Journal of Alzheimer's Disease - Volume 92, issue 4

Authors: Zawar, Ifrah | Mattos, Meghan K. | Manning, Carol | Patrie, James | Quigg, Mark

Article Type: Research Article

Abstract: Background: The effect of nighttime behaviors on cognition has not been studied independently from other neuropsychiatric symptoms. Objective: We evaluate the following hypotheses that sleep disturbances bring increased risk of earlier cognitive impairment, and more importantly that the effect of sleep disturbances is independent from other neuropsychiatric symptoms that may herald dementia. Methods: We used the National Alzheimer’s Coordinating Center database to evaluate the relationship between Neuropsychiatric Inventory Questionnaire (NPI-Q) determined nighttime behaviors which served as surrogate for sleep disturbances and cognitive impairment. Montreal Cognitive Assessment scores defined two groups: conversion from 1) normal to mild …cognitive impairment (MCI) and 2) MCI to dementia. The effect of nighttime behaviors at initial visit and covariates of age, sex, education, race, and other neuropsychiatric symptoms (NPI-Q), on conversion risk were analyzed using Cox regression. Results: Nighttime behaviors predicted earlier conversion time from normal cognition to MCI (hazard ratio (HR): 1.09; 95% CI: [1.00, 1.48], p  = 0.048) but were not associated with MCI to dementia conversion (HR: 1.01; [0.92, 1.10], p  = 0.856). In both groups, older age, female sex, lower education, and neuropsychiatric burden increased conversion risk. Conclusion: Our findings suggest that sleep disturbances predict earlier cognitive decline independently from other neuropsychiatric symptoms that may herald dementia. Show more

Keywords: Dementia, mild cognitive impairment, neuropsychiatric symptoms, nighttime behaviors, sleep disturbances

DOI: 10.3233/JAD-221244

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1427-1438, 2023

Authors: Piao, Sirong | Chen, Keliang | Wang, Na | Bao, Yifang | Liu, Xueling | Hu, Bin | Lu, Yucheng | Yang, Liqin | Geng, Daoying | Li, Yuxin

Article Type: Research Article

Abstract: Background: Structural-functional connectivity (SC– FC) coupling is related to various cognitive functions and more sensitive for the detection of subtle brain alterations. Objective: To investigate whether decoupling of SC-FC was detected in mild cognitive impairment (MCI) patients on a modular level, the interaction effect of aging and disease, and its relationship with network efficiency. Methods: 73 patients with MCI and 65 healthy controls were enrolled who underwent diffusion tensor imaging and resting-state functional MRI to generate structural and functional networks. Five modules were defined based on automated anatomical labeling 90 atlas, including default mode network (DMN), …frontoparietal attention network (FPN), sensorimotor network (SMN), subcortical network (SCN), and visual network (VIS). Intra-module and inter-module SC-FC coupling were compared between two groups. The interaction effect of aging and group on modular SC-FC coupling was further analyzed by two-way ANCOVA. The correlation between the coupling and network efficiency was finally calculated. Results: In MCI patients, aberrant intra-module coupling was noted in SMN, and altered inter-module coupling was found in the other four modules. Intra-module coupling exhibited significant age-by-group effects in DMN and SMN, and inter-module coupling showed significant age-by-group effects in DMN and FPN. In MCI patients, both positive or negative correlations between coupling and network efficiency were found in DMN, FPN, SCN, and VIS. Conclusion: SC-FC coupling could reflect the association of SC and FC, especially in modular levels. In MCI, SC-FC coupling could be affected by the interaction effect of aging and disease, which may shed light on advancing the pathophysiological mechanisms of MCI. Show more

Keywords: Connectome, functional connectivity, mild cognitive impairment, structural connectivity, structural-functional coupling

DOI: 10.3233/JAD-220837

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1439-1450, 2023

Authors: Man, Shulei | Chen, Boran | Zhang, Yifan | Xu, Hanyue | Liu, Yu | Gao, Yuzhu | Chen, Yi | Chen, Qing | Zhang, Ming

