Journal of Alzheimer's Disease - Volume 86, issue 4

Authors: Takechi, Hajime | Yoshino, Hiroshi | Kawakita, Hitomi

Article Type: Research Article

Abstract: Background: Dementia cafés have been attracting attention as a new approach to dementia care, but the effects of the participation of medical professionals remain unclear. Objective: To clarify the significance of collaboration between medical professionals and dementia cafés. Methods: Questionnaires regarding the numbers of staff and guests, whether medical professionals introduced guests, whether cafés announced their activities to medical institutions, and whether people with dementia played a role were sent to dementia cafés throughout Japan. The responding dementia cafés were then divided into two groups according to the presence or involvement of medical professionals and institutions …and compared. Results: Responses were received from 148 dementia cafés, among which, medical professionals participated in 96 (64.9%). Significantly more people with dementia living at home attended cafés run or staffed with medical professionals (p  = 0.021 and p  = 0.017, respectively), as well as when medical professionals introduced guests to the café or when the café announced their activities to medical institutions (p  = 0.001 and p  = 0.002, respectively). Significantly more people with dementia played a role in cafés where medical professionals were administrators or staff (p  = 0.008 and p  = 0.018, respectively). Similar effects were observed for family caregivers. Conclusion: The participation and involvement of medical professionals and institutions in dementia cafés increased the attendance of people with dementia, especially those living at home. These results suggest that dementia cafés are an effective hub for connecting care for dementia with medical care, and thus help avoid fragmentation in dementia care. Show more

Keywords: Caregiver, community network, dementia, psychosocial intervention, social support

DOI: 10.3233/JAD-215472

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1775-1782, 2022

Authors: Ji, Xintong | Li, Chenxia | Zhu, Xiaozheng | Yu, Wenlei | Cai, Yanyu | Zhu, Xinyi | Lu, Linjie | Qian, Qiwei | Hu, Yu | Zhu, Xuan | Wang, Huanhuan

Article Type: Research Article

Abstract: Background: Fine particulate matter (particulate matter 2.5, PM2.5 ) is considered one of the harmful factors to neuronal functions. Apoptosis is one of the mechanisms of neuronal injury induced by PM2.5 . Methylcobalamine (MeCbl) has been shown to have anti-apoptotic and neuroprotective effects. Objective: The current work tried to explore the neuroprotective effects and mechanisms that MeCbl protects mice against cognitive impairment and neuronal apoptosis induced by chronic real-time PM2.5 exposure. Methods: Twenty-four 6-week-old male C57BL/6 mice were exposed to ambient PM2.5 and fed with MeCbl for 6 months. Morris water maze was used …to evaluate the changes of spatial learning and memory ability in mice. PC12 cells and primary hippocampal neurons were applied as the in vitro model. Cell viability, cellular reactive oxygen species (ROS) and the expressions of apoptosis-related proteins were examined. And cells were stained with JC-1 and mitochondrial membrane potential was evaluated. Results: In C57BL/6 mice, MeCbl supplementation alleviated cognitive impairment and apoptosis-related protein expression induced by PM2.5 exposure. In in vitro cell model, MeCbl supplementation could effectively rescue the downregulation of cell viability induced by PM2.5 , and inhibited the increased levels of ROS, cellular apoptosis, and the expressions of apoptosis related proteins related to PM2.5 treatment, which may be associated with modulation of mitochondrial function. Conclusion: MeCbl treatment alleviated cognitive impairment and neuronal apoptosis induced by PM2.5 both in vivo and in vitro . The mechanism for the neuroprotective effects of MeCbl may at least be partially dependent on the regulation of mitochondrial apoptosis. Show more

Keywords: Methylcobalamine, mitochondria, neuronal apoptosis, PM2.5

DOI: 10.3233/JAD-215384

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1783-1796, 2022

Authors: Abdullah, Shahbaz | Critchfield, Matthew | Maltby, John | Mukaetova-Ladinska, Elizabeta B.

