Journal of Alzheimer's Disease - Volume 93, issue 1

Authors: Fortea, Juan | García-Arcelay, Elena | Terrancle, Ángeles | Gálvez, Blanca | Díez-Carreras, Verónica | Rebollo, Pablo | Maurino, Jorge | Garcia-Ribas, Guillermo

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) biomarkers reflect key elements of pathophysiology and improve the diagnostic process. However, their use in routine clinical practice is still limited. Objective: We aimed to assess neurologists' barriers and enablers to early AD diagnosis using core AD biomarkers. Methods: We conducted an online study in collaboration with the Spanish Society of Neurology. Neurologists answered a survey exploring their attitudes towards AD diagnosis using biomarkers in mild cognitive impairment (MCI) or mild AD dementia. Multivariate logistic regression analyses were conducted to determine the association between neurologists’ characteristics and diagnostic attitudes. Results: …We included 188 neurologists with a mean age (SD) of 40.6 (11.3) years, 52.7% male. Most participants had access to AD biomarkers, mainly in cerebrospinal fluid (CSF) (89.9%,#x0025;, n  = 169). The majority of participants (95.2%,#x0025;, n  = 179) considered CSF biomarkers useful for an etiological diagnosis in MCI. However, 85.6% of respondents (n  = 161) used them in less than 60% of their MCI patients in routine clinical practice. Facilitating patients and their families to plan for the future was the most frequent enabler for the use of biomarkers. Short consultation time and practicalities associated with the programming of a lumbar puncture were the most common barriers. A younger neurologist age (p  = 0.010) and a higher number of patients managed weekly (p  = 0.036) were positively associated with the use of biomarkers. Conclusion: Most neurologists had a favorable attitude to the use of biomarkers, especially in MCI patients. Improvements in resources and consultation time may increase their use in routine clinical practice. Show more

Keywords: Alzheimer’s disease, biomarkers, decision making, diagnosis, neurologists

DOI: 10.3233/JAD-221160

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 275-282, 2023

Authors: Sun, Yan | Hu, He-Ying | Hu, Hao | Huang, Liang-Yu | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Cerebral small vessel disease (CSVD) has been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD). Objective: This study aimed to comprehensively investigated the associations of CSVD burden with cognition and AD pathologies. Methods: A total of 546 non-demented participants (mean age, 72.1 years, range, 55–89; 47.4% female) were included. The longitudinal neuropathological and clinical correlates of CSVD burden were assessed using linear mixed-effects and Cox proportional-hazard models. Partial least squares structural equation model (PLS-SEM) was used to assess the direct and indirect effects of CSVD burden on cognition. …Results: We found that higher CSVD burden was associated with worse cognition (MMSE, β= –0.239, p  = 0.006; MoCA, β= –0.493, p  = 0.013), lower cerebrospinal fluid (CSF) Aβ level (β= –0.276, p  < 0.001) and increased amyloid burden (β= 0.048, p  = 0.002). In longitudinal, CSVD burden contributed to accelerated rates of hippocampus atrophy, cognitive decline, and higher risk of AD dementia. Furthermore, as the results of PLS-SEM, we observed both significant direct and indirect impact of advanced age (direct, β= –0.206, p  < 0.001; indirect, β= –0.002, p  = 0.043) and CSVD burden (direct, β= –0.096, p  = 0.018; indirect, β= –0.005, p  = 0.040) on cognition by Aβ-p-tau-tau pathway. Conclusion: CSVD burden could be a prodromal predictor for clinical and pathological progression. Simultaneously, we found that the effects were mediated by the one-direction-only sequence of pathological biomarker changes starting with Aβ, through abnormal p-tau, and neurodegeneration. Show more

Keywords: Alzheimer’s disease, cerebral small vessel disease, cerebrospinal fluid biomarkers, cognition, partial least squares structural equation pathway model

DOI: 10.3233/JAD-221207

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 283-294, 2023

Authors: Lv, Xuedan | Chu, Min | Liu, Yang | Jing, Donglai | Liu, Li | Cui, Yue | Wang, Yihao | Jiang, Deming | Song, Weiqun | Yang, Caishui | Wu, Liyong