Article Type: Research Article

Abstract: Background: The relationship between cataracts and Alzheimer’s disease (AD) has been reported in recent observational studies. However, it is still unclear whether a causal effect of cataracts on AD or reverse causation exists. Objective: To explore the association between cataracts and AD genetically, we performed a bidirectional two-sample Mendelian randomization study. Methods: We obtained genetic instrumental variables related to cataracts and AD from recently published genome-wide association studies (GWASs). SNP-outcome associations for AD were obtained from a GWAS with 111,326 cases and 677,663 controls. SNP-outcome associations for cataracts were drawn from two sources: a GWAS with …67,844 cases and 517,399 controls and the FinnGen consortium (42,843 cases and 262,698 controls). Inverse variance weighted (IVW) was used as the primary method for Mendelian randomization (MR) analyses. Results: No genetic evidence suggested that cataracts were associated with the risk of AD (IVW odds ratio =1.04, 95% confidence interval: 0.98-1.10, p=0.199). In contrast, an effect of genetically determined AD on a decreased risk of cataract was observed with suggestive evidence (IVW odds ratio =0.96, 95% confidence interval: 0.93-0.99, p=0.004). However, this result might be distorted by survival bias. Conclusion: Genetically determined cataracts were not related to AD, as demonstrated by our study. In contrast, there was suggestive evidence that AD might prevent cataract development, but there might be potential survival bias. To define the exact association between the two diseases, more prospective research and studies on the pathogenesis are needed. Show more

Keywords: Alzheimer’s disease, cataract, causal effect, Mendelian randomization analysis

DOI: 10.3233/JAD-221137

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1451-1458, 2023

Authors: Li, Ran | Song, Beibei | Xu, Lu | Zheng, Jiali | Pan, Wenhao | Cai, Fang | Wang, Juelu | Wu, Yili | Song, Weihong

Article Type: Research Article

Abstract: Background: Trisomy 21, an extra copy of human chromosome 21 (HSA21), causes most Down’s syndrome (DS) cases. Individuals with DS inevitably develop Alzheimer’s disease (AD) neuropathological phenotypes after middle age including amyloid plaques and tau neurofibrillary tangles. Ubiquitin Specific Peptidase 25 (USP25), encoding by USP25 gene located on HSA21, is a deubiquitinating enzyme, which plays an important role in both DS and AD pathogenesis. However, the regulation of USP25 remains unclear. Objective: We aimed to determine the regulation of USP25 by specificity protein 1 (SP1) in neuronal cells and its potential role in amyloidogenesis. Methods: The …transcription start site and promoter activity was identified by SMART-RACE and Dual-luciferase assay. Functional SP1-responsive elements were examined by EMSA. USP25 expression was examined by RT-PCR and immunoblotting. Student’s t -test or one-way ANOVA were applied or statistical analysis. Results: The transcription start site of human USP25 gene was identified. Three functional SP1 responsive elements in human USP25 gene were revealed. SP1 promotes USP25 transcription and subsequent USP25 protein expression, while SP1 inhibition significantly reduces USP25 expression in both non-neuronal and neuronal cells. Moreover, SP1 inhibition dramatically reduces amyloidogenesis. Conclusion: We demonstrates that transcription factor SP1 regulates USP25 gene expression, which associates with amyloidogenesis. It suggests that SP1 signaling may play an important role in USP25 regulation and contribute to USP25-mediated DS and AD pathogenesis. Show more

Keywords: Amyloidogenesis, gene regulation, specificity protein 1, Ubiquitin Specific Peptidase 25

DOI: 10.3233/JAD-221184

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1459-1472, 2023

Authors: Ervasti, Kaijus | Kotkas, Toomas | Issakainen, Mervi | Teiska, Minna | Mäki-Petäjä-Leinonen, Anna

