Volume 80, Number 2, 2021

Pages 475-492

Luciano Piubelli*, Giulia Murtas*, Valentina Rabattoni, Loredano Pollegioni *These authors contributed equally to this work.
The Role of D-Amino Acids in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD), the main cause of dementia worldwide, is characterized by a complex and multifactorial etiology. In large part, excitatory neurotransmission in the central nervous system is mediated by glutamate and its receptors are involved in synaptic plasticity. The N-methyl-D-aspartate (NMDA) receptors, which require the agonist glutamate and a coagonist such as glycine or the D-enantiomer of serine for activation, play a main role here. A second D-amino acid, D-aspartate, acts as agonist of NMDA receptors. D-amino acids, present in low amounts in nature and long considered to be of bacterial origin, have distinctive functions in mammals. In recent years, alterations in physiological levels of various D-amino acids have been linked to various pathological states, ranging from chronic kidney disease to neurological disorders. Actually, the level of NMDA receptor signaling must be balanced to promote neuronal survival and prevent neurodegeneration: this signaling in AD is affected mainly by glutamate availability and modulation of the receptor’s functions. Here, we report the experimental findings linking D-serine and D-aspartate, through NMDA receptor modulation, to AD and cognitive functions. Interestingly, AD progression has been also associated with the enzymes related to D-amino acid metabolism as well as with glucose and serine metabolism. Furthermore, the D-serine and D-/total serine ratio in serum have been recently proposed as biomarkers of AD progression. A greater understanding of the role of D-amino acids in excitotoxicity related to the pathogenesis of AD will facilitate novel therapeutic treatments to cure the disease and improve life expectancy.

Pages 493-504

Efthymios Chalkias, Fotis Topouzis, Thomas Tegos, Magda Tsolaki
The Contribution of Ocular Biomarkers in the Differential Diagnosis of Alzheimer’s Disease versus Other Types of Dementia and Future Prospects
Abstract: With dementia becoming increasingly prevalent, there is a pressing need to become better equipped with accurate diagnostic tools that will favorably influence its course via prompt and specific intervention. The overlap in clinical manifestation, imaging, and even pathological findings between different dementia syndromes is one of the most prominent challenges today even for expert physicians. Since cerebral microvasculature and the retina share common characteristics, the idea of identifying potential ocular biomarkers to facilitate diagnosis is not a novel one. Initial efforts included studying less quantifiable parameters such as aspects of visual function, extraocular movements, and funduscopic findings. However, the really exciting prospect of a non-invasive, safe, fast, reproducible, and quantifiable method of pinpointing novel biomarkers has emerged with the advent of optical coherence tomography (OCT) and, more recently, OCT angiography (OCTA). The possibility of analyzing multiple parameters of retinal as well as retinal microvasculature variables in vivo represents a promising opportunity to investigate whether specific findings can be linked to certain subtypes of dementia and aid in their earlier diagnosis. The existing literature on the contribution of the eye in characterizing dementia, with a special interest in OCT and OCTA parameters will be reviewed and compared, and we will explicitly focus our effort in advancing our understanding and knowledge of relevant biomarkers to facilitate future research in the differential diagnosis between Alzheimer’s disease and common forms of cognitive impairment, including vascular dementia, frontotemporal dementia, and dementia with Lewy bodies.

Pages 505-519

Dharma Singh Khalsa, Andrew Newberg
Spiritual Fitness: A New Dimension in Alzheimer’s Disease Prevention
Abstract: Background: Religious and spiritual interventions may have an effect on Alzheimer's disease prevention. Kirtan Kriya meditation has been shown to mitigate the deleterious effects of chronic stress on cognition, reverse memory loss, and create psychological and spiritual wellbeing, which may reduce multiple drivers of Alzheimer's disease risk. Objective: To detail a new concept in medicine called Spiritual Fitness, a merging of stress reduction, basic wellbeing, and psycho/spiritual wellbeing to prevent Alzheimer's disease. Methods: The literature on the topics mentioned above is described, including an in-depth discussion on why and how each are critical to advancing the future of Alzheimer's disease prevention. The many negative effects of chronic stress, and the benefits of Kirtan Kriya, are reviewed. The four pillars of basic wellbeing, six practical aspects of psychological wellbeing, and the four new non-sectarian features of spiritual fitness are then disclosed. Moreover, instructions on practicing Kirtan Kriya are offered in the Supplementary Material. Conclusion: Religious and spiritual practices, including Kirtan Kriya, are crucial components in the development of enhanced cognition and well-being, which may help prevent and, in some cases, reverse cognitive decline. The key point of this review is that making a commitment to live a brain longevity lifestyle including spiritual fitness is critically important way for aging Alzheimer's disease free. We hope that this article will inspire scientists, clinicians, and patients to embrace this new concept of spiritual fitness and make it part of every multidomain program for the prevention of cognitive disability.

Pages 521-526
Short Communication

Joost M. Riphagen, Maxime Van Egroo, Heidi I.L. Jacobs
Elevated Norepinephrine Metabolism Gauges Alzheimer’s Disease-Related Pathology and Memory Decline
Abstract: The noradrenergic (NE) locus coeruleus (LC) is vulnerable to hyperphosphorylated tau, and dysregulated NE-metabolism is linked to greater tau and disease progression. We investigated whether elevated NE-metabolism alone predicts memory decline or whether concomitant presence of tau and amyloid-β is required. Among 114 memory clinic participants, time trends (max. six years) showed dose-response declines in learning across groups with elevated NE-metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) with no, one, or two Alzheimer’s disease biomarkers; and no decline in the low MHPG group. Elevated MHPG is required and sufficient to detect learning declines, supporting a pathophysiologic model including the LC-NE system contributing to initial Alzheimer’s disease-related processes.

