Journal of Alzheimer's Disease - Volume 87, issue 2

Authors: Liu, Xiang | Yan, Jie | Liu, Fangbo | Zhou, Peipei | Lv, Xinyue | Cheng, Nengneng | Liu, Li

Article Type: Research Article

Abstract: Background: RE1-silencing transcription factor (REST) is known to silence target genes involved in synaptic plasticity and neuronal differentiation. Although previous studies implicate REST in neurodegenerative diseases, its function in the progression of Alzheimer’s disease (AD) is uncertain. Objective: The aim of the present work was to explore the mechanisms of AD and determine whether and how REST was involved in the pathogenesis of AD. Methods: We investigated the differentially expressed genes and key transcription factors in AD using bioinformatics analysis. In addition, we assessed the expression of REST under the influence of AD-related factors. Mice overexpressing …REST were generated and analyzed by proteomics analysis. We used transmission electron microscopy, Golgi-cox staining, immunohistochemistry, and western blotting to examine the impact of REST on neurons. Results: The results of bioinformatics analysis revealed REST as a hub transcriptional regulator in AD. We demonstrate that the mRNA expression of REST was significantly upregulated compared with that in the control groups, not only in AD patients but also in APP/PS1 transgenic mice, lipopolysaccharide-induced neuroinflammatory mice, and oxidative and glutamate stressed neurons. Using proteomics analysis, we showed that the upregulation of REST increased the expression of genes involved in apoptotic and mitochondrial pathways. Long-term overexpression of REST significantly reduced the number of dendritic spines and increased the mitochondrial defect and apoptosis. Reduction of the cofilin phosphorylation may be one of its mechanisms, and cofilin activity could be affected through the P38 MAPK/CREB signaling pathway. Conclusion: These results demonstrated the possible mechanism underlying AD and indicated REST as a potential therapeutic target for AD. Show more

Keywords: Alzheimer’s disease, apoptosis, cofilin, dendritic spine, mitochondrial defect, REST

DOI: 10.3233/JAD-210285

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 873-886, 2022

Authors: Girtler, Nicola | Chincarini, Andrea | Brugnolo, Andrea | Doglione, Elisa | Orso, Beatrice | Morbelli, Silvia | Massa, Federico | Peira, Enrico | Biassoni, Erica | Donniaquio, Andrea | Grisanti, Stefano | Pardini, Matteo | Arnaldi, Dario | Nobili, Flavio

Article Type: Research Article

Abstract: Background: Neuropsychological assessment is still the basis for the first evaluation of patients with cognitive complaints. The Free and Cued Selective Reminding Test (FCSRT) generates several indices that could have different accuracy in the differential diagnosis between Alzheimer’s disease (AD) and other disorders. Objective: In a consecutive series of naturalistic patients, the accuracy of the FCSRT indices in differentiating patients with either mild cognitive impairment (MCI) due to AD or AD dementia from other competing conditions was evaluated. Methods: We evaluated the accuracy of the seven FCSRT indices in differentiating patients with AD from other competing …conditions in 434 consecutive outpatients, either at the MCI or at the early dementia stage. We analyzed these data through the receiver operating characteristics curve, and we then generated the odds-ratio map of the two indices with the best discriminative value between pairs of disorders. Results: The immediate and the delayed free total recall, the immediate total recall, and the index of sensitivity of cueing were the most useful indices and allowed to distinguish AD from dementia with Lewy bodies and psychiatric conditions with very high accuracy. Accuracy was instead moderate in distinguishing AD from behavioral variant frontotemporal dementia, vascular cognitive impairment, and other conditions. Conclusion: By using odd-ratio maps and comparison-customized cut-off scores, we confirmed that the FCSRT represents a useful tool to characterize the memory performance of patients with MCI and thus to assist the clinician in the diagnosis process, though with different accuracy values depending on the clinical hypothesis. Show more

Keywords: Alzheimer’s disease, dementia, Free and Cued Selective Reminding Test, memory, mild cognitive impairment

DOI: 10.3233/JAD-215043

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 887-899, 2022

Authors: Gherardelli, Camila | Cisternas, Pedro | Vera-Salazar, Roberto F. | Mendez-Orellana, Carolina | Inestrosa, Nibaldo C.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by a high etiological and clinical heterogeneity, which has obscured the diagnostic and treatment efficacy, as well as limited the development of potential drugs. Sex differences are among the risk factors that contribute to the variability of disease manifestation. Unlike men, women are at greater risk of developing AD and suffer from higher cognitive deterioration, together with important changes in pathological features. Alterations in glucose metabolism are emerging as a key player in the pathogenesis of AD, which appear even decades before the presence of clinical symptoms. Objective: We aimed to study …whether AD-related sex differences influence glucose metabolism. Methods: We used male and female APPswe/PS1dE9 (APP/PS1) transgenic mice of different ages to examine glucose metabolism effects on AD development. Results: Our analysis suggests an age-dependent decline of metabolic responses, cognitive functions, and brain energy homeostasis, together with an increase of Aβ levels in both males and females APP/PS1 mice. The administration of Andrographolide (Andro), an anti-inflammatory and anti-diabetic compound, was able to restore several metabolic disturbances, including the glycolytic and the pentose phosphate pathway fluxes, ATP levels, AMPKα activity, and Glut3 expression in 8-month-old mice, independent of the sex, while rescuing these abnormalities only in older females. Similarly, Andro also prevented Aβ accumulation and cognitive decline in all but old males. Conclusion: Our study provides insight into the heterogeneity of the disease and supports the use of Andro as a potential drug to promote personalized medicine in AD. Show more

Keywords: Alzheimer’s disease, andrographolide, glucose metabolism, neuroprotection, sex differences

DOI: 10.3233/JAD-215273

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 901-917, 2022

Authors: Cheval, Boris | Maltagliati, Silvio | Sieber, Stefan | Cullati, Stéphane | Zou, Liye | Ihle, Andreas | Kramer, Arthur F. | Yu, Qian | Sander, David | Boisgontier, Matthieu P.

