Journal of Alzheimer's Disease - Volume 71, issue 4

Authors: Mattos, Meghan K. | Sereika, Susan M. | Beach, Scott R. | Kim, Hyejin | Klunk, William E. | Knox, Melissa | Nadkarni, Neelesh K. | Parker, Lisa S. | Roberts, J. Scott | Schulz, Richard | Tamres, Lisa | Lingler, Jennifer H.

Article Type: Review Article

Abstract: As calls for transparency in human subjects research grow, investigators conducting Alzheimer’s disease (AD) biomarker research are increasingly required to consider their ethical obligations regarding the return of AD biomarker test results to research participants. When disclosing these test results to potentially vulnerable participants, investigators may face unique challenges to identify adverse events, particularly psychological events. The purpose of this paper is to describe our research team’s experience with developing and implementing a process for enhanced adverse event monitoring following the return of amyloid-β (Aβ) imaging results to research participants with mild cognitive impairment (MCI). Ethical and logistical considerations are …presented along with preliminary findings from an ongoing randomized controlled trial of Aβ imaging results disclosure in MCI. Following receipt of amyloid imaging results, participants underwent 14 days of adverse event monitoring using ecological momentary assessment (EMA), a strategy to capture health, behaviors, and mood as they occur in participants’ natural settings in real time. EMA telephone calls were placed at random during waking hours to screen for mood changes. Investigators were alerted for positive depression, anxiety, suicidal ideation screenings, or for two days of failed call attempts. Preliminary feasibility of twenty-four participants with MCI who participated in EMA mood assessments was successfully completed 83% (SD = 0.4) of the time over 14 days with no alerts for anxiety or depression screening items. EMA, when used with standard adverse event monitoring, is a promising and novel approach to maximize early detection of negative psychological reactions following AD biomarker results disclosed in research settings. Show more

Keywords: Amyloid, cognitive dysfunction, ecological momentary assessment, ethics, research subjects

DOI: 10.3233/JAD-190091

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1071-1079, 2019

Authors: Nebeker, Camille | Leow, Alex D. | Moore, Raeanne C.

Article Type: Review Article

Abstract: The implementation of digital health technologies into research studies for Alzheimer’s disease and other clinical populations is on the rise. Digital tools and strategies create opportunities to further expand the framework for conducting research beyond the traditional medical research model. The combination of participatory and community-based research methods, electronic health records, and the creation of multi-dimensional, large-scale research platforms to support precision medicine, along with the Internet of Things era, have led to more engaged and informed research participants. Research participants increasingly possess an expectation they will play a critical role as partners in the design and conduct of research. …Moreover, there is growing interest among research participants to have access to individual-level research data in real-time and/or at study completion. The traditional medical research model is largely one-directional where participants contribute data that is analyzed by researchers to yield generalizable knowledge. In this Ethics Review, we discuss a framework for a more nuanced intermediate research model, which is largely bidirectional and individually customized. Based on the seven ethical guidelines adopted by the National Institutes of Health, we speak to the ethical challenges of this intermediate type research. We also introduce a concept we are calling “MyTerms,” in which prospective participants tailor the terms and conditions of informed consent to their personalized preferences for receiving information, including research results. Digital health technologies offer a convenient and flexible approach for researchers to develop protocols that make it possible for participants to obtain access to their study data in a personalized and meaningful way. Show more

Keywords: Cognitive dysfunction, digital medicine, disclosure, information dissemination, informed consent, mobile health, patient rights, privacy, research ethics, return of results

DOI: 10.3233/JAD-190589

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1081-1088, 2019

Authors: Mattos, Meghan K. | Lingler, Jennifer H.

Article Type: Review Article

Abstract: New advances in digital technologies and data-collection methods support expansion of the traditional research model in the current Digital Age. As researchers continue to explore ways to collect, manage, and share individual-level research study data, investigators must also acknowledge new ethical considerations that arise. To ensure protection of research participants, participants must remain a priority across the research continuum by researchers, institutional review boards, funding agencies, and consumers. Big data and data sharing also require additional investments and oversight to ensure proper management and, and even more important, protection of human subjects.