Article Type: Research Article

Abstract: Background: Research on posterior cortical atrophy (PCA) has focused on cognitive decline, especially visual processing deficits. However, few studies have examined the impact of PCA on activities of daily living (ADL) and the neurofunctional and neuroanatomic bases of ADL. Objective: To identify brain regions associated with ADL in PCA patients. Methods: A total of 29 PCA patients, 35 typical Alzheimer’s disease (tAD) patients, and 26 healthy volunteers were recruited. Each subject completed an ADL questionnaire that included basic and instrumental subscales (BADL and IADL, respectively), and underwent hybrid magnetic resonance imaging and 18 …F fluorodeoxyglucose positron emission tomography. Voxel-wise regression multivariable analysis was conducted to identify specific brain regions associated with ADL. Results: General cognitive status was similar between PCA and tAD patients; however, the former had lower total ADL scores and BADL and IADL scores. All three scores were associated with hypometabolism in bilateral parietal lobes (especially bilateral superior parietal gyri) at the whole-brain level, PCA-related hypometabolism level, and PCA-specific hypometabolism level. A cluster that included the right superior parietal gyrus showed an ADL×group interaction effect that was correlated with the total ADL score in the PCA group (r  = –0.6908, p  = 9.3599e–5 ) but not in the tAD group (r  = 0.1006, p  = 0.5904). There was no significant association between gray matter density and ADL scores. Conclusion: Hypometabolism in bilateral superior parietal lobes contributes to a decline in ADL in patients with PCA and can potentially be targeted by noninvasive neuromodulatory interventions. Show more

Keywords: Alzheimer’s disease, posterior cortical atrophy, activities of daily living, FDG-PET, neuroimaging

DOI: 10.3233/JAD-221229

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 295-305, 2023

Authors: Jang, Sehwan | Chorna, Nataliya | Rodríguez-Graciani, Keishla M. | Inyushin, Mikhail | Fossati, Silvia | Javadov, Sabzali

Article Type: Research Article

Abstract: Background: An increasing number of experimental and clinical studies show a link between Alzheimer’s disease and heart diseases such as heart failure, ischemic heart disease, and atrial fibrillation. However, the mechanisms underlying the potential role of amyloid-β (Aβ) in the pathogenesis of cardiac dysfunction in Alzheimer’s disease remain unknown. We have recently shown the effects of Aβ1 - 40 and Aβ1 - 42 on cell viability and mitochondrial function in cardiomyocytes and coronary artery endothelial cells. Objective: In this study, we investigated the effects of Aβ1 - 40 and Aβ1 - 42 on the metabolism of cardiomyocytes and coronary artery …endothelial cells. Methods: Gas chromatography-mass spectrometry was used to analyze metabolomic profiles of cardiomyocytes and coronary artery endothelial cells treated with Aβ1 - 40 and Aβ1 - 42 . In addition, we determined mitochondrial respiration and lipid peroxidation in these cells. Results: We found that the metabolism of different amino acids was affected by Aβ1 - 42 in each cell type, whereas the fatty acid metabolism is consistently disrupted in both types of cells. Lipid peroxidation was significantly increased, whereas mitochondrial respiration was reduced in both cell types in response to Aβ1 - 42 . Conclusion: This study revealed the disruptive effects of Aβ on lipid metabolism and mitochondria function in cardiac cells. Show more

Keywords: Alzheimer’s disease, amyloid-β , cardiomyocytes, coronary artery endothelial cells, metabolomics, mitochondria

DOI: 10.3233/JAD-221199

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 307-319, 2023

Authors: El-Hayeck, Rita | Wehbé, Amine | Baddoura, Rafic | Khoury, Rita | Bassil, Nazem | Abou Khaled, Karine | Koussa, Salam | Richa, Sami | Alameddine, Abbas | Sellal, François

Article Type: Research Article

Abstract: Background: Verbal fluency tasks are frequently used for neuropsychological assessment in clinical practice and research. It consists of two tasks namely category and letter fluency tests. Objective: To determine normative values in category (animals, vegetables, fruits) and letter fluency [Mim ( ) “M”, Alif ( ) “A”, Baa ( ) “B”] tasks in Arabic language in 60 s. Methods: This study was a cross-sectional national survey and included 859 community-dwelling, cognitively intact Lebanese residents aged ≥55 years. Norms were presented according to age (55–64 years, 65–74 years, ≥75 years), sex and level of education (illiterate, no diploma, …primary certificate, baccalaureate or higher). Results: Level of education had the most significant positive effect on verbal fluency tasks performance amongst Lebanese older adults. The negative effect of older age was more prominent in the category fluency task compared to the letter fluency task. Women outperformed men in vegetables and fruits categories. Conclusion: This study provides clinicians with normative scores of category and letter fluency tests, which can be used for neuropsychological assessment of older Lebanese patients being evaluated for cognitive disorders. Show more

