Journal of Alzheimer's Disease - Volume 94, issue 1

Authors: Dorey, C. Kathleen | Gierhart, Dennis | Fitch, Karlotta A. | Crandell, Ian | Craft, Neal E.

Article Type: Research Article

Abstract: Background: Oxidative stress contributes to pathogenesis and progression of Alzheimer’s disease (AD). Higher levels of the dietary antioxidants— carotenoids and tocopherols— are associated with better cognitive functions and lower risk for AD, and lower levels of multiple carotenoids are found in serum and plasma of patients with AD. Although brains donated by individuals with mild cognitive impairment had significantly lower levels of lutein and beta-carotene, previous investigators found no significant difference in carotenoid levels of brains with AD and cognitively normal brains. Objective: This study tested the hypothesis that micronutrients are significantly lower in donor brains with AD …than in healthy elderly brains. Methods: Samples of donor brains with confirmed AD or verified health were dissected into grey and white matter, extracted with organic solvents and analyzed by HPLC. Results: AD brains had significantly lower levels of lutein, zeaxanthin, anhydrolutein, retinol, lycopene, and alpha-tocopherol, and significantly increased levels of XMiAD, an unidentified xanthophyll metabolite. No meso-zeaxanthin was detected. The overlapping protective roles of xanthophylls, carotenes, α- and γ -tocopherol are discussed. Conclusion: Brains with AD had substantially lower concentrations of some, but not all, xanthophylls, carotenes, and tocopherols, and several-fold higher concentrations of an unidentified xanthophyll metabolite increased in AD (XMiAD). Show more

Keywords: Alzheimer’s disease, antioxidants, brain, carotenoids, deficiency, lutein, lycopene, meso-zeaxanthin, oxidation, tocopherols, zeaxanthin

DOI: 10.3233/JAD-220460

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 1-17, 2023

Authors: Dilcher, Roxane | Malpas, Charles B. | O’Brien, Terence J. | Vivash, Lucy

Article Type: Review Article

Abstract: Behavioral variant frontotemporal dementia (bvFTD) belongs to the spectrum of frontotemporal lobar degeneration (FTLD) and is characterized by frontal dysfunction with executive deficits and prominent socioemotional impairments. Social cognition, such as emotion processing, theory of mind, and empathy may significantly impact daily behavior in bvFTD. Abnormal protein accumulation of tau or TDP-43 are the main causes of neurodegeneration and cognitive decline. Differential diagnosis is difficult due to the heterogeneous pathology in bvFTD and the high clinicopathological overlap with other FTLD syndromes, especially in late disease stages. Despite recent advances, social cognition in bvFTD has not yet received sufficient attention, nor …has its association with underlying pathology. This narrative review evaluates social behavior and social cognition in bvFTD, by relating these symptoms to neural correlates and underlying molecular pathology or genetic subtypes. Negative and positive behavioral symptoms, such as apathy and disinhibition, share similar brain atrophy and reflect social cognition. More complex social cognitive impairments are probably caused by the interference of executive impairments due to increasing neurodegeneration. Evidence suggests that underlying TDP-43 is associated with neuropsychiatric and early social cognitive dysfunction, while patients with underlying tau pathology are marked by strong cognitive dysfunction with increasing social impairments in later stages. Despite many current research gaps and controversies, finding distinct social cognitive markers in association to underlying pathology in bvFTD is essential for validating biomarkers, for clinical trials of novel therapies, and for clinical practice. Show more

Keywords: Alzheimer’s disease, behavior, frontotemporal dementia, pathology, social cognition

DOI: 10.3233/JAD-221171

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 19-38, 2023

Authors: Hui, Herbert Y.H. | Ran, An Ran | Dai, Jia Jia | Cheung, Carol Y.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) remains a global health challenge in the 21st century due to its increasing prevalence as the major cause of dementia. State-of-the-art artificial intelligence (AI)-based tests could potentially improve population-based strategies to detect and manage AD. Current retinal imaging demonstrates immense potential as a non-invasive screening measure for AD, by studying qualitative and quantitative changes in the neuronal and vascular structures of the retina that are often associated with degenerative changes in the brain. On the other hand, the tremendous success of AI, especially deep learning, in recent years has encouraged its incorporation with retinal imaging for predicting …systemic diseases. Further development in deep reinforcement learning (DRL), defined as a subfield of machine learning that combines deep learning and reinforcement learning, also prompts the question of how it can work hand in hand with retinal imaging as a viable tool for automated prediction of AD. This review aims to discuss potential applications of DRL in using retinal imaging to study AD, and their synergistic application to unlock other possibilities, such as AD detection and prediction of AD progression. Challenges and future directions, such as the use of inverse DRL in defining reward function, lack of standardization in retinal imaging, and data availability, will also be addressed to bridge gaps for its transition into clinical use. Show more