Article Type: Research Article

Abstract: Background: Exceptional circumstances such as the COVID-19 pandemic increase the risk for vulnerability among people living with dementia. Objective: This article discusses the well-being and rights of people living with dementia in Finland during the pandemic and analyses the legal framework covering the restrictions of their rights during that period. Methods: The empirical research comprises a survey of persons with dementia (n  = 31) and their family members (n  = 168). The participants completed a total of 13 survey items involving questions about their well-being during the pandemic, restrictions on freedom, access to services, information on pandemic regulations …and guidelines as well as possible problems with authorities. The survey included both multiple choice and open-ended questions. Results: According to people with dementia and their family members, by spring 2021, the pandemic had reduced meaningful activities available to people living with dementia in Finland and decreased the number of meetings between them and other people. Many reported a decline in their physical and/or mental well-being or greater difficulty or delays in accessing social and health services. Over a third of respondents found that the right to meet people was restricted among people with dementia, and almost half of the respondents took the view that their freedom of movement was restricted. There were also major shortcomings in terms of information on restrictions. Conclusion: The results highlight the importance of bearing in mind the negative effects that restrictions on mobility, meeting other people and meaningful activities can have on the well-being of people living with dementia. This should be considered, for example, when reforming legislation. Show more

Keywords: COVID-19, dementia, fundamental rights, law and society, pandemic, sociolegal studies, well-being

DOI: 10.3233/JAD-221096

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1473-1485, 2023

Authors: Bayat, Sayeh | Roe, Catherine M. | Schindler, Suzanne | Murphy, Samantha A. | Doherty, Jason M. | Johnson, Ann M. | Walker, Alexis | Ances, Beau M. | Morris, John C. | Babulal, Ganesh M.

Article Type: Research Article

Abstract: Background: Driving behavior as a digital marker and recent developments in blood-based biomarkers show promise as a widespread solution for the early identification of Alzheimer’s disease (AD). Objective: This study used artificial intelligence methods to evaluate the association between naturalistic driving behavior and blood-based biomarkers of AD. Methods: We employed an artificial neural network (ANN) to examine the relationship between everyday driving behavior and plasma biomarker of AD. The primary outcome was plasma Aβ42 /Aβ40 , where Aβ42 /Aβ40  < 0.1013 was used to define amyloid positivity. Two ANN models were trained and tested for predicting the …outcome. The first model architecture only includes driving variables as input, whereas the second architecture includes the combination of age, APOE ɛ4 status, and driving variables. Results: All 142 participants (mean [SD] age 73.9 [5.2 ] years; 76 [53.5%] men; 80 participants [56.3% ] with amyloid positivity based on plasma Aβ42 /Aβ40 ) were cognitively normal. The six driving features, included in the ANN models, were the number of trips during rush hour, the median and standard deviation of jerk, the number of hard braking incidents and night trips, and the standard deviation of speed. The F1 score of the model with driving variables alone was 0.75 [0.023] for predicting plasma Aβ42 /Aβ40 . Incorporating age and APOE ɛ4 carrier status improved the diagnostic performance of the model to 0.80 [>0.051]. Conclusion: Blood-based AD biomarkers offer a novel opportunity to establish the efficacy of naturalistic driving as an accessible digital marker for AD pathology in driving research. Show more

Keywords: Alzheimer’s disease, amyloid, artificial intelligence, naturalistic, plasma biomarkers

DOI: 10.3233/JAD-221268

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1487-1497, 2023

Authors: Lerner, Alan J.

Article Type: Book Review

Keywords: Aging, dementia, life planning, caregiving

DOI: 10.3233/JAD-230163

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1499-1500, 2023

Authors: Jia, Jianping | Zhang, Yue | Shi, Yuqing | Yin, Xuping | Wang, Shiyuan | Li, Yan | Zhao, Tan | Liu, Wenying | Zhou, Aihong | Jia, Longfei

Article Type: Correction

DOI: 10.3233/JAD-239001

Citation: Journal of Alzheimer's Disease, vol. 92, no. 4, pp. 1501-1502, 2023