Keywords: Data disclosure, data management, data sharing, ecological momentary assessment, ethics, research subjects

DOI: 10.3233/JAD-190725

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1089-1091, 2019

Authors: Taheri-Targhi, Somaiyeh | Gjedde, Albert | Araj-Khodaei, Mostafa | Rikhtegar, Reza | Parsian, Zahra | Zarrintan, Sina | Torbati, Mohammadali | Vafaee, Manouchehr Seyedi

Article Type: Review Article

Abstract: According to the World Health Organization (WHO), dementia is a disorder that occurs as result of a neurodegenerative process in brain, and usually is chronic or progressive by nature. Most descriptions of senile dementia date back to Alois Alzheimer. In 1906, Alzheimer described the first patient, Auguste Deter, who suffered from the disorder that later became known as Alzheimer’s disease. Although, the history of the disease before 1906 is quite rich, little has been said about the contributions of ancient and medieval physicians to the understanding of dementia. Over the centuries, the concept of senile dementia changed from an inevitable …mental decline with aging, to different sets of clinical features with narrow limits of diagnosis of a disease in its own right. Documentation of the historical origins of prevention, diagnosis, and therapies of dementia would make an important contribution to a more complete understanding of this pathological degeneration of dementia. The present review focuses on the contributions of Avicenna (AD 980–1037) to the development of diagnosis and the discovery of etiology of different forms of dementia, with the goal of revealing the extent to which dementia was understood in the golden age of Islam in Persia. Show more

Keywords: Alzheimer’s disease, Avicenna, dementia, history of medicine, Persian medicine

DOI: 10.3233/JAD-190345

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1093-1098, 2019

Authors: Moss, Donald E.

Article Type: Article Commentary

Abstract: The currently approved cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) produce gastrointestinal toxicity which limits dosing to that which produces only about 25% to 35% CNS cholinesterase inhibition in Alzheimer’s disease patients undergoing treatment, below the minimum therapeutic target of about 40% to 50% CNS inhibition considered necessary to treat cognitive impairment. A recent strategy for producing high-level CNS acetylcholinesterase (AChE) inhibition (50% or higher) is to co-administer a muscarinic anticholinergic with the AChE inhibitor to block the dose-limiting cholinergic overstimulation of the gastrointestinal system, allow more robust AChE inhibition in the CNS, and improve efficacy in the treatment of Alzheimer’s …disease. Unfortunately, most common muscarinic anticholinergics, including solifenacin, readily penetrate the CNS and are directly associated with long-term exacerbation of the underlying neuropathology of Alzheimer’s disease and increased brain atrophy. The co-administration of an anticholinergic with an AChE inhibitor is a rational strategy for improving efficacy in the symptomatic treatment of dementia, but there are significant long-term risks that have not yet been considered. For long-term safety against accelerating the underlying disease processes in Alzheimer’s disease, anticholinergics used to increase the tolerability of AChE inhibitors should not penetrate, or have very limited penetration, of the blood-brain barrier. Neurotrophic-mediated mechanisms by which cholinergic drugs may affect neurodegeneration in Alzheimer’s disease are explored and improved treatment options are suggested. Show more

Keywords: Alzheimer’s disease, anticholinergic, antimuscarinic, brain atrophy, cholinesterase inhibition, cognition, dementia, nerve growth factor, solifenacin, trospium

DOI: 10.3233/JAD-190626

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1099-1103, 2019

Authors: Lanham, David | Ali, Sana | Davis, Daniel | Rawle, Mark James

Article Type: Research Article

Abstract: Background: Cardiovascular disease remains the most common cause of death in industrialized countries. The use of beta-blockers is well established as a secondary prevention of myocardial infarction. However, little is known about the benefits of beta-blockers for people living with dementia. Objective: To evaluate the use of beta-blockers in people with dementia who have had a myocardial infarction, in order to identify associations between medication use, mortality, re-infarction and functional decline. Methods: We searched for all studies (randomized trials, observational cohorts) reporting beta-blocker use in populations with both dementia and previous myocardial infarction. Relevant keywords were …used in Medline, Embase, and Web of Science up to October 2018. Titles and abstracts were independently screened by two reviewers. Quality of eligible studies was assessed using the Newcastle-Ottawa Scale. PRISMA recommendations were followed throughout. Results: Two observational studies were included, representing 10,992 individuals in a community setting and 129,092 individuals from a hospital record-linkage study. One showed use of beta-blockers reduced all-cause mortality (HR 0.74 (95% CI 0.64– 0.86) alongside evidence for an increased rate of functional decline in individuals aged≥65 with moderate to severe cognitive impairment (OR 1.34 (95% CI 1.11– 1.61)). The second study did not find an association between beta-blocker use and mortality in the population living with dementia. Conclusion: There is insufficient evidence to support use of beta-blockers to persons living with dementia. A single study provides limited evidence that beta-blockers improve survival rates but with associated detrimental effects on functional status in nursing home residents with cognitive impairment. Decisions to continue beta-blockers in persons living with dementia should be made on an individual basis. Show more

