Journal of Alzheimer's Disease - Volume 95, issue 4

Authors: Fleischman, Debra A. | Arfanakis, Konstantinos | Zhang, Shengwei | Leurgans, Sue E. | Barnes, Lisa L. | Bennett, David A. | Marquez, David X. | Lamar, Melissa

Article Type: Research Article

Abstract: Background: Latinos are at higher risk of developing mild cognitive impairment (MCI) and Alzheimer’s disease than non-Latino Whites. Acculturation factors may influence this risk, yet there are few studies that have examined associations of acculturation, particularly in the context of socioenvironmental and familial factors, and brain health in older Latinos. Objective: To examine potential associations between acculturation in context and brain health in older Latinos. Methods: Using three previously established composites of acculturation-in-context, (acculturation-related: nativity status, language preference, acculturation scores; contextually-related socioenvironmental: perceived discrimination, loneliness/social isolation, social network size; and familism), and diffusion-tensor imaging (DTI), associations …with white matter structural integrity were examined in 92 Latino adults without dementia participating in one of three epidemiological studies of aging. Linear regression models were used to test associations with DTI-derived metrics (fractional anisotropy, FA; trace) as separate outcomes and acculturation composite scores as individual predictors, while adjusting for age, sex, education, scanner, and white matter hyperintensities (voxelwise and total volumes normalized by intracranial volume). Results: Higher scores on the socioenvironmental composite were associated with lower FA in two clusters of left-hemisphere connections. Cluster 1 was dominated by both short association pathways connecting frontal regions and projection pathways connecting frontal regions with the thalamus. Cluster 2 was dominated by long association pathways connecting parietal, frontal, and temporal regions. Conclusions: This study of older Latino adults demonstrated an association between reduced brain white matter integrity and contextually related socioenvironmental experiences known to increase risk of MCI and Alzheimer’s disease. Show more

Keywords: Acculturation, Alzheimer’s disease, brain structure, diffusion-tensor imaging, Hispanic, Latino, social determinants of health

DOI: 10.3233/JAD-230491

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1585-1595, 2023

Authors: Sejunaite, Karolina | Gaucher, Frederic | Lanza, Claudia | Riepe, Matthias W.

Article Type: Research Article

Abstract: Background: Clock Drawing Test (CDT) is a commonly used screening tool for cognitive disorders, known for its ease of administration and scoring. Despite frequent use by clinicians, CDT is criticized for its poor predictive value in mild cases of impairment. Objective: To evaluate CDT as a screening tool for early stage of cognitive impairment in biomarker-verified Alzheimer’s disease (AD) and depressive disorder (DD). Methods: We analyzed CDT of 172 patients with verified AD, 70 patients with DD, in whom neurodegenerative disorder was excluded using cerebrospinal fluid biomarkers, and 58 healthy older adults. CDT …was scored using the semi-quantitative (Shulman) and itemized criteria (adapted from Mendez). Results: Logistic regression showed that for both DD and AD patients with high Mini-Mental State Examination (MMSE) scores (27 and above) the significant predicting variable is uneven number spacing. As MMSE deteriorates (24-26 points), an additional error of setting clock hands is predictive of the disease. In the low MMSE condition, CDT showed an acceptable discrimination for AD (AUC itemized 0.740, Shulman 0.741) and DD (AUC itemized 0.827, Shulman 0.739) using both scoring methods. In the high MMSE condition, discrimination rates were acceptable using itemized scoring but poor using Shulman scoring for both AD (AUC itemized 0.707, Shulman 0.677) and DD (AUC itemized 0.755, Shulman 0.667) groups. Conclusion: Ideally, modern diagnostic process should take place before the cognitive performance drops beneath the healthy range. This makes CDT of little use when screening patients with very mild cognitive deficits. Show more

Keywords: Alzheimer’s disease, dementia, depressive disorder, mental status and dementia tests, screening

DOI: 10.3233/JAD-230110

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1597-1608, 2023

Authors: O’Bryant, Sid E. | Zhang, Fan | Johnson, Leigh A. | Hall, James | Petersen, Melissa | Oh, Esther S. | Lyketsos, Constantine G. | Rissman, Robert A.

