Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Xia, Mingxu | Su, Ya | Fu, Jiayu | Xu, Jiajie | Wang, Qiong | Gao, Feng | Shen, Yong | Dong, Qiang | Cheng, Xin

Article Type: Research Article

Abstract: Background: Neuroimaging has played a primary role in predicting intracerebral hemorrhage (ICH) recurrence of cerebral amyloid angiopathy (CAA); however, the utilities of biomarkers in CAA-related ICH and cognitive impairment remain unexplored. Objective: To investigate the correlations of serum levels of matrix metalloproteinase-2 (MMP-2), MMP-3, and MMP-9 with CAA-related MRI markers, ICH recurrence, and cognitive status. Methods: 68 cases with first probable CAA-ICH and 69 controls were recruited. Clinical and imaging data were obtained at baseline and serum MMPs in the acute phase were measured by Luminex multiplex assays. Cognitive status was assessed with the Chinese version …of Mini-Mental State Examination within 10–14 days after ICH onset. Results: Serum MMP-2 level was significantly lower in CAA-ICH patients than controls while MMP-9 was significantly higher. In CAA-ICH patients, MMP-3 level was significantly associated with lobar cerebral microbleeds count after adjusting age, sex, and hypertension (adjusted coefficient 0.368, 95%CI 0.099–0.637, p  = 0.008). During a median follow-up of 2.4 years, higher level of MMP-2 predicted lower CAA-ICH recurrence after adjusting age (adjusted HR 0.326, 95%CI 0.122–0.871, p  = 0.025), ICH volume (adjusted HR 0.259, 95%CI 0.094–0.715, p  = 0.009), total MRI burden of SVD score (adjusted HR 0.350, 95%CI 0.131–0.936, p  = 0.037) respectively. Besides, higher level of MMP-2 was significantly associated with decreased risk of cognitive impairment independent of age and ICH volume (adjusted OR 0.054, 95%CI 0.005–0.570, p  = 0.015). Conclusion: Serum MMP-2 in acute phase might be a promising biomarker to predict CAA-ICH recurrence and to evaluate the risk of cognitive impairment. Show more

Keywords: Cerebral amyloid angiopathy, cognitive impairment, cerebral microbleeds, intracerebral hemorrhage, matrix metalloproteinases

DOI: 10.3233/JAD-210288

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Klooster, Nathaniel | Humphries, Stacey | Cardillo, Eileen | Hartung, Franziska | Xie, Long | Das, Sandhitsu | Yushkevich, Paul | Pilania, Arun | Wang, Jieqiong | Wolk, David A. | Chatterjee, Anjan

Article Type: Research Article

Abstract: Background: Sensitive measures of cognition are needed in preclinical and prodromal Alzheimer’s disease (AD) to track cognitive change and evaluate potential interventions. Neurofibrillary tangle pathology in AD is first observed in Brodmann Area 35 (BA35), the medial portion of the perirhinal cortex. The importance of the perirhinal cortex for semantic memory may explain early impairments of semantics in preclinical AD. Additionally, our research has tied figurative language impairment to neurodegenerative disease. Objective: We aim to identify tasks that are sensitive to cognitive impairment in individuals with mild cognitive impairment (MCI), and that are sensitive to atrophy in BA35. …Methods: Individuals with MCI and cognitively normal participants (CN) were tested on productive and receptive experimental measures of semantic memory and experimental tests of figurative language comprehension (including metaphor and verbal analogy). Performance was related to structural imaging and standard neuropsychological assessment. Results: On the experimental tests of semantics and figurative language, people with MCI performed worse than CN participants. The experimental semantic memory tasks are sensitive and specific; performance on the experimental semantic memory tasks related to medial temporal lobe structural integrity, including BA35, while standard neuropsychological assessments of semantic memory did not, demonstrating the sensitivity of these experimental measures. A visuo-spatial analogy task did not differentiate groups, confirming the specificity of semantic and figurative language tasks. Conclusion: These experimental measures appear sensitive to cognitive change and neurodegeneration early in the AD trajectory and may prove useful in tracking cognitive change in clinical trials aimed at early intervention. Show more