Article Type: Research Article

Abstract: Background: Cognitive decline is classically attributed to organic causes such as dementia; however, depression can play a role in cognitive decline. Objective: To evaluate cognitive screening tools and the 4-item Geriatric Depression Scale (GDS-4) for use in primary care to distinguish cognitive decline secondary to depression. Method: Clinical data collected over 2.5 years for assessed patients in a secondary clinical service for younger adults. Cognitive screening tools (General Practitioner Assessment of Cognition, Addenbrooke’s Cognitive Examination-III, Rowland Universal Dementia Assessment Scale, Salzburg Dementia Test Prediction) and GDS-4 were analyzed for their accuracy to differentiate …patients with cognitive decline due to depression from those with subjective cognitive complaints. Results: 180 young adults seen in a memory clinic setting (< 65 years) were included. These individuals either had a diagnosis of depression (n  = 46) or no cognitive impairment on assessment (n  = 134) despite having subjective cognitive complaints. All used cognitive tools had poor accuracy in differentiating cognitive decline secondary to depression from subjective cognitive complaints. The GDS-4 alone, however, was able to differentiate with high accuracy (AUC = 0.818) individuals who had cognitive problems secondary to depression. Conclusion: Cognitive screening tools used alone are ineffective in discriminating cognitive decline secondary to depression. Incorporating the GDS-4 into the screening process by primary practitioners could facilitate early identification and treatment of depression in younger people, avoiding unnecessary referrals memory services. Show more

Keywords: Cognitive decline, cognitive tools, depression, 4-item geriatric depression score

DOI: 10.3233/JAD-215552

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1797-1804, 2022

Authors: Li, Wenchao | Yang, Defu | Yan, Chenggang | Chen, Minghan | Li, Quefeng | Zhu, Wentao | Wu, Guorong | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Mounting evidence shows that the neuropathological burdens manifest preference in affecting brain regions during the dynamic progression of Alzheimer’s disease (AD). Since the distinct brain regions are physically wired by white matter fibers, it is reasonable to hypothesize the differential spreading pattern of neuropathological burdens may underlie the wiring topology, which can be characterized using neuroimaging and network science technologies. Objective: To study the dynamic spreading patterns of neuropathological events in AD. Methods: We first examine whether hub nodes with high connectivity in the brain network (assemble of white matter wirings) are susceptible to a …higher level of pathological burdens than other regions that are less involved in the process of information exchange in the network. Moreover, we propose a novel linear mixed-effect model to characterize the multi-factorial spreading process of neuropathological burdens from hub nodes to non-hub nodes, where age, sex, and APOE4 indicators are considered as confounders. We apply our statistical model to the longitudinal neuroimaging data of amyloid-PET and tau-PET, respectively. Results: Our meta-data analysis results show that 1) AD differentially affects hub nodes with a significantly higher level of pathology, and 2) the longitudinal increase of neuropathological burdens on non-hub nodes is strongly correlated with the connectome distance to hub nodes rather than the spatial proximity. Conclusion: The spreading pathway of AD neuropathological burdens might start from hub regions and propagate through the white matter fibers in a prion-like manner. Show more

Keywords: Alzheimer’s disease, brain networks, hub node, linear mixed-effect model, longitudinal neuroimages

DOI: 10.3233/JAD-215596

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1805-1816, 2022

Authors: Vacher, Michael | Porter, Tenielle | Milicic, Lidija | Bourgeat, Pierrick | Dore, Vincent | Villemagne, Victor L | Laws, Simon M. | Doecke, James D.

Article Type: Research Article

Abstract: Background: The blood-brain barrier (BBB) is formed by a high-density lining of endothelial cells, providing a border between circulating blood and the brain interstitial fluid. This structure plays a key role in protecting the brain microenvironment by restricting passage of certain molecules and circulating pathogens. Objective: To identify associations between brain volumetric changes and a set of 355 BBB-related single nucleotide polymorphisms (SNP). Method: In a population of 721 unrelated individuals, linear mixed effect models were used to assess if specific variants were linked to regional rates of atrophy over a 12-year time span. Four brain …regions were investigated, including cortical grey matter, cortical white matter, ventricle, and hippocampus. Further, we also investigated the potential impact of history of hypertension, diabetes, and the incidence of stroke on regional brain volume change. Results: History of hypertension, diabetes, and stroke was not associated with longitudinal brain volume change. However, we identified a series of genetic variants associated with regional brain volume changes. The associations were independent of variation due to the APOE ɛ 4 allele and were significant post correction for multiple comparisons. Conclusion: This study suggests that key genes involved in the regulation of BBB integrity may be associated with longitudinal changes in specific brain regions. The derived polygenic risk scores indicate that these interactions are multigenic. Further research needs to be conducted to investigate how BBB functions maybe compromised by genetic variation. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, brain atrophy, linear mixed model, MRI, single nucleotide polymorphisms