Article Type: Research Article

Abstract: Background: The Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT) was the first-ever large-scale anti-inflammatory prevention trial targeting Alzheimer’s disease. Objective: The overall goal of this study was to evaluate predictive blood biomarker profiles that identified individuals most likely to be responders on NSAID treatment or placebo at 12 and 24 months. Methods: Baseline (n  = 193) and 12-month (n  = 562) plasma samples were assayed. The predictive biomarker profile was generated using SVM analyses with response on treatment (yes/no) as the outcome variable. Results: Baseline (AUC = 0.99) and 12-month (AUC = 0.99) predictive biomarker profiles were highly accurate in predicting …response on Celecoxib arm at 12 and 24 months. The baseline (AUC = 0.95) and 12-month (AUC = 0.9) predictive biomarker profile predicting response on Naproxen were also highly accurate at 12 and 24 months. The baseline (AUC = 0.93) and 12-month (AUC = 0.99) predictive biomarker profile was also highly accurate in predicting response on placebo. As with our prior work, the profiles varied by treatment arm. Conclusions: The current results provide additional support for a precision medicine model for treating and preventing Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, bioinformatics, biomarkers, clinical trial, inflammation, precision medicine, prevention, proteomics

DOI: 10.3233/JAD-230317

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1609-1622, 2023

Authors: Blusztajn, Jan Krzysztof | Aytan, Nurgul | Rajendiran, Thekkelnaycke | Mellott, Tiffany J. | Soni, Tanu | Burant, Charles F. | Serrano, Geidy E. | Beach, Thomas G. | Lin, Honghuang | Stein, Thor D.

Article Type: Research Article

Abstract: Background: Multiple studies have reported brain lipidomic abnormalities in Alzheimer’s disease (AD) that affect glycerophospholipids, sphingolipids, and fatty acids. However, there is no consensus regarding the nature of these abnormalities, and it is unclear if they relate to disease progression. Objective: Monogalactosyl diglycerides (MGDGs) are a class of lipids which have been recently detected in the human brain. We sought to measure their levels in postmortem human brain and determine if these levels correlate with the progression of the AD-related traits. Methods: We measured MGDGs by ultrahigh performance liquid chromatography tandem mass spectrometry in postmortem dorsolateral …prefrontal cortex gray matter and subcortical corona radiata white matter samples derived from three cohorts of participants: the Framingham Heart Study, the Boston University Alzheimer’s Disease Research Center, and the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program (total n  = 288). Results: We detected 40 molecular species of MGDGs (including diacyl and alkyl/acyl compounds) and found that the levels of 29 of them, as well as total MGDG levels, are positively associated with AD-related traits including pathologically confirmed AD diagnosis, clinical dementia rating, Braak and Braak stage, neuritic plaque score, phospho-Tau AT8 immunostaining density, levels of phospho-Tau396 and levels of Aβ40 . Increased MGDG levels were present in both gray and white matter, indicating that they are widespread and likely associated with myelin-producing oligodendrocytes—the principal cell type of white matter. Conclusions: Our data implicate the MGDG metabolic defect as a central correlate of clinical and pathological progression in AD. Show more

Keywords: Alzheimer’s disease, cerebral cortex, cerebrosides, gray matter, lipidomics, monogalactosyldiacylglycerol, white matter

DOI: 10.3233/JAD-230543

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1623-1634, 2023

Authors: Bruinsma, Jeroen | Heger, Irene | Loukas, Vasileios S. | Kassiotis, Thomas | Karanasiou, Georgia | Fotiadis, Dimitrios I. | Hanke, Sten | Crutzen, Rik

Article Type: Research Article

Abstract: Background: There is accumulating evidence that addressing modifiable risk and protective factors has an impact on dementia rates. Insight into the public’s perspectives on dementia risk reduction is needed to inform future individual-level interventions and public health approaches. Objective: This study explores the publics’ openness towards dementia risk reduction and willingness towards changing lifestyle behavior to reduce the future risk for dementia. Methods: Using a screening questionnaire, participants were purposively selected based on lifestyle behaviors that are associated with dementia risk. One-on-one interviews were used to explore their openness towards dementia risk reduction and willingness towards …behavior change. Independently, two researchers performed an inductive content analysis. Results: Interviews were conducted with 23 participants aged from 40 to 79 years. Main themes that were identified from the data were: 1) abstractness of dementia risk reduction, 2) ambivalence towards changing behavior, 3) negative self-image and low behavioral control, and 4) all-or-nothing thinking about lifestyle change. Conclusions: The concept of dementia risk reduction seems difficult to translate to the personal context, particularly if individuals perceive that dementia would occur decades in the future. This is problematic because a large proportion of the public needs a healthier lifestyle to reduce the incidence of dementia. Translating healthy intentions into behavior is complex and involves overcoming a variety of barriers that complicate dementia risk reduction initiatives. Support is needed for individuals who experience additional obstacles that obstruct commencing to a healthier lifestyle (e.g., negative self-image, engaging in multiple unhealthy behaviors, unrealistic perceptions about lifestyle change). Show more

Keywords: Alzheimer’s disease, behavior change, dementia, health promotion, prevention, public health

