Journal of Alzheimer's Disease - Volume 82, issue 1

Authors: Ng, Kok Pin | Cheng, Grand H.-L. | Yatawara, Chathuri | Rosa-Neto, Pedro | Gauthier, Serge | Kandiah, Nagaendran | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid t-tau (CSF t-tau) is a measure of neurodegeneration in Alzheimer’s disease (AD) and has been increasingly demonstrated to be a non-specific biomarker within the AD continuum. Objective: We sought to test whether t-tau influences the longitudinal effects of amyloid-β (Aβ) and phospho-tau (p-tau) on memory and executive function (EF) in mild cognitive impairment (MCI). Methods: 319 MCI individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with baseline and 2-year CSF Aβ, p-tau, t-tau, and neuropsychological assessments were studied. Mediation and moderation analyses evaluated the role of t-tau in the effects of Aβ and …p-tau on memory and EF over 2 years. Results: We found that high baseline p-tau but not Aβ was associated with higher t-tau and lower memory scores at 2 years follow-up. The association between p-tau and memory impairment was partially mediated by t-tau, whereby higher p-tau was indirectly associated with lower memory via higher t-tau. t-tau also moderated the association between p-tau and memory. When t-tau level was relatively lower, higher p-tau was associated with lower memory scores at 2 years. When t-tau level was higher, the memory scores were low regardless of the p-tau level. Conclusion: Tau-induced neurodegeneration is one key pathway by which AD pathology (p-tau) affects memory impairment. Furthermore, in individuals with lower levels of tau-induced neurodegeneration, higher levels of p-tau were required for memory impairment. Our findings suggest that t-tau plays a significant role in how early AD pathology affects cognitive outcomes. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, cognitive dysfunction, executive function, memory, mild cognitive impairment

DOI: 10.3233/JAD-201425

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 159-167, 2021

Authors: Ou, Guan-yong | Lin, Wen-wen | Zhao, Wei-jiang

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disease that seriously impairs both cognitive and memory functions mainly in the elderly, and its incidence increases with age. Recent studies demonstrated that long noncoding RNAs (lncRNAs) play important roles in AD by acting as competing endogenous RNAs (ceRNAs). Objective: In this study, we aimed to construct lncRNA-associated ceRNA regulatory networks composed of potential biomarkers in AD based on the ceRNA hypothesis. Methods: A total of 20 genes (10 upregulated genes and 10 downregulated genes) were identified as the hub differentially expressed genes (DEGs). The functional enrichment analysis …showed that the most significant pathways of DEGs involved include retrograde endocannabinoid signaling, synaptic vesicle circle, and AD. The upregulated hub genes were mainly enriched in the cytokine-cytokine receptor interaction pathway, whereas downregulated hub genes were involved in the neuroactive ligand-receptor interaction pathway. After convergent functional genomic (CFG) ranks and expression level analysis in different brain regions of hub genes, we found that CXCR4, GFAP, and GNG3 were significantly correlated with AD. We further identified crucial miRNAs and lncRNAs of targeted genes to construct lncRNA-associated ceRNA regulatory networks. Results: The results showed that two lncRNAs (NEAT1, MIAT), three miRNAs (hsa-miR-551a, hsa-miR-133b and hsa-miR-206), and two mRNA (CXCR4 and GNG3), which are highly related to AD, were preliminarily identified as potential AD biomarkers. Conclusion: Our study provides new insights for understanding the pathogenic mechanism underlying AD, which may potentially contribute to the ceRNA mechanism in AD. Show more

Keywords: Alzheimer’s disease, biomarkers, ceRNA regulatory network, differently expressed genes, lncRNA

DOI: 10.3233/JAD-210068

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 169-183, 2021

Authors: Wang, Tianqi | Hong, Yin | Wang, Quanyi | Su, Rongfeng | Ng, Manwa Lawrence | Xu, Jun | Wang, Lan | Yan, Nan

