Journal of Alzheimer's Disease - Volume 84, issue 4

Authors: Shojaie, Mehdi | Tabarestani, Solale | Cabrerizo, Mercedes | DeKosky, Steven T. | Vaillancourt, David E. | Loewenstein, David | Duara, Ranjan | Adjouadi, Malek

Article Type: Research Article

Abstract: Background: Machine learning is a promising tool for biomarker-based diagnosis of Alzheimer’s disease (AD). Performing multimodal feature selection and studying the interaction between biological and clinical AD can help to improve the performance of the diagnosis models. Objective: This study aims to formulate a feature ranking metric based on the mutual information index to assess the relevance and redundancy of regional biomarkers and improve the AD classification accuracy. Methods: From the Alzheimer’s Disease Neuroimaging Initiative (ADNI), 722 participants with three modalities, including florbetapir-PET, flortaucipir-PET, and MRI, were studied. The multivariate mutual information metric was utilized to …capture the redundancy and complementarity of the predictors and develop a feature ranking approach. This was followed by evaluating the capability of single-modal and multimodal biomarkers in predicting the cognitive stage. Results: Although amyloid-β deposition is an earlier event in the disease trajectory, tau PET with feature selection yielded a higher early-stage classification F1-score (65.4%) compared to amyloid-β PET (63.3%) and MRI (63.2%). The SVC multimodal scenario with feature selection improved the F1-score to 70.0% and 71.8% for the early and late-stage, respectively. When age and risk factors were included, the scores improved by 2 to 4%. The Amyloid-Tau-Neurodegeneration [AT(N)] framework helped to interpret the classification results for different biomarker categories. Conclusion: The results underscore the utility of a novel feature selection approach to reduce the dimensionality of multimodal datasets and enhance model performance. The AT(N) biomarker framework can help to explore the misclassified cases by revealing the relationship between neuropathological biomarkers and cognition. Show more

Keywords: Alzheimer’s disease, amyloid-β , classification, feature selection, information theory, machine-learning, multimodal imaging, tau

DOI: 10.3233/JAD-210064

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1497-1514, 2021

Authors: Brück, Chiara C. | Wolters, Frank J. | Ikram, M. Arfan | de Kok, Inge M.C.M.

Article Type: Research Article

Abstract: Background: The burden of dementia is changing due to population aging and changes in incidence and risk factor profiles. Reliable projections of future disease burden require accurate estimates of disease duration across different stages of dementia severity. Objective: To provide an overview of current evidence on severity stage and disease duration in patients with dementia. Methods: We reviewed the literature on duration of mild cognitive impairment (MCI), dementia, and various dementia severity stages. Data on study setting, country, sample size, severity stages, dementia type, and definition of disease duration was collected. Weighted averages and Q-statistics were …calculated within severity stages and duration definitions. Results: Of 732 screened articles, 15 reported the duration of one or more severity stages and only half of those reported severity stage onset to conversion to the following stage. In those studies, MCI, very mild dementia, and mild dementia stages lasted 3-4 years and moderate and severe dementia stages lasted 1-2 years. Information on the disease duration was reported in 93 (13%) of screened articles and varied from 1 to 17 years. Reporting of dementia severity stage and disease duration in the literature was highly heterogeneous, which was accounted for only in part by dementia type, study setting, or continent of data collection. Conclusion: The duration of dementia disease stages shortens with advancing stage. However, reliable modelling of future dementia burden and informing of intervention strategies will require more consistently reported duration estimates from studies that follow individuals longitudinally throughout their entire disease course. Show more

Keywords: Alzheimer’s disease, dementia, disease duration, review, severity, survival

DOI: 10.3233/JAD-210544

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1515-1522, 2021

Authors: Speh, Andreja | Wang, Rui | Winblad, Bengt | Kramberger, Milica G. | Bäckman, Lars | Qiu, Chengxuan | Laukka, Erika J.

