Journal of Alzheimer's Disease - Volume 82, issue 3

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. 82, no. 3, pp. 1123-1136, 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 Hamilton Depression Rating Scale and Auditory Verbal Learning Test-recognition 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. 82, no. 3, pp. 1137-1145, 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. 82, no. 3, pp. 1147-1157, 2021

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. 82, no. 3, pp. 1159-1170, 2021

Authors: Herd, Pamela | Sicinski, Kamil | Asthana, Sanjay

Article Type: Research Article

Abstract: Background: There is a robust consensus, most recently articulated in the 2020 Lancet Commission, that the roots of dementia can be traced to early life, and that the path to prevention may start there as well. Indeed, a growing body of research demonstrates that early life disadvantage may influence the risk for later life dementia and cognitive decline. A still understudied risk, however, is early life rural residence, a plausible pathway given related economic and educational disadvantages, as well as associations between later life rural living and lower levels of cognitive functioning. Objective: We aim to examine whether …living in rural environments during early life has long term implications for cognitive health in later life. Methods: We employed the Wisconsin Longitudinal Study, which tracked 1 in every 3 high school graduates from the class of 1957, from infancy to ∼age 72. The data include a rich array of prospectively collected early life data, unique among existing studies, as well as later life measures of cognitive functioning. Results: We found a robust relationship between early life rural residence, especially living on a farm, and long-term risk for reduced cognitive performance on recall and fluency tasks. Controls for adolescent cognitive functioning, APOE ɛ 2 and APOE ɛ 4, as well as childhood and adult factors, ranging from early life socioeconomic conditions to later life health and rural and farm residency, did not alter the findings. Conclusion: Rural living in early life is an independent risk for lower levels of cognitive functioning in later life. Show more

Keywords: Aging, cognitive function, early life, rural, socioeconomic status

DOI: 10.3233/JAD-210224

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1171-1182, 2021

Authors: Paulo, Sara L. | Ribeiro-Rodrigues, Leonor | Rodrigues, Rui S. | Mateus, Joana M. | Fonseca-Gomes, João | Soares, Rita | Diógenes, Maria J. | Solá, Susana | Sebastião, Ana M. | Ribeiro, Filipa F. | Xapelli, Sara

Article Type: Research Article

Abstract: Background: The use of Alzheimer’s disease (AD) models obtained by intracerebral infusion of amyloid-β (Aβ) has been increasingly reported in recent years. Nonetheless, these models may present important challenges. Objective: We have focused on canonical mechanisms of hippocampal-related neural plasticity to characterize a rat model obtained by an intracerebroventricular (icv) injection of soluble amyloid-β42 (Aβ42 ). Methods: Animal behavior was evaluated in the elevated plus maze, Y-Maze spontaneous or forced alternation, Morris water maze, and open field, starting 2 weeks post-Aβ42 infusion. Hippocampal neurogenesis was assessed 3 weeks after Aβ42 injection. Aβ deposition, …tropomyosin receptor kinase B levels, and neuroinflammation were appraised at 3 and 14 days post-Aβ42 administration. Results: We found that immature neuronal dendritic morphology was abnormally enhanced, but proliferation and neuronal differentiation in the dentate gyrus was conserved one month after Aβ42 injection. Surprisingly, animal behavior did not reveal changes in cognitive performance nor in locomotor and anxious-related activity. Brain-derived neurotrophic factor related-signaling was also unchanged at 3 and 14 days post-Aβ icv injection. Likewise, astrocytic and microglial markers of neuroinflammation in the hippocampus were unaltered in these time points. Conclusion: Taken together, our data emphasize a high variability and lack of behavioral reproducibility associated with these Aβ injection-based models, as well as the need for its further optimization, aiming at addressing the gap between preclinical AD models and the human disorder. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, behavior, hippocampal plasticity, memory

DOI: 10.3233/JAD-201567

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1183-1202, 2021

Authors: Stickel, Ariana M. | Tarraf, Wassim | Gonzalez, Kevin A. | Isasi, Carmen R. | Kaplan, Robert | Gallo, Linda C. | Zeng, Donglin | Cai, Jianwen | Pirzada, Amber | Daviglus, Martha L. | Goodman, Zachary T. | Schneiderman, Neil | González, Hector M.