Pages 527-532
Short Communication

Amy Brodtmann, Mohamed Salah Khlif, Laura J. Bird, Toby Cumming, Emilio Werden
Hippocampal Volume and Amyloid PET Status Three Years After Ischemic Stroke: A Pilot Study
Abstract: Hippocampal atrophy is seen in many neurodegenerative disorders and may be a cardinal feature of vascular neurodegeneration. We examined hippocampal volume (HV) in a group of ischemic stroke survivors with amyloid 18F-NAV4694 PET imaging three years after stroke. We compared HV between the amyloid-positive (n=4) and amyloid-negative (n=29) groups, and associations with co-morbidities using Charlson Comorbidity Indices and multi-way ANOVA. Amyloid status was not associated with verbal or visual delayed free recall memory indices or cognitive impairment. We found no association between amyloid status and HV in this group of ischemic stroke survivors.

Pages 533-537
Short Communication

Nuria Carcavilla, Ana Sofía Pozo, Belén González, Débora Moral, José Joaquín Roldán, Victoria Erice, Ana Remírez
Needs of Dementia Family Caregivers in Spain During the COVID-19 Pandemic
Abstract: We explored the experience from caregivers of people with dementia (PwD) during mandatory confinement due to the COVID-19 pandemic in Spain. An online survey, which studied the perceptions of the main problems and consequences experienced during confinement, was answered by 106 family caregivers of PwD. Results showed that family caregivers of PwD experienced psychological problems, like anxiety, mood, sleep, or eating disorders during confinement and felt less supported when they had to handle challenging behaviors or offer meaningful activities. An innovative multi-tiered supportive approach is needed which considers a post-pandemic reality and ensures the continuity of quality care for PwD and their family careers.

Pages 539-553
Enyan Yu, Zhengluan Liao, Weixing Fan, Weiming Hu, Guoqiang Tian, Ke Chen, Sunke Chen, Haoshui Hua, Hong Zheng, Xiangming Fang, Guorong Li, Jian Xie, Shaochang Wu (Handling Associate Editor: Jianping Jia)
The Economic Burden of Alzheimer’s Disease in Zhejiang Province
Abstract: Background: The World Alzheimer Report has described and predicted the economic burden of Alzheimer's disease (AD) patients in detail for four consecutive years. There was a large-scale national survey in China launched by Professor Jianping Jia in 2015, but it did not adequately represent the average economic burden of AD patients in Zhejiang Province. Objective: To investigate the economic burden and main factors influencing Alzheimer's disease (AD) in Zhejiang Province. Methods: We recruited 830 patients from 10 cities in Zhejiang Province, evaluated their per capita and total cost related to AD treatment and care in 2017, and analyzed the main factors affecting economic burden from the perspective of demographic characteristics and disease severity. Results: In 2017, per capita cost of AD was 114,343.7 yuan, while the total cost was 27.53 billion yuan, accounting for 0.77% of Zhejiang Province’s GDP (5176.8 billion yuan). Total cost, direct medical cost, and indirect cost have different correlations with age, education level, type of work, marital status, comorbidity, and disease severity. Conclusion: The economic burden of AD in Zhejiang Province is heavy, similar to the national burden, and interventions based on demographic characteristics and disease severity can help reduce it.

Pages 555-565
Pamela Almeida-Meza, Andrew Steptoe, Dorina Cadar (Handling Associate Editor: Suzanne Tyas)
Is Engagement in Intellectual and Social Leisure Activities Protective Against Dementia Risk? Evidence from the English Longitudinal Study of Ageing
Abstract: Background: Studies have suggested that mentally stimulating activities and socially engaged lifestyles may reduce dementia risk; however, it is unclear which activities are more beneficial. Objective: We investigated intellectual and social leisure activities in relation to dementia incidence and explored the modifying role of sex and marital status in these associations. Methods: The sample was comprised of 8,030 participants aged 50+ from the English Longitudinal Study of Ageing, who joined at wave 1 (2002-2003), or waves 3 (2006-2007), or 4 (2008-2009). The end of the study period was wave 8 (2016-2017). Subdistribution hazard models investigated the role of leisure activities grouped into intellectual and social domains in relation to dementia while accounting for the risk of death. Subsequent analyses were conducted with individual leisure activities. Results: During the study period of up to 15 years, 412 participants developed dementia, and 2,192 died. We found that increased engagement in the intellectual activities’ domain was associated with a decreased dementia incidence (SHR 0.85, 95% CI 0.76-0.96, p=0.007), independent of the risk of death in married individuals, but not in those who were single, divorced, or widowed. Individual analyses for each leisure activity showed independent associations for reading newspapers in females (SHR 0.65, 95% CI 0.49-0.84, p=0.001), mobile phone usage in males (SHR 0.61, 95% CI 0.45-0.84, p=0.002), and having hobbies for married individuals (SHR 0.70, 95%CI 0.51-0.95, p=0.02). Conclusion: We found that intellectual leisure activities contribute to lower dementia risk in a representative population of English adults, suggesting intervention opportunities.

