Journal of Alzheimer's Disease - Volume 87, issue 3

Authors: Zhao, Yan | Li, Yan | Wang, Lijing | Song, Zihe | Di, Tengsen | Dong, Xinyi | Song, Xiaohan | Han, Xintong | Zhao, Yanyan | Wang, Bingfei | Cui, HuiXian | Chen, Haiying | Li, Sha

Article Type: Systematic Review

Abstract: Background: Epidemiologic evidence suggests that physical activity benefits cognition, but results from randomized trials in sedentary individuals are limited and inconsistent. Objective: To evaluate the effects of physical activity on cognition among sedentary older adults. Objective: A systematic literature search for eligible studies published up to January 1, 2021, was performed on six international (PubMed, Cochrane Library, Web of Science, Sinomed, FMRS, and OVID) and three Chinese databases (Wanfang, China National Knowledge Infrastructure, and VIP). We estimated the effect of physical activity on the cognition of sedentary elderly by standardized mean differences (SMD) and 95% confidence …intervals (CI) using a random-effects model. We evaluated publication bias using funnel plots and heterogeneity using I2 statistics. Subgroup analyses were conducted by baseline cognition, intervention duration, activity type, and country. Results: Seven randomized controlled trials (RCTs) comprising 321 (experimental group, 164; control group, 157) sedentary older adults were included in the meta-analysis. Physical activity significantly improved cognition in sedentary elderly adults compared with controls (SMD: 0.50, 95% CI:0.09–0.92). Subgroup analyses showed significant effects of baseline cognition impairment (SMD: 9.80, 95% CI: 5.81–13.80), intervention duration > 12 weeks (SMD: 2.85, 95% CI: 0.73–4.96), aerobic exercise (SMD: 0.74, CI: 0.19–1.29), and countries other than the United States (SMD: 10.50, 95% CI: 7.08–13.92). Conclusion: Physical activity might have a general positive effect on the cognition of sedentary older adults. Intervention > 12 weeks and aerobic exercise can effectively delay their cognitive decline; however, more rigorous RCTs are needed to support our findings. Show more

Keywords: Cognition, cognitive function, exercise, meta-analysis, older adults, physical activity, sedentary lifestyle

DOI: 10.3233/JAD-220073

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 957-968, 2022

Authors: Graham, Alicia | Livingston, Gill | Purnell, Lucy | Huntley, Jonathan

Article Type: Systematic Review

Abstract: Background: Traumatic brain injury (TBI) increases the risk of future dementia and Alzheimer’s disease (AD). However, it is unclear whether this is true for mild TBI (mTBI). Objective: To explore the association between mTBI and subsequent risk of developing AD. Method: We systematically searched four electronic databases from January 1954 to April 2020. We included studies reporting primary data and where mTBI preceded AD by≥5 years. We meta-analyzed included studies for both high quality studies and studies with a follow up of > 10 years. Result: We included 5 of the 10,435 results found. Meta-analysis found …a history of mTBI increased risk of AD (pooled relative risk = 1.18, 95% CI 1.11–1.25, N  = 3,149,740). The sensitivity analysis including only studies in which mTBI preceded AD by > 10 years, excluded two very large studies and resulted in wider confidence intervals (RR = 2.02, 95% CI 0.66–6.21, N  = 2307). Conclusion: There is an increased risk of AD following mTBI. Our findings of increased risk even with mTBI means it cannot be assumed that mild head injuries from sports are harmless. The sensitivity analysis suggests that we cannot exclude reverse causation, and longer follow up times are needed. Implementation of policy to reduce mTBIs, including in children and sportsmen, are urgently needed. Further research is needed on the effect of frequency and age at injury of mTBIs. Show more

Keywords: Alzheimer’s disease, meta-analysis, risk factor, systematic review, traumatic brain injury

DOI: 10.3233/JAD-220069

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 969-979, 2022

Authors: Wiloth, Stefanie Sandra | Kiefer, Anna | Wittek, Maren | Arroyo y Villora, Tatjana | Obermeier, Monika | Schmitt, Eric | Kruse, Andreas