Article Type: Research Article

Abstract: Background: The relationships between obesity and cognitive decline in aging are mixed and understudied among Hispanics/Latinos. Objective: To understand associations between central obesity, cognitive aging, and the role of concomitant cardiometabolic abnormalities among Hispanics/Latinos. Methods: Participants included 6,377 diverse Hispanics/Latinos enrolled in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and SOL-Investigation for Neurocognitive Aging (SOL-INCA). Participants were 45 years and older at the first cognitive testing session (Visit 1). Cognitive outcomes (z-score units) included global composite and domain specific (learning, memory, executive functioning, processing speed) measures at a second visit (SOL-INCA, on average, 7 years …later), and 7-year change. We used survey linear regression to examine associations between central obesity (waist circumference≥88 cm and≥102 cm for women and men, respectively) and cognition. We also tested whether the relationships between obesity and cognition differed by cardiometabolic status (indication of/treatment for 2 + of the following: high triglycerides, hypertension, hyperglycemia, low high-density lipoprotein cholesterol). Results: Central obesity was largely unassociated with cognitive outcomes, adjusting for covariates. However, among individuals with central obesity, cardiometabolic abnormality was linked to poorer cognitive function at SOL-INCA (ΔGlobalCognition  =–0.165, p  < 0.001) and to more pronounced cognitive declines over the average 7 years (ΔGlobalCognition  = –0.109, p  < 0.05); this was consistent across cognitive domains. Conclusion: Central obesity alone was not associated with cognitive function. However, presence of both central obesity and cardiometabolic abnormalities was robustly predictive of cognition and 7-year cognitive declines, suggesting that in combination these factors may alter the cognitive trajectories of middle-aged and older Hispanics/Latinos. Show more

Keywords: Aging, cardiometabolic risk factors, cognition, diabetes mellitus, Hispanics, hyperlipidemias, hypertension, Latinos, obesity

DOI: 10.3233/JAD-210314

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1203-1218, 2021

Authors: Talbot, Louise A. | Thomas, Margaret | Bauman, Adrian | Manera, Karine E. | Smith, Ben J.

Article Type: Research Article

Abstract: Background: The number of people living with dementia is rising globally due to population aging. Mass media campaigns which aim to reduce the risk of people developing dementia have been conducted across many countries, but few have reported evaluation findings. Objective: The present study investigated the impact of the Your Brain Matters dementia risk reduction campaign in Australia. Methods: The campaign was evaluated by observational cross-sectional surveys of 1000 Australian adults aged 18–75 years before and 24 months after delivery. The national campaign utilized multiple media channels to promote messages about the importance of brain …health and reducing the risk of dementia. Dementia risk reduction knowledge, confidence, intentions and actions were measured at baseline and follow-up, and analyzed 2019–2020. Results: Earned television and radio were the most common exposure channels. The proportion of people who understood that it is beneficial to take action to reduce dementia risk before middle age increased (54.1% to 59.4%, OR 1.20 95% CI: 1.01–1.44). There was also an increase (28.5% to 32.8%, OR 1.30, 95% CI: 1.07–1.59) in the proportion who reported taking action to improve brain health. There was no improvement in knowledge about vascular risk factors, or confidence to reduce personal dementia risk. Conclusion: The findings showed some receptivity and positive responses to messages about the benefits of taking action to reduce the risk of dementia. The campaign demonstrated the potential for generating news coverage about this issue, which should highlight the preventive benefits of vascular health behaviors. Show more

Keywords: Alzheimer’s disease, dementia, dementia vascular, health behavior, healthy lifestyle

DOI: 10.3233/JAD-210317

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1219-1228, 2021

Authors: Pereiro, Arturo Xosé | Valladares-Rodríguez, Sonia | Felpete, Alba | Lojo-Seoane, Cristina | Campos-Magdaleno, María | Mallo, Sabela Carme | Facal, David | Anido-Rifón, Luis | Belleville, Sylvie | Juncos-Rabadán, Onésimo

