Journal of Alzheimer's Disease - Volume 85, issue 3

Authors: Sun, Hao-Lun | Zhou, Fa-Ying | Chen, Dong-Wan | Tan, Cheng-Rong | Zeng, Gui-Hua | Liu, Yu-Hui | Wang, Jun | Bu, Xian-Le | Wang, Yan-Jiang | Li, Hui-Yun | Jin, Wang-Sheng

Article Type: Research Article

Abstract: Background: Recent studies have shown that monocytes can phagocytize the tau protein, which may ameliorate tau-type pathology in Alzheimer’s disease (AD). However, there are few clinical studies on the relationship between monocytes and tau-type pathology in AD patients. Objective: We aimed to explore changes in peripheral monocytes and their association with tau protein in AD patients. Methods: A total of 127 clinically diagnosed AD patients and 100 age- and sex-matched cognitively normal controls were recruited for analysis of the correlation of plasma tau levels with the blood monocyte count. Cerebrospinal fluid (CSF) samples from 46 AD …patients and 88 controls were further collected to analyze the correlation of CSF tau and amyloid-β (Aβ) levels with the blood monocyte count. 105 clinically diagnosed mild cognitive impairment (MCI) patients and 149 age- and sex-matched cognitively normal controls were recruited from another cohort for verification. Results: Compared to normal controls, AD patients showed a significant reduction in the blood monocyte count. In addition, the monocyte count of AD patients was negatively correlated with CSF t-tau and p-tau levels but not with plasma tau levels. In normal people, monocyte count lack correlation with tau levels both in plasma and CSF. Monocyte count were not correlated with CSF Aβ levels in either group but were negatively correlated with CSF tau/Aβ42 levels in the AD group. We had further verified the correlations of monocyte count with CSF tau levels in another cohort. Conclusion: This study suggests that monocytes may play an important role in the clearance of tau protein in the brain. Show more

Keywords: Alzheimer’s disease, monocytes, pathogenesis, tau

DOI: 10.3233/JAD-210692

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1321-1328, 2022

Authors: Chen, Jiu | Chen, Rong | Xue, Chen | Qi, Wenzhang | Hu, Guanjie | Xu, Wenwen | Chen, Shanshan | Rao, Jiang | Zhang, Fuquan | Zhang, Xiangrong

Article Type: Research Article

Abstract: Background: Altered hippocampal subregions (HIPsub) and their network connectivity relate to episodic memory decline in amnestic mild cognitive impairment (aMCI), which is significantly limited by over-dependence on correlational associations. Objective: To identify whether restoration of HIPsub and its network connectivity using repetitive transcranial magnetic stimulation (rTMS) is causally linked to amelioration of episodic memory in aMCI. Methods: In the first cohort, analysis of HIPsub grey matter (GM) and its functional connectivity was performed to identify an episodic memory-related circuit in aMCI by using a pattern classification approach. In the second cohort, this circuit was experimentally modulated …with rTMS. Structural equation modeling was employed to investigate rTMS regulatory mechanism in amelioration of episodic memory. Results: First, in the first cohort, this study identified HIPsub circuit pathology of episodic memory decline in aMCI patients. Second, in the second cohort, restoration of HIPc GM and its connectivity with left middle temporal gyrus (MTG.L) are causally associated with amelioration of episodic memory in aMCI after 4 weeks of rTMS. Especially important, the effects of HIPc GM changes on the improvement of episodic memory were significantly mediated by HIPc connectivity with MTG.L changes in aMCI. Conclusion: This study provides novel experimental evidence about a biological substrate for the treatment of the disabling episodic memory in aMCI patients. Correction of breakdown in HIPc structure and its connectivity with MTG can causally ameliorate episodic memory in aMCI. Show more

Keywords: Amnestic mild cognitive impairment, episodic memory, functional connectivity, grey matter, hippocampalsubregion, pattern classification, repetitive transcranial magnetic stimulation

DOI: 10.3233/JAD-210661

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1329-1342, 2022

Authors: Tropea, Maria Rosaria | Sanfilippo, Giulia | Giannino, Federico | Davì, Valentina | Gulisano, Walter | Puzzo, Daniela

