Journal of Alzheimer's Disease - Volume 90, issue 2

Authors: Zarbock, Katie R. | Han, Jessica H. | Singh, Ajay P. | Thomas, Sydney P. | Bendlin, Barbara B. | Denu, John M. | Yu, John-Paul J. | Rey, Federico E. | Ulland, Tyler K.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common aging-associated neurodegenerative disease; nevertheless, the etiology and progression of the disease is still incompletely understood. We have previously shown that the microbially-derived metabolite trimethylamine N -oxide (TMAO) is elevated in the cerebrospinal fluid (CSF) of individuals with cognitive impairment due to AD and positively correlates with increases in CSF biomarkers for tangle, plaque, and neuronal pathology. Objective: We assessed the direct impact of TMAO on AD progression. Methods: To do so, transgenic 5XFAD mice were supplemented with TMAO for 12 weeks. Neurite density was assessed through quantitative brain …microstructure imaging with neurite orientation dispersion and density imaging magnetic resonance imaging (MRI). Label-free, quantitative proteomics was performed on cortex lysates from TMAO-treated and untreated animals. Amyloid-β plaques, astrocytes, and microglia were assessed by fluorescent immunohistochemistry and synaptic protein expression was quantified via western blot. Results: Oral TMAO administration resulted in significantly reduced neurite density in several regions of the brain. Amyloid-β plaque mean intensity was reduced, while plaque count and size remained unaltered. Proteomics analysis revealed that TMAO treatment impacted the expression of 30 proteins (1.5-fold cut-off) in 5XFAD mice, including proteins known to influence neuronal health and amyloid-β precursor protein processing. TMAO treatment did not alter astrocyte and microglial response nor cortical synaptic protein expression. Conclusion: These data suggest that elevated plasma TMAO impacts AD pathology via reductions in neurite density. Show more

Keywords: Alzheimer’s disease, neurites, trimethylamine N-oxide

DOI: 10.3233/JAD-220413

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 585-597, 2022

Authors: Chino, Brenda | Zegarra-Valdivia, Jonathan | de Frutos-Lucas, Jaisalmer | Paredes-Manrique, Carmen | Custodio, Nilton

Article Type: Research Article

Abstract: Background: Cognitive impairment and dementia may result from a combination of modifiable and nonmodifiable risk and protective factors, such as the environment, educational attainment, time devoted to cognitively stimulating activities, and physical activity. Objective: This study aimed to investigate the mediating role of sociodemographic characteristics and lifestyle factors in the years of education and cognitive performance in Peruvian adults. Methods: This cross-sectional study included 1,478 subjects assessed by Addenbrooke’s Cognitive Examination Revised (ACE-R). Using mediation models, we evaluated the mediation role of parents’ educational level, reading time (RT), and physical activity time (PAT) in the years …of education (IYE) and cognitive performance. Results: People who reported having lived in an urban area during their childhood are estimated to have, on average, 2.085 years more formal education than those who lived in rural areas. In addition, 49% of cognitive performance scores are explained by the mediation effect of reading and physical activity time in the IYE. This implies that higher levels of education, mediated by RT and PAT per week, are 1.596 units associated with higher scores on the ACE-R. Conclusion: Despite the fact that nonmodifiable factors (i.e., childhood residence area, parents’ educational level) seem to exert an effect on older adults’ cognition, their influence is mediated by other factors that are indeed modifiable (i.e., reading time, physical activity engagement). In this sense, lifestyle changes could help prevent or decrease the risk of cognitive impairment and reduce the disease’s impact on vulnerable environments in Latin American and Caribbean countries. Show more

Keywords: Aging, cognitive performance, lifestyle, sociodemographic characteristics, vulnerable populations

DOI: 10.3233/JAD-220428

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 599-608, 2022

Authors: Wang, Zhuo | Wang, Jie | Liu, Ning | Liu, Caiyan | Li, Xiuxing | Dong, Liling | Zhang, Rui | Mao, Chenhui | Duan, Zhichao | Zhang, Wei | Gao, Jing | Wang, Jianyong