Article Type: Research Article

Abstract: Background: Previous studies explored the use of noninvasive biomarkers of speech and language for the detection of mild cognitive impairment (MCI). Yet, most of them employed single task which might not have adequately captured all aspects of their cognitive functions. Objective: The present study aimed to achieve the state-of-the-art accuracy in detecting individuals with MCI using multiple spoken tasks and uncover task-specific contributions with a tentative interpretation of features. Methods: Fifty patients clinically diagnosed with MCI and 60 healthy controls completed three spoken tasks (picture description, semantic fluency, and sentence repetition), from which multidimensional features were …extracted to train machine learning classifiers. With a late-fusion configuration, predictions from multiple tasks were combined and correlated with the participants’ cognitive ability assessed using the Montreal Cognitive Assessment (MoCA). Statistical analyses on pre-defined features were carried out to explore their association with the diagnosis. Results: The late-fusion configuration could effectively boost the final classification result (SVM: F1 = 0.95; RF: F1 = 0.96; LR: F1 = 0.93), outperforming each individual task classifier. Besides, the probability estimates of MCI were strongly correlated with the MoCA scores (SVM: –0.74; RF: –0.71; LR: –0.72). Conclusion: Each single task tapped more dominantly to distinct cognitive processes and have specific contributions to the prediction of MCI. Specifically, picture description task characterized communications at the discourse level, while semantic fluency task was more specific to the controlled lexical retrieval processes. With greater demands on working memory load, sentence repetition task uncovered memory deficits through modified speech patterns in the reproduced sentences. Show more

Keywords: Language, machine learning, mild cognitive impairment, screening, speech

DOI: 10.3233/JAD-201387

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 185-204, 2021

Authors: Mao, Chenhui | Sha, Longze | Li, Jie | Huang, Xinying | Chu, Shanshan | Lei, Dan | Wang, Jie | Dong, Liling | Liu, Caiyan | Xu, Qi | Peng, Bin | Gao, Jing

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) biomarkers are widely accepted as manifestations of Alzheimer’s disease (AD) pathogenesis and incorporated into biological definition of AD. However, the correlations between CSF and other biomarkers such as neuroimaging and neuropsychiatric evaluation are complicated and inconsistent. Objective: We aimed to better interpreting CSF biomarkers results accompanying with other indexes in improving accurate diagnosis of AD. Methods: 112 AD patients and 30 cognitive normal controls were selected. Commercial accessible ELISA kits were introduced for measurement of CSF t-tau, p-tau181 , Aβ1–42 , and NfL based on standard protocol. MRI examinations were performed using …a 3-T MRI scanner and visual rating scales including medial temporal atrophy score and Koedam’s scale were used to evaluate medial temporal atrophy and posterior region atrophy. Results: CSF biomarkers’ profile including decreased concentration of Aβ1–42 , increased concentration of t-tau, p-tau181 , t-tau/Aβ 1–42 , and NfL were diagnostic between AD and control. CSF biomarkers profile was not influenced by the APOE genotype. Increased concentration of t-tau and NfL, as well as ratio of t-tau/Aβ 1–42 were related to decrease of Mini-Mental State Examination (MMSE) score while concentration of Aβ1–42 not. Visual assessed cortical atrophy was related to MMSE score, but most of the CSF biomarkers were not related to atrophy, except that increased concentration of p-tau181 was significantly associated with atrophy of posterior cortical region. Conclusion: Our results supported CSF biomarkers were helpful in diagnosis of AD. However, CSF biomarkers were cross-sectional reflection of pathogenesis, which did not correlate well with clinical progression. CSF biomarkers should be interpreted in combination with MRI and cognitive evaluation in clinical use. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, cognition, cortical atrophy

DOI: 10.3233/JAD-210344

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 205-214, 2021

Authors: Frings, Lars | Henninger, Franziska | Treppner, Martin | Köber, Göran | Boeker, Martin | Meyer, Philipp T.