Article Type: Research Article

Abstract: Background: The presence of subjective cognitive complaints (SCCs) is a core criterion for diagnosis of subjective cognitive decline (SCD); however, no standard procedure for distinguishing normative and non-normative SCCs has yet been established. Objective: To determine whether differentiation of participants with SCD according to SCC severity improves the validity of the prediction of progression in SCD and MCI and to explore validity metrics for two extreme thresholds of the distribution in scores in a questionnaire on SCCs. Methods: Two hundred and fifty-three older adults with SCCs participating in the Compostela Aging Study (CompAS) were classified as …MCI or SCD at baseline. The participants underwent two follow-up assessments and were classified as cognitively stable or worsened. Severity of SCCs (low and high) in SCD was established by using two different percentiles of the questionnaire score distribution as cut-off points. The validity of these cut-off points for predicting progression using socio-demographic, health, and neuropsychological variables was tested by machine learning (ML) analysis. Results: Severity of SCCs in SCD established considering the 5th percentile as a cut-off point proved to be the best metric for predicting progression. The variables with the main role in conforming the predictive algorithm were those related to memory, cognitive reserve, general health, and the stability of diagnosis over time. Conclusion: Moderate to high complainers showed an increased probability of progression in cognitive decline, suggesting the clinical relevance of standard procedures to determine SCC severity. Our findings highlight the important role of the multimodal ML approach in predicting progression. Show more

Keywords: Cognitive dysfunction, dementia, diagnosis, follow-up studies

DOI: 10.3233/JAD-210334

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1229-1242, 2021

Authors: Targum, Steven D. | Fosdick, Lisa | Drake, Kristen E. | Rosenberg, Paul B. | Burke, Anna D. | Wolk, David A. | Foote, Kelly D. | Asaad, Wael F. | Sabbagh, Marwan | Smith, Gwenn S. | Lozano, Andres M. | Lyketsos, Constantine G.

Article Type: Research Article

Abstract: Background: Age may affect treatment outcome in trials of mild probable Alzheimer’s disease (AD). Objective: We examined age as a moderator of outcome in an exploratory study of deep brain stimulation targeting the fornix (DBS-f) region in participants with AD. Methods: Forty-two participants were implanted with DBS electrodes and randomized to double-blind DBS-f stimulation (“on”) or sham DBS-f (“off”) for 12 months. Results: The intervention was safe and well tolerated. However, the selected clinical measures did not differentiate between the “on” and “off” groups in the intent to treat (ITT) population. There was a …significant age by time interaction with the Alzheimer’s Disease Assessment Scale; ADAS-cog-13 (p  = 0.028). Six of the 12 enrolled participants < 65 years old (50%) markedly declined on the ADAS-cog-13 versus only 6.7%of the 30 participants≥65 years old regardless of treatment assignment (p  = 0.005). While not significant, post-hoc analyses favored DBS-f “off” versus “on” over 12 months in the < 65 age group but favored DBS-f “on” versus “off” in the≥65 age group on all clinical metrics. On the integrated Alzheimer’s Disease rating scale (iADRS), the effect size contrasting DBS-f “on” versus “off” changed from +0.2 (favoring “off”) in the < 65 group to –0.52 (favoring “on”) in the≥65 age group. Conclusion: The findings highlight issues with subject selection in clinical trials for AD. Faster disease progression in younger AD participants with different AD sub-types may influence the results. Biomarker confirmation and genotyping to differentiate AD subtypes is important for future clinical trials. Show more

Keywords: Age, Alzheimer’s disease, deep brain stimulation, clinical trials, subject selection

DOI: 10.3233/JAD-210530

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1243-1257, 2021

Authors: Bahar, Bojlul | Kanagasingam, Shalini | Tambuwala, Murtaza M. | Aljabali, Alaa A.A. | Dillon, Stephanie A. | Doaei, Saeid | Welbury, Richard | Chukkapalli, Sasanka S. | Singhrao, Sim K.