Keywords: Alzheimer’s disease, deep learning, deep reinforcement learning, reinforcement learning, retinal imaging

DOI: 10.3233/JAD-230055

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 39-50, 2023

Authors: Andersson, Marcus J. | Stone, Jonathan

Article Type: Review Article

Abstract: This review deals with an unwelcome reality about several forms of dementia, including Alzheimer’s disease— that these dementias are caused, in part or whole, by the aging of the vasculature. Since the vasculature ages in us all, dementia is our fate, sealed by the realit!ies of the circulation; it is not a disease with a cure pending. Empirically, cognitive impairment before our 7th decade is uncommon and considered early, while a diagnosis in our 11th decade is late but common in that cohort (>40%). Projections from earlier ages suggest that the prevalence of dementia in people surviving into their 12th …decade exceeds 80%. We address the question why so few of many interventions known to delay dementia are recognized as therapy; and we try to resolve this few-and-many paradox, identifying opportunities for better treatment, especially pre-diagnosis. The idea of dementia as a fate is resisted, we argue, because it negates the hope of a cure. But the price of that hope is lost opportunity. An approach more in line with the evidence, and more likely to limit suffering, is to understand the damage that accumulates with age in the cerebral vasculature and therefore in the brain, and which eventually gives rise to cognitive symptoms in late life, too often leading to dementia. We argue that hope should be redirected to delaying that damage and with it the onset of cognitive loss; and, for each individual, it should be redirected to a life-long defense of their brain. Show more

Keywords: Alzheimer’s disease, cerebral vasculature, chronic traumatic encephalopathy, dementia, dementia pugilistica, traumatic brain injury

DOI: 10.3233/JAD-230429

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 51-66, 2023

Authors: Chen, Hong-Li | Li, Cheng | Wang, Jing | Fei, Yang | Min, Min | Zhao, Yue | Shan, En-Fang | Yin, Yue-Heng | Liu, Chong-Yuan | Li, Xian-Wen

Article Type: Systematic Review

Abstract: Background: Feeding and eating disorders related to cognitive and psycho-behavioral symptoms are strongly associated with health status in persons with dementia (PWD). Non-pharmacological interventions have been the priority selection to address this significant issue. However, the direct targets of non-pharmacological interventions are unclear and there is no consistent evidence of recommendations on the intervention of different dementia stages and the settings of intervention practice. Objective: To provide caregivers with a set of self-help non-pharmacological interventions for feeding and eating disorders in PWD. Methods: Based on the process of evidence summary, a systematic literature search was performed …on dementia websites and seven databases. Two researchers screened the studies independently and appraise the quality. The evidence was graded by Joanna Briggs Institute Grades of Recommendation. Results: Twenty-eight articles were included. Twenty-three non-pharmacological intervention recommendations were categorized into six themes containing oral nutritional supplementation, assistance with eating and drinking, person-centered mealtime care, environmental modification, education or training, and multi-component intervention. These interventions corresponded to three direct targets including improving engagement, making up for loss ability, and increasing food intake directly. They were applied to different stages of dementia and most interventions were targeted at PWD in long-term care institutions. Conclusion: This article summarized the direct targets and the specific implementation of recommendations at different stages of dementia to provide caregivers with self-help non-pharmacological interventions. The practice of recommendations was more applicable to institutionalized PWD. When applied to PWD at home, caregivers need to identify the specific feeding and eating conditions at different stages and adopted the interventions in conjunction with the wishes of the PWD and professional advice. Show more

Keywords: Alzheimer’s disease, caregivers, dementia, feeding and eating disorders, non-pharmacological intervention

DOI: 10.3233/JAD-221032

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 67-88, 2023

Authors: Zinman, Julia | Kapoor, Arunima | Si, Kevin | Sujanthan, Sajeevan | Southwell, Alisia | Cayley, Megan L. | Sicard, Michelle N. | Lien, Karen | Murray, Brian J. | Lanctôt, Krista | Herrmann, Nathan | Dowlatshahi, Dar | Sahlas, Demetrios J. | Saposnik, Gustavo | Mandzia, Jennifer L. | Casaubon, Leanne K. | Hassan, Ayman | Perez, Yael | Swartz, Richard H.