Article Type: Research Article

Abstract: Background: Modifiable vascular risk factors have been associated with late-life cognitive impairment. The Life Simple 7 (LS7) score comprises seven cardiovascular health metrics: smoking, diet, physical activity, body mass index, plasma glucose, total serum cholesterol, and blood pressure. Objective: To investigate the association between individual and composite LS7 metrics and rate of cognitive decline, and potential differences in these associations between young-old and old-old individuals. Methods: This cohort study included 1,950 participants aged≥60 years (M  = 70.7 years) from the Swedish National Study on Aging and Care-Kungsholmen (SNAC-K), who underwent repeated neuropsychological testing (episodic and semantic memory, …verbal fluency, processing speed, global cognition) across 12 years. The LS7 score was assessed at baseline and categorized as poor, intermediate, or optimal. Level and change in cognitive performance as a function of LS7 categories were estimated using linear mixed-effects models. Results: Having an optimal LS7 total score was associated with better performance (expressed in standard deviation units) at baseline for perceptual speed (β= 0.21, 95%CI 0.12–0.29), verbal fluency (β= 0.08, 0.00–0.16), and global cognition (β= 0.06, 0.00–0.12) compared to the poor group. Age-stratified analyses revealed associations for cognitive level and change only in the young-old (< 78 years) group. For the specific metrics, diverging patterns were observed for young-old and old-old individuals. Conclusion: Meeting the LS7 criteria for ideal cardiovascular health in younger old age is associated with slower rate of cognitive decline. However, the LS7 criteria may have a different meaning for cognitive function in very old adults. Show more

Keywords: Aging, cardiovascular risk factors, cognition, epidemiology

DOI: 10.3233/JAD-210280

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1523-1537, 2021

Authors: Mattos, Meghan K. | Manning, Carol A. | Quigg, Mark | Davis, Eric M. | Barnes, Laura | Sollinger, Ann | Eckstein, Michelle | Ritterband, Lee M.

Article Type: Research Article

Abstract: Background: Approximately 50% of older adults with cognitive impairment suffer from insomnia. When untreated, pre-existing cognitive problems may be exacerbated and potentially contribute to further cognitive decline. One promising approach to maintain cognitive health is to improve sleep quantity and quality. Objective: To determine feasibility, acceptability, and preliminary efficacy of Sleep Health Using the Internet for Older Adult Sufferers of Insomnia and Sleeplessness (SHUTi OASIS), an Internet-delivered cognitive behavioral therapy for insomnia (CBT-I) program in older adults with mild cognitive impairment (MCI). Methods: Older adults with MCI and insomnia were recruited from hospital-based memory and sleep …disorders clinics and enrolled in a single-arm pilot study. Participants completed the six cores of SHUTi OASIS, over nine weeks with two-week baseline and post-assessments using self-reported sleep diaries. Feasibility and acceptability were informed by usage statistics and qualitative interviews; preliminary efficacy was informed by patient-generated sleep data. Results: Twelve participants enrolled and, on average, were 75.8 years of age. Ten participants completed the study and logged in most days. Most participants reported a positive overall experience, and interviews revealed successful and independent program management and completion. There were significant changes on all baseline to post-assessment sleep measures, including clinically meaningful improvements on the Insomnia Severity Index (13.5 to 8.3, p  < 0.01), sleep efficiency, wake after sleep onset, and sleep onset latency (ps < 0.02). There was no statistically significant change in cognitive measures (p  > 0.05). Conclusion: This study supports that older adults with cognitive impairment can independently complete CBT-I via the Internet and achieve clinical sleep improvements. Show more

Keywords: Aged, behavioral intervention, cognitive dysfunction, insomnia, Internet, mild cognitive impairment, research

DOI: 10.3233/JAD-210657

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1539-1550, 2021

Authors: Han, Fanglei | Zhao, Jia | Zhao, Guoqing

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease which shows a set of symptoms involving cognitive changes and psychological changes. Given that AD is the most common form of dementia in aging population and the increasing demand for anesthesia/surgery with aging, there has been significant interest in the exact impact of volatile anesthetics on cognitive function and pathological alterations in AD population. Objective: This study aimed to investigate behavioral changes and neuropathology in the 5xFAD mouse model of Alzheimer’s disease with short-term exposure or long-term exposure to desflurane, sevoflurane, or isoflurane. Methods: In this study, …we exposed 5xFAD mouse model of AD to isoflurane, sevoflurane, or desflurane in two different time periods (30 min and 6 h), and the memory related behaviors as well as the pathological changes in 5xFAD mice were evaluated 7 days after the anesthetic exposure. Results: We found that short-term exposure to volatile anesthetics did not affect hippocampus dependent memory and the amyloid-β (Aβ) deposition in the brain. However, long-term exposure to sevoflurane or isoflurane significantly increased the Aβ deposition in CA1 and CA3 regions of hippocampus, as well as the glial cell activation in amygdala. Besides, the PSD-95 expression was decreased in 5xFAD mice with exposure to sevoflurane or isoflurane and the caspase-3 activation was enhanced in isoflurane, sevoflurane, and desflurane groups. Conclusion: Our results demonstrate the time-dependent effects of common volatile anesthetics and implicate that desflurane has the potential benefits to prolonged anesthetic exposure in AD patients. Show more