Article Type: Research Article

Abstract: Background: Dopamine transporter (DAT) SPECT is an established diagnostic procedure in dementia diagnostics, yet its prognostic value is currently unknown. Objective: We evaluated the prognostic value of DAT SPECT in patients assessed for differential diagnosis of dementia. Methods: We included all patients who had received DAT SPECT for differential diagnosis of dementia from 10/2008 to 06/2016 at our site and whose survival status could be obtained in 09/2019. Clinical SPECT reports, categorizing scans into positive or negative for nigrostriatal degeneration (NSD), were tested for their prognostic value (Cox regressions, adjusted for age and sex). In addition, …an automated region-of-interest analysis (striatum, occipital cortex as reference) was performed. Results: Median follow-up of 97 included patients was 6.6 years. Patients with NSD had a significantly higher mortality risk than those without NSD (HR = 3.6 [2.0–6.7], p  < 0.001). Results were confirmed by region-of-interest analysis: higher mortality risk was associated with lower striatal DAT binding (HR = 1.8 per standard deviation loss). Conclusion: Beyond its established utility in dementia diagnostics, DAT SPECT also conveys important prognostic information. Show more

Keywords: DAT SPECT, dementia, [123I]FP-CIT SPECT, prognosis, survival

DOI: 10.3233/JAD-210062

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 215-220, 2021

Authors: Besser, Lilah M. | Chang, Lun-Ching | Evenson, Kelly R. | Hirsch, Jana A. | Michael, Yvonne L. | Galvin, James E. | Rapp, Stephen R. | Fitzpatrick, Annette L. | Heckbert, Susan R. | Kaufman, Joel D. | Hughes, Timothy M.

Article Type: Research Article

Abstract: Background: Preliminary evidence suggests associations between neighborhood park access and better late-life cognition and reduced Alzheimer’s disease (AD) risk. Objective: Examine associations between neighborhood park access and longitudinal change in cognition among U.S. older adults without dementia. Methods: We used 2000–2018 observational data from the population-based, multi-site Multi-Ethnic Study of Atherosclerosis (n  = 1,733). Measures included proportion of neighborhood park space (park access), distance to nearest park, and 6-year dichotomous and continuous change in scores on the Cognitive Abilities Screening Instrument (CASI; global cognition) and Digit Symbol Coding task (processing speed). Multivariable random intercept models tested main …associations and mediation by depressive symptoms, physical activity, and PM2.5 exposure. Effect modification by race (African Americans/Blacks versus Whites) was tested using interaction terms. Results: Greater park access (equivalent to 10%more in 1/2-mile around home) was associated with maintained/improved CASI score over six years independent of several covariates including individual- and neighborhood-level socioeconomic status (Odds ratio: 1.04; 95%confidence interval: 1.00–1.08). No other associations were observed with the dichotomous or continuous measures of cognitive change and no mediators were found. While a borderline association was seen between greater park access and maintained/improved CASI for African Americans/Blacks but not for Whites, effect modification was not confirmed by testing interaction terms. Conclusion: Neighborhood park access may help maintain/improve late-life global cognition. However, our findings need replication in other population-based studies and regions. Additionally, studies are needed to determine if associations between park access and change in cognition vary by race/ethnicity to inform intervention efforts. Show more

Keywords: Aging, Alzheimer’s disease, cognition, epidemiology, environment, lifestyle, residence characteristics

DOI: 10.3233/JAD-210370

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 221-233, 2021

Authors: Lauriola, Michele | D’Onofrio, Grazia | Ciccone, Filomena | Germano, Carmela | Cascavilla, Leandro | Paris, Francesco | Greco, Antonio