Article Type: Research Article

Abstract: A growing number of people with dementia, a simultaneous decline of professional caregivers, and changing family structures clearly illustrate the societal relevance of the question of how dementia care can be arranged and delivered in the future. The demand for innovative solutions especially to support family carers requires a deeper insight into their life situation and a focused perception of their needs. This article presents the main hypothesis that specific forms of social integration and participation based on an equal dialogue between family caregivers, the public, and policymakers is needed to achieve that. Therefore, the main point here is to …give family caregivers of people with dementia a voice to learn how to better support them in caring as well as self-care. A learning process triggered by a dialogue might result in a higher level of community readiness to implement new forms of support or social innovations. The hypothesis will be supported by John Dewey’s theory of political and democratic learning and the model of transformative learning according to Jack Mezirow indicating that learning particularly succeeds in interpersonal communication. In this context, the Town-Hall Meeting method and its potential to promote interpersonal communication and reflexive learning is discussed. The article addresses an important debate, namely that of how dementia care and support of family carers can succeed. It also sets the direction for future empirical research as the Town-Hall Meeting method might be applicable for gerontological action and participatory research. Show more

Keywords: Caregivers, communication, dementia, participation, social integration

DOI: 10.3233/JAD-215582

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 981-990, 2022

Authors: Pilotto, Andrea | Parigi, Marta | Bonzi, Giulio | Battaglio, Beatrice | Ferrari, Elisabetta | Mensi, Lorenza | Benussi, Alberto | Caratozzolo, Salvatore | Cosseddu, Maura | Turrone, Rosanna | Archetti, Silvana | Ashton, Nicholas J. | Zetterberg, Henrik | Giliani, Silvia | Padovani, Alessandro

Article Type: Short Communication

Abstract: Plasma phosphorylated tau species have been recently proposed as peripheral markers of Alzheimer’s disease (AD) pathology. In this cross-sectional study including 91 subjects, plasma and cerebrospinal fluid (CSF) p-tau181 and p-tau231 levels were elevated in the early symptomatic stages of AD. Plasma p-tau231 and p-tau181 were strongly related to CSF phosphorylated tau, total tau and amyloid and exhibited a high accuracy—close to CSF p-tau231 and p-tau181—to identify AD already in the early stage of the disease. The findings might support the use as diagnostic and prognostic peripheral AD biomarkers in both research and clinical settings.

Keywords: Alzheimer’s disease, cerebrospinal fluid, phosphorylated-tau, plasma biomarkers

DOI: 10.3233/JAD-215646

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 991-997, 2022

Authors: Whitehouse, Peter J. | Saini, Vikas

Article Type: Article Commentary

Abstract: U.S. Food and Drug Administration–s (FDA) approval of aducanumab (Aduhelm® in the US) as a treatment for mild cognitive impairment of the Alzheimer type and Alzheimer–s disease has raised such major concerns about efficacy, safety, FDA processes, and regulatory capture that Biogen–s license to market this biologic should be immediately withdrawn. Aducanumab has not demonstrated benefit to patients, failed to meet regulatory guidelines, and is likely to cause both individual and societal harm.

Keywords: Accelerated approval, aducanumab, Alzheimer’s disease, clinical trials, FDA

DOI: 10.3233/JAD-220264

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 999-1001, 2022

Authors: Whitehouse, Peter | Gandy, Sam | Saini, Vikas | George, Daniel R. | Larson, Eric B. | Alexander, G. Caleb | Avorn, Jerry | Brownlee, Shannon | Camp, Cameron | Chertkow, Howard | Fugh-Berman, Adriane | Howard, Rob | Kesselheim, Aaron | Langa, Kenneth M. | Perry, George | Richard, Edo | Schneider, Lon

