Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Reimand, Juhan | Groot, Colin | Teunissen, Charlotte E. | Windhorst, Albert D. | Boellaard, Ronald | Barkhof, Frederik | Nazarenko, Sergei | van der Flier, Wiesje M. | van Berckel, Bart N.M. | Scheltens, Philip | Ossenkoppele, Rik | Bouwman, Femke

Article Type: Research Article

Abstract: Background: Amyloid-β PET and cerebrospinal fluid (CSF) Aβ42 are considered interchangeable for clinical diagnosis of Alzheimer’s disease. Objective: To explore the clinical reasoning for requesting additional amyloid-β PET after performing CSF biomarkers. Methods: We retrospectively identified 72 memory clinic patients who underwent amyloid-β PET after CSF biomarkers analysis for clinical diagnostic evaluation between 2011 and 2019. We performed patient chart reviews to identify factors which led to additional amyloid-β PET. Additionally, we assessed accordance with appropriate-use-criteria (AUC) for amyloid-β PET. Results: Mean patient age was 62.0 (SD = 8.1) and mean Mini-Mental State Exam score …was 23.6 (SD = 3.8). CSF analysis conflicting with the clinical diagnosis was the most frequent reason for requesting an amyloid-β PET scan (n  = 53, 74%), followed by incongruent MRI (n  = 16, 22%), unusual clinical presentation (n  = 11, 15%) and young age (n  = 8, 11%). An amyloid-β PET scan was rarely (n  = 5, 7%) requested in patients with a CSF Aβ+/tau+ status. Fifteen (47%) patients with a post-PET diagnosis of AD had a predominantly non-amnestic presentation. In n  = 11 (15%) cases, the reason that the clinician requested amyloid-β was not covered by AUC. This happened most often (n  = 7) when previous CSF analysis did not support current clinical diagnosis, which led to requesting amyloid-β PET. Conclusion: In this single-center study, the main reason for requesting an amyloid-β PET scan after performing CSF biomarkers was the occurrence of a mismatch between the primary clinical diagnosis and CSF Aβ/tau results. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, positron emission tomography, tau proteins

DOI: 10.3233/JAD-190836

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Schnaider, Lee | Arnon, Zohar | Gazit, Ehud

Article Type: Research Article

Abstract:  Alzheimer’s disease (AD) is the most common cause of dementia. Despite substantial investment in research, there are no current effective treatments to prevent or delay the onset and development of AD and the exact molecular mechanism of AD pathogenesis is still not fully understood. Researchers have long suspected that microbial infections may play a role in AD; however, this hypothesis has been greatly overlooked for decades, only recently gaining a traction and recognition within the broad scientific community due to new overwhelming evidence on the association of various pathogenic microbes and AD. Here, we provide our perspective on the significance …of these findings, which shed light on the interplay between molecular self-assembly, neurodegeneration, and antimicrobial peptides, as well as propose an amendment to the amyloid cascade hypothesis. It is important to note that this association does not yet prove a causal link, but these reports warrant a thorough investigation into the microbial infection-AD hypothesis which might in turn deliver the elusive therapeutic target the scientific community has been so desperately searching for. Show more

Keywords: Alzheimer’s disease, antimicrobial peptides, infectious diseases, neurodegeneration, self-assembly

DOI: 10.3233/JAD-190765

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2019

Authors: Francis, Nikita | Robison, Lisa S. | Popescu, Dominique L. | Michaelos, Michalis | Hatfield, Joshua | Xu, Feng | Zhu, Xiaoyue | Davis, Judianne | Anderson, Maria E. | Anderson, Brenda J. | Van Nostrand, William E. | Robinson, John K.

Article Type: Research Article

Abstract: Exercise has been shown to be protective against the risk of dementias, including Alzheimer’s disease (AD). Intervention studies have demonstrated its ability to mitigate cognitive and behavioral impairments and reduce disease in both humans and animals. However, information is lacking in regard to the volume and intensity, as well as timing of exercise onset with respect to disease stage, which produces optimal benefits. Here, utilizing the Tg2576 mouse, a model of AD-like parenchymal amyloid pathology and cognitive impairment, we sought to understand the effects of different lengths of daily access to a running wheel on advanced stage disease. This study …is the first to determine the benefits of long-term exercise (4 months of voluntary running) and different periods of daily access to a running wheel (0 h, 1 h, 3 h, and 12 h running wheel access) beginning in 14-month-old Tg2576 mice, an age with significant amyloid pathology. We found that exercising Tg2576 animals showed lower levels of some aspects of AD pathology and reduced behavioral dysfunction compared to sedentary Tg2576 animals. High intensity exercise, rather than high volume exercise, was generally most beneficial in reducing amyloid pathology. Our results suggest that engaging in vigorous exercise programs, even after living a sedentary life, may lead to a measurable reduction in AD pathology and preservation of some cognitive abilities. Show more

