small vessel disease. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are common anti-hypertensive treatments, but have differential effects on cortical amyloid. Objective: The objective of this study was to evaluate associations between anti-hypertensive treatment, brain volume, and cognition, using a propensity-weighted analysis to account for confounding by indication. Methods: We identified a cohort of normal elderly adults and individuals with mild cognitive impairment (MCI) or AD (N = 886; mean age = 75.0) from the Alzheimer’s Disease Neuroimaging Initiative. Primary outcomes were brain parenchymal …fraction, total hippocampal volume, and white matter hyperintensity (WMH) volume. Secondary outcomes were standardized scores on neuropsychological tests. Propensity-weighted adjusted multivariate linear regression was used to estimate associations between anti-hypertensive treatment class and MRI volumes and cognition. Results: Individuals treated with ARBs showed larger hippocampal volumes (R2  = 0.83, p  = 0.05) and brain parenchymal fraction (R2  = 0.83, p  = 0.01) than those treated with ACEIs. When stratified by diagnosis, this effect remained only in normal elderly adults and MCI patients, and a significant association between ARBs and lower WMH volume (R2  = 0.83, p  = 0.03) emerged for AD patients only. ARBs were also associated with significantly better performance on tests of episodic and verbal memory, language, and executive function (all p  < 0.05). Conclusions: Findings are consistent with evidence for a neuroprotective effect of treatment with ARBs for brain structure and cognition. This study has potential implications for the treatment of hypertension, particularly in elderly adults at risk of cognitive decline and AD. Show more

Keywords: Alzheimer’s disease, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, hypertension, white matter hyperintensities

DOI: 10.3233/JAD-170238

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1113-1122, 2017

Authors: Sinclair, Lindsey I. | Love, Seth

Article Type: Research Article

Abstract: Background: Possession of APOE ɛ 4 is a strong risk factor for late-onset Alzheimer’s disease and is associated with loss of synaptic proteins in the elderly even in the absence of Alzheimer’s disease. Objective: We hypothesized that ɛ 4 allele possession in non-demented adults aged under-75 would also be associated with alterations in the levels of synaptic proteins. Methods: We measured synaptophysin, PSD95, drebrin, SNAP-25, and septin 7 by ELISA in hippocampus and superior temporal gyrus from 103 adults aged <75 without dementia. Corresponding gene expression was measured by RT-PCR. Results: There was no …evidence that ɛ 4 affected levels of the proteins measured. Instead we found an increase in post-synaptic proteins in the hippocampi of those with an ɛ 32 genotype. The evidence was strongest for drebrin (p  = 0.011). There was some evidence of increased synaptic protein gene expression in ɛ 4 carriers. Conclusions: People with an APOE ɛ 32 genotype have a reduced risk of Alzheimer’s disease. It may be relevant that they have a higher level of post-synaptic proteins in the hippocampus even in earlier adulthood. Show more

Keywords: Alzheimer’s disease, APOE, dementia, drebrin, genetics, postmortem tissue, PSD-95, synaptic proteins, synaptophysin

DOI: 10.3233/JAD-170316

Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 1123-1137, 2017