Pages 567-576
Fei Han*, Fei-Fei Zhai*, Ming-Li Li, Li-Xin Zhou, Jun Ni, Ming Yao, Zheng-Yu Jin, Li-Ying Cui, Shu-Yang Zhang, Yi-Cheng Zhu *These authors contributed equally to this work.
Arterial Stiffness Is Associated with White Matter Disruption and Cognitive Impairment: A Community-Based Cohort Study
Abstract: Background: Mechanisms through which arterial stiffness impacts cognitive function are crucial for devising better strategies to prevent cognitive decline. Objective: To examine the associations of arterial stiffness with white matter integrity and cognition in community dwellings, and to investigate whether white matter injury was the intermediate of the associations between arterial stiffness and cognition. Methods: This study was a cross-sectional analysis on 952 subjects (aged 55.5±9.1 years) who underwent diffusion tensor imaging and measurement of brachial-ankle pulse wave velocity (baPWV). Both linear regression and tract-based spatial statistics were used to investigate the association between baPWV and white matter integrity. The association between baPWV and global cognitive function, measured as the mini-mental state examination (MMSE) was evaluated. Mediation analysis was performed to assess the influence of white matter integrity on the association of baPWV with MMSE. Results: Increased baPWV was significantly associated with lower mean global fractional anisotropy (β=-0.118, p<0.001), higher mean diffusivity (β=0.161, p<0.001), axial diffusivity (β=0.160, p<0.001), and radial diffusivity (β=0.147, p<0.001) after adjustment of age, sex, and hypertension, which were measures having a direct effect on arterial stiffness and white matter integrity. After adjustment of age, sex, education, apolipoprotein E ε4, cardiovascular risk factors, and brain atrophy, we found an association of increased baPWV with worse performance on MMSE (β=-0.093, p=0.011). White matter disruption partially mediated the effect of baPWV on MMSE. Conclusion: Arterial stiffness is associated with white matter disruption and cognitive decline. Reduced white matter integrity partially explained the effect of arterial stiffness on cognition.

Pages 577-590
Weina Yao, Haifeng Chen, Caimei Luo, Xiaoning Sheng, Hui Zhao, Yun Xu, Feng Bai, Alzheimer’s Disease Neuroimaging Initiative
Hyperconnectivity of Self-Referential Network as a Predictive Biomarker of the Progression of Alzheimer’s Disease
Abstract: Background: Self-referential processing is associated with the progression of Alzheimer’s disease (AD), and cerebrospinal fluid (CSF) proteins have become accepted biomarkers of AD. Objective: Our objective in this study was to focus on the relationships between the self-referential network (SRN) and CSF pathology in AD-spectrum patients. Methods: A total of 80 participants, including 20 cognitively normal, 20 early mild cognitive impairment (EMCI), 20 late MCI (LMCI), and 20 AD, were recruited for this study. Independent component analysis was used to explore the topological SRN patterns, and the abnormalities of this network were identified at different stages of AD. Finally, CSF pathological characteristics (i.e., CSF Aβ, t-tau, and p-tau) that affected the abnormalities of the SRN were further determined during the progression of AD. Results: Compared to cognitively normal subjects, AD-spectrum patients (i.e., EMCI, LMCI, and AD) showed a reversing trend toward an association between CSF pathological markers and the abnormal SRN occurring during the progression of AD. However, a certain disease state (i.e., the present LMCI) with a low concentration of CSF tau could evoke more hyperconnectivity of the SRN than other patients with progressively increasing concentrations of CSF tau (i.e., EMCI and AD), and this fluctuation of CSF tau was more sensitive to the hyperconnectivity of the SRN than the dynamic changes of CSF Aβ. Conclusion: The integrity of the SRN was closely associated with CSF pathological characteristics, and these findings support the view that the hyperconnectivity of the SRN will play an important role in monitoring the progression of the pre-dementia state to AD.

Pages 591-599
Giulia Grande*, Jing Wu*, Petter L.S. Ljungman, Massimo Stafoggia, Tom Bellander, Debora Rizzuto *These authors contributed equally to this work.
Long-Term Exposure to PM2.5 and Cognitive Decline: A Longitudinal Population-Based Study
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 (8.6 μg/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.

Pages 601-617
Ayda Rostamzadeh*, Carolin Schwegler*, Silvia Gil-Navarro, Maitée Rosende-Roca, Vanessa Romotzky, Gemma Ortega, Pilar Canabate, Mariola Moreno, Björn Schmitz-Luhn, Mercè Boada, Frank Jessen, Christiane Woopen *These authors contributed equally to this work.
Biomarker-Based Risk Prediction of Alzheimer’s Disease Dementia in Mild Cognitive Impairment: Psychosocial, Ethical, and Legal Aspects. Study Protocol of the PreDADQoL Project
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.

Pages 619-637
Jessica Grothe, Georg Schomerus, Jens Dietzel, Steffi Riedel-Heller, Susanne Röhr (Handling Associate Editor: Thomas Benke)
Instruments to Assess Social Functioning in Individuals with Dementia: A Systematic Review
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.

Pages 639-646
Akinori Futamura, Sotaro Hieda, Yukiko Mori, Kensaku Kasuga, Azusa Sugimoto, Hideyo Kasai, Takeshi Kuroda, Satoshi Yano, Mayumi Tsuji, Takeshi Ikeuchi, Kazuhiro Irie, Kenjiro Ono (Handling Associate Editor: Kengo Uemura)
Toxic Amyloid-β42 Conformer May Accelerate the Onset of Alzheimer’s Disease in the Preclinical Stage
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.

Pages 647-663
Dalin Yang, Keum-Shik Hong
Quantitative Assessment of Resting-State for Mild Cognitive Impairment Detection: A Functional Near-Infrared Spectroscopy and Deep Learning Approach
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.

Pages 665-672
Ling-Xiao Shen, Yu-Xiang Yang, Kevin Kuo, Hong-Qi Li, Shi-Dong Chen, Ke-Liang Chen, Qiang Dong, Lan Tan, Jin-Tai Yu (Handling Associate Editor: Ling-Qiang Zhu)
Social Isolation, Social Interaction, and Alzheimer’s Disease: A Mendelian Randomization Study
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.

Pages 673-681
Jin Wang, Xiaojuan Guo, Wenhui Lu, Jie Liu, Hong Zhang, Qingyun Quan, Hang Su, Li Ma, Fan Gao, Qiumin Qu
Donepezil Combined with DL-3-n-Butylphthalide Delays Cognitive Decline in Patients with Mild to Moderate Alzheimer’s Disease: A Multicenter, Prospective Cohort Study
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.

