Journal of Alzheimer's Disease - Volume 80, issue 2

Authors: Grande, Giulia | Wu, Jing | Ljungman, Petter L.S. | Stafoggia, Massimo | Bellander, Tom | Rizzuto, Debora

Article Type: Research Article

Abstract: Background: A growing but contrasting evidence relates air pollution to cognitive decline. The role of cerebrovascular diseases in amplifying this risk is unclear. Objectives: 1) Investigate the association between long-term exposure to air pollution and cognitive decline; 2) Test whether cerebrovascular diseases amplify this association. Methods: We examined 2,253 participants of the Swedish National study on Aging and Care in Kungsholmen (SNAC-K). One major air pollutant (particulate matter ≤2.5μm, PM2.5 ) was assessed yearly from 1990, using dispersion models for outdoor levels at residential addresses. The speed of cognitive decline (Mini-Mental State Examination, MMSE) was estimated …as the rate of MMSE decline (linear mixed models) and further dichotomized into the upper (25%fastest cognitive decline), versus the three lower quartiles. The cognitive scores were used to calculate the odds of fast cognitive decline per levels of PM2.5 using regression models and considering linear and restricted cubic splines of 10 years exposure before the baseline. The potential modifier effect of cerebrovascular diseases was tested by adding an interaction term in the model. Results: We observed an inverted U-shape relationship between PM2.5 and cognitive decline. The multi-adjusted piecewise regression model showed an increased OR of fast cognitive decline of 81%(95%CI = 1.2–3.2) per interquartile range difference up to mean PM2.5 level (8.6μg/m3 ) for individuals older than 80. Above such level we observed no further risk increase (OR = 0.89;95%CI = 0.74–1.06). The presence of cerebrovascular diseases further increased such risk by 6%. Conclusion: Low to mean PM2.5 levels were associated with higher risk of accelerated cognitive decline. Cerebrovascular diseases further amplified such risk. Show more

Keywords: Air pollution, cerebrovascular diseases, cognitive decline, particulate matter, population-based study

DOI: 10.3233/JAD-200852

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 591-599, 2021

Authors: Rostamzadeh, Ayda | Schwegler, Carolin | Gil-Navarro, Silvia | Rosende-Roca, Maitée | Romotzky, Vanessa | Ortega, Gemma | Canabate, Pilar | Moreno, Mariola | Schmitz-Luhn, Björn | Boada, Mercè | Jessen, Frank | Woopen, Christiane

Article Type: Research Article

Abstract: Background: Today, a growing number of individuals with mild cognitive impairment (MCI) wish to assess their risk of developing Alzheimer’s disease (AD) dementia. The expectations as well as the effects on quality of life (QoL) in MCI patients and their close others through biomarker-based dementia risk estimation are not well studied. Objective: The PreDADQoL project aims at providing empirical data on effects of such prediction on QoL and at developing an ethical and legal framework of biomarker-based dementia risk estimation in MCI. Methods: In the empirical study, 100 MCI-patients and their close others will be recruited …from two sites (Germany and Spain). They receive standardized counselling on cerebrospinal fluid (CSF) biomarker-based prediction of AD dementia and a risk disclosure based on their AD biomarker status. A mixed methods approach will be applied to assess outcomes. Results: The pilot-study yielded a specification of the research topics and newly developed questionnaires for the main assessment. Within this binational quantitative and qualitative study, data on attitudes and expectations toward AD risk prediction, QoL, risk communication, coping strategies, mental health, lifestyle changes, and healthcare resource utilization will be obtained. Together with the normative part of the project, an empirically informed ethical and legal framework for biomarker-based dementia risk estimation will be developed. Conclusion: The empirical research of the PreDADQoL study together with the ethical and legal considerations and implications will help to improve the process of counselling and risk disclosure and thereby positively affect QoL and health of MCI-patients and their close others in the context of biomarker-based dementia risk estimation. Show more

Keywords: Alzheimer’s disease, biomarker, caregiver, dementia, disclosure, ethics, mild cognitive impairment, quality of life, risk