Keywords: Alzheimer’s disease, figurative language, medial temporal lobe, mild cognitive impairment, perirhinal cortex, semantic memory

DOI: 10.3233/JAD-201280

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Qu, Mingyue | Shi, Hanxu | Wang, Kai | Wang, Xinggang | Yu, Nan | Guo, Baoshi

Article Type: Research Article

Abstract: Background: Multiple lines of evidence indicate protective effects of carotenoids in Alzheimer’s disease (AD). However, previous epidemiological studies reported inconsistent results regarding the associations between carotenoids levels and the risk of AD. Objective: Our study aims to evaluate the associations of six major members of carotenoids with the occurrence of AD by conducting a systematic review and meta-analysis. Methods: Following PRISMA guidelines, a comprehensive literature search of PubMed, Web of Science, Ebsco, and PsycINFO databases was conducted, and the quality of each included studies was evaluated by a validated scoring systems. Standardized mean differences (SMD) with …95%confidence intervals (CI) were determined by using a random effects model. Heterogeneity was evaluated by I2 statistics. Publication bias was detected using funnel plots and Egger’s test. Results: Sixteen studies, with 10,633 participants were included. Pooled analysis showed significantly lower plasma/serum levels of lutein (SMD = –0.86, 95%CI: –1.67 to –0.05, p  = 0.04) and zeaxanthin (SMD = –0.59; 95%CI: –1.12 to –0.06, p  = 0.03) in patients with AD versus cognitively intact controls, while α-carotene (SMD = 0.21, 95%CI: –0.68 to 0.26, p  = 0.39), β-carotene (SMD = 0.04, 95%CI: –0.57 to 0.65, p  = 0.9), lycopene (SMD = –0.12, 95%CI: –0.96 to 0.72, p  = 0.78), and β-cryptoxanthin (SMD = –0.09, 95%CI: –0.83 to 0.65, p  = 0.81) did not achieve significant differences. Conclusion: Of six major members of carotenoids, only lutein and zeaxanthin concentrations in plasma/serum were inversely related to the risk of AD. More high-quality longitudinal studies are needed to verify these findings. Show more

Keywords: Alzheimer’s disease, carotenes, carotenoids, xanthophylls

DOI: 10.3233/JAD-210384

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Chang, Yu-Ling | Zhuo, Yi-Yuan | Luo, Di-Hua

Article Type: Research Article

Abstract: Background: Studies have reported that apolipoprotein E epsilon 4 (APOE ɛ4) has adverse effects on executive functions (EFs) in late adulthood. However, the results have been inconsistent. Insufficient measurements of executive functioning, uncontrolled clinical and demographic confounders, and moderation effects from other environmental factors are suspected to account for the inconsistency. Objective: This study used aggregate measures to examine the effects of APOE ɛ4 on four components of EFs, namely switching, working memory, inhibition, and reasoning. We further investigated whether high educational attainment, a proxy measure for cognitive reserve, moderates the adverse effects of ɛ4 on …EFs. Methods: Cognitively unimpaired older participants were divided into groups based on APOE genotype and into subgroups based on educational attainment level. The demographic and clinical variables were matched between the groups. Four core components of the EFs were measured using a relatively comprehensive battery. Results: The results revealed that although no main effect of the APOE genotype was observed across the four EF components, the potentially adverse effects of ɛ4 on inhibition were alleviated by high educational attainment. A main effect of education on the reasoning component was also observed. The moderation analysis revealed that for older adults with 12 years of education or fewer, the relationship between the APOE ɛ4 genotype and inhibition performance became increasingly negative. Conclusion: This study highlights the distinctive role of response inhibition in the gene–environment interaction and underlines the importance of considering factors of both nature and nurture to understand the complex process of cognitive aging. Show more

Keywords: Apolipoproteins E, cognitive aging, cognitive reserve, education, executive function