Keywords: Cognitive aging, dementia, language tests, Lebanon, neuropsychological tests, reference standards

DOI: 10.3233/JAD-221121

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 321-332, 2023

Authors: Nakamura, Takumi | Kawarabayashi, Takeshi | Ueda, Tetsuya | Shimomura, Sachiko | Hoshino, Masaki | Itoh, Ken | Ihara, Kazushige | Nakaji, Shigeyuki | Takatama, Masamitsu | Ikeda, Yoshio | Shoji, Mikio

Article Type: Research Article

Abstract: Background: APOE4 is the strongest risk factor for Alzheimer’s disease (AD). However, limited information is currently available on APOE4 and the pathological role of plasma apolipoprotein E (ApoE) 4 remains unclear. Objective: The aims of the present study were to measure plasma levels of total ApoE (tE), ApoE2, ApoE3, and ApoE4 using mass spectrometry and elucidate the relationships between plasma ApoE and blood test items. Methods: We herein examined plasma levels of tE, ApoE2, ApoE3, and ApoE4 in 498 subjects using liquid chromatograph-mass spectrometry (LC-MS/MS). Results: Among 498 subjects, mean age was …60 years and 309 were female. tE levels were distributed as ApoE2/E3 = ApoE2/E4 >ApoE3/E3 = ApoE3/E4 >ApoE4/E4. In the heterozygous group, ApoE isoform levels were distributed as ApoE2 >ApoE3 >ApoE4. ApoE levels were not associated with aging, the plasma amyloid-β (Aβ) 40/42 ratio, or the clinical diagnosis of AD. Total cholesterol levels correlated with the level of each ApoE isoform. ApoE2 levels were associated with renal function, ApoE3 levels with low-density lipoprotein cholesterol and liver function, and ApoE4 levels with triglycerides, high-density lipoprotein cholesterol, body weight, erythropoiesis, and insulin metabolism. Conclusion: The present results suggest the potential of LC-MS/MS for the phenotyping and quantitation of plasma ApoE. Plasma ApoE levels are regulated in the order of ApoE2 >ApoE3 >ApoE4 and are associated with lipids and multiple metabolic pathways, but not directly with aging or AD biomarkers. The present results provide insights into the multiple pathways by which peripheral ApoE4 influences the progression of AD and atherosclerosis. Show more

Keywords: Alzheimer’s disease, amyloid-β , ApoE, biomarkers, cholesterol, HDL, isoform, LDL

DOI: 10.3233/JAD-220996

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 333-348, 2023

Authors: Widjaya, Michael Anekson | Cheng, Yu-Jung | Kuo, Yu-Min | Liu, Chia-Hsin | Cheng, Wei-Chung | Lee, Shin-Da

Article Type: Research Article

Abstract: Background: Research reported exercise could reduce Alzheimer’s disease (AD) symptoms in human and animals. However, the molecular mechanism of exercise training via transcriptomic analysis was unclear especially in AD in the cortex area. Objective: Investigate potential significant pathways in the cortex area that were affected by exercise during AD. Methods: RNA-seq analysis, differential expressed genes, functional enrichment analysis, and GSOAP clustering analysis were performed in the isolated cerebral cortex from eight 3xTg AD mice (12 weeks old) randomly and equally divided into control (AD) and exercise training (AD-EX) group. Swimming exercise training in AD-EX group was …conducted 30 min/day for 1 month. Results: There were 412 genes significant differentially expressed in AD-EX group compared to AD group. Top 10 upregulated genes in AD-EX group against AD group mostly correlated with neuroinflammation, while top 10 downregulated genes mostly had connection with vascularization, membrane transport, learning memory, and chemokine signal. Pathway analysis revealed the upregulated interferon alpha beta signaling in AD-EX had association with cytokines delivery in microglia cells compared to AD and top 10 upregulated genes involved in interferon alpha beta were Usp18 , Isg15 , Mx1 , Mx2 , Stat1 , Oas1a , and Irf9 ; The downregulated extracellular matrix organization in AD-EX had correlation with Aβ and neuron cells interaction and Vtn was one of the top 10 downregulated genes involved in this pathway. Conclusion: Exercise training influenced 3xTg mice cortex through interferon alpha beta signaling upregulation and extracellular matrix organization downregulation based on transcriptomics analysis. Show more

Keywords: Alzheimer’s disease, bioinformatics, cortex, exercise

DOI: 10.3233/JAD-221139

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 349-363, 2023

Authors: Tetlow, Amber M. | Jackman, Brianna M. | Alhadidy, Mohammed M. | Perumal, Varshini | Morgan, David G. | Gordon, Marcia N.