Article Type: Research Article

Abstract: Background: Periodontal disease(s) and metabolic illnesses negatively impact the quality of life and, eventually mental health. Objective: This study investigated the effect of Porphyromonas gingivalis (W83) oral infection on the development of Alzheimer’s disease (AD) pathophysiology in a wild-type obese, diabetic (db/db) mouse model. Methods: The db/db mice were either orally infected with P. gingivalis and Fusobacterium nucleatum or sham infected for 16 weeks. The presence of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) were assessed using a silver impregnation technique and subsequently by immunohistochemistry for tau and neuroinflammation. The mRNA abundance of a …panel of 184 genes was performed using quantitative real-time PCR, and the differentially expressed genes were analyzed by Ingenuity Pathway Analysis. Results: While no Aβ plaques and NFTs were evident by silver impregnation, immunohistochemistry (glial cell markers) of the P. gingivalis -infected mice tissue sections exhibited neuroinflammation in the form of reactive microglia and astrocytes. Anti-tau immunopositivity, in addition to cells, was prominent in thickened axons of hippocampal CA neurons. The mRNA abundance of crucial genes in the insulin signaling pathway (INSR, IGF1, IRS, IDE, PIK3R, SGK1, GYS, GSK3B, AKT1 ) were upregulated, potentially exacerbating insulin resistance in the brain by P. gingivalis oral infection. Increased mRNA abundance of several kinases, membrane receptors, transcription factors, and pro-inflammatory mediators indicated hyperactivation of intracellular cascades with potential for tau phosphorylation and Aβ release in the same infection group. Conclusion: P. gingivalis W83 infection of db/db mice provides a disease co-morbidity model with the potential to reproduce AD pathophysiology with induced periodontal disease. Show more

Keywords: Alzheimer’s disease, diabetes genes, insulin resistance, Porphyromonas gingivalis

DOI: 10.3233/JAD-210465

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1259-1275, 2021

Authors: Akushevich, Igor | Yashkin, Arseniy P. | Kravchenko, Julia | Yashin, Anatoliy I.

Article Type: Research Article

Abstract: Background: Understanding the dynamics of epidemiologic trends in Alzheimer’s disease (AD) and related dementias (ADRD) and their epidemiologic causes is vital to providing important insights into reducing the burden associated with these conditions. Objective: To model the time trends in age-adjusted AD/ADRD prevalence and incidence-based mortality (IBM), and identify the main causes of the changes in these measures over time in terms of interpretable epidemiologic quantities. Methods: Trend decomposition was applied to a 5%sample of Medicare beneficiaries between 1991 and 2017. Results: Prevalence of AD was increasing between 1992 and 2011 and declining thereafter, …while IBM increased over the study period with a significant slowdown in its rate of growth from 2011 onwards. For ADRD, prevalence and IBM increased through 2014 prior to taking a downwards turn. The primary determinant responsible for declines in prevalence and IBM was the deceleration in the increase and eventual decrease in incidence rates though changes in relative survival began to affect the overall trends in prevalence/IBM in a noticeable manner after 2008. Other components showed only minor effects. Conclusion: The prevalence and IBM of ADRD is expected to continue to decrease. The directions of these trends for AD are not clear because AD incidence, the main contributing component, is decreasing but at a decreasing rate suggesting a possible reversal. Furthermore, emerging treatments may contribute through their effects on survival. Improving ascertainment of AD played an important role in trends of AD/ADRD over the 1991-2009/10 period but this effect has exhausted itself by 2017. Show more

Keywords: Alzheimer’s disease, decomposition, dementia, incidence, Medicare, partitioning, relative survival, time trends

DOI: 10.3233/JAD-210273

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1277-1289, 2021

Authors: Umegaki, Hiroyuki | Suzuki, Yusuke | Komiya, Hitoshi | Watanabe, Kazuhisa | Yamada, Yosuke | Nagae, Masaaki | Kuzuya, Masafumi