Article Type: Research Article

Abstract: Background: Physical activity has been associated with better cognitive function and better sleep quality. Yet, whether the beneficial effect of physical activity on cognitive function can be explained by an indirect pathway involving better sleep quality is unclear. Objective: To investigate whether sleep quality mediates the association between physical activity and cognitive function in adults 50 years of age or older. Methods: 86,541 community-dwelling European adults were included in the study. Physical activity and sleep quality were self-reported. Indicators of cognitive function (immediate recall, delayed recall, verbal fluency) were assessed using objective tests. All measures were …collected six times between 2004 and 2017. The mediation was tested using multilevel mediation analyses. Results: Results showed that self-reported physical activity was associated with better self-reported sleep quality, which was associated with better performance in all three indicators of cognitive function, demonstrating an indirect effect of physical activity on cognitive function through sleep quality. The mediating effect of sleep quality accounted for 0.41%, 1.46%, and 8.88% of the total association of physical activity with verbal fluency, immediate recall, and delayed recall, respectively. Conclusion: These findings suggest that self-reported sleep quality partly mediates the association between self-reported physical activity and cognitive function. These results need to be confirmed by device-based data of physical activity and sleep quality. Show more

Keywords: Aging, cognition, longitudinal studies, mediation analysis, physical activity, sleep

DOI: 10.3233/JAD-215484

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 919-931, 2022

Authors: Basta, Maria | Vgontzas, Alexandros N. | Fernandez-Mendoza, Julio | Antypa, Despina | Li, Yun | Zaganas, Ioannis | Panagiotakis, Symeon | Karagkouni, Efthalia | Simos, Panagiotis

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is frequent in elderly and a risk factor for dementia. Both insomnia and increased cortisol levels are risk factors for MCI. Objective: We examined cross-sectionally whether increased cortisol levels are associated with short sleep duration (SSD) and/or the insomnia short sleep duration (ISS) phenotype, in elderly with MCI. Methods: One hundred twenty-four participants with MCI and 84 cognitively non-impaired controls (CNI)≥60 years underwent medical history, physical examination, neuropsychiatric evaluation, neuropsychological testing, 3-day actigraphy, assessment of subjective insomnia symptoms, and a single morning plasma cortisol level. The short sleep phenotypes were defined …by sleep efficiency below the median of the entire sample (i.e.,≤81%) with at least one insomnia symptom (ISS) or without (SSD). ANOVA models were used to compare the various sleep phenotypes to those who did not present either short sleep or insomnia symptoms [non-insomnia (NI)]. Results: MCI participants had higher cortisol levels compared to the CNI group (p  = 0.009). MCI participants with insomnia (n  = 44) or SSD (n  = 38) had higher cortisol levels compared to the NI group (n  = 42; p  = 0.014 and p  = 0.045, respectively). Furthermore, MCI participants with ISS phenotype but not those with insomnia with normal sleep duration had higher cortisol levels compared to NI (p  = 0.011 and p  = 0.4, respectively). Both linear trend analyses showed that cortisol reached the highest levels in the ISS phenotype. Conclusion: The ISS and SSD phenotypes are associated with increased cortisol levels in elderly with MCI. Improving sleep quality and duration and decreasing cortisol levels may delay further cognitive decline. Show more

Keywords: Cortisol, insomnia, mild cognitive impairment, sleep duration

DOI: 10.3233/JAD-215523

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 933-944, 2022

Authors: Gabel, Matthew | Bollinger, Rebecca M. | Coble, Dean W. | Grill, Joshua D. | Edwards, Dorothy F. | Lingler, Jennifer H. | Chin, Erin | Stark, Susan L.

Article Type: Research Article

Abstract: Background: Retention of study participants is essential to advancing Alzheimer’s disease (AD) research and developing therapeutic interventions. However, recent multi-year AD studies have lost 10% to 54% of participants. Objective: We surveyed a random sample of 443 participants (Clinical Dementia Rating [CDR]≤1) at four Alzheimer Disease Research Centers to elucidate perceived facilitators and barriers to continued participation in longitudinal AD research. Methods: Reasons for participation were characterized with factor analysis. Effects of perceived fulfillment of one’s own goals and complaints on attendance and likelihood of dropout were estimated with logistic regression models. Open-ended responses suggesting study …improvements were analyzed with a Latent Dirichlet Allocation topic model. Results: Factor analyses revealed two categories, personal benefit and altruism, as drivers of continued participation. Participants with cognitive impairment (CDR > 0) emphasized personal benefits more than societal benefits. Participants with higher trust in medical researchers were more likely to emphasize broader social benefits. A minority endorsed any complaints. Higher perceived fulfillment of one’s own goals and fewer complaints were related to higher attendance and lower likelihood of dropout. Facilitators included access to medical center support and/or future treatment, learning about AD and memory concerns, and enjoying time with staff. Participants’ suggestions emphasized more feedback about individual test results and AD research. Conclusion: The results confirmed previously identified facilitators and barriers. Two new areas, improved communication about individual test results and greater feedback about AD research, emerged as the primary factors to improve participation. Show more

Keywords: Alzheimer’s disease, barriers, facilitators, retention

DOI: 10.3233/JAD-215710

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 945-955, 2022