Article Type: Research Article

Abstract: Background: Accurate, cheap, and easy to promote methods for dementia prediction and early diagnosis are urgently needed in low- and middle-income countries. Integrating various cognitive tests using machine learning provides promising solutions. However, most effective machine learning models are black-box models that are hard to understand for doctors and could hide potential biases and risks. Objective: To apply cognitive-test-based machine learning models in practical dementia prediction and diagnosis by ensuring both interpretability and accuracy. Methods: We design a framework adopting Rule-based Representation Learner (RRL) to build interpretable diagnostic rules based on the cognitive tests selected by …doctors. According to the visualization and test results, doctors can easily select the final rules after analysis and trade-off. Our framework is verified on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset (n  = 606) and Peking Union Medical College Hospital (PUMCH) dataset (n  = 375). Results: The predictive or diagnostic rules learned by RRL offer a better trade-off between accuracy and model interpretability than other representative machine learning models. For mild cognitive impairment (MCI) conversion prediction, the cognitive-test-based rules achieve an average area under the curve (AUC) of 0.904 on ADNI. For dementia diagnosis on subjects with a normal Mini-Mental State Exam (MMSE) score, the learned rules achieve an AUC of 0.863 on PUMCH. The visualization analyses also verify the good interpretability of the learned rules. Conclusion: With the help of doctors and RRL, we can obtain predictive and diagnostic rules for dementia with high accuracy and good interpretability even if only cognitive tests are used. Show more

Keywords: Deep learning, dementia, interpretability, machine learning, neuropsychological tests

DOI: 10.3233/JAD-220502

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 609-624, 2022

Authors: Rovčanin Dragović, Isidora | Popović, Nataša | Ždralević, Maša | Radulović, Ljiljana | Vuković, Tijana | Marzano, Flaviana | Tullo, Apollonia | Radunović, Miodrag

Article Type: Research Article

Abstract: Background: Pathological and clinical features of Alzheimer’s disease (AD) are in temporal discrepancy and currently accepted clinical tests provide the diagnosis decades after the initial pathophysiological events. In order to enable a more timely detection of AD, research efforts are directed to identification of biomarkers of the early symptomatic stage. Neuroinflammatory signaling pathways and inflammation-related microRNAs (miRNAs) could possibly have a crucial role in AD, making them promising potential biomarkers. Objective: We examined the expression of circulatory miRNAs with a documented role in AD pathophysiology: miR-29a/b, miR-101, miR-125b, miR-146a, and miR-155 in the plasma of AD patients (AD, …n  = 12), people with mild cognitive impairment (MCI, n  = 9), and normocognitive group (CTRL, n  = 18). We hypothesized that these miRNA expression levels could correlate with the level of participants’ cognitive decline. Methods: The study participants completed the standardized interview, neurological examination, neuropsychological assessment, and biochemical analyses. miRNA expression levels were assessed by RT-PCR. Results: Neurological and laboratory findings could not account for MCI, but miR-146a and -155 were upregulated in the MCI group compared to the control. miR-146a, known to mediate early neuroinflammatory AD events, was also upregulated in the MCI compared to AD group. ROC curve analysis for miRNA-146a showed 77.8% sensitivity and 94.4% specificity and 66.7% sensitivity and 88.9% specificity for miR-155. Conclusion: Determination of circulatory inflamma-miRs-146a and -155 expression, together with neuropsychological screening, could become a non-invasive tool for detecting individuals with an increased risk for AD, but research on a larger cohort is warranted. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, miR-146a, miR-155, neuroinflammation

DOI: 10.3233/JAD-220676

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 625-638, 2022

Authors: Godefroy, Valérie | Batrancourt, Bénédicte | Charron, Sylvain | Bouzigues, Arabella | Sezer, Idil | Bendetowicz, David | Carle, Guilhem | Rametti-Lacroux, Armelle | Bombois, Stéphanie | Cognat, Emmanuel | Migliaccio, Raffaella | Levy, Richard