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) may be a vascular disorder with neurodegenerative consequences opening possibility of preventing AD by targeting vascular risk factors including homocysteine. Objective: The study aims were to assess homocysteine distribution in different forms and severity of cognitive impairment (CogI) [mild cognitive impairment (MCI), probable AD (Prob-AD), possible AD (Poss-AD), and vascular dementia (VaD)] and in NoCogI, and to estimate possible association between hyperhomocysteinemia levels with functional deficit severity and psychobehavioral complications. Methods: In total, 929 (M = 366, F = 563; mean age of 72.55±6.24 years) patients were evaluated with cognitive, neuropsychiatric, affective, and functional assessment scales. …Homocysteine serum was set on two levels: between 0 and 10μ mol/L and > 10μ mol/L. For each patient, blood concentration of folate, vitamin B12, hemoglobin, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), cholesterol, triglycerides, and glycemia were measured. Results: CogI patients demonstrated significantly a higher frequency of homocysteine > 10 (p  = 0.003), than NoCogI patients. Patients with moderate and severe dementia had a higher frequency of homocysteine > 10 (p  < 0.0001), than MCI and mild dementia. Poss-AD and VaD had a higher frequency of homocysteine > 10 (p  = 0.003), than Prob-AD patients. Homocysteine > 10 frequency is directly proportional to increased neuropsychiatric symptom severity (p  < 0.0001), and functional impairment severity respectively for ADL (p  < 0.0001) and IADL (p  < 0.0001). Conclusion: Higher homocysteine level seems to be significantly related to cognitive impairment frequency and severity, possible AD and VaD, neuropsychiatric symptom severity, and functional impairment severity. Show more

Keywords: Activities of daily living, Alzheimer’s disease, homocysteine, mild cognitive impairment, neuropsychiatric symptoms, vascular dementia

DOI: 10.3233/JAD-210166

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 235-248, 2021

Authors: Gonzales, Mitzi M. | Samra, Jasmeet | O’Donnell, Adrienne | Mackin, R. Scott | Salinas, Joel | Jacob, Mini E. | Satizabal, Claudia L. | Aparicio, Hugo J. | Thibault, Emma G. | Sanchez, Justin S. | Finney, Rebecca | Rubinstein, Zoe B. | Mayblyum, Danielle V. | Killiany, Ron J. | Decarli, Charlie S. | Johnson, Keith A. | Beiser, Alexa S. | Seshadri, Sudha

Article Type: Research Article

Abstract: Background: Depressive symptoms predict increased risk for dementia decades before the emergence of cognitive symptoms. Studies in older adults provide preliminary evidence for an association between depressive symptoms and amyloid-β (Aβ) and tau accumulation. It is unknown if similar alterations are observed in midlife when preventive strategies may be most effective. Objective: The study aim was to evaluate the association between depressive symptoms and cerebral Aβ and tau in a predominately middle-aged cohort with examination of the apolipoprotein (APOE ) ɛ4 allele as a moderator. Methods: Participants included 201 adults (mean age 53±8 years) who underwent …11 C-Pittsburgh Compound B amyloid and 18 F-Flortaucipir tau positron emission tomography (PET) imaging. Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression Scale (CES-D) at the time of PET imaging, as well as eight years prior. Associations between depressive symptoms at both timepoints, as well as depression (CES-D≥16), with regional Aβ and tau PET retention were evaluated with linear regression adjusting for age and sex. Interactions with the APOE ɛ4 allele were explored. Results: Depressive symptoms and depression were not associated with PET outcomes in the overall sample. However, among APOE ɛ4 allele carriers, there was a significant cross-sectional association between depressive symptoms and increased tau PET uptake in the entorhinal cortex (β= 0.446, SE = 0.155, p  = 0.006) and amygdala (β= 0.350, SE = 0.133, p  = 0.012). Conclusion: Although longitudinal studies are necessary, the results suggest that APOE ɛ4 carriers with depressive symptoms may present with higher susceptibility to early tau accumulation in regions integral to affective regulation and memory consolidation. Show more

Keywords: Amygdala, amyloid-β, APOE, depression, depressive symptoms, entorhinal, PET imaging, tau