Article Type: Research Article

Abstract: Background: Object recognition task (ORT) is a widely used behavioral paradigm to assess memory in rodent models, due to its easy technical execution, the lack of aversive stressful stimuli, and the possibility to repeat the test on the same animals. However, mouse exploration might be strongly influenced by a variety of variables. Objective: To study whether innate preferences influenced exploration in male and female wild type mice and the Alzheimer’s disease (AD) model 3xTg. Methods: We first evaluated how object characteristics (material, size, and shape) influence exploration levels, latency, and exploration modality. Based …on these findings, we evaluated whether these innate preferences biased the results of ORT performed in wild type mice and AD models. Results: Assessment of Exploration levels, i.e., the time spent in exploring a certain object in respect to the total exploration time, revealed an innate preference for objects made in shiny materials, such as metal and glass. A preference for bigger objects characterized by higher affordance was also evident, especially in male mice. When performing ORT, exploration was highly influenced by these innate preferences. Indeed, both wild type and AD mice spent more time in exploring the metal object, regardless of its novelty. Furthermore, the use of objects with higher affordance such as the cube was a confounding factor leading to “false” results that distorted ORT interpretation. Conclusion: When designing exploration-based behavioral experiments aimed at assessing memory in healthy and AD mice, object characteristics should be carefully evaluated to improve scientific outcomes and minimize possible biases. Show more

Keywords: Alzheimer’s mice, exploration, object preference, object recognition task

DOI: 10.3233/JAD-215209

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1343-1356, 2022

Authors: Kwak, Seyul | Oh, Dae Jong | Jeon, Yeong-Ju | Oh, Da Young | Park, Su Mi | Kim, Hairin | Lee, Jun-Young

Article Type: Research Article

Abstract: Background: In assessing the levels of clinical impairment in dementia, a summary index of neuropsychological batteries has been widely used in describing the overall functional status. Objective: It remains unexamined how complex patterns of the test performances can be utilized to have specific predictive meaning when the machine learning approach is applied. Methods: In this study, the neuropsychological battery (CERAD-K) and assessment of functioning level (Clinical Dementia Rating scale and Instrumental Activities of Daily Living) were administered to 2,642 older adults with no impairment (n  = 285), mild cognitive impairment (n  = 1,057), and Alzheimer’s …disease (n  = 1,300). Predictive accuracy on functional impairment level with the linear models of the single total score or multiple subtest scores (Model 1, 2) and support vector regression with low or high complexity (Model 3, 4) were compared across different sample sizes. Results: The linear models (Model 1, 2) showed superior performance with relatively smaller sample size, while nonlinear models with low and high complexity (Model 3, 4) showed an improved accuracy with a larger dataset. Unlike linear models, the nonlinear models showed a gradual increase in the predictive accuracy with a larger sample size (n  > 500), especially when the model training is allowed to exploit complex patterns of the dataset. Conclusion: Our finding suggests that nonlinear models can predict levels of functional impairment with a sufficient dataset. The summary index of the neuropsychological battery can be augmented for specific purposes, especially in estimating the functional status of dementia. Show more

Keywords: Dementia, functional status, machine learning, neuropsychological tests

DOI: 10.3233/JAD-215244

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1357-1372, 2022

Authors: Yuen, Sze Chung | Lee, Simon Ming-Yuen | Leung, Siu-wai

Article Type: Research Article

Abstract: Background: Neuronal cell cycle re-entry (CCR) is a mechanism, along with amyloid-β (Aβ) oligomers and hyperphosphorylated tau proteins, contributing to toxicity in Alzheimer’s disease (AD). Objective: This study aimed to examine the putative factors in CCR based on evidence corroboration by combining meta-analysis and co-expression analysis of omic data. Methods: The differentially expressed genes (DEGs) and CCR-related modules were obtained through the differential analysis and co-expression of transcriptomic data, respectively. Differentially expressed microRNAs (DEmiRNAs) were extracted from the differential miRNA expression studies. The dysregulations of DEGs and DEmiRNAs as binary outcomes were independently …analyzed by meta-analysis based on a random-effects model. The CCR-related modules were mapped to human protein-protein interaction databases to construct a network. The importance score of each node within the network was determined by the PageRank algorithm, and nodes that fit the pre-defined criteria were treated as putative CCR-related factors. Results: The meta-analysis identified 18,261 DEGs and 36 DEmiRNAs, including genes in the ubiquitination proteasome system, mitochondrial homeostasis, and CCR, and miRNAs associated with AD pathologies. The co-expression analysis identified 156 CCR-related modules to construct a protein-protein interaction network. Five genes, UBC , ESR1 , EGFR , CUL3 , and KRAS , were selected as putative CCR-related factors. Their functions suggested that the combined effects of cellular dyshomeostasis and receptors mediating Aβ toxicity from impaired ubiquitination proteasome system are involved in CCR. Conclusion: This study identified five genes as putative factors and revealed the significance of cellular dyshomeostasis in the CCR of AD. Show more

Keywords: Alzheimer’s disease, cell cycle re-entry, co-expression analysis, meta-analysis, pagerank algorithm

DOI: 10.3233/JAD-215349

Citation: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1373-1398, 2022