Article Type: Research Article

Abstract: Background: Apathy is highly frequent in behavioral variant frontotemporal dementia (bvFTD). It is presumed to involve different pathophysiological mechanisms and neuroanatomical regions. Objective: We explored the hypothesis that subgroups showing distinct profiles of apathy and distinct patterns of atrophy within frontal lobes could be disentangled in bvFTD. Methods: Using data-driven clustering applied to 20 bvFTD patients, we isolated subgroups according to their profiles on the three subscales of the Dimensional Apathy Scale (DAS). We explored their apathy profiles and atrophy patterns. Apathy profiles were characterized through both subjective measures of apathy by questionnaires and measures including …objective behavioral metrics. Atrophy patterns were obtained by voxel-based morphometry, contrasting each bvFTD subgroup with healthy controls (N = 16). Results: By clustering based on DAS dimensions, we disentangled three subgroups of bvFTD patients, with distinct apathy profiles and atrophy patterns. One subgroup, which presented the smallest pattern of atrophy (including orbitofrontal cortex) with a right asymmetry, was characterized by high self-reported emotional and initiation apathy and by a self-initiation deficit reversible by external guidance. In other subgroups showing more diffuse bilateral atrophies extending to lateral prefrontal cortex, apathy was not reversible by external guidance and more difficulty to focus on goal-management was observed, especially in the subgroup with the largest atrophy and highest levels of executive apathy. Conclusion: Distinct clinical profiles of apathy, corresponding to distinct anatomical subtypes of bvFTD, were identified. These findings have implications for clinicians in a perspective of precision medicine as they could contribute to personalize treatments of apathy. Show more

Keywords: Apathy, apathy subtypes, exploratory clustering, frontotemporal dementia, grey matter atrophy, voxel-based morphometry

DOI: 10.3233/JAD-220370

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 639-654, 2022

Authors: Zhang, Yanchun | Li, Chenxi | Chen, Deqiang | Tian, Rui | Yan, Xinyue | Zhou, Yingwen | Song, Yancheng | Yang, Yanlong | Wang, Xiaoxuan | Zhou, Bo | Gao, Yuhong | Jiang, Yujuan | Zhang, Xi

Article Type: Research Article

Abstract: Background: Early intervention of amnestic mild cognitive impairment (aMCI) may be the most promising way for delaying or even preventing the progression to Alzheimer’s disease. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that has been recognized as a promising approach for the treatment of aMCI. Objective: In this paper, we aimed to investigate the modulating mechanism of tDCS on the core neurocognitive networks of brain. Methods: We used repeated anodal high-definition transcranial direct current stimulation (HD-tDCS) over the left dorsolateral prefrontal cortex and assessed the effect on cognition and dynamic functional brain …network in aMCI patients. We used a novel method called temporal variability to depict the characteristics of the dynamic brain functional networks. Results: We found that true anodal stimulation significantly improved cognitive performance as measured by the Montreal Cognitive Assessment after simulation. Meanwhile, the Mini-Mental State Examination scores showed a clear upward trend. More importantly, we found significantly altered temporal variability of dynamic functional connectivity of regions belonging to the default mode network, central executive network, and the salience network after true anodal stimulation, indicating anodal HD-tDCS may enhance brain function by modulating the temporal variability of the brain regions. Conclusion: These results imply that ten days of anodal repeated HD-tDCS over the LDLPFC exerts beneficial effects on the temporal variability of the functional architecture of the brain, which may be a potential neural mechanism by which HD-tDCS enhances brain functions. Repeated HD-tDCS may have clinical uses for the intervention of brain function decline in aMCI patients. Show more

Keywords: High-definition transcranial direct current stimulation (HD-tDCS), mild cognitive disorder, temporal variability, triple network model

DOI: 10.3233/JAD-220539

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 655-666, 2022

Authors: Morrow, Autumn | Panyard, Daniel J. | Deming, Yuetiva K. | Jonaitis, Erin | Dong, Ruocheng | Vasiljevic, Eva | Betthauser, Tobey J. | Kollmorgen, Gwendlyn | Suridjan, Ivonne | Bayfield, Anna | Van Hulle, Carol A. | Zetterberg, Henrik | Blennow, Kaj | Carlsson, Cynthia M. | Asthana, Sanjay | Johnson, Sterling C. | Engelman, Corinne D.