DOI: 10.3233/JAD-210644

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1817-1829, 2022

Authors: Rahmani, Farzaneh | Wang, Qing | McKay, Nicole S. | Keefe, Sarah | Hantler, Nancy | Hornbeck, Russ | Wang, Yong | Hassenstab, Jason | Schindler, Suzanne | Xiong, Chengjie | Morris, John C. | Benzinger, Tammie L.S. | Raji, Cyrus A.

Article Type: Research Article

Abstract: Background: Obesity is an increasingly recognized modifiable risk factor for Alzheimer’s disease (AD). Increased body mass index (BMI) is related to distinct changes in white matter (WM) fiber density and connectivity. Objective: We investigated whether sex differentially affects the relationship between BMI and WM structural connectivity. Methods: A cross-sectional sample of 231 cognitively normal participants were enrolled from the Knight Alzheimer Disease Research Center. Connectome analyses were done with diffusion data reconstructed using q-space diffeomorphic reconstruction to obtain the spin distribution function and tracts were selected using a deterministic fiber tracking algorithm. Results: We …identified an inverse relationship between higher BMI and lower connectivity in the associational fibers of the temporal lobe in overweight and obese men. Normal to overweight women showed a significant positive association between BMI and connectivity in a wide array of WM fibers, an association that reversed in obese and morbidly obese women. Interaction analyses revealed that with increasing BMI, women showed higher WM connectivity in the bilateral frontoparietal and parahippocampal parts of the cingulum, while men showed lower connectivity in right sided corticostriatal and corticopontine tracts. Subgroup analyses demonstrated comparable results in participants with and without positron emission tomography or cerebrospinal fluid evidence of brain amyloidosis, indicating that the relationship between BMI and structural connectivity in men and women is independent of AD biomarker status. Conclusion: BMI influences structural connectivity of WM differently in men and women across BMI categories and this relationship does not vary as a function of preclinical AD. Show more

Keywords: Aging, Alzheimer’s disease, body mass index, connectome, diffusion magnetic resonance imaging, white matter

DOI: 10.3233/JAD-215329

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1831-1848, 2022

Authors: Hu, Hao | Fu, Jun-Ting | Bi, Yan-Lin | Ma, Ya-Hui | Huang, Yu-Yuan | Wang, Xin | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Although cigarette smoking is an important modifiable factor of cognitive impairment, the roles of the Alzheimer’s disease (AD) core pathologies in modulating this process have not been fully delineated. Objective: This study aimed to explore associations of cigarette smoking with cognition and cerebrospinal fluid (CSF) AD biomarkers. Methods: A total of 1,079 non-demented participants were included from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study. Associations of cigarette smoking with cognition and CSF AD biomarkers were explored by multiple linear regression models. The mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation …effects. Results: Heavy cigarette smokers (pack-years > 20) had poorer global cognition as well as higher levels of CSF p-tau and t-tau compared with the non-smokers (p  < 0.01). Time-dose effect analysis among smokers also suggested that both cognitive impairment and tau pathologies markedly deteriorated with greater cumulative cigarette exposure, independently of the Aβ pathology (p  < 0.01). In addition, smokers with older age or APOE ɛ 4 showed more obvious influences on CSF tau pathologies but not on cognition. Overall, the influence of smoking on cognition was partially mediated by tau pathologies (estimated proportion: 12%), which still remained in late-life (10% ∼11%) and increased in APOE ɛ 4 carriers (18% ∼24%). Encouragingly, long-term smoking cessation mitigated both cognitive impairment and tau pathologies (p  < 0.05). Conclusion: Cigarette smoking was associated with both cognitive impairment and tau pathologies, which were accompanied by time-dose effects. Tau pathology might be a key mediator for influences of cigarette smoking on cognitive impairments. Show more