DOI: 10.3233/JAD-210183

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Wang, Zuo-Teng | Li, Kun-Yan | Tan, Chen-Chen | Xu, Wei | Shen, Xue-Ning | Cao, Xi-Peng | Wang, Ping | Bi, Yan-Lin | Dong, Qiang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: The relationship between alcohol consumption and Alzheimer’s disease (AD) pathology is unclear. Amyloid-β (Aβ) and tau biomarkers in cerebrospinal fluid (CSF) have been proven valuable in establishing prognosis in pre-clinical AD. Objective: We sought to examine the associations between alcohol consumption and CSF AD biomarkers in cognitive intact subjects. Methods: A total of 806 cognitively intact participants who had measurements of CSF Aβ, pTau, and total Tau proteins and drinking characteristics were included from the Chinese Alzheimer’s Biomarker and Lifestyle (CABLE) study. Linear and logistic regression analyses were utilized to explore the associations of alcohol …consumption with CSF AD biomarkers. We examined the interaction effects of age, gender, and apolipoprotein epsilon (APOE ) ɛ4 status on the relationships between the frequency of drinking and CSF biomarkers. Results: The multiple linear regression analyses revealed significant differences in CSF AD biomarkers between infrequent drinking (<  1 times/week) and frequent drinking groups (≥1 times/week). Participants in frequent drinking group had higher CSF p-tau/Aβ 42 and tTau/Aβ42 . Frequent drinking was significantly associated with greater pTau and tTau abnormalities compared to the infrequent drinking group in older (>  65 years) participants. Conclusion: The present study showed significant associations between drinking frequency and CSF AD biomarkers in cognitively intact older adults. Alcohol consumption may have an influence on AD by modulating amyloid deposition and tau phosphorylation in the preclinical stage. Show more

Keywords: Alcohol consumption, Alzheimer’s disease, amyloid, cerebrospinal fluid, magnetic resonance imaging, tau proteins

DOI: 10.3233/JAD-210140

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Babiloni, Claudio | Ferri, Raffaele | Noce, Giuseppe | Lizio, Roberta | Lopez, Susanna | Lorenzo, Ivan | Tucci, Federico | Soricelli, Andrea | Nobili, Flavio | Arnaldi, Dario | Famà, Francesco | Orzi, Francesco | Buttinelli, Carla | Giubilei, Franco | Cipollini, Virginia | Marizzoni, Moira | Güntekin, Bahar | Aktürk, Tuba | Hanoğlu, Lutfu | Yener, Görsev | Özbek, Yağmur | Stocchi, Fabrizio | Vacca, Laura | Frisoni, Giovanni B. | Del Percio, Claudio

Article Type: Research Article

Abstract: Background: In relaxed adults, staying in quiet wakefulness at eyes closed is related to the so-called resting state electroencephalographic (rsEEG) rhythms, showing the highest amplitude in posterior areas at alpha frequencies (8–13 Hz). Objective: Here we tested the hypothesis that age may affect rsEEG alpha (8–12 Hz) rhythms recorded in normal elderly (Nold) seniors and patients with mild cognitive impairment due to Alzheimer’s disease (ADMCI). Methods: Clinical and rsEEG datasets in 63 ADMCI and 60 Nold individuals (matched for demography, education, and gender) were taken from an international archive. The rsEEG rhythms were investigated at individual delta, theta, …and alpha frequency bands, as well as fixed beta (14–30 Hz) and gamma (30–40 Hz) bands. Each group was stratified into three subgroups based on age ranges (i.e., tertiles). Results: As compared to the younger Nold subgroups, the older one showed greater reductions in the rsEEG alpha rhythms with major topographical effects in posterior regions. On the contrary, in relation to the younger ADMCI subgroups, the older one displayed a lesser reduction in those rhythms. Notably, the ADMCI subgroups pointed to similar cerebrospinal fluid AD diagnostic biomarkers, gray and white matter brain lesions revealed by neuroimaging, and clinical and neuropsychological scores. Conclusion: The present results suggest that age may represent a deranging factor for dominant rsEEG alpha rhythms in Nold seniors, while rsEEG alpha rhythms in ADMCI patients may be more affected by the disease variants related to earlier versus later onset of the AD. Show more