DOI: 10.3233/JAD-210232

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 249-260, 2021

Authors: Zhang, Jinbiao | Chi, Haiyan | Wang, Tong | Zhang, Shukun | Shen, Tengqun | Leng, Bing | Sun, Hairong | Li, Zhenguang | Li, Fang

Article Type: Research Article

Abstract: Background: Emerging evidence suggests a role for orthostatic hypotension (OH) in contributing to the progression of Alzheimer’s disease (AD). The exosomes in the blood can reflect the pathological changes in the brain. Objective: To investigate whether neural-derived plasma exosomes pathogenic proteins of AD levels are associated with OH in diabetes mellitus (DM) patients. Methods: There were 274 subjects without dementia included in the study: 81 control participants (controls), 101 normotensive patients with DM without OH, and 92 patients with DM and neurogenic OH (DMOH). Neural-derived exosomal proteins were measured by ELISA kits for amyloid-β (Aβ) and …tau. Results: The neural-derived exosome levels of Aβ42 , total tau (T-tau), and tau phosphorylated at threonine 181 (P-T181-tau) in the DM with OH group were higher than those in the DM and control groups. Multivariable linear regression analysis showed that the presence of OH in patients with DM was associated with elevated exosomal Aβ42 (β= 0.172, p  = 0.018), T-tau (β= 0.159, p  = 0.030), and P-T181-tau (β= 0.220, p  = 0.003) levels after adjustment for age, sex, APOE ɛ4, duration of type 2 diabetes, HbA1c, and cardiovascular risk factors. Furthermore, the levels of Aβ42 , T-tau, and P-T181-tau in neural-derived exosomes were correlated with HIF-1α levels and the drop in mean cerebral blood flow velocity from the supine to upright position. Conclusion: The presence of OH in DM patients was independently associated with elevated the Aβ42 , T-tau, and P-T181-tau levels in neural-derived plasma exosomes. Cerebral hypoperfusion from DM with OH are likely candidate mechanisms. Show more

Keywords: Amyloid-β proteins, cognition function, exosomes, orthostatic hypotension, tau proteins, type 2 diabetes mellitus

DOI: 10.3233/JAD-210216

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 261-272, 2021

Authors: Cai, Wen-Jie | Tian, Yan | Ma, Ya-Hui | Dong, Qiang | Tan, Lan | Yu, Jin-Tai | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The pathophysiological process of amyloid-β, tau deposition, and neurodegeneration of Alzheimer’s disease (AD) begin in a preclinical phase, while anxiety is associated with an increased risk of AD in preclinical phase. Objective: To examine the relationships between anxiety and amyloid-β, tau deposition, and neurodegeneration. To test the hypothesis that anxiety could predict clinical progression in the elderly without dementia. Methods: 1,400 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database were included in the study and were studied over a median period of 3 years. In multivariable models, the cross-sectional and longitudinal associations between anxiety …and amyloid-β PET, tau PET, and FDG PET SUVRs in participants without dementia were explored using Spearman rank correlation, logistic regression model, multiple linear regression model, Kaplan-Meier survival curves, and Cox proportional hazards model. The association between baseline anxiety and clinical progression was also explored. Results: There was a positive correlation between anxiety and amyloid-β deposition (r  = 0.11, p  = 0.0017) and a negative correlation between anxiety and neurodegeneration (r  = –0.13, p  = 0.00022). MCI participants with anxiety showed a faster clinical progression of dementia (HR = 1.56, p  = 0.04). Non-anxious participants with more amyloid-β deposition or more severe neurodegeneration displayed accelerated development into anxiety (HR = 2.352, p  < 0.0001; HR = 2.254, p  < 0.0001). Conclusion: Anxiety was associated with amyloid-β deposition and neurodegeneration in non-dementia elderly. Anxiety in MCI predicted conversion to dementia. Anxiety may play a selective role and prediction of disease progression in the early phase of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, anxiety, biomarkers, dementia, neurodegeneration, tauopathies

DOI: 10.3233/JAD-210020

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 273-283, 2021