Keywords: Amyloid, behavior, dementia, exercise, transgenic

DOI: 10.3233/JAD-190810

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2019

Authors: Feng, Maoxiao | Cui, Donghai | Li, Yi | Shi, Jian | Xiang, Lan | Bian, Hong | Ma, Zhiyong | Xia, Wen | Wei, Guangwei

Article Type: Research Article

Abstract: The cell surface level of apolipoprotein E receptor 2 (ApoER2) increases by cyclic transport of ApoER2 and then activates Reelin signaling pathway to exert neuroprotective function in AD. ApoER2 ligand Apolipoprotein E4 (ApoE4) inhibits the recycling of ApoER2 to the cell surface rendering neurons unresponsive to Reelin. Carnosic acid (CA) is proven to possess neuroprotective and neurotrophic functions in Alzheimer’s disease (AD) mouse model. However, there are no reports about how ApoE4 impairs the recycling of ApoER2 and if CA can affect the cyclic transport of ApoER2. In this study, we demonstrated that ApoE4 attenuates the binding of sorting nexin …17 (SNX17) to ApoER2 and inhibits the recycling of ApoER2, resulting in decreased cell surface level of ApoER2. Further, we found that CA enhances the binding of SNX17 to ApoER2, counteracts the negative effects of ApoE4 on the cell surface level of ApoER2 to reverse the ApoE4-induced reduction in Reelin signaling activation by increasing the phosphorylation of the N-methyl-D-aspartate receptor (NMDAR) and cAMP-response element-binding protein (CREB) and the expression of Gria2. Thus, CA promotes neurite growth inhibited by ApoE4. Our work suggests that CA may be a potential approach to attenuate the risk of ApoE4-associated AD. Show more

Keywords: Apolipoprotein E receptor 2, Apolipoprotein E4, carnosic acid, Reelin signaling pathway, sorting nexin 17

DOI: 10.3233/JAD-190914

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Yin, Ping | Wang, Shuang | Wei, Yafen | Wang, Xu | Zhang, Jingdian | Yin, Xiang | Feng, Jiachun | Zhu, Mingqin

Article Type: Research Article

Abstract: Inflammation resolution is regulated by specialized pro-resolving lipid mediators (SPMs) and the levels of SPMs are found decreased in Alzheimer’s disease (AD) brain. We have previously found that one of the SPMs, Maresin1 (MaR1), improved neuronal survival and increase microglial phagocytosis of amyloid-β 1-42 (Aβ42 ); however, the mechanisms underlying the protective mechanism remain further investigation. We aim to investigate the effects of MaR1 on microglial chemotaxis and activation in this study. Both indirect and direct primary neuron and microglia co-culture system was used in this study. Our results showed MaR1 downregulated the increased microglial chemotaxis induced by Aβ42 . …The microglial inactivation marker CD200R was downregulated by Aβ42 and upregulated by MaR1. Pro-inflammatory cytokines secretion such as tumor necrosis factor (TNF)-α were increased by Aβ42 and these changes were revised by MaR1 treatment. In addition, the levels of chemokine monocyte chemoattractant protein (MCP)-1 were increased while the levels of anti-inflammatory factor IL-10 secretion were decreased by Aβ42 , and these changes were abolished by MaR1 treatment. Moreover, by proteomics analysis, we identified cell signaling pathways affected by MaR1 were not only limited to inflammation-related pathways such as P38, but also in pathways involved in cell survival, autophagy, axon formation, and apoptosis, including PI3K/AKT, mTOR, ERK, caspase3, Cdc42, and p75NTR. In conclusion, MaR1 promoted inflammation resolution by inhibiting chemotaxis and regulating activation of microglia. MaR1 played a neuroprotective role by affecting cell signaling pathways involving inflammation, cell survival, autophagy, axon formation, and apoptosis inhibition. Show more

Keywords: Alzheimer’s disease, chemotaxis, Maresin1, microglia, proteomics, resolution of inflammation

DOI: 10.3233/JAD-190682

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Robinson, Andrew C. | Chew-Graham, Stephen | Davidson, Yvonne S. | Horan, Michael A. | Roncaroli, Federico | Minshull, James | du Plessis, Daniel | Pal, Piyali | Payton, Antony | Pendleton, Neil | Mann, David M.A.