Article Type: Research Article

Abstract: Background: Few studies have investigated associations between types of clock drawing test (CDT) errors and cognitive impairment. Objective: To explore associations of qualitative errors in the CDT with comprehensive neurocognitive assessment scores and clinical diagnosis. Methods: Outpatients at a memory clinic were enrolled. Frequencies of errors determined by Cahn’s method were explored according to cognitive status (cognitively normal [CN] (n  = 279), mild cognitive impairment [MCI] (n  = 321), and Alzheimer’s disease [AD]) (n  = 575). Neuropsychological assessment scores were compared between participants with and without errors. Results: Stimulus-bound response (SB) was relatively rare (6.8%) in the …CN group but was markedly more common in the MCI (23.4%) and AD (33.2%) groups. Conceptual deficit (CD) was found in more than 20%of CN individuals, as well as about 50%of AD patients. Planning deficit (PD) frequencies were relatively similar among the groups. SB in both of CN and MCI individuals, and CD in both of CN and MCI individuals were associated with lower scores in several neuropsychological assessments. Meanwhile, PD was not associated with lower assessment scores in any of CN, MCI, or AD individuals. Conclusion: The frequencies of SB and CD increased from CN, MCI, to AD but showed somewhat different patterns. Both SB and CD were associated with lower cognition in all three cognitive stages. Show more

Keywords: Alzheimer’s disease, executive function, memory clinic, mild cognitive impairment, neuropsychological assessments

DOI: 10.3233/JAD-210456

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1291-1300, 2021

Authors: François, Maxime | Karpe, Avinash | Liu, Jian-Wei | Beale, David | Hor, Maryam | Hecker, Jane | Faunt, Jeff | Maddison, John | Johns, Sally | Doecke, James | Rose, Stephen | Leifert, Wayne R.

Article Type: Research Article

Abstract: Background: The metabolomic and proteomic basis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) is poorly understood and the relationships between systemic abnormalities in metabolism and AD/AMCI pathogenesis are unclear. Objective: The aim of the study was to compare the metabolomic and proteomic signature of saliva from cognitively normal and patients diagnosed with MCI or AD, to identify specific cellular pathways altered with the progression of the disease. Methods: We analyzed 80 saliva samples from individuals with MCI or AD as well as age- and gender-matched healthy controls. Saliva proteomic and metabolomic analyses were conducted …utilizing mass spectrometry methods and data combined using pathway analysis. Results: We found significant alterations in multiple cellular pathways, demonstrating that at the omics level, disease progression impacts numerous cellular processes. Multivariate statistics using SIMCA showed that partial least squares-data analysis could be used to provide separation of the three groups. Conclusion: This study found significant changes in metabolites and proteins from multiple cellular pathways in saliva. These changes were associated with AD, demonstrating that this approach might prove useful to identify new biomarkers based upon integration of multi-omics parameters. Show more

Keywords: Alzheimer’s disease, metabolomics, multi-omics integration, proteomics, saliva, systems biology

DOI: 10.3233/JAD-210283

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1301-1313, 2021

Authors: Phitthayaphong, Phansa | Kumfu, Sirinart | Chattipakorn, Nipon | Chattipakorn, Siriporn C.

Article Type: Research Article

Abstract: Background: Palmitic acid (PA) promotes brain pathologies including Alzheimer’s disease (AD)-related proteins, neuroinflammation, and microglial activation. The activation of neurons and microglia via their Fc gamma receptors (Fcγ Rs) results in producing inflammatory cytokines. Objective: To investigate the expression of Fcγ Rs, Fcγ R signaling proteins, AD-related proteins, proinflammatory cytokines, and cell viability of neurons and microglia in association with PA exposure as well as the effects of Fcγ R blockade on these parameters in response to PA. Methods: 200 and 400μM PA-conjugated BSA were applied to SH-SY5Y and HMC3 cells for 24 h. For Fcγ R …blockage experiment, both cells were exposed to Fcγ R blocker before receiving of 200 and 400μM of PA-conjugated BSA for 24 h. Results: PA significantly increased AD-related proteins, including Aβ and BACE1, as well as increasing TNFα, IL-1β, and IL-6 in SH-SY5Y and HMC3 cells. However, the p-Tau/Tau ratio was only increased in SH-SY5Y cells. These results were associated with an increase in Fcγ Rs activation and a decrease in cell viability in both cell types. Fcγ Rs blockage diminished the activation of Fcγ R in SH-SY5Y and HMC3 cells. Interestingly, blocking Fcγ Rs before PA exposure reduced the increment of AD-related proteins, proinflammatory cytokines caused by PA. Fcγ Rs blocking also inhibits cell death for 23%of SH-SY5Y cells and 64%of HMC3 cells, respectively. Conclusion: These findings suggest that PA is a risk factor for AD via the increased AD-related pathologies, inflammation, Fcγ Rs activation, and brain cell death, while Fcγ R blockage can alleviate these effects. Show more