Article Type: Short Communication

Abstract: While women have greater incidence of dementia, men have higher prevalence of vascular risk factors. This study examined sex differences in risk of screening positive for cognitive impairment after stroke. Ischemic stroke/TIA patients (N = 5969) participated in this prospective, multi-centered study, which screened for cognitive impairment using a validated brief screen. Men showed a higher risk of screening positive for cognitive impairment after adjusting for age, education, stroke severity, and vascular risk factors, suggesting that other factors may be contributing to increased risk among men (OR = 1.34, CI 95% [1.16, 1.55], p  < 0.001). The effect of sex on cognitive impairment after stroke …warrants further attention. Show more

Keywords: Alzheimer’s disease, cognitive impairment, sex difference, stroke, transient ischemic attack

DOI: 10.3233/JAD-230021

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 89-94, 2023

Authors: González, Andrea | Calfio, Camila | Lüttges, Valentina | González-Madrid, Antonia | Guzmán, Cristian

Article Type: Short Communication

Abstract: Alzheimer’s disease (AD) is the most common form of dementia in the elderly. AD is a multifactorial disease, affected by several factors including amyloid-β42 oligomers, self-assembled tau, microbiota molecules, etc. However, inflammatory components are critical to trigger AD. Neuroinflammatory pathology links glial activation by “damage signals” with tau hyperphosphorylation, as explained by the Neuroimmunomodulation Theory, discovered by the ICC laboratory. This theory elucidates the onset and progression of several degenerative diseases and concept of “multitarget” therapy. These studies led to the rationale to identify inflammatory targets for the action of bioactive molecules or drugs against AD.

Keywords: Alzheimer’s disease, anti-inflammatory agents, blood-brain barrier, immunomodulation, neuroinflammation, proinflammatory markers

DOI: 10.3233/JAD-230150

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 95-100, 2023

Authors: De Anda-Duran, Ileana | Kolachalama, Vijaya B. | Carmichael, Owen T. | Hwang, Phillip H. | Fernandez, Camilo | Au, Rhoda | Bazzano, Lydia A. | Libon, David J.

Article Type: Research Article

Abstract: Background: Individuals with Alzheimer’s disease (AD) often present with coexisting vascular pathology that is expressed to different degrees and can lead to clinical heterogeneity. Objective: To examine the utility of unsupervised statistical clustering approaches in identifying neuropsychological (NP) test performance subtypes that closely correlate with carotid intima-media thickness (cIMT) in midlife. Methods: A hierarchical agglomerative and k-means clustering analysis based on NP scores (standardized for age, sex, and race) was conducted among 1,203 participants (age 48±5.3 years) from the Bogalusa Heart Study. Regression models assessed the association between cIMT ≥50th percentile and NP profiles, and …global cognitive score (GCS) tertiles for sensitivity analysis. Results: Three NP profiles were identified: Mixed-low performance [16%, n  = 192], scores ≥1 SD below the mean on immediate, delayed free recall, recognition verbal memory, and information processing; Average [59%, n  = 704]; and Optimal [26%, n  = 307] NP performance. Participants with greater cIMT were more likely to have a Mixed-low profile [OR = 3.10, 95% CI (2.13, 4.53), p  < 0.001] compared to Optimal. After adjusting for education and cardiovascular (CV) risks, results remained. The association with GCS tertiles was more attenuated [lowest (34%, n  = 407) versus highest (33%, n  = 403) tertile: adjusted OR = 1.66, 95% CI (1.07, 2.60), p  = 0.024]. Conclusion: As early as midlife, individuals with higher subclinical atherosclerosis were more likely to be in the Mixed-low profile, underscoring the potential malignancy of CV risk as related to NP test performance, suggesting that classification approaches may aid in identifying those at risk for AD/vascular dementia spectrum illness. Show more

Keywords: Alzheimer’s disease, atherosclerosis, cognition, midlife, neuropsychological subtyping, vascular risk