Article Type: Meeting Report

Abstract: The controversial approval in June 2021 by the Food and Drug Administration (FDA) of aducanumab (marketed as Aduhelm), Biogen’s monoclonal antibody for patients with Alzheimer’s disease, raises significant concerns for the dementia field and drug approval process, considering its lack of adequate evidence for clinical efficacy, safety issues, and cost. On 15 December 2021, an international group of clinicians, basic science experts, psychological and social science researchers, lay people with lived experience of dementia, and advocates for public health met to discuss making a recommendation for whether aducanumab’s approval should be withdrawn. Attendees considered arguments both in favor of and …in opposition to withdrawal and voted unanimously to recommend that the FDA withdraw its approval for aducanumab and to support the Right Care Alliance’s filing of a formal Citizen Petition to this effect. Show more

Keywords: Aducanumab, Alzheimer’s disease, monoclonal antibody

DOI: 10.3233/JAD-220262

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1003-1007, 2022

Authors: Costa, Tommaso | Cauda, Franco

Article Type: Research Article

Abstract: Background: In December 2019, in light of additional blinded data, Biogen claimed efficacy of the drug Aducanumab (ADU). Objective: We conducted a reanalysis of the phase III ADU summary statistics, focusing in particular on the Clinical Dementia Rating-Sum of Boxes. Methods: We used a Bayesian framework to mitigate the problems of the null-hypothesis significance testing framework. In particular, we used Bayes Factor (BF) to analyze the summary statistics. The BF is the comparison of how well two hypotheses predict the data. Results: Our results showed that the evidence for ADU efficacy is very low. …The results show that the only data with a BF value in favor of the alternative hypothesis (i.e., drug efficacy) is the high-dose condition in the EMERGE trial. However, the obtained BF falls within the range of values considered anecdotal, meaning a low level of evidence. Conclusion: We provide a clearer interpretation of the results of the clinical trials based on the Bayesian framework, as this may be useful for future development and research in the field. Show more

Keywords: Alzheimer’s disease, bayesian statistics, clinical trial, drugs

DOI: 10.3233/JAD-220132

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1009-1012, 2022

Authors: Beishon, Lucy C. | Haunton, Victoria J. | Bradbury-Jones, Caroline | Subramaniam, Hari | Mukaetova-Ladinska, Elizabeta B. | Panerai, Ronney B. | Robinson, Thompson G. | Evley, Rachel

Article Type: Research Article

Abstract: Background: Cognitive training (CT) may be beneficial in delaying the onset or slowing dementia progression. CT has been evaluated quantitatively and qualitatively, but none have used mixed methods approaches. Objective: The aim of this study was to use a mixed methods approach to identify those who may selectively benefit from CT. Methods: This was an explanatory sequential mixed methods study involving a quantitative randomized trial of 12 weeks multi-domain CT in healthy older adults (HC, n  = 20), and people living with mild cognitive impairment (MCI; n  = 12) and dementia (n  = 24). Quantitative outcomes included: cognition, mood, …quality of life, and activities of daily living. 28 (10 HC, 6 MCI, 12 dementia) training participants completed semi-structured interviews with their carer. Quantitative and qualitative data were integrated using joint displays. Results: Three participants dropped out from the training early-on, leaving 25 participants with follow-up data for full integration (10 HC, 6 MCI, 9 dementia). Dropouts and lower adherence to training were more common in dementia participants with greater non-modifiable barriers. High adherers were more resilient to negative emotions, and poorer or fluctuating performance. Integrated analysis found the majority of participants (n  = 24) benefited across outcomes, with no clear profile of individuals who benefited more than others. Participants made a number of key recommendations to improve adherence and minimize dropout to CT. Conclusion: Reasons for dropout and low adherence were identified, with recommendations provided for the design of CT for dementia. An individual approach to training should be adopted and low adherence should not preclude engagement with CT. Show more

Keywords: Alzheimer’s disease, brain training, cognitive intervention, mild cognitive impairment, qualitative