Keywords: Alzheimer’s disease, Fc gamma receptor, microglia, neuroblastoma, obesity, palmitic acid

DOI: 10.3233/JAD-210417

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1315-1332, 2021

Authors: Sato, Kenichiro | Mano, Tatsuo | Iwata, Atsushi | Toda, Tatsushi

Article Type: Research Article

Abstract: Background: Memantine, an NMDA receptor antagonist, is used for the treatment of Alzheimer’s disease. There is a caution to refrain from administrating memantine in combination with some specific drugs such as amantadine or dextromethorphan due to potential interactions that might augment the adverse effects of memantine. Objective: This notification has not been validated in real-world data, which we aim to address using a large self-reporting database from Japan. Methods: We conducted a disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database reported between April 2004 and March 2019 for detecting the neuropsychiatric adverse event …(AE) signals associated with memantine and other potentially interactive drugs including amantadine, dextromethorphan, cimetidine, ranitidine, procainamide, quinidine, acetazolamide, citrate, and bicarbonate. Drug-drug interactions between memantine and these drugs were assessed using multiplicative and additive models. Results: There was no statistically robust evidence to support multiplicative or additive interactions between memantine and the aforementioned drugs to increase the reporting of any included neuropsychiatric AEs or AE categories. Conclusion: The real-world JADER data did not raise the concern about the interactive increase in the neuropsychiatric AEs in patients with dementia taking memantine in combination with amantadine or dextromethorphan, suggesting there may be no urgent need to prohibit the co-administration of these drugs presently. Show more

Keywords: Adverse events, drug-drug interactions, drug safety, JADER, memantine, pharmacovigilance, real-world data

DOI: 10.3233/JAD-210524

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1333-1344, 2021

Authors: Zhu, Wenwen | Xu, Lan | Zhang, Haoqiang | Tian, Sai | An, Ke | Cao, Wuyou | Shi, Jijing | Tang, Wei | Wang, Shaohua

Article Type: Research Article

Abstract: Background: Elevated free fatty acid (FFA) induces lipotoxicity, attributed to diabetes and cognitive decline. Sterol regulatory element-binding protein-1c (SREBP-1c) regulates lipid metabolism. Objective: We investigated the roles of FFA in mild cognitive impairment (MCI) of type 2 diabetes mellitus (T2DM) patients and determine its association with rs11868035 polymorphism. Methods: We recruited 191 Chinese T2DM patients into two groups through Montreal Cognitive Assessment. Demographic and clinical data were collected, multiple domain cognitive functions were tested, plasma FFA levels were measured through ELISA, and SREBP-1c rs11868035 genotype was detected using the Seqnome method. Results: In comparison …with the healthy-cognition group (n  = 128), the MCI group (n  = 63) displayed lower glucose control (p  = 0.012) and higher plasma FFA level (p  = 0.021), which were independent risk factors of MCI in T2DM patients in multivariate regression analysis (OR = 1.270, p  = 0.003; OR = 1.005, p  = 0.036). Additionally, the plasma FFA levels of MCI patients were positively correlated with Stroop color word test-C time scores (r  = 0.303, p  = 0.021) and negatively related to apolipoprotein A1 levels (r  = –0.311, p  = 0.017), which are associated positively with verbal fluency test scores (r  = 0.281, p  = 0.033). Both scores reflected attention ability and executive function. Moreover, the G allele carriers of rs11868035 showed higher digit span test scores than non-carriers in T2DM patients (p  = 0.019) but without correlation with plasma FFA levels. Conclusion: In T2DM, elevated plasma level of FFA, when combined with lower apolipoprotein A1 level portends abnormal cholesterol transport, were susceptible to early cognitive impairment, especially for attention and execution deficits. The G allele of SREBP-1c rs11868035 may be a protective factor for memory. Show more