DOI: 10.3233/JAD-230217

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1635-1642, 2023

Authors: Nik Akhtar, Shayan | Lu, Qun

Article Type: Research Article

Abstract: Background: RhoA signaling is widely reported to be dysregulated in Alzheimer’s disease (AD), but its therapeutic targeting demonstrated mixed outcomes. We hypothesize that the activation and inactivation states of RhoA and LIMK are different in the cortex and in subregions of hippocampus along the rostral-caudal dimensions. Objective: We intended to elucidate the plane and spatial dependent RhoA signaling in association with AD. Methods: We applied antibody pRhoA that recognizes an inactive state of RhoA (S188 phosphorylation) and antibody pLIMK against an active state of LIMK (T508 phosphorylation) to investigate RhoA signaling in wildtype (WT) and triple …transgenic AD (3xTg-AD) mouse model. We prepared serial sections from the rostral to caudal coronal planes of the entire mouse brain followed by immunofluorescence staining with pRhoA and pLIMK antibodies. Results: Both pRhoA and pLIMK elicited a shift of expression pattern from rostral to caudal planes. Additionally, pRhoA demonstrated dynamic redistribution between the nucleus and cytoplasm. pLIMK did not show such nucleus and cytoplasm redistribution but the expression level was changed from rostral to caudal planes. At some planes, pRhoA showed an increasing trend in expression in the cortex but a decreasing trend in the dentate gyrus of the 3xTg-AD mouse hippocampus. pLIMK tends to decrease in the cortex but increase in the dentate gyrus of 3xTg-AD mouse hippocampus. Conclusions: RhoA activation is dysregulated in both human and mouse AD brains, and the RhoA-LIMK signaling axis reveals spatial dysregulation along the rostral-caudal plane dimensions. Show more

Keywords: Alzheimer’s disease, cell signaling, LIM kinase, mouse models, planar distribution, Rho GTPases, spatial expression

DOI: 10.3233/JAD-230408

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1643-1656, 2023

Authors: Sakurai, Keita | Kaneda, Daita | Morimoto, Satoru | Uchida, Yuto | Inui, Shohei | Kimura, Yasuyuki | Kato, Takashi | Ito, Kengo | Hashizume, Yoshio

Article Type: Research Article

Abstract: Background: Due to confusing clinicoradiological features such as amnestic symptoms and hippocampal atrophy in frontotemporal lobar degeneration (FTLD), antemortem differentiation between FTLD and Alzheimer’s disease (AD) can be challenging. Although asymmetric atrophy of the cerebral peduncle is regarded as a representative imaging finding in some disorders of the FTLD spectrum, the utility of this finding has not been sufficiently evaluated for differentiating between FTLD and AD. Objective: This study aimed to explore the diagnostic performance of asymmetric cerebral peduncle atrophy on axial magnetic resonance imaging as a simple radiological discriminator between FTLD and AD. Methods: Seventeen …patients with pathologically confirmed FTLD, including six with progressive supranuclear palsy, three with corticobasal degeneration, eight with TAR DNA-binding protein 43 (FTLD-TDP), and 11 with pathologically confirmed AD, were investigated. Quantitative indices representing the difference between the volumes of the bilateral cerebral peduncles (i.e., cerebral peduncular asymmetry index [CPAI]), the voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD) Z-score representing the degree of hippocampal atrophy, and semiquantitative visual analysis to evaluate the asymmetry of the cerebral peduncle (visual assessment of cerebral peduncular asymmetry: VACPA) were compared between the two groups. Results: Contrary to the VSRAD Z-score, the CPAI and VACPA scores demonstrated higher diagnostic performance in differentiating patients with FTLD from those with AD (areas under the receiver operating characteristic curve of 0.88, 082, and 0.60, respectively). Conclusions: Quantitative and visual analytical techniques can differentiate between FTLD and AD. These simple methods may be useful in daily clinical practice. Show more

Keywords: Alzheimer’s disease, asymmetric atrophy, cerebral peduncle, corticobasal degeneration, frontotemporal lobar degeneration, magnetic resonance imaging, progressive supranuclear palsy, TDP-43 proteinopathy

DOI: 10.3233/JAD-230441

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1657-1665, 2023

Authors: Parreño Torres, Alfonso | Roncero-Parra, Carlos | Borja, Alejandro L. | Mateo-Sotos, Jorge