Pages 683-693
Marina Buciuc, Nirubol Tosakulwong, Mary M. Machulda, Jennifer L. Whitwell, Stephen D. Weigand, Melissa E. Murray, R. Ross Reichard, Joseph E. Parisi, Dennis W. Dickson, Bradley F. Boeve, David S. Knopman, Ronald C. Petersen, Keith A. Josephs (Handling Associate Editor: Andrew Robinson)
TAR DNA-Binding Protein 43 Is Associated with Rate of Memory and Functional and Global Cognitive Decline in the Decade Prior to Death
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%) TDP-43 limited to amygdala, and 93 (24%) 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.

Pages 695-713
Li Yuan, Jun Zhang, Jun-Hong Guo, Christian Holscher, Jun-Ting Yang, Mei-Na Wu, Zhao-Jun Wang, Hong-Yan Cai, Ling-Na Han, Hui Shi, Yu-Fei Han, Jin-Shun Qi
DAla2-GIP-GLU-PAL Protects Against Cognitive Deficits and Pathology in APP/PS1 Mice by Inhibiting Neuroinflammation and Upregulating cAMP/PKA/CREB Signaling Pathways
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-κB 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.

Pages 715-726
Da Ma*, Evangeline Yee*, Jane K. Stocks, Lisanne M. Jenkins, Karteek Popuri, Guillaume Chausse, Lei Wang, Stephan Probst, Mirza Faisal Beg (Handling Associate Editor: Kaarin Anstey) *These authors contributed equally to this work.
Blinded Clinical Evaluation for Dementia of Alzheimer’s Type Classification Using FDG-PET: A Comparison Between Feature-Engineered and Non-Feature-Engineered Machine Learning Methods
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.

Pages 727-734
Seunghyun Lee, Joon Yul Choi, Wanhyung Lee
The Impact of Long Working Hours on Cognitive Function: A Follow-Up Study with Gender Stratification
Abstract: Background: Recent studies have shown that long working hours can have adverse consequences on health and possibly trigger biological processes that mediate the relationship between long working hours and cognitive decline. Objective: To investigate whether long working hours and the overall duration such exposure is associated with a decline in cognitive function. Methods: Data obtained during the Korean Longitudinal Study on Aging (n = 2,518) during the period 2006-2018 were used to explore the relationship between long working hours and cognitive decline. Korean version of the Mini-Mental State Examination (K-MMSE) scores were used to evaluate cognitive function. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), which were used to evaluate declines in K-MMSE scores over the 12-year study period. Results: Overall HR (95% CI) for a decline in cognitive function in long working hours group was 1.13 (0.73–1.17). When categorized by sex, women with long working hours had an HR (95% CI) of 1.50 (1.05–2.22), K-MMSE scores decreased significantly after working long hours for 5 years (p < 0.01). Conclusion: The study furthers understanding of the effects of long working hours on cognitive decline among female workers. Further research is required to determine the effects of long working hours on cognitive functions.

Pages 735-747
Ajay Sood, Valory Pavlik, Eveleen Darby, Wenyaw Chan, Rachelle Doody
Different Cognitive Profiles Are Associated with Progression Rate and Age at Death in Probable Alzheimer’s Disease
Abstract: Background: Cognitive profiles characterized by primarily language or visuospatial deficits have been documented in individuals meeting diagnostic criteria for probable Alzheimer’s disease (AD), but their association with progression rate or overall survival is not well described. Objective: To compare time from diagnosis to severe disease stage and death in probable AD patients classified into three groups based on neuropsychological test performance: marked verbal impairment (Verb-PI) with relatively preserved visuospatial function, marked visuospatial impairment with preserved verbal function (Vis-PI), and balanced verbal and visuospatial impairments (Bal-PI). Methods: This prospective cohort study included 540 probable AD patients attending an academic memory clinic who were enrolled from 1995-2013 and followed annually. Eligible individuals had a Mini-Mental State Exam (MMSE) score ≥10 at baseline, and at least one annual follow up visit. We used Cox proportional hazards modeling to analyze the association of cognitive profiles with time to decline in MMSE and CDR Global Score. Results: Sixty-one (11.3%) individuals had a Verb-PI profile, 86 (16%) had a Vis-PI profile, and 393 (72.8%) a Bal-PI profile. MMSE decline to < 10 was faster in Verb-PI than Vis-PI (HR 2.004, 95% CI, 1.062-3.780; p = 0.032). Progression to CDR-GS =3 was faster in Verb-PI individuals compared to Bal-PI (HR 1.604, 95% CI, 1.022-2.515; p = 0.04) or Vis-PI (HR 2.388, 95% CI, 1.330-4.288; p = 0.004) individuals. Baseline cognitive profile did not affect mortality. Conclusion: A recognition of different AD profiles may help to personalize care by providing a better understanding of pathogenesis and expected progression.

Pages 749-759
Albert Lladó, Lutz Froelich, Rezaul K. Khandker, Montserrat Roset, Christopher M. Black, Nuria Lara, Farid Chekani, Baishali M. Ambegaonkar
Assessing the Progression of Alzheimer’s Disease in Real-World Settings in Three European Countries
Abstract: Background: There exists considerable variation in disease progression rates among patients with Alzheimer’s disease (AD). Objective: The primary objective of this observational study is to assess the progression of AD by characterizing cognitive, functional, and behavioral changes during the follow-up period between 6 and 24 months. Methods: A longitudinal prospective study with community-dwelling patients with an established clinical diagnosis of AD of mild to moderate severity was conducted in Germany, Spain and the UK. A sample of 616 patients from 69 sites was included. Results: Patients had a mean of 1.9 years (SD=1.9) since AD diagnosis at study inclusion. Cognitive symptoms were reported to have first occurred a mean of 1.1 years (SD=1.7) prior to AD diagnosis and 1.4 (SD=1.8) years prior to AD treatment. Patients initially diagnosed with mild and moderate AD spent a median (95% CI) of 3.7 (2.8; 4.4) and 11.1 (6.1, ‘not reached’) years until progression to moderate and severe AD, respectively, according to the Mini-Mental Stat Examination (MMSE) scores. A mixed model developed for cognitive, functional, and neuropsychiatric scores, obtained from study patients at baseline and during follow-up period, showed progressive deterioration of AD patients over time. Conclusion: The study showed a deterioration of cognitive, functional, and neuropsychiatric functions during the follow-up period. Cognitive deterioration was slightly faster in patients with moderate AD compared to mild AD. The duration of moderate AD can be overestimated due to the use of retrospective data, lack of availability of MMSE scores in clinical charts and exclusion of patients at time of institutionalization.