Article Type: Research Article

Abstract: Background: Advanced age is the greatest risk factor for the development of Alzheimer’s disease (AD). This implies that some aspect of the aged milieu is possibly accelerating the development of AD related pathologies. Objective: We hypothesized that intracranially injected with AAV9 tauP301L may cause a greater degree of pathology in old versus young mice. Methods: Animals were injected with viral vectors overexpressing the mutant tauP301L or control protein (green fluorescent protein, GFP) into the brains of mature, middle-aged, and old C57BL/6Nia mice. The tauopathy phenotype was monitored four months after injection using behavioral, histological, …and neurochemical measures. Results: Phosphorylated-tau immunostaining (AT8) or Gallyas staining of aggregated tau increased with age, but other measures of tau accumulation were not significantly affected. Overall, AAV-tau injected mice had impaired radial arm water maze performance, increased microglial activation, and showed evidence of hippocampal atrophy. Aging impaired open field and rotarod performance in both AAV-tau and control mice. The efficiency of viral transduction and gene expression were the same at all animal ages. Conclusion: We conclude that tauP301L over expression results in a tauopathy phenotype with memory impairment and accumulation of aggregated tau. However, the effects of aging on this phenotype are modest and not detected by some markers of tau accumulation, similar to prior work on this topic. Thus, although age does influence the development of tauopathy, it is likely that other factors, such as ability to compensate for tau pathology, are more responsible for the increased risk of AD with advanced age. Show more

Keywords: Adeno-associated virus, aging, animal disease models, tauopathy

DOI: 10.3233/JAD-221276

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 365-378, 2023

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

Article Type: Research Article

Abstract: Background: Due to clinicoradiological similarities, including amnestic cognitive impairment and limbic atrophy, differentiation of argyrophilic grain disease (AGD) from Alzheimer’s disease (AD) is often challenging. Minimally invasive biomarkers, especially magnetic resonance imaging (MRI), are valuable in routine clinical practice. Although it is necessary to explore radiological clues, morphometry analyses using new automated analytical methods, including whole-brain voxel-based morphometry (VBM) and surface-based morphometry (SBM), have not been sufficiently investigated in patients with pathologically confirmed AGD and AD. Objective: This study aimed to determine the volumetric differences in VBM and SBM analyses between patients with pathologically confirmed AGD and AD. …Methods: Eight patients with pathologically confirmed AGD with a lower Braak neurofibrillary tangle stage (<III), 11 patients with pathologically confirmed AD without comorbid AGD, and 10 healthy controls (HC) were investigated. Gray matter volumetric changes in VBM and cortical thickness changes in SBM were compared between the two patient groups (i.e., AGD and AD) and the HC group. Results: In contrast to widespread gray matter volume or cortical thickness loss in the bilateral limbic, temporoparietal, and frontal lobes of the AD group, these were limited, especially in the limbic lobes, in the AGD group, compared with that of the HC group. Although bilateral posterior dominant gray matter volume loss was identified in the AD group compared with the AGD group on VBM, there was no significant cluster between these patient groups on SBM. Conclusion: VBM and SBM analyses both showed a different distribution of atrophic changes between AGD and AD. Show more

Keywords: Alzheimer’s disease, argyrophilic grain disease, computational anatomy toolbox 12, statistical parametric mapping, surface-based morphometry, voxel-based morphometry

DOI: 10.3233/JAD-230068

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 379-387, 2023

Authors: Kawakatsu, Shinobu | Kobayashi, Ryota

Article Type: Article Commentary

Abstract: In this issue, Sakurai et al. report on relevant findings for the clinical diagnosis of argyrophilic grain disease (AGD). Their study describes a characteristic atrophy distribution restricted to the limbic lobes, namely the ambient gyrus, in AGD versus Alzheimer’s disease (AD), in pathologically confirmed patients using magnetic resonance imaging by voxel- and surface-based morphometry. Here, we discuss the possibility of employing functional or molecular brain imaging to further improvement of diagnosis of AGD. Additional research is required to elucidate the contributions of comorbid AD and transactive response DNA-binding protein 43 kDa pathologies in patients with AGD.

Keywords: Alzheimer’s disease, argyrophilic grain disease, MRI, SPECT, suspected non-Alzheimer’s disease pathophysiology, tau PET, TDP-43

DOI: 10.3233/JAD-230247

Citation: Journal of Alzheimer's Disease, vol. 93, no. 1, pp. 389-392, 2023