DOI: 10.3233/JAD-200484

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 601-617, 2021

Authors: Grothe, Jessica | Schomerus, Georg | Dietzel, Jens | Riedel-Heller, Steffi | Röhr, Susanne

Article Type: Research Article

Abstract: Background: Social functioning is an important parameter for the early detection and diagnosis of dementia, as well as the description of its course and the assessment of intervention effects. Therefore, valid and reliable instruments to measure social functioning in individuals with dementia are needed. Objective: We aimed to provide an overview of such instruments including information on feasibility and psychometric properties. Methods: The review is informed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Relevant literature was identified using a pre-specified search string in the databases MEDLINE, PsycINFO, and Web of Science. …Information on the characteristics, feasibility, and psychometric properties of the identified instruments were extracted, summarized, and discussed. Results: Out of 5,307 articles, 8 were selected to be included in the study, describing a total of three instruments for measuring social functioning in individuals with dementia: the Nurses’ Observation Scale for Geriatric Patients (NOSGER; dimension “social behavior”), the Socioemotional Dysfunction Scale (SDS), and the Social Functioning in Dementia Scale (SF-DEM). The validity of all the three instruments was overall acceptable. Reliability was high for the NOSGER scale “social behavior” and the SF-DEM. Information on the usability of the instruments tended to be scarce. Conclusion: There are a few valid and reliable instruments to assess social functioning in individuals with dementia. Further considerations could comprise their feasibility with regard to measuring changes in social functioning over time, in additional target groups, e.g., different types and stages of dementia, and adaptions to different languages and cultural backgrounds. Show more

Keywords: Assessment, dementia, instrument, measurement, psychometric properties, reliability, social functioning, systematic review, validity

DOI: 10.3233/JAD-200762

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 619-637, 2021

Authors: Futamura, Akinori | Hieda, Sotaro | Mori, Yukiko | Kasuga, Kensaku | Sugimoto, Azusa | Kasai, Hideyo | Kuroda, Takeshi | Yano, Satoshi | Tsuji, Mayumi | Ikeuchi, Takeshi | Irie, Kazuhiro | Ono, Kenjiro

Article Type: Research Article

Abstract: Background: Toxic amyloid-β protein (Aβ) conformers play an important role in the progression of Alzheimer’s disease (AD). The ratio of toxic conformer to total Aβ42 in cerebrospinal fluid (CSF) was significantly high in AD and mild cognitive impairment (MCI) due to AD using an enzyme-linked immunosorbent assay kit with a 24B3 antibody. Objective: We compared the toxic Aβ42 , conformer at different stages of AD to identify its contribution to AD pathogenesis. Methods: We compared 5 patients with preclinical AD, 11 patients with MCI due to AD, 21 patients with AD, and 5 healthy controls …to measure CSF levels of total Aβ42 , total tau, tau phosphorylated at threonine 181 (p-tau), and toxic Aβ conformers. All were classified using the Clinical Dementia Rating. Cognitive function was assessed using the Japanese version of the Mini-Mental State Examination (MMSE-J). Results: Toxic Aβ conformer level was insignificant between groups, but its ratio to Aβ42 was significantly higher in AD than in preclinical AD (p  < 0.05). Toxic Aβ42 conformer correlated positively with p-tau (r  = 0.67, p  < 0.01) and p-tau correlated negatively with MMSE-J (r  = –0.38, p  < 0.05). Conclusion: Toxic Aβ conformer triggers tau accumulation leading to neuronal impairment in AD pathogenesis. Show more

Keywords: Alzheimer’s disease, amyloid-β protein, cerebrospinal fluid, preclinical Alzheimer’s disease, tau protein, toxic conformer