Pages 761-774
Bijayani Sahu, Amy R. Mackos, Angela M. Floden, Loren E. Wold, Colin K. Combs
Particulate Matter Exposure Exacerbates Amyloid-β Plaque Deposition and Gliosis in APP/PS1 Mice
Abstract: Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques, neuroinflammation, and neuronal death. There are several well-established genetic and environmental factors hypothesized to contribute to AD progression including air pollution. However, the molecular mechanisms by which air pollution exacerbates AD are unclear. Objective: This study explored the effects of particulate matter exposure on AD-related brain changes using the APP/PS1 transgenic model of disease. Methods: Male C57BL/6;C3H wild type and APP/PS1mice were exposed to either filtered air (FA) or particulate matter sized under 2.5 μm (PM2.5) for 6 h/day, 5 days/week for 3 months and brains were collected. Immunohistochemistry for Aβ, GFAP, Iba1, and CD68 and western blot analysis for PS1, BACE, APP, GFAP, and Iba1 were performed. Aβ ELISAs and cytokine arrays were performed on frozen hippocampal and cortical lysates, respectively. Results: The Aβ plaque load was significantly increased in the hippocampus of PM2.5-exposed APP/PS1 mice compared to their respective FA controls. Additionally, in the PM2.5-exposed APP/PS1 group, increased astrocytosis and microgliosis were observed as indicated by elevated GFAP, Iba1, and CD68 immunoreactivities. PM2.5 exposure also led to an elevation in the levels of PS1 and BACE in APP/PS1 mice. The cytokines TNF-α, IL-6, IL-1β, IFN-γ, and MIP-3α were also elevated in the cortices of PM2.5-exposed APP/PS1 mice compared to FA controls. Conclusion: Our data suggest that chronic particulate matter exposure exacerbates AD by increasing Aβ plaque load, gliosis, and the brain inflammatory status.

Pages 775-786
Timothy M. Shoup, Ana Griciuc, Marc D. Normandin, Luisa Quinti, Lindsay V. Walsh, Maeva Dhaynaut, Sung-Hyun Moon, Nicolas J. Guehl, Pedro Brugarolas, David R. Elmaleh, Georges El Fakhri, Rudolph E. Tanzi
Evaluation of Fluorinated Cromolyn Derivatives as Potential Therapeutics for Alzheimer’s Disease
Abstract: Background: Cromolyn is an anti-neuroinflammatory modulator with a multifactorial mechanism of action that has been shown to inhibit amyloid-β (Aβ) aggregation and enhance microglial uptake and clearance of Aβ. Objective: We report the effects of fluoro-cromolyn derivatives on microglial cell toxicity and microglial clearance of Aβ42. Methods: Microglial cell toxicity for cromolyn derivatives were determined in naive BV2 microglial cells. Microglial clearance assays were performed with Aβ42 in naive BV2 microglial cell line and single cell clone BV2 line expressing CD33WT. PET imaging was performed for three F-18 analogs in a rhesus macaque. Results: All compounds but derivative 8 exhibited low microglial cell toxicity. Cromolyn 1 and derivatives 2, 4, and 7 displayed an increased uptake on Aβ42 in naïve BV2 microglial cells. Derivative 4 increased Aβ42 uptake in a dose-dependent manner and at 75 μM resulted in a one-fold increase in Aβ42 uptake in BV2-CD33WT. PET imaging for three [18F]cromolyn analogs revealed the order of brain tracer penetration to be 4a > 10 > 2a. Tracer 4a exhibited enhanced uptake in areas of high perfusion (putamen, grey matter, and cerebellum) and lower signal in areas of lower perfusion (caudate, thalamus, and white matter). Conclusion: Substantial uptake of Aβ42 in both naïve BV2 and BV2-CD33WT cells observed with 4 indicate conversion of microglial cells from a pro-inflammatory to an activation state favoring Aβ phagocytosis/clearance. These findings suggest that a fluoro-cromolyn analog could reduce fibril-prone Aβ42 in vivo and thereby serve as a therapeutic for the treatment and prevention of AD.

Pages 787-797
Yi-Zhen Wang, Lei Meng, Qi-Shuai Zhuang, Liang Shen
Screening Traditional Chinese Medicine Combination for Cotreatment of Alzheimer’s Disease and Type 2 Diabetes Mellitus by Network Pharmacology
Abstract: Background: In recent years, the efficacy of type 2 diabetes mellitus (T2DM) drugs in the treatment of Alzheimer's disease (AD) has attracted extensive interest owing to the close associations between the two diseases. Objective: Here, we screened traditional Chinese medicine (TCM) and multi-target ingredients that may have potential therapeutic effects on both T2DM and AD from T2DM prescriptions. Methods: Network pharmacology and molecular docking were used. Results: Firstly, the top 10 frequently used herbs and corresponding 275 active ingredients were identified from 263 T2DM-related TCM prescriptions. Secondly, through the comparative analysis of 208 potential targets of ingredients, 1,740 T2DM-related targets, and 2,060 AD-related targets, 61 common targets were identified to be shared. Thirdly, by constructing pharmacological network, 26 key targets and 154 representative ingredients were identified. Further enrichment analysis showed that common targets were involved in regulating multiple pathways related to T2DM and AD, while network analysis also found that the combination of Danshen (Radix Salviae)-Gancao (Licorice)-Shanyao (Rhizoma Dioscoreae) contained the vast majority of the representative ingredients and might be potential for the cotreatment of the two diseases. Fourthly, MAPK1, PPARG, GSK3B, BACE1, and NR3C1 were selected as potential targets for virtual screening of multi-target ingredients. Further docking studies showed that multiple natural compounds, including salvianolic acid J, gancaonin H, gadelaidic acid, icos-5-enoic acid, and sigmoidin-B, exhibited high binding affinities with the five targets. Conclusion: To summarize, the present study provides a potential TCM combination that might possess the potential advantage of cotreatment of AD and T2DM.