Keywords: Beta-blockers, dementia, myocardial infarction, secondary prevention, systematic review

DOI: 10.3233/JAD-190503

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1105-1114, 2019

Authors: Li, Yuxia | Kang, Meimei | Wang, Hongxing | Jin, He | Wang, Xiaozhen | Gan, Wenjing | Zhao, Mingyan | Zhao, Xing | Wang, Rong | Han, Ying

Article Type: Research Article

Abstract: Subjective cognitive decline (SCD) is a risk factor for Alzheimer’s disease (AD). Urinary Alzheimer-associated neuronal thread protein (AD7c-NTP) has been identified as a biomarker for AD. It was hypothesized that if urinary AD7c-NTP were also elevated in SCD, as it is in prodromal AD (mild cognitive impairment stage), it could be a convenient and efficient clinical biomarker for the early diagnosis of SCD. SCD is often accompanied by a depressive state (DS), and the impact of DS on urinary AD7c-NTP levels remains unknown. A total of 297 right-handed Chinese Han subjects were recruited, including 98 subjects with SCD, 92 patients …with DS, and 107 well-matched cognitively normal controls (NC). The levels of AD7c-NTP in urine samples were measured using an enzyme-linked immunosorbent assay AD7c-NTP kit. Our results demonstrated that urinary AD7c-NTP levels in the SCD group (0.7561±0.5657 ng/mL) were not significantly higher than in either the DS (0.7527±0.5607 ng/mL) or NC (0.7214±0.5077 ng/mL) groups. Furthermore, urinary AD7c-NTP levels were not correlated with Hamilton Depression Rating Scale and Hamilton Anxiety Scale scores, but they were negatively associated with Mini-Mental State Examination scores (r  = –0.222, p  = 0.033) and Montreal Cognitive Assessment-Basic scores (r  = –0.207, p  = 0.048). Urinary AD7c-NTP level is not elevated in SCD and is unaffected by DS. Urinary AD7c-NTP may therefore not be a good potential biomarker for SCD and DS, although it may become elevated with more severe cognitive decline. Show more

Keywords: Alzheimer-associated neuronal thread protein, Alzheimer’s disease, biomarker, depressive state, subjective cognitive decline

DOI: 10.3233/JAD-190401

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1115-1123, 2019

Authors: Rudenko, Lauren K. | Wallrabe, Horst | Periasamy, Ammasi | Siller, Karsten H. | Svindrych, Zdenek | Seward, Matthew E. | Best, Merci N. | Bloom, George S.

Article Type: Research Article

Abstract: Abnormal folding and aggregation of the microtubule-associated protein, tau, is a hallmark of several neurodegenerative disorders, including Alzheimer’s disease (AD). Although normal tau is an intrinsically disordered protein, it does exhibit tertiary structure whereby the N- and C-termini are often in close proximity to each other and to the contiguous microtubule-binding repeat domains that extend C-terminally from the middle of the protein. Unfolding of this paperclip-like conformation might precede formation of toxic tau oligomers and filaments, like those found in AD brain. While there are many ways to monitor tau aggregation, methods to monitor changes in tau folding are not …well established. Using full length human 2N4R tau doubly labeled with the Förster resonance energy transfer (FRET) compatible fluorescent proteins, Venus and Teal, on the N- and C-termini, respectively (Venus-Tau-Teal), intensity and lifetime FRET measurements were able to distinguish folded from unfolded tau in living cells independently of tau-tau intermolecular interactions. When expression was restricted to low levels in which tau-tau aggregation was minimized, Venus-Tau-Teal was sensitive to microtubule binding, phosphorylation, and pathogenic oligomers. Of particular interest is our finding that amyloid-β oligomers (AβOs) trigger Venus-Tau-Teal unfolding in cultured mouse neurons. We thus provide direct experimental evidence that AβOs convert normally folded tau into a conformation thought to predominate in toxic tau aggregates. This finding provides further evidence for a mechanistic connection between Aβ and tau at seminal stages of AD pathogenesis. Show more