DOI: 10.3233/JAD-201407

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 639-646, 2021

Authors: Yang, Dalin | Hong, Keum-Shik

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is considered a prodromal stage of Alzheimer’s disease. Early diagnosis of MCI can allow for treatment to improve cognitive function and reduce modifiable risk factors. Objective: This study aims to investigate the feasibility of individual MCI detection from healthy control (HC) using a minimum duration of resting-state functional near-infrared spectroscopy (fNIRS) signals. Methods: In this study, nine different measurement durations (i.e., 30, 60, 90, 120, 150, 180, 210, 240, and 270 s) were evaluated for MCI detection via the graph theory analysis and traditional machine learning approach, such as linear discriminant analysis, …support vector machine, and K-nearest neighbor algorithms. Moreover, feature representation- and classification-based transfer learning (TL) methods were applied to identify MCI from HC through the input of connectivity maps with 30 and 90 s duration. Results: There was no significant difference among the nine various time windows in the machine learning and graph theory analysis. The feature representation-based TL showed improved accuracy in both 30 and 90 s cases (i.e., 30 s: 81.27% and 90 s: 76.73%). Notably, the classification-based TL method achieved the highest accuracy of 95.81% using the pre-trained convolutional neural network (CNN) model with the 30 s interval functional connectivity map input. Conclusion: The results indicate that a 30 s measurement of the resting-state with fNIRS could be used to detect MCI. Moreover, the combination of neuroimaging (e.g., functional connectivity maps) and deep learning methods (e.g., CNN and TL) can be considered as novel biomarkers for clinical computer-assisted MCI diagnosis. Show more

Keywords: Alzheimer’s disease, convolutional neural network, functional connectivity, functional near-infrared spectroscopy, mild cognitive impairment, resting state, transfer learning

DOI: 10.3233/JAD-201163

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 647-663, 2021

Authors: Shen, Ling-Xiao | Yang, Yu-Xiang | Kuo, Kevin | Li, Hong-Qi | Chen, Shi-Dong | Chen, Ke-Liang | Dong, Qiang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Social isolation and social interaction have been suggested to be associated with Alzheimer’s disease. However, the causality cannot be unambiguously assessed as traditional epidemiological methods are easily subject to unmeasured confounders and potential bias. Objective: To examine bidirectional relationships between social isolation, social interaction, and Alzheimer’s disease using Mendelian randomization method for assessing potential causal inference. Methods: This bidirectional two-sample Mendelian randomization study used independent genetic variants associated with social isolation and social interaction (n  = 302,567–487,647), and Alzheimer’s disease (n  = 455,258). MR analyses were performed using the inverse-variance-weighted (IVW) as the main MR analytical method …to estimate the causal effect. For sensitivity analyses, we applied weighted median, MR Egger to further assess the credibility of the causal effect. Results: Of the five types of social engagement examined in our study, only one showed evidence of an association with the risk of Alzheimer’s disease. Attendance at a gym or sports club (IVW OR per SD change: 0.670; 95% CI: 0.463–0.970; p  = 0.034) was inversely associated with the risk of Alzheimer’s disease. We also found that AD may reduce the attendance at religious group (IVW OR per SD change: 1.017; 95% CI: 1.005–1.030; p  = 0.004). Conclusion: This study suggests that regular attendance at a gym or sports club is causally associated with reduced risk of Alzheimer’s disease. Further studies are warranted to elucidate potential mechanisms. Show more

Keywords: Alzheimer’s disease, causal relations, social interaction, social isolation, Mendelian randomization

DOI: 10.3233/JAD-201442

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 665-672, 2021

Authors: Wang, Jin | Guo, Xiaojuan | Lu, Wenhui | Liu, Jie | Zhang, Hong | Quan, Qingyun | Su, Hang | Ma, Li | Gao, Fan | Qu, Qiumin