Pages 799-811
Claudio Di Lorito, Alessandro Bosco, Maureen Godfrey, Marianne Dunlop, Juliette Lock, Kristian Pollock, Rowan H. Harwood, Veronika van der Wardt (Handling Associate Editor: Lori Newkirk)
Mixed-Methods Study on Caregiver Strain, Quality of Life, and Perceived Health
Abstract: Background: Caring for someone with dementia is associated with negative and positive experiences. There is little evidence based on large datasets. Objective: To present data around the experience of caring for someone with dementia, to identify support (emotional and practical) needs, and inform future service provision. Methods: A mixed-methods study embedded in the Promoting Activity, Independence and Stability in Early Dementia (PrAISED) Randomized Controlled Trial. We administered questionnaires on strain, quality of life (QoL), and perceived health to 301 caregivers and assessment of cognitive performance, depression, anxiety, and disability in activities of daily living to 301 participants with dementia. Data were analyzed through descriptive and modelling statistics. A subsample of 20 patient-caregiver dyads were qualitatively interviewed. Data around caregivers’’ experience of providing care were extrapolated and analyzed through inductive thematic analysis. Results: There were significant negative associations between caregiver strain and QoL (p < 0.01) and between caregiver age and QoL (p < 0.01), and significant positive associations between caregiver strain and disability (p < 0.01), cognitive impairment (p < 0.01), depression (p < 0.05), and anxiety of the person with dementia (p < 0.05). Older caregivers reported a lack of support, reinforced by their reluctance to seek help. All caregivers reported contradictory emotions associated with caring and accumulation of strain over time. Conclusion: While there is recognition that it is essential to support caregivers, dedicated intervention programs, and support strategies to respond to the needs of older caregivers are still needed.

Pages 813-829
Wim Hendricus Quint, Irena Matečko-Burmann, Irene Schilcher, Tina Löffler, Michael Schöll, Björn Marcus Burmann, Thomas Vogels
Bispecific Tau Antibodies with Additional Binding to C1q or Alpha-Synuclein
Abstract: Background: Alzheimer’s disease (AD) and other tauopathies are neurodegenerative disorders characterized by cellular accumulation of aggregated tau protein. Tau pathology within these disorders is accompanied by chronic neuroinflammation, such as activation of the classical complement pathway by complement initiation factor C1q. Additionally, about half of the AD cases present with inclusions composed of aggregated alpha-synuclein called Lewy bodies. Lewy bodies in disorders such as Parkinson’s disease and Lewy body dementia also frequently occur together with tau pathology. Objective: Immunotherapy is currently the most promising treatment strategy for tauopathies. However, the presence of multiple pathological processes within tauopathies makes it desirable to simultaneously target more than one disease pathway. Methods: Herein, we have developed three bispecific antibodies based on published antibody binding region sequences. One bispecific antibody binds to tau plus alpha-synuclein and two bispecific antibodies bind to tau plus C1q. Results: Affinity of the bispecific antibodies to their targets compared to their monospecific counterparts ranged from nearly identical to one order of magnitude lower. All bispecific antibodies retained binding to aggregated protein in patient-derived brain sections. The bispecific antibodies also retained their ability to inhibit aggregation of recombinant tau, regardless of whether the tau binding sites were in IgG or scFv format. Mono- and bispecific antibodies inhibited cellular seeding induced by AD-derived pathological tau with similar efficacy. Finally, both Tau-C1q bispecific antibodies completely inhibited the classical complement pathway. Conclusion: Bispecific antibodies that bind to multiple pathological targets may therefore present a promising approach to treat tauopathies and other neurodegenerative disorders.

Pages 831-840
Sepehr Golriz Khatami, Daniel Domingo-Fernández, Sarah Mubeen, Charles Tapley Hoyt, Christine Robinson, Reagon Karki, Anandhi Iyappan, Alpha Tom Kodamullil, Martin Hofmann-Apitius
A Systems Biology Approach for Hypothesizing the Effect of Genetic Variants on Neuroimaging Features in Alzheimer’s Disease
Abstract: Background: Neuroimaging markers provide quantitative insight into brain structure and function in neurodegenerative diseases, such as Alzheimer's disease, where we lack mechanistic insights to explain pathophysiology. These mechanisms are often mediated by genes and genetic variations and are often studied through the lens of genome-wide association studies. Linking these two disparate layers (i.e., imaging and genetic variation) through causal relationships between biological entities involved in the disease’s etiology would pave the way to large-scale mechanistic reasoning and interpretation. Objective: We explore how genetic variants may lead to functional alterations of intermediate molecular traits, which can further impact neuroimaging hallmarks over a series of biological processes across multiple scales. Methods: We present an approach in which knowledge pertaining to single nucleotide polymorphism (SNPs) and imaging readouts is extracted from the literature, encoded in Biological Expression Language, and used in a novel workflow to assist in the functional interpretation of SNPs in a clinical context. Results: We demonstrate our approach in a case scenario which proposes KANSL1 as a candidate gene that accounts for the clinically reported correlation between the incidence of the genetic variants and hippocampal atrophy. We find that the workflow prioritizes multiple mechanisms reported in the literature through which KANSL1 may have an impact on hippocampal atrophy such as through the dysregulation of cell proliferation, synaptic plasticity, and metabolic processes. Conclusion: We have presented an approach that enables pinpointing relevant genetic variants as well as investigating their functional role in biological processes spanning across several, diverse biological scales.