Keywords: Aging, exact Low-resolution brain electromagnetic source tomography, mild cognitive impairment due to Alzheimer’s disease, resting state electroencephalographic rhythms

DOI: 10.3233/JAD-201271

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-30, 2021

Authors: Ni, Lianghui | Zhao, Mingyan | Hu, Zhishan | Yang, Kun | Zhao, Xing | Niu, Haijing | Lin, Hua

Article Type: Research Article

Abstract: Background: A growing awareness about non-pharmacological intervention for cognitively impaired individuals may represent an alternative therapeutic approach that is actively accepted by patients with very early stage of Alzheimer’s disease. Understanding the neural basis of non-pharmacological intervention is a crucial step toward wide use for patients with cognitive disorders. Objective: To investigate the underlying neural mechanism of shentai tea polyphenols in subjects with subjective cognitive decline (SCD) using functional near-infrared spectroscopy (fNIRS). Methods: A total number of 36 patients with SCD participated in the study and received supplementation with shentai tea polyphenols for three months. All …participants underwent a series of tests on neuropsychological function and fNIRS assessment during n-back tasks at baseline and follow-up. Results: After intervention with shentai tea polyphenols in SCD, increased cerebral activity was observed in left dorsolateral prefrontal cortex (DLPFC), left premotor cortex (PMC), left primary somatosensory cortex (PSC), right inferior frontal gyrus (IFG), and premotor cortex (PMC). Moreover, shentai tea polyphenols intervention of three months significantly improved SCD subjects’ cognitive functions (memory, language, and subjective cognitive ability) and depression condition. We further found that the improvement of HAMD and AVLT-R scores had positive correlations with increased brain activity in right IFG and left DLPFC, respectively. Conclusion: This study provides new evidence that the frontal cortex was found to be specifically activated after non-pharmacological intervention of shentai tea polyphenols in SCD, which may be associated with cognitive enhancement and mental wellbeing. These findings provide important implications for the selection of shentai tea polyphenols interventions for SCD. Show more

Keywords: Functional near-infrared spectroscopy, non-pharmacological intervention, shentai tea polyphenols, subjective cognitive decline

DOI: 10.3233/JAD-210469

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Espay, Alberto J. | Sturchio, Andrea | Schneider, Lon S. | Ezzat, Kariem

Article Type: Research Article

Abstract: Brain proteins function in their soluble, native conformation and cease to function when transformed into insoluble aggregates, also known as amyloids. Biophysically, the soluble-to-insoluble phase transformation represents a process of polymerization, similar to crystallization, dependent on such extrinsic factors as concentration, pH, and a nucleation surface. The resulting cross-β conformation of the insoluble amyloid is markedly stable, making it an unlikely source of toxicity. The spread of brain amyloidosis can be fully explained by mechanisms of spontaneous or catalyzed polymerization and phase transformation instead of active replication, which is an enzyme- and energy-requiring process dependent on a specific nucleic acid …code for the transfer of biological information with high fidelity. Early neuronal toxicity in Alzheimer’s disease may therefore be mediated to a greater extent by a reduction in the pool of soluble, normal-functioning protein than its accumulation in the polymerized state. This alternative loss-of-function hypothesis of pathogenicity can be examined by assessing the clinical and neuroimaging effects of administering non-aggregating peptide analogs to replace soluble amyloid-β levels above the threshold below which neuronal toxicity may occur. Correcting the depletion of soluble amyloid-β, however, would only exemplify ‘rescue medicine.’ Precision medicine will necessitate identifying the pathogenic factors catalyzing the protein aggregation in each affected individual. Only then can we stratify patients for etiology-specific treatments and launch precision medicine for Alzheimer’s disease and other neurodegenerative disorders. Show more