Article Type: Research Article

Abstract: Background: Vascular factors and mitochondria dysfunction contribute to the pathogenesis of Alzheimer’s disease (AD). DL-3-n-butylphthalide (NBP) has an effect in protecting mitochondria and improving microcirculation. Objective: The aim was to investigate the effect of donepezil combined NBP therapy in patients with mild-moderate AD. Methods: It was a prospective cohort study. 92 mild-moderate AD patients were classified into the donepezil alone group (n  = 43) or the donepezil combined NBP group (n  = 49) for 48 weeks. All patients were evaluated with Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-cog), Clinician’s Interview-Based Impression of Change plus caregiver input (CIBIC-plus), Alzheimer’s Disease …Cooperative Study-Activities of Daily Living (ADCS-ADL), and Neuropsychiatric Inventory (NPI) every 12 weeks. All patients were monitored for adverse events (AEs). The efficacy was analyzed using multivariate logistic regression analysis. Results: The multivariate logistic regression analysis showed that the changes of ADAS-cog score (OR = 2.778, 95% CI: [1.087, 7. 100], p  = 0.033) and ADCS-ADL score (OR = 2.733, 95% CI: [1.002, 7.459], p  = 0.049) had significant difference between donepezil alone group and donepezil combined NBP group, while the changes of NPI (OR = 1.145, 95% CI: [0.463, 2.829], p  = 0.769), MMSE (OR = 1.563, 95% CI: [0.615, 3.971], p  = 0.348) and CIBIC-plus (OR = 2.593, 95% CI: [0.696, 9.685], p  = 0.156) had no significant difference. The occurrence of AEs was similar in the two groups. Conclusion: Over the 48-week treatment period, donepezil combined NBP group had slower cognitive decline and better activities of daily living in patients with mild to moderate AD. These indicated that the multi-target therapeutic effect of NBP may be a new choice for AD treatment. Show more

Keywords: Alzheimer’s disease, clinical trial, DL–3-n-butylphthalide, drug treatment, prospective cohort study

DOI: 10.3233/JAD-201381

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 673-681, 2021

Authors: Buciuc, Marina | Tosakulwong, Nirubol | Machulda, Mary M. | Whitwell, Jennifer L. | Weigand, Stephen D. | Murray, Melissa E. | Reichard, R. Ross | Parisi, Joseph E. | Dickson, Dennis W. | Boeve, Bradley F. | Knopman, David S. | Petersen, Ronald C. | Josephs, Keith A.

Article Type: Research Article

Abstract: Background: Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with memory impairment and overall cognitive decline. It is unclear how TDP-43 contributes to the rate of clinical decline. Objective: To determine whether cross-sectional and longitudinal cognitive and functional decline are associated with anatomical distribution of TDP-43 in the brain. Methods: Longitudinal clinical-neuropathologic autopsy cohort study of 385 initially cognitively normal/mildly impaired older adults prospectively followed until death. We investigated how TDP-43, amyloid-β (Aβ), tau neurofibrillary tangles (NFT), Lewy body disease (LBD), age, sex, and genetics are associated with clinical scores and rates of their longitudinal …decline. Results: Of 385 participants, 260 (68%) had no TDP-43, 32 (8%) had TDP-43 limited to amygdala, and 93 (24%) had TDP-43 in the hippocampus and beyond. Higher TDP-43 and Braak NFT stages independently were associated with faster decline in global cognition, functional performance measured by Clinical Dementia Rating scale, and naming and episodic memory, whereas older age was associated with slower rate of cognitive, psychiatric, and functional decline. Cross-sectionally the following associations were found: higher TDP-43 and Braak NFT - worse performance; higher Aβ burden - worse global cognition, more behavioral changes, the latter also with higher LBD; older age - worse naming, lower frequency of behavioral changes; female sex - more impaired naming and better preserved episodic memory. There were no genetic associations. Conclusion: The association of TDP-43 distribution with decline in cognitive and functional performance suggests that TDP-43 is playing a role in the clinical progression to dementia. Further characterization of clinical features associated with TDP-43 can facilitate establishment of antemortem diagnosis. Show more

Keywords: Alzheimer’s disease, clinical decline, dementia, neuropsychology, TDP-43 proteinopathy

DOI: 10.3233/JAD-201166

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 683-693, 2021

Authors: Yuan, Li | Zhang, Jun | Guo, Jun-Hong | Holscher, Christian | Yang, Jun-Ting | Wu, Mei-Na | Wang, Zhao-Jun | Cai, Hong-Yan | Han, Ling-Na | Shi, Hui | Han, Yu-Fei | Qi, Jin-Shun