Pages 841-853
Tsubasa Tomoto, Jie Liu, Benjamin Y, Tseng, Evan P. Pasha, Danilo Cardim, Takashi Tarumi, Linda S. Hynan, C. Munro Cullum, Rong Zhang (Handling Associate Editor: Jack de la Torre)
One-Year Aerobic Exercise Reduced Carotid Arterial Stiffness and Increased Cerebral Blood Flow in Amnestic Mild Cognitive Impairment
Abstract: Background: Central arterial stiffness and brain hypoperfusion are emerging risk factors of Alzheimer’s disease (AD). Aerobic exercise training (AET) may improve central arterial stiffness and brain perfusion. Objective: To investigate the effects of AET on central arterial stiffness and cerebral blood flow (CBF) in patients with amnestic mild cognitive impairment (MCI), a prodromal stage of AD. Methods: This is a proof-of-concept, randomized controlled trial that assigned 70 amnestic MCI patients into a 12-month program of moderate-to-vigorous AET or stretching-and-toning (SAT) intervention. Carotid β-stiffness index and CBF were measured by color-coded duplex ultrasonography and applanation tonometry. Total CBF was measured as the sum of CBF from both the internal carotid and vertebral arteries, and divided by total brain tissue mass assessed with MRI to obtain normalized CBF (nCBF). Episodic memory and executive function were assessed using standard neuropsychological tests (CVLT-II and D-KEFS). Changes in cardiorespiratory fitness were measured by peak oxygen uptake (VO2peak). Results: Total 48 patients (29 in SAT and 19 in AET) were completed one-year training. AET improved VO2peak, decreased carotid β-stiffness index and CBF pulsatility, and increased nCBF. Changes in VO2peak were associated positively with changes in nCBF (r=0.388, p=0.034) and negatively with carotid β-stiffness index (r=-0.418, p=0.007) and CBF pulsatility (r=-0.400, p=0.014). Decreases in carotid β-stiffness were associated with increases in cerebral perfusion (r=-0.494, p=0.003). AET effects on cognitive performance were minimal compared with SAT. Conclusion: AET reduced central arterial stiffness and increased CBF which may precede its effects on neurocognitive function in patients with MCI.

Pages 855-864
Katharine K. Brewster, Mei-Chen Hu, Melanie M. Wall, Patrick J. Brown, Sigal Zilcha-Mano, Steven P. Roose, Alexandra Stein, Justin S. Golub, Bret R. Rutherford
Age-Related Hearing Loss, Neuropsychological Performance, and Incident Dementia in Older Adults
Abstract: Background: Age-related hearing loss (HL) has been associated with dementia, though the neurocognitive profile of individuals with HL is poorly understood. Objective: To characterize the neurocognitive profile of HL. Methods: N=8,529 participants from the National Alzheimer’s Coordinating Center ≥60 years and free of cognitive impairment who were characterized as Untreated-, Treated-, or No HL. Outcomes included executive function (Trail Making Test [TMT] Part B), episodic memory (Immediate/Delayed Recall), language fluency (Vegetables, Boston Naming Test), and conversion to dementia. Regression models were fit to examine associations between HL and neurocognitive performance at baseline. Cox proportional hazards models examined the links between HL, neurocognitive scores, and development of dementia over follow-up. Results: At baseline, those with Untreated HL (versus No HL) had worse neurocognitive performance per standardized difference on executive function (TMT Part B [mean difference=0.05 (95% CI 0.00, 0.10)]) and language fluency (Vegetables [mean difference=-0.07 (95% CI -0.14, -0.01)], Boston Naming Test [mean difference=-0.07 (95% CI -0.13, -0.01)]). No differences in these neurocognitive performance scores were demonstrated between Treated HL and No HL groups other than MMSE [mean difference=-0.06 (95% CI -0.12, 0.00)]. Through follow-up, executive dysfunction differed by hearing group (χ2(2)=46.08, p<0.0001) and was present among 39.12% in No HL, 44.85% in Untreated HL, and 49.40% in Treated HL. Worse performance across all cognitive domains predicted incident dementia. Conclusion: The observed association between Untreated HL and lower cognitive ability that improved when hearing aids were worn may reflect an inability to hear the test instructions. Future studies using cognitive assessments validated for use in HL are needed to evaluate the neuropsychological profile of HL and identify individuals at risk for dementia.

Pages 865-875
Mallorie T. Tam, Jill A. Dosso, Julie M. Robillard
The Impact of a Global Pandemic on People Living with Dementia and Their Care Partners: Analysis of 417 Lived Experience Reports
Abstract: Background: The COVID-19 pandemic is impacting the physical and emotional health of older adults living with dementia and their care partners. Objective: Using a patient-centered approach, we explored the experiences and needs of people living with dementia and their care partners during the COVID-19 pandemic as part of an ongoing evaluation of dementia support services in British Columbia, Canada. Methods: A survey instrument was developed around the priorities identified in the context of the COVID-19 and Dementia Task Force convened by the Alzheimer Society of Canada. Results: A total of 417 surveys were analyzed. Overall, respondents were able to access information that was helpful for maintaining their own health and a period of social distancing. Care partners reported a number of serious concerns, including the inability to visit the person that they care for in long-term or palliative care. Participants also reported that the pandemic increased their levels of stress overall and that they felt lonelier and more isolated than they did before the pandemic. The use of technology was reported as a way to connect socially with their loved ones, with the majority of participants connecting with others at least twice per week. Conclusion: Looking at the complex effects of a global pandemic through the experiences of people living with dementia and their care partners is vital to inform healthcare priorities to restore their quality of life and health and better prepare for the future.