Keywords: Free fatty acid, lipid profile, mild cognitive impairment, sterol regulatory element-binding protein-1c, type 2 diabetes mellitus.

DOI: 10.3233/JAD-210403

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1345-1356, 2021

Authors: Xu, Ling-Zhi | Li, Fang-Yu | Li, Bing-Qiu | Cao, Shu-Man | Li, Yan | Xu, Jin | Jia, Jian-Ping

Article Type: Research Article

Abstract: Background: Alterations in levels of peripheral insulin-like growth factor-1 (IGF-1) in Alzheimer’s disease (AD) have been reported in several studies, and results are inconsistent. Objective: We conducted a meta-analysis to investigate the relationship between peripheral and cerebrospinal fluid IGF-1 levels and AD or mild cognitive impairment (MCI). Methods: A systematic search in PubMed, Medline, Web of Science, Embase, and Cochrane Library was conducted and 18 studies were included. Results: Results of random-effects meta-analysis showed that there was no significant difference between AD patients and healthy control (17 studies; standard mean difference [SMD], –0.01; 95%CI, …–0.35 to 0.32) and between MCI patients and healthy control (6 studies; SMD, –0.20; 95%CI, –0.52 to 0.13) in peripheral IGF-1 levels. Meta-regression analyses identified age difference might explain the heterogeneity (p  = 0.017). However, peripheral IGF-1 levels were significantly decreased in AD subjects (9 studies; SMD, –0.44; 95%CI, –0.81 to –0.07) and MCI subjects exhibited a decreasing trend (4 studies; SMD, –0.31; 95%CI, –0.72 to 0.11) in studies with sample size≥80. Cerebrospinal fluid IGF-1 levels also significantly decreased in AD subjects (3 studies; SMD, –2.40; 95%CI, –4.36 to –0.43). Conclusion: These findings suggest that decreased peripheral and cerebrospinal fluid IGF-1 levels might be a potential marker for the cognitive decline and progression of AD. Show more

Keywords: Alzheimer’s disease, cognitive impairment, insulin-like growth factor-1, meta-analysis.

DOI: 10.3233/JAD-210516

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1357-1367, 2021

Authors: Driscoll, Ira | Ma, Yue | Gallagher, Catherine L. | Johnson, Sterling C. | Asthana, Sanjay | Hermann, Bruce P. | Sager, Mark A. | Blennow, Kaj | Zetterberg, Henrik | Carlsson, Cynthia M. | Engelman, Corinne D. | Dubal, Dena B. | Okonkwo, Ozioma C.

Article Type: Correction

DOI: 10.3233/JAD-219006

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1369-1370, 2021

Authors: Dekker, Alain D. | Ulgiati, Aurora M. | Groen, Henk | Boxelaar, Vincent A. | Sacco, Silvia | Falquero, Ségolène | Carfi, Angelo | di Paola, Antonella | Benejam, Bessy | Valldeneu, Silvia | Fopma, Roelie | Oosterik, Marjo | Hermelink, Marloes | Beugelsdijk, Gonny | Schippers, Mieke | Henstra, Hepie | Scholten-Kuiper, Martine | Willink-Vos, Judith | de Ruiter, Lisa | Willems, Liesbeth | Loonstra-de Jong, Anneke | Coppus, Antonia M.W. | Tollenaere, Marleen | Fortea, Juan | Onder, Graziano | Rebillat, Anne-Sophie | Van Dam, Debby | De Deyn, Peter P.

Article Type: Correction

DOI: 10.3233/JAD-219007

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1371-1371, 2021