Article Type: Research Article

Abstract: Background: In pursuit of diagnostic tools capable of targeting distinct stages of Alzheimer’s disease (AD), this study explores the potential of electroencephalography (EEG) combined with machine learning (ML) algorithms to identify patients with mild or moderate AD (ADM) and advanced AD (ADA). Objective: This study aims to assess the classification accuracy of six classical ML algorithms using a dataset of 668 patients from multiple hospitals. Methods: The dataset comprised measurements obtained from 668 patients, distributed among control, ADM, and ADA groups, collected from five distinct hospitals between 2011 and 2022. For classification purposes, six classical ML …algorithms were employed: support vector machine, Bayesian linear discriminant analysis, decision tree, Gaussian Naïve Bayes, K-nearest neighbor and random forest. Results: The RF algorithm exhibited outstanding performance, achieving a remarkable balanced accuracy of 93.55% for ADA classification and 93.25% for ADM classification. The consistent reliability in distinguishing ADA and ADM patients underscores the potential of the EEG-based approach for AD diagnosis. Conclusions: By leveraging a dataset sourced from multiple hospitals and encompassing a substantial patient cohort, coupled with the straightforwardness of the implemented models, it is feasible to attain notably robust results in AD classification. Show more

Keywords: Alzheimer’s disease, machine learning, EEG, feature extraction, ADM, ADA

DOI: 10.3233/JAD-230525

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1667-1683, 2023

Authors: Yang, Yanyan | Li, Mengfan | Leng, Bing | Yao, Ran | Xue, Song | Tan, Ming | Sun, Hairong | Zhang, Jinbiao

Article Type: Research Article

Abstract: Background: Cognitive impairment is common in patients with obstructive sleep apnea (OSA). Previous studies indicated that intermittent hypoxia, sleep fragmentation, and depressive symptoms were associated with cognitive impairment in OSA patients. Objective: The study aimed to investigate whether sleep characteristics and depressive symptoms affected cognitive abilities mediated by Alzheimer’s disease (AD) biomarkers and complement proteins in OSA patients without dementia. Methods: A total of 317 subjects without dementia who had undergone polysomnography, cognitive and neuropsychological evaluations, were recruited. Neuronal-derived exosomes (NDEs) levels for amyloid-β (Aβ), total tau (T-tau), and tau phosphorylated 62 at threonine 181 (P-T181-tau) …and astrocyte-derived exosomes (ADEs) levels for complement proteins were measured. Mediation analysis were performed to explore the mediation effects of AD biomarkers (Aβ42 , T-tau, P-T181-tau) and complement proteins (C3b and C5b-9) on cognition. Results: The findings revealed that the association between sleep fragmentation and cognition was mediated by Aβ42 (the percentage varied from 18.25% to 30.6%), P-T181-tau (the percentage varied from 24.36% to 32.3%), and C5b-9 (the percentage varied from 30.88% to 60.7%). The influence of depressive symptoms on cognition was only mediated via C3b (the percentage varied from 24.1% to 36.6%). Conclusions: In OSA patients without dementia, Aβ42 and P-T181-tau levels in NDEs, and C5b-9 levels in ADEs mediated the impact of sleep fragmentation on cognitive impairment, and C3b levels in ADEs mediated the impact of depressive symptoms on cognitive impairment. Show more

Keywords: Alzheimer’s disease biomarkers, cognition function, complement proteins, depressive symptoms, obstructive sleep apnea, sleep characteristics

DOI: 10.3233/JAD-221288

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1685-1696, 2023

Authors: Watts, Amber | Haneline, Stephen | Welsh-Bohmer, Kathleen A. | Wu, Jingtao | Alexander, Robert | Swerdlow, Russell H. | Burns, Daniel K. | Saunders, Ann M.

Article Type: Research Article

Abstract: Background: TOMM40 ‘523 has been associated with cognitive performance and risk for developing Alzheimer’s disease independent of the effect of APOE genotype. Few studies have considered the longitudinal effect of this genotype on change in cognition over time. Objective: Our objective was to evaluate the relationship between TOMM40 genotype status and change in cognitive performance in the TOMMORROW study, which was designed to prospectively evaluate an algorithm that includes TOMM40 ‘523 for genetic risk for conversion to mild cognitive impairment. Methods: We used latent growth curve models to estimate the effect …of TOMM40 allele carrier (short, very long) status on the intercept and slope of change in cognitive performance in four broad cognitive domains (attention, memory, executive function, and language) and a combined overall cognitive score over 30 months. Results: TOMM40 very long allele carriers had significantly lower baseline performance for the combined overall cognitive function score (B = –0.088, p  = 0.034) and for the executive function domain score (B = –0.143, p  = 0.013). Slopes for TOMM40 very long carriers had significantly greater increases over time for the executive function domain score only. In sensitivity analyses, the results for executive function were observed in participants who remained clinically stable, but not in those who progressed clinically over the study duration. Conclusions: Our results add to the growing body of evidence that TOMM40, in the absence of APOE ɛ 4, may contribute to cognitive changes with aging and dementia and support the view that mitochondrial function is an important contributor to Alzheimer’s disease risk. Show more

Keywords: Alzheimer’s disease, APOE , cognition, executive function, longitudinal, TOMM40

DOI: 10.3233/JAD-230066

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1697-1707, 2023