Pages 877-883
Kentaro Hirao, Fumio Yamashita, Akito Tsugawa, Rieko Haime, Raita Fukasawa, Tomohiko Sato, Hidekazu Kanetaka, Takahiko Umahara, Hirofumi Sakurai, Haruo Hanyu, Soichiro Shimizu
Association of White Matter Hyperintensity Progression with Cognitive Decline in Patients with Amnestic Mild Cognitive Impairment
Abstract: Background: White matter hyperintensities (WMH) on MRI have been reported to increase the risk of conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). However, effects of the progression of WMH on the cognition of patients with MCI remains unclear to date. Objective: To investigate the association between WMH progression and cognitive decline in amnestic MCI patients. Methods: Thirty-eight subjects with amnestic MCI were analyzed prospectively every year for 2 years. Fourteen MCI subjects dropped out on the final visit, and therefore 24 subjects with MCI were analyzed for the entire duration. The volumes of periventricular hyperintensities (PVH) and deep WMH (DWMH) were measured on T2 FLAIR using the 3D-slicer. The associations between PVH/DWMH progression and cognitive decline were investigated. Results: An increase in DWMH volume significantly correlated with changes in Mini-Mental State Examination and category verbal fluency scores, whereas an increase in PVH volume did not correlate with changes in any item. Conclusion: DWMH progression was closely associated with a decline in frontal lobe function and semantic memory, suggesting that WMH progression might affect some AD pathophysiologies in amnestic MCI patients.

Pages 885-893
Simona Daniele, Filippo Baldacci, Rebecca Piccarducci, Giovanni Palermo, Linda Giampietri, Maria Laura Manca, Deborah Pietrobono, Daniela Frosini, Valentina Nicoletti, Gloria Tognoni, Filippo Sean Giorgi, Annalisa Lo Gerfo, Lucia Petrozzi, Chiara Cavallini, Ferdinando Franzoni, Roberto Ceravolo, Gabriele Siciliano, Maria Letizia Trincavelli, Claudia Martini, Ubaldo Bonuccelli *These authors contributed equally to this work.
α-Synuclein Heteromers in Red Blood Cells of Alzheimer’s Disease and Lewy Body Dementia Patients
Abstract: Background: Red blood cells (RBCs) contain the majority of α-synuclein (α-syn) in blood, representing an interesting model for studying the peripheral pathological alterations proved in neurodegeneration. Objective: The current study aimed to investigate the diagnostic value of total α-syn, amyloid-β (Aβ1-42), tau, and their heteroaggregates in RBCs of Lewy body dementia (LBD) and Alzheimer’s disease (AD) patients compared to healthy controls (HC). Methods: By the use of enzyme-linked immunosorbent assays, RBCs concentrations of total α-syn, Aβ1-42, tau, and their heteroaggregates (α-syn/Aβ1-42 and α-syn/tau) were measured in 27 individuals with LBD (Parkinson’s disease dementia, n = 17; dementia with Lewy bodies, n = 10), 51 individuals with AD (AD dementia, n = 37; prodromal AD, n = 14), and HC (n = 60). Results: The total α-syn and tau concentrations as well as α-syn/tau heterodimers were significantly lower in the LBD group and the AD group compared with HC, whereas α-syn/Aβ1-42 concentrations were significantly lower in the AD dementia group only. RBC α-syn/tau heterodimers had a higher diagnostic accuracy for differentiating patients with LBD versus HC (AUROC = 0.80). Conclusion: RBC α-syn heteromers may be useful for differentiating between neurodegenerative dementias (LBD and AD) and HC. In particular, RBC α-syn/tau heterodimers have demonstrated good diagnostic accuracy for differentiating LBD from HC. However, they are not consistently different between LBD and AD. Our findings also suggest that α-syn, Aβ1-42, and tau interact in vivo to promote the aggregation and accumulation of each other.

Pages 895-904
Aung Zaw Zaw Phyo, David A. Gonzalez-Chica, Nigel P. Stocks, Elsdon Storey, Robyn L. Woods, Anne M. Murray, Suzanne G. Orchard, Raj C. Shah, Danijela Gasevic, Rosanne Freak-Poli, Joanne Ryan on behalf of the ASPREE Investigator Group
The Utility of Assessing Health-Related Quality of Life to Predict Cognitive Decline and Dementia
Abstract: Background: Health-related quality of life (HRQoL) has been shown to predict adverse health outcome in the general population. Objective: We examined the cross-sectional association between HRQoL and cognitive performance at baseline. Next, we explored whether baseline HRQoL predicted 5-year incident cognitive decline and dementia and whether there were gender differences. Methods: 19,106 community-dwelling participants from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, aged 65–98 years, free of major cognitive impairments, and completed the HRQoL 12-item short-form (SF-12) at baseline (2010-2014), were followed until June 2017. The physical (PCS) and mental component scores (MCS) of SF-12 were calculated. The cognitive tests were assessed at baseline, year 1, 3, 5, and 7 or close-out visit. Cognitive decline was defined as >1.5 SD drop from baseline on any of the cognitive tests. Dementia was adjudicated according to DSM-IV criteria. Linear and Cox proportional-hazards regressions were used to examine the cross-sectional and longitudinal associations respectively. Results: At baseline, higher PCS and MCS were associated with better cognition. Over a median 4.7-year follow-up, higher MCS was associated with a reduced risk of cognitive decline and dementia (12% and 15% respectively, per 10-unit increase) and a 10-unit higher PCS was associated with a 6% decreased risk of cognitive decline. PCS did not predict dementia incidence. Findings were not different by gender. Conclusion: Our study found that higher HRQoL, in particular MCS, predicted a reduced risk of cognitive decline and dementia over time in community-dwelling older people.