Keywords: Alzheimer’s disease, amyloid-β, FRET, tauopathies, tau

DOI: 10.3233/JAD-190226

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1125-1138, 2019

Authors: Ding, Meng-Yuan | Xu, Yi | Wang, Ying-Zhe | Li, Pei-Xi | Mao, Yi-Ting | Yu, Jin-Tai | Cui, Mei | Dong, Qiang

Article Type: Research Article

Abstract: Background: Post-stroke cognitive impairment (PSCI) significantly affects stroke survivors’ quality of life and rehabilitation. A risk model identifying cognitive decline at admission would help to improve early detection and management of post-stroke patients. Objective: To develop a new clinical risk score for ischemic stroke survivors in predicting 6–12 months PSCI. Methods: We prospectively enrolled 179 patients diagnosed with acute ischemic stroke within a 7-day onset. Data were analyzed based on baseline demographics, clinical risk factors, and radiological parameters. Logistic regression and area under the receiver operating curve (AUROC) were used to evaluate model efficiency. …Results: One hundred forty-five subjects completed a 6–12-month follow-up visit, and 77 patients (53.1%) were diagnosed with PSCI. Age (β= 0.065, OR = 1.067, 95% CI = 1.016–1.120), years of education (β= –0.346, OR = 0.707, 95% CI = 0.607–0.824), periventricular hyperintensity grading (β= 1.253, OR = 3.501, 95% CI = 1.652–7.417), diabetes mellitus (β= 1.762, OR = 5.825, 95% CI = 2.068–16.412), and the number of acute nonlacunar infarcts (β= 0.569, OR = 1.766, 95% CI = 1.243–2.510) were independently associated with 6–12 month PSCI, constituting a model with optimal predictive efficiency (AUC = 0.884, 95% CI = 0.832–0.935). Conclusions: The optimized risk model was effective in screening stroke survivors at high risk of developing 6–12 months PSCI in a simple and pragmatic way. It could be a potential tool to identify patients with a high risk of PSCI at an early stage in clinical practice after further independent external cohort validation. Show more

Keywords: Cognitive dysfunction, cohort studies, predictors, stroke

DOI: 10.3233/JAD-190382

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1139-1151, 2019

Authors: Rouch, Isabelle | Padovan, Catherine | Pongan, Elodie | Boublay, Nawéle | Laurent, Bernard | Dorey, Jean-Michel | Krolak-Salmon, Pierre

Article Type: Research Article

Abstract: Background: A link between personality traits and cognitive performance has been shown in normal adults and elderly individuals. Very few studies have evaluated this link in Alzheimer’s disease (AD). Objective: To better understand cognitive performance as regards to personality traits, our study was aimed to evaluate the role of premorbid personality on cognitive functioning in a population of patients presenting prodromal or mild AD. Methods: 181 elderly with prodromal or mild AD participated in a cross-sectional, prospective cohort study. The participants completed a personality inventory and a neuropsychological battery exploring memory, attention, executive function, language, and …praxis. Cognitive performance were compared according to the level of each personality trait, using multivariate MANOVA models. Results: A higher level of neuroticism was associated with lower performance at similarities test (D = 9.49, p  = 0.003), delayed Free and Cued Selective Reminding test (D  = 5.22, p  = 0.02), and digit span score (D = 7.99, p  = 0.006). A higher level of openness was related to better performance at similarities (D = 4.33, p  = 0.04), letter fluency (D = 11.45, p  = 0.001), and category fluency test (D = 5.85, p  = 0.02). Neuroticism interfered negatively with cognitive functioning at the prodromal stage; the association between openness and cognitive function was observed at both prodromal and mild AD stage. Conclusion: These results suggest that personality traits, in particular neuroticism and openness, modulate cognitive abilities in patients with early AD. These results encourage the development of stress management programs to prevent its negative effects on cognitive aging. Show more

Keywords: Alzheimer’s disease, cognitive function, neuroticism, openness, personality

DOI: 10.3233/JAD-190459

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1153-1162, 2019