Article Type: Research Article

Abstract: In the present study, we have characterized and compared individuals whose brains were donated as part of The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age (UoM) with those donated through the Manchester arm of the UK Brains for Dementia Research (BDR) program. The aim of this study was to investigate how differences in study recruitment may affect final pathological composition of cohort studies. The UoM cohort was established as a longitudinal study of aging and cognition whereas the BDR program was established, prima facie , to collect brains from both demented and non-demented individuals for …the purpose of building a tissue research resource. Consequently, the differences in recruitment patterns generated differences in demographic, clinical, and neuropathological characteristics. There was a higher proportion of recruits with dementia [mostly Alzheimer’s disease (AD)] within the BDR cohort than in the UoM cohort. In pathological terms, the BDR cohort was more ‘polarized’, being more composed of demented cases with high Braak pathology scores and non-demented cases with low Braak scores, and fewer non-AD pathology cases, than the UoM cohort. In both cohorts, cerebral amyloid angiopathy tended to be greater in demented than non-demented individuals. Such observations partly reflect the recruitment of demented and non-demented individuals into the BDR cohort, and also that insufficient study time may have elapsed for disease onset and development in non-demented individuals to take place. Conversely, in the UoM cohort, where there had been nearly 30 years of study time, a broader spread of AD-type pathological changes had ‘naturally’ evolved in the brains of both demented and non-demented participants. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, cohort studies, dementia, longitudinal studies, neuropathology

DOI: 10.3233/JAD-190580

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: Reas, Emilie T. | Hagler Jr. , Donald J. | Kuperman, Joshua M. | Wierenga, Christina E. | Galasko, Douglas | White, Nathan S. | Dale, Anders M. | Banks, Sarah J. | McEvoy, Linda K. | Brewer, James B.

Article Type: Research Article

Abstract: Background: Although amyloid-β (Aβ) and microstructural brain changes are both effective biomarkers of Alzheimer’s disease, their independent or synergistic effects on cognitive decline are unclear. Objective: To examine associations of Aβ and brain microstructure with cognitive decline in amnestic mild cognitive impairment and dementia. Methods: Restriction spectrum imaging, cerebrospinal fluid Aβ, and longitudinal cognitive data were collected on 23 healthy controls and 13 individuals with mild cognitive impairment or mild to moderate Alzheimer’s disease. Neurite density (ND) and isotropic free water diffusion (IF) were computed in fiber tracts and cortical regions of interest. We examined associations …of Aβ with regional and whole-brain microstructure, and assessed whether microstructure mediates effects of Aβ on cognitive decline. Results: Lower ND in limbic and association fibers and higher medial temporal lobe IF predicted baseline impairment and longitudinal decline across multiple cognitive domains. ND and IF predicted cognitive outcomes after adjustment for Aβ or whole-brain microstructure. Correlations between microstructure and cognition were present for both amyloid-positive and amyloid-negative individuals. Aβ correlated with whole-brain, rather than regional, ND and IF. Conclusion: Aβ correlates with widespread microstructural brain changes, whereas regional microstructure correlates with cognitive decline. Microstructural abnormalities predict cognitive decline regardless of amyloid, and may inform about neural injury leading to cognitive decline beyond that attributable to amyloid. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, cognitive decline, dementia, diffusion imaging, magnetic resonance imaging, memory, mild cognitive impairment

DOI: 10.3233/JAD-190871

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Chen, Haoyu | Liang, Lu | Xu, Hua | Xu, Jia | Yao, Leyi | Li, Yanling | Tan, Yufan | Li, Xiaofen | Huang, Qingtian | Yang, Zhenjun | Wu, Jiawen | Chen, Jinghong | Huang, Hongbiao | Wang, Xuejun | Zhang, Chang-E. | Liu, Jinbao