Keywords: Aβ deposits, Alzheimer’s disease, cognitive impairment, desflurane, glial cells, hippocampus, isoflurane, sevoflurane, 5xFAD transgenic mice

DOI: 10.3233/JAD-210374

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1551-1562, 2021

Authors: Galvin, James E. | Chrisphonte, Stephanie | Chang, Lun-Ching

Article Type: Research Article

Abstract: Background: Socioeconomic status (SES), race, ethnicity, and medical comorbidities may contribute to Alzheimer’s disease and related disorders (ADRD) health disparities. Objective: Analyze effects of social and medical determinants on cognition in 374 multicultural older adults participating in a community-based dementia screening program. Methods: We used the Montreal Cognitive Assessment (MoCA) and AD8 as measures of cognition, and a 3-way race/ethnicity variable (White, African American, Hispanic) and SES (Hollingshead index) as predictors. Potential contributors to health disparities included: age, sex, education, total medical comorbidities, health self-ratings, and depression. We applied K -means cluster analyses to study medical …and social dimension effects on cognitive outcomes. Results: African Americans and Hispanics had lower SES status and cognitive performance compared with similarly aged Whites. We defined three clusters based on age and SES. Cluster #1 and #3 differed by SES but not age, while cluster #2 was younger with midlevel SES. Cluster #1 experienced the worse health outcomes while cluster #3 had the best health outcomes. Within each cluster, White participants had higher SES and better health outcomes, African Americans had the worst physical performance, and Hispanics had the most depressive symptoms. In cross-cluster comparisons, higher SES led to better health outcomes for all participants. Conclusion: SES may contribute to disparities in access to healthcare services, while race and ethnicity may contribute to disparities in the quality and extent of services received. Our study highlights the need to critically address potential interactions between race, ethnicity, and SES which may better explain disparities in ADRD health outcomes. Show more

Keywords: Alzheimer’s disease, brain health, cognitive impairment, dementia, ethnicity, health disparities, race, socioeconomic status

DOI: 10.3233/JAD-215020

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1563-1576, 2021

Authors: Karami, Vania | Nittari, Giulio | Traini, Enea | Amenta, Francesco

Article Type: Research Article

Abstract: Background: It is desirable to achieve acceptable accuracy for computer aided diagnosis system (CADS) to disclose the dementia-related consequences on the brain. Therefore, assessing and measuring these impacts is fundamental in the diagnosis of dementia. Objective: This study introduces a new CADS for deep learning of magnetic resonance image (MRI) data to identify changes in the brain during Alzheimer’s disease (AD) dementia. Methods: The proposed algorithm employed a decision tree with genetic algorithm rule-based optimization to classify input data which were extracted from MRI. This pipeline is applied to the healthy and AD subjects of the …Open Access Series of Imaging Studies (OASIS). Results: Final evaluation of the CADS and its comparison with other systems supported the potential of the proposed model as a novel tool for investigating the progression of AD and its great ability as an innovative computerized help to facilitate the decision-making procedure for the diagnosis of AD. Conclusion: The one-second time response, together with the identified high accurate performance, suggests that this system could be useful in future cognitive and computational neuroscience studies. Show more

Keywords: Alzheimer’s disease, decision tree, dementia, genetic algorithm, MRI

DOI: 10.3233/JAD-210626

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1577-1584, 2021

Authors: Udina, Cristina | Ayers, Emmeline | Inzitari, Marco | Verghese, Joe

Article Type: Research Article

Abstract: Background: Motoric cognitive risk syndrome (MCR) combines slow gait and cognitive complaints and has been proposed as a predementia syndrome. The nature of dual-task performance in MCR has not been established. Objective: To assess differences in dual-task performance between participants with and without MCR and to study the prefrontal cortex (PFC)-based brain activity during dual-task using functional near-infrared spectroscopy. Methods: Cohort study of community-dwelling non-demented older adults included in the “Central Control of Mobility in Aging” study. Comprehensive assessment included global cognition and executive function tests along with clinical variables. Dual-task paradigm consisted in walking while …reciting alternate letters of the alphabet (WWT) on an electronic walkway. We compared dual-task performance between MCR (n  = 60) and No MCR (n  = 478) participants and assessed the relationship of dual-task performance with cognitive function. In a subsample, we compared PFC oxygenation during WWT between MCR (n  = 32) and No MCR (n  = 293). Results: In our sample of 538 high-functioning older adults (76.6±6.5 years), with 11.2% prevalence of MCR, dual-task cost was not significantly different, compared to No MCR participants. Among MCR participants, no significant relationship was found between WWT velocity and cognitive function, whereas No MCR participants with better cognitive function showed faster WWT velocities. PFC oxygenation during WWT was higher in MCR compared to No MCR (1.02±1.25 versus 0.66±0.83, p  = 0.03). Conclusion: MCR participants showed no significant differences in the dual-task cost while exhibiting higher PFC oxygenation during dual-task walking. The dual-task performance (WWT velocity) in MCR participants was not related to cognition. Show more