DOI: 10.3233/JAD-220931

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 101-113, 2023

Authors: Liu, Jieyi | Xie, Yirong | Lu, Yao | Zhao, Zhiqiang | Zhuang, Zhixiong | Yang, Linqing | Huang, Haiyan | Li, Hongya | Mao, Zhiyi | Pi, Shurong | Chen, Fubin | He, Yun

Article Type: Research Article

Abstract: Background: There is limited information about gene-environment interaction on the occurrence and the progression of Alzheimer’s disease. Objective: To explore the effect of environmental low-dose cadmium (Cd) exposure on the progress of Alzheimer’s disease and the underlining mechanism. Methods: We administered 1 mg/L, 10 mg/L cadmium chloride (treated groups), and water (control group) to C57BL/6J and APP/PS1 mice through drinking water, from one week before mating, until the offspring were sacrificed at 6 months of age. The behaviors, Cd level, blood-brain barrier (BBB) leakage, Aβ1-42 deposition, and inflammation expression were evaluated in these mice. Results: …Mice of both genotypes had similar blood Cd levels after exposure to the same dose of Cd. The toxic effects of Cd on the two genotypes differed little in terms of neuronal histomorphology and BBB permeability. Cd caused a series of pathological morphological changes in the mouse brains and more fluorescent dye leakage at higher doses. Furthermore, the APP/PS1 mice had more severe damage than the C57BL/6J mice, based on the following five criteria. They were increasing anxiety-like behavior and chaos movement, spatial reference memory damage, Aβ plaque deposition in mouse brains, increasing microglia expression in the brain, and IL-6 higher expression in the cortex and in the serum. Conclusion: Low-dose Cd exposure for 6 months increases Aβ plaque deposition and BBB permeability, exacerbates inflammatory responses, and activates microglia, in APP/PS1 mice. APP/PS1 gene-environmental Cd interaction aggravates the progression of Alzheimer’s disease in mice. Show more

Keywords: Alzheimer’s disease, APP/PS1 gene, blood-brain barrier, cadmium, gene-environment interaction, inflammatory response

DOI: 10.3233/JAD-221205

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 115-136, 2023

Authors: Fu, Yu | Li, Xiaolong | Wang, Ting | Yan, Shuhua | Zhang, Xisheng | Hu, Geng | Zhou, Jin | Wang, Yan | Liu, ChangShu | Wang, Sai | Cong, Yang | Chen, Liangkai | Li, Tingting | Rong, Shuang

Article Type: Research Article

Abstract: Background: The consistent definition of sarcopenic obesity (SO) is limited, its association with mild cognitive impairment (MCI) has not been clarified. Objective: This study aimed to evaluate the prevalence and agreement of SO using different definitions and the association between SO and MCI. Methods: SO was diagnosed by the co-existence of sarcopenia defined by the Asia Working Group for Sarcopenia (AWGS) and obesity by body mass index (BMI), visceral fat area (VFA), waist circumference (WC), or body fat percentage (BF%). Cohen’s kappa was used to assess the agreement between the different definitions. The association between SO …and MCI was assessed using multivariable logistic regression. Results: Among 2,451 participants, the prevalence of SO ranged from 1.7% to 8.0% under different definitions. SO defined by AWGS and BMI (AWGS+BMI) showed fair agreements with the other three criteria (κ ranged from 0.334 to 0.359). The other criteria showed good agreements with each other. The κ statistics were 0.882 for AWGS+VFA and AWGS+BF%, 0.852 for AWGS+VFA and AWGS+WC, and 0.804 for AWGS+BF% and AWGS+WC, respectively. When using different diagnoses of SO, compared with the health group, the adjusted ORs of MCI for SO were 1.96 (95% CI: 1.29-2.99, SO: AWGS+WC), 1.75 (95% CI: 1.14-2.68, SO: AWGS+VFA), 1.94 (95% CI: 1.29-2.93, SO: AWGS+BF%), and 1.45 (95% CI: 0.67-3.12, SO: AWGS+BMI), respectively. Conclusion: Using different obesity indicators combined with AWGS to diagnose SO, BMI had lower prevalence and agreement compared with other three indicators. SO was associated with MCI under different methods (WC, VFA, or BF%). Show more

Keywords: Alzheimer’s disease, cross-sectional study, diagnostic agreement, mild cognitive impairment, prevalence, sarcopenic obesity

DOI: 10.3233/JAD-221232

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 137-146, 2023