Article Type: Research Article

Abstract: Hyperbilirubinemia may increase the risk of Alzheimer’s disease (AD) but its mechanistic role in AD pathogenesis remains obscure. Here, we used animal models to investigate the short- and long-term effects of neonatal systemic exposure to bilirubin on brain histology and function as well as the acute effect of lateral ventricle injection of bilirubin in adult rats. We found that three days exposure to bilirubin in newborn rats could induce AD-like pathological changes in late life, including tau protein hyperphosphorylation at multiple sites, increased Aβ production in brain tissues, and spatial learning and memory injury. Bilirubin activated the activities of several …protein kinases (GSK-3β, CDK5, and JNK), which were positively correlated with hyperphosphorylated tau; simultaneously increased the expression of AβPP γ -secretase PS2 and decreased the expression of α -secretase ADAM17, which were positively correlated with Aβ production. The above results were well replicated in primary hippocampal cell cultures. These data demonstrate that bilirubin encephalopathy is an AD-like disease, suggesting a potent role of bilirubin in AD. Show more

Keywords: AβPP, α-secretase, Alzheimer’s disease, amyloid-β, bilirubin, γ-secretase, protein kinase, spatial learning and memory injury, tau hyperphosphorylation, tau protein

DOI: 10.3233/JAD-190945

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2019

Authors: Agca, Cansu | Klakotskaia, Diana | Stopa, Edward G. | Schachtman, Todd R. | Agca, Yuksel

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is one of the most devastating and costly diseases, and prevalence of AD increases with age. Furthermore, females are twice as likely to suffer from AD compared to males. The cessation of reproductive steroid hormone production during menopause is hypothesized to cause this difference. Two rodent AD models, APP21 and APP+PS1, and wild type (WT) rats underwent an ovariectomy or sham surgery. Changes in learning and memory, brain histology, amyloid-β (Aβ) deposition, levels of mRNAs involved in Aβ production and clearance, and synaptic and cognitive function were determined. Barnes maze results showed that regardless of ovariectomy status, …APP+PS1 rats learned slower and had poor memory retention. Ovariectomy caused learning impairment only in the APP21 rats. High levels of Aβ42 and very low levels of Aβ40 were observed in the brain cortices of APP+PS1 rats indicating limited endogenous PS1. The APP+PS1 rats had 43-fold greater formic acid soluble Aβ42 than Aβ40 at 17 months. Furthermore, levels of formic acid soluble Aβ42 increased 57-fold in ovariectomized APP+PS1 rats between 12 and 17 months of age. The mRNA encoding Grin1 significantly decreased due to ovariectomy whereas levels of Bace1, Chat, and Prkcb all decreased with age. The expression levels of mRNAs involved in Aβ degradation and AβPP cleavage (Neprilysin, Ide, Adam9, and Psenen) were found to be highly correlated with each other as well as hippocampal Aβ deposition. Taken together, these results indicate that both ovariectomy and genotype influence AD markers in a complex manner. Show more

Keywords: Alzheimer’s disease, amyloid-β , estrogen, gene expression, ovarian hormones, ovariectomy, progesterone, rat, transgenic

DOI: 10.3233/JAD-190935

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Bastrup, Joakim | Kastaniegaard, Kenneth | Asuni, Ayodeji A. | Volbracht, Christiane | Stensballe, Allan

Article Type: Research Article

Abstract: Amyloid plaques are one of the hallmarks of Alzheimer’s disease (AD). The main constituent of amyloid plaques is amyloid-β peptides, but a complex interplay of other infiltrating proteins also co-localizes. We hypothesized that proteomic analysis could reveal differences between amyloid plaques and adjacent control tissue in the transgenic mouse model of AD (APPPS1-21) and in similar regions from non-transgenic littermates. Our microproteomic strategy included isolation of regions of interest by laser capture microdissection and analysis by liquid chromatography mass spectrometry-based label-free relative quantification. We consistently identified 183, 224, and 307 proteins from amyloid plaques, adjacent control and non-tg samples, respectively. …Pathway analysis revealed 27 proteins that were significantly regulated when comparing amyloid plaques and corresponding adjacent control regions. We further elucidated that co-localized proteins were subjected to post-translational modifications and are the first to report 193 and 117 unique modifications associated to amyloid plaques and adjacent control extracts, respectively. The three most common modifications detected in proteins from the amyloid plaques were oxidation, deamidation, and pyroglutamylation. Together, our data provide novel information about the biological processes occurring within and around amyloid plaques in the APPPS1-21 mouse model of AD. Show more

Keywords: Alzheimer’s disease, amyloid plaque, mass spectrometry, microdissection, pyroglutamate

DOI: 10.3233/JAD-190652

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2019