Keywords: Cognition, dual-task, motoric cognitive risk syndrome, near-infrared spectroscopy, prefrontal cortex

DOI: 10.3233/JAD-210239

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1585-1596, 2021

Authors: Hin, Nhi | Newman, Morgan | Pederson, Stephen | Lardelli, Michael

Article Type: Research Article

Abstract: Background: Iron trafficking and accumulation is associated with Alzheimer’s disease (AD) pathogenesis. However, the role of iron dyshomeostasis in early disease stages is uncertain. Currently, gene expression changes indicative of iron dyshomeostasis are not well characterized, making it difficult to explore these in existing datasets. Objective: To identify sets of genes predicted to contain iron responsive elements (IREs) and use these to explore possible iron dyshomeostasis-associated gene expression responses in AD. Methods: Comprehensive sets of genes containing predicted IRE or IRE-like motifs in their 3′ or 5′ untranslated regions (UTRs) were identified in human, mouse, and …zebrafish reference transcriptomes. Further analyses focusing on these genes were applied to a range of cultured cell, human, mouse, and zebrafish gene expression datasets. Results: IRE gene sets are sufficiently sensitive to distinguish not only between iron overload and deficiency in cultured cells, but also between AD and other pathological brain conditions. Notably, changes in IRE transcript abundance are among the earliest observable changes in zebrafish familial AD (fAD)-like brains, preceding other AD-typical pathologies such as inflammatory changes. Unexpectedly, while some IREs in the 3′ untranslated regions of transcripts show significantly increased stability under iron deficiency in line with current assumptions, many such transcripts instead display decreased stability, indicating that this is not a generalizable paradigm. Conclusion: Our results reveal IRE gene expression changes as early markers of the pathogenic process in fAD and are consistent with iron dyshomeostasis as an important driver of this disease. Our work demonstrates how differences in the stability of IRE-containing transcripts can be used to explore and compare iron dyshomeostasis-associated gene expression responses across different species, tissues, and conditions. Show more

Keywords: Alzheimer’s disease, computational biology, familial Alzheimer’s disease, gene expression, iron homeostasis, iron responsive element, transcriptomics

DOI: 10.3233/JAD-210200

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1597-1630, 2021

Authors: Schneider, Julia | Miller, Jennifer | Teschauer, Winfried | Kruse, Andreas | Teichmann, Birgit

Article Type: Research Article

Abstract: Background: Entering the hospital via an Emergency Department (ED) is a pivotal moment in the life of People with Dementia (PwD) and often starts an avoidable downward spiral. Therefore, it is required to further educate ED staff to raise awareness of the needs of PwD. Although there are many studies about existing dementia training programs for the hospital setting, empirical evidence for the ED setting and cross-level training evaluations are lacking. Objective: The study aims to evaluate a two-day dementia training course for ED staff on the outcome levels of learning, individual performance, and organizational performance. Furthermore, the …study examines whether the training fulfilled participants’ expectations. Methods: Mixed methods were used to assess data from head nurses, nursing, and administrative staff working in EDs. We conducted semi-structured interviews three weeks before (N  = 18) and eight months after (N  = 9) the training. Questionnaire data were assessed before the training, three months, and six months after the training (N  = 44). A qualitative content analysis was conducted to analyze qualitative data; quantitative data was described descriptively. Results: The intervention seems to be effective on both learning and individual performance levels. However, we did not observe any changes in the organizational performance. The training program met attendees’ expectations only partly. The working environment of EDs needs to be taken more into account. Conclusion: Hospital staffs’ expectations of a dementia training program depend on the work area in which they operate. Results support the implementation of intervention bundles to enable sustainable cross-level changes. Show more

Keywords: Education, health care facilities, health personnel, neurocognitive disorders, program evaluation

DOI: 10.3233/JAD-210505

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1631-1644, 2021