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

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