DOI: 10.3233/JAD-215726

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1013-1031, 2022

Authors: Isella, Valeria | Rosazza, Cristina | Ferri, Francesca | Gazzotti, Maria | Impagnatiello, Valentina | Mapelli, Cristina | Morzenti, Sabrina | Crivellaro, Cinzia | Appollonio, Ildebrando M. | Ferrarese, Carlo

Article Type: Research Article

Abstract: Background: Analysis of subtypes of picture naming errors produced by patients with Alzheimer’s disease (AD) have seldom been investigated yet may clarify the cognitive and neural underpinnings of naming in the AD spectrum. Objective: To elucidate the neurocognitive bases of picture naming in AD through a qualitative analysis of errors. Methods: Over 1000 naming errors produced by 70 patients with amnestic, visuospatial, linguistic, or frontal AD were correlated with general cognitive tests and with distribution of hypometabolism on FDG-PET. Results: Principal component analysis identified 1) a Visual processing factor clustering visuospatial tests and unrecognized …stimuli, pure visual errors and visual-semantic errors, associated with right parieto-occipital hypometabolism; 2) a Concept-Lemma factor grouping language tests and anomias, circumlocutions, superordinates, and coordinates, correlated with left basal temporal hypometabolism; 3) a Lemma-Phonology factor including the digit span and phonological errors, linked with left temporo-parietal hypometabolism. Regression of brain metabolism on individual errors showed that errors due to impairment of basic and higher-order processing of object visual attributes, or of their interaction with semantics, were related with bilateral occipital and left occipito-temporal dysfunction. Omissions and superordinates were linked to degradation of broad and basic concepts in the left basal temporal cortex. Semantic-lexical errors derived from faulty semantically- and phonologically-driven lexical retrieval in the left superior and middle temporal gyri. Generation of nonwords was underpinned by impairment of phonology within the left inferior parietal cortex. Conclusion: Analysis of individual naming errors allowed to outline a comprehensive anatomo-functional model of picture naming in classical and atypical AD. Show more

Keywords: Alzheimer’s disease, aphasia, brain metabolism, dementia, FDG-PET, language, naming, naming errors

DOI: 10.3233/JAD-220053

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1033-1053, 2022

Authors: Nagata, Koki | Tsunoda, Kenji | Fujii, Yuya | Tsuji, Taishi | Okura, Tomohiro

Article Type: Research Article

Abstract: Background: Moderate- to vigorous-intensity physical activity (PA) may reduce the risk of dementia; however, few studies have examined the effects of PA intensity on dementia risk. Objective: To prospectively examine the dose-response relationship of PA intensity with the incidence of suspected dementia in community-dwelling older adults. Methods: We conducted a baseline mail survey with an 8-year follow-up of 3,722 older adults in Japan. We assessed PA levels using the International Physical Activity Questionnaire short form and calculated the amount of time per week spent performing moderate- and vigorous-intensity PA (VPA). Information regarding suspected dementia was obtained …from the city database during the follow-up period. Cox proportional-hazard models with age as time scale, and delayed entry and restricted cubic spline regression as variables were used to estimate risk of developing suspected dementia, excluding cases occurring < 1 year after baseline evaluation. Results: The cumulative incidence of suspected dementia during the follow-up period was 12.7%. Compared with those who did not practice moderate-intensity PA (MPA), those who practiced≥300 min (hazard ratio, 0.73; 95% confidence interval 0.56–0.95) of MPA showed a lower risk of developing suspected dementia. Furthermore, when the dose-response relationship was examined, the hazard of developing suspected dementia decreased almost linearly with MPA. A significantly lower hazard was observed from 815 minutes/week. There was no significant association between VPA and suspected dementia. Conclusion: This study suggested that MPA is often practiced in older adults and this PA intensity has a sufficiently favorable effect on dementia prevention. Show more

Keywords: Cognitive decline, cognitive function, exercise, prospective study, walking

DOI: 10.3233/JAD-220104

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1055-1064, 2022