Keywords: Alzheimer’s disease, clinico-pathologic, disease modification, precision medicine, neuroprotection

DOI: 10.3233/JAD-210415

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Lourenco, Mychael V. | Ribeiro, Felipe C. | Santos, Luis E. | Beckman, Danielle | Melo, Helen M. | Sudo, Felipe K. | Drummond, Cláudia | Assunção, Naima | Vanderborght, Bart | Tovar-Moll, Fernanda | De Felice, Fernanda G. | Mattos, Paulo | Ferreira, Sergio T.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and Lewy body disease (LBD) are complex neurodegenerative disorders that have been associated with brain inflammation and impaired neurotransmission. Objective: We aimed to determine concentrations of multiple cytokines, chemokines, and neurotransmitters previously associated with brain inflammation and synapse function in cerebrospinal fluid (CSF) from AD and LBD patients. Methods: We examined a panel of 50 analytes comprising neurotransmitters, cytokines, chemokines, and hormones in CSF in a cohort of patients diagnosed with mild cognitive impairment (MCI), AD, LBD, or non-demented controls (NDC). Results: Among neurotransmitters, noradrenaline (NA) was increased in AD …CSF, while homovanillic acid (HVA), a dopamine metabolite, was reduced in both AD and LBD CSF relative to NDC. Six cytokines/chemokines out of 30 investigated were reliably detected in CSF. CSF vascular endothelial growth factor (VEGF) was significantly reduced in LBD patients relative to NDC. Conclusions: CSF alterations in NA, HVA, and VEGF in AD and LBD may reflect pathogenic features of these disorders and provide tools for improved diagnosis. Future studies are warranted to replicate current findings in larger, multicenter cohorts. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, cytokines, homovanillic acid, inflammation, Lewy body disease, neurotransmitters, noradrenaline, vascular endothelial growth factor.

DOI: 10.3233/JAD-210147

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Castillo-Mendieta, Tzayaka | Arana-Lechuga, Yoaly | Campos-Peña, Victoria | Sosa, Ana Luisa | Orozco-Suarez, Sandra | Pinto-Almazán, Rodolfo | Segura-Uribe, Julia | Javier Rodríguez-Sánchez de Tagle, Aldo | Ruiz-Sánchez, Elizabeth | Guerra-Araiza, Christian

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) causes memory deficit and alterations in other cognitive functions, mainly in adults over 60 years of age. As the diagnosis confirmation is performed by a postmortem neuropathological examination of the brain, this disease can be confused with other types of dementia at early stages. About 860,000 Mexicans are affected by dementia, most of them with insufficient access to adequate comprehensive health care services. Plasma biomarkers could be a rapid option for early diagnosis of the disease. Objective: This study aimed to analyze some plasma biomarkers (amyloid-β , tau, and lipids) in Mexican AD patients …and control subjects with no associated neurodegenerative diseases. Methods: Plasma amyloid-β peptides (Aβ 40 and Aβ 42 ), total and phosphorylated tau protein (T-tau and P-tau), and cholesterol and triglyceride levels were quantified enzyme-linked immunosorbent assay in AD patients and control subjects. Results: In Mexican AD patients, we found significantly lower levels of Aβ 42 (p  <  0.05) compared to the control group. In contrast, significantly higher levels of P-tau (p  <  0.05) and triglycerides (p  <  0.05) were observed in AD patients compared to controls. Furthermore, a significant correlation was found between the severity of dementia and plasma P-tau levels, Aβ 42 /Aβ 40 and P-tau/T-tau ratios, and triglycerides concentrations. This correlation increased gradually with cognitive decline. Conclusion: The detection of these plasma biomarkers is an initial step in searching for a timely, less invasive, and cost-efficient diagnosis in Mexicans. Show more

Keywords: Alzheimer’s disease, amyloid-β, early diagnosis, Mexican patients, tau protein

DOI: 10.3233/JAD-200912

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021