Article Type: Research Article

Abstract: Background: Sphingomyelin (SM) levels have been associated with Alzheimer’s disease (AD), but the association direction has been inconsistent and research on cerebrospinal fluid (CSF) SMs has been limited by sample size, breadth of SMs examined, and diversity of biomarkers available. Objective: Here, we seek to build on our understanding of the role of SM metabolites in AD by studying a broad range of CSF SMs and biomarkers of AD, neurodegeneration, and neuroinflammation. Methods: Leveraging two longitudinal AD cohorts with metabolome-wide CSF metabolomics data (n  = 502), we analyzed the relationship between the levels of 12 CSF SMs, …and AD diagnosis and biomarkers of pathology, neurodegeneration, and neuroinflammation using logistic, linear, and linear mixed effects models. Results: No SMs were significantly associated with AD diagnosis, mild cognitive impairment, or amyloid biomarkers. Phosphorylated tau, neurofilament light, α -synuclein, neurogranin, soluble triggering receptor expressed on myeloid cells 2, and chitinase-3-like-protein 1 were each significantly, positively associated with at least 5 of the SMs. Conclusion: The associations between SMs and biomarkers of neurodegeneration and neuroinflammation, but not biomarkers of amyloid or diagnosis of AD, point to SMs as potential biomarkers for neurodegeneration and neuroinflammation that may not be AD-specific. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, metabolomics, neurodegeneration, neuroinflammation, sphingolipid, sphingomyelin

DOI: 10.3233/JAD-220349

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 667-680, 2022

Authors: Song, Yang | Quan, Meina | Li, Tingting | Jia, Jianping

Article Type: Research Article

Abstract: Background: Although elevated levels of homocysteine (Hcy) are associated with cognitive impairment and dementia, the relevance of Hcy, vitamin B12 , and folate levels to subtypes of dementia are still unknown. Objective: To investigate the changes of Hcy, vitamin B12 , and folate levels in mild cognitive impairment (MCI) and subtypes of dementia including Alzheimer’s disease (AD), vascular dementia (VaD), frontotemporal dementia (FTD), and Lewy body dementia (LBD), and their relationships with cognitive function and magnetic resonance imaging (MRI) markers. Methods: We measured serum levels of Hcy, vitamin B12 , and folate in 257 subjects. Each …subject underwent cognitive function assessment and brain MRI test. The Fazekas and temporal lobe atrophy (MTA) visual rating scales were used to assess the degree of white matter hyperintensities and MTA, respectively. Results: Serum levels of Hcy was higher and vitamin B12 was lower in AD, VaD, FTD, and LBD groups than cognitively normal controls. No significant differences of folate levels were found among 6 groups. Hcy levels were positively correlated with MTA total score in AD (r  = 0.448, p  < 0.001). Vitamin B12 levels were positively correlated with MoCA in VaD (r  = 0.497), and negatively correlated with MTA total score in AD (r  = – 0.325) (p s < 0.05). Hyperhomocysteinemia may increase the risk of AD (OR = 2.744), VaD (OR = 3.600), and FTD (OR = 3.244) in the adjusted model (p s < 0.05). Conclusion: Hcy and vitamin B12 levels are associated with MTA in AD. Vitamin B12 levels are associated with general cognition in VaD. Hyperhomocysteinemia is a risk factor for not only AD and VaD but also FTD. Show more

Keywords: Alzheimer’s disease, B vitamin, dementia, frontotemporal dementia, homocysteine, Lewy body dementia, mild cognitive impairment, vascular dementia

DOI: 10.3233/JAD-220410

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 681-691, 2022

Authors: Yamada, Yasunori | Kobayashi, Masatomo | Shinkawa, Kaoru | Nemoto, Miyuki | Ota, Miho | Nemoto, Kiyotaka | Arai, Tetsuaki