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive function. Type 2 diabetes mellitus (T2DM) is an important risk factor for AD. Glucose-dependent insulinotropic polypeptide (GIP) has been identified to be effective in T2DM treatment and neuroprotection. Objective: The present study investigated the neuroprotective effects and possible mechanisms of DAla2GIP-Glu-PAL, a novel long-lasting GIP analogue, in APP/PS1 AD mice. Methods: Multiple behavioral tests were performed to examine the cognitive function of mice. In vivo hippocampus late-phase long-term potentiation (L-LTP) was recorded to reflect synaptic plasticity. Immunohistochemistry and immunofluorescence were used …to examine the Aβ plaques and neuroinflammation in the brain. IL-1β, TNF-α , and cAMP/PKA/CREB signal molecules were also detected by ELISA or western blotting. Results: DAla2GIP-Glu-PAL increased recognition index (RI) of APP/PS1 mice in novel object recognition test, elevated spontaneous alternation percentage of APP/PS1 mice in Y maze test, and increased target quadrant swimming time of APP/PS1 mice in Morris water maze test. DAla2GIP-Glu-PAL treatment enhanced in vivo L-LTP of APP/PS1 mice. DAla2GIP-Glu-PAL significantly reduced Aβ deposition, inhibited astrocyte and microglia proliferation, and weakened IL-1β and TNF-α secretion. DAla2GIP-Glu-PAL also upregulated cAMP/PKA/CREB signal transduction and inhibited NF-κ B activation in the hippocampus of APP/PS1 mice. Conclusion: DAla2GIP-Glu-PAL can improve cognitive behavior, synaptic plasticity, and central pathological damage in APP/PS1 mice, which might be associated with the inhibition of neuroinflammation, as well as upregulation of cAMP-/PKA/CREB signaling pathway. This study suggests a potential benefit of DAla2GIP-Glu-PAL in the treatment of AD. Show more

Keywords: Amyloid-β, cognitive behaviors, DAla2GIP-Glu-PAL, long-term synaptic plasticity, neuroinflammation

DOI: 10.3233/JAD-201262

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 695-713, 2021

Authors: Ma, Da | Yee, Evangeline | Stocks, Jane K. | Jenkins, Lisanne M. | Popuri, Karteek | Chausse, Guillaume | Wang, Lei | Probst, Stephan | Beg, Mirza Faisal

Article Type: Research Article

Abstract: Background: Advanced machine learning methods can aid in the identification of dementia risk using neuroimaging-derived features including FDG-PET. However, to enable the translation of these methods and test their usefulness in clinical practice, it is crucial to conduct independent validation on real clinical samples, which has yet to be properly delineated in the current literature. Objective: In this paper, we present our efforts to enable such clinical translational through the evaluation and comparison of two machine-learning methods for discrimination between dementia of Alzheimer’s type (DAT) and Non-DAT controls. Methods: FDG-PET-based dementia scores were generated on an …independent clinical sample whose clinical diagnosis was blinded to the algorithm designers. A feature-engineered approach (multi-kernel probability classifier) and a non-feature-engineered approach (3D convolutional neural network) were analyzed. Both classifiers were pre-trained on cognitively normal subjects as well as subjects with DAT. These two methods provided a probabilistic dementia score for this previously unseen clinical data. Performance of the algorithms were compared against ground-truth dementia rating assessed by experienced nuclear physicians. Results: Blinded clinical evaluation on both classifiers showed good separation between the cognitively normal subjects and the patients diagnosed with DAT. The non-feature-engineered dementia score showed higher sensitivity among subjects whose diagnosis was in agreement between the machine-learning models, while the feature-engineered approach showed higher specificity in non-consensus cases. Conclusion: In this study, we demonstrated blinded evaluation using data from an independent clinical sample for assessing the performance in DAT classification models in a clinical setting. Our results showed good generalizability for two machine-learning approaches, marking an important step for the translation of pre-trained machine-learning models into clinical practice. Show more

Keywords: Alzheimer’s disease, blinded clinical evaluation, dementia of Alzheimer’s type, FDG-PET, feature-engineered classification, non-feature-engineered classification

DOI: 10.3233/JAD-201591

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 715-726, 2021