Article Type: Research Article

Abstract: Background: Early differential diagnosis of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) is important for treatment and disease management, but it remains challenging. Although computer-based drawing analysis may help differentiate AD and DLB, it has not been studied. Objective: We aimed to identify the differences in features characterizing the drawing process between AD, DLB, and cognitively normal (CN) individuals, and to evaluate the validity of using these features to identify and differentiate AD and DLB. Methods: We collected drawing data with a digitizing tablet and pen from 123 community-dwelling older adults in three clinical …diagnostic groups of mild cognitive impairment or dementia due to AD (n  = 47) or Lewy body disease (LBD; n  = 27), and CN (n  = 49), matched for their age, sex, and years of education. We then investigated drawing features in terms of the drawing speed, pressure, and pauses. Results: Reduced speed and reduced smoothness in speed and pressure were observed particularly in the LBD group, while increased pauses and total durations were observed in both the AD and LBD groups. Machine-learning models using these features achieved an area under the receiver operating characteristic curve (AUC) of 0.80 for AD versus CN, 0.88 for LBD versus CN, and 0.77 for AD versus LBD. Conclusion: Our results indicate how different types of drawing features were particularly discriminative between the diagnostic groups, and how the combination of these features can facilitate the identification and differentiation of AD and DLB. Show more

Keywords: Cognitive impairment, dementia, digital biomarker, handwriting, machine learning

DOI: 10.3233/JAD-220546

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 693-704, 2022

Authors: Alvarez, X. Anton | Winston, Charisse N. | Barlow, James W. | Sarsoza, Floyd M. | Alvarez, Irene | Aleixandre, Manuel | Linares, Carlos | García-Fantini, Manuel | Kastberger, Birgit | Winter, Stefan | Rissman, Robert A.

Article Type: Research Article

Abstract: Background: Plasma neuronal-derived extracellular vesicles (NDEV) contain proteins of pathological, diagnostic, and therapeutic relevance. Objective: We investigated the associations of six plasma NDEV markers with Alzheimer’s disease (AD) severity, cognition and functioning, and changes in these biomarkers after Cerebrolysin®, donepezil, and a combination therapy in AD. Methods: Plasma NDEV levels of Aβ42 , total tau, P-T181-tau, P-S393-tau, neurogranin, and REST were determined in: 1) 116 mild to advanced AD patients and in 20 control subjects; 2) 110 AD patients treated with Cerebrolysin®, donepezil, or combination therapy in a randomized clinical trial (RCT). Samples for NDEV determinations …were obtained at baseline in the NDEV study and at baseline and study endpoint in the RCT. Cognition and functioning were assessed at the same time points. Results: NDEV levels of Aβ42 , total tau, P-T181-tau, and P-S393-tau were higher and those of neurogranin and REST were lower in mild-to-moderate AD than in controls (p  < 0.05 to p  < 0.001). NDEV total tau, neurogranin, and REST increased with AD severity (p  < 0.05 to p  < 0.001). NDEV Aβ42 and P-T181-tau correlated negatively with serum BDNF (p  < 0.05), and total-tau levels were associated to plasma TNF-α (p  < 0.01) and cognitive impairment (p  < 0.05). Combination therapy reduced NDEV Aβ42 with respect to monotherapies (p  < 0.05); and NDEV total tau, P-T181-tau, and P-S396-tau were decreased in Cerebrolysin-treated patients compared to those on donepezil monotherapy (p  < 0.05). Conclusion: The present results demonstrate the utility of NDEV determinations of pathologic and synaptic proteins as effective AD biomarkers, as markers of AD severity, and as potential tools for monitoring the effects of anti-AD drugs. Show more

Keywords: Aβ42 , Alzheimer disease, Cerebrolysin®, combination therapy, donepezil, plasma neuronal-derived extracellular vesicles, tau

DOI: 10.3233/JAD-220575

Citation: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 705-717, 2022