Keywords: Alzheimer’s diseases, cerebrospinal fluid biomarkers, cigarette smoking, cognitive impairment

DOI: 10.3233/JAD-215618

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1849-1859, 2022

Authors: Cao, Han | Zhou, Xiaopu | Chen, Yu | Ip, Fanny C.F. | Chen, Yuewen | Lai, Nicole C.H. | Lo, Ronnie M.N. | Tong, Estella P.S. | Mok, Vincent C.T. | Kwok, Timothy C.Y. | Alzheimer’s Disease Neuroimaging Initiative | Fu, Amy K.Y. | Ip, Nancy Y.

Article Type: Research Article

Abstract: Background: Genetic studies reveal that single-nucleotide polymorphisms (SNPs) of SPI1 are associated with Alzheimer’s disease (AD), while their effects in the Chinese population remain unclear. Objective: We aimed to examine the AD-association of SPI1 SNPs in the Chinese population and investigate the underlying mechanisms of these SNPs in modulating AD risk. Methods: We conducted a genetic analysis of three SPI1 SNPs (i.e., rs1057233, rs3740688, and rs78245530) in a Chinese cohort (n  = 333 patients with AD, n  = 721 normal controls). We also probed public European-descent AD cohorts and gene expression datasets to investigate the …putative functions of those SNPs. Results: We showed that SPI1 SNP rs3740688 is significantly associated with AD in the Chinese population (odds ratio [OR] = 0.72 [0.58–0.89]) and identified AD-protective SPI1 haplotypes β (tagged by rs1057233 and rs3740688) and γ (tagged by rs3740688 and rs78245530). Specifically, haplotypes β and γ are associated with decreased SPI1 gene expression level in the blood and brain tissues, respectively. The regulatory roles of these haplotypes are potentially mediated by changes in miRNA binding and the epigenetic landscape. Our results suggest that the AD-protective SPI1 haplotypes regulate pathways involved in immune and neuronal functions. Conclusion: This study is the first to report a significant association of SPI1 with AD in the Chinese population. It also identifies SPI1 haplotypes that are associated with SPI1 gene expression and decreased AD risk. Show more

Keywords: Alzheimer’s disease, genetics, haplotype analysis, SPI1, transcriptome

DOI: 10.3233/JAD-215311

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1861-1873, 2022

Authors: Kalecký, Karel | German, Dwight C. | Montillo, Albert A. | Bottiglieri, Teodoro

Article Type: Research Article

Abstract: Background: Metabolites are biological compounds reflecting the functional activity of organs and tissues. Understanding metabolic changes in Alzheimer’s disease (AD) can provide insight into potential risk factors in this multifactorial disease and suggest new intervention strategies or improve non-invasive diagnosis. Objective: In this study, we searched for changes in AD metabolism in plasma and frontal brain cortex tissue samples and evaluated the performance of plasma measurements as biomarkers. Methods: This is a case-control study with two tissue cohorts: 158 plasma samples (94 AD, 64 controls; Texas Alzheimer’s Research and Care Consortium – TARCC) and 71 postmortem …cortex samples (35 AD, 36 controls; Banner Sun Health Research Institute brain bank). We performed targeted mass spectrometry analysis of 630 compounds (106 small molecules: UHPLC-MS/MS, 524 lipids: FIA-MS/MS) and 232 calculated metabolic indicators with a metabolomic kit (Biocrates MxP® Quant 500). Results: We discovered disturbances (FDR≤0.05) in multiple metabolic pathways in AD in both cohorts including microbiome-related metabolites with pro-toxic changes, methylhistidine metabolism, polyamines, corticosteroids, omega-3 fatty acids, acylcarnitines, ceramides, and diglycerides. In AD, plasma reveals elevated triglycerides, and cortex shows altered amino acid metabolism. A cross-validated diagnostic prediction model from plasma achieves AUC = 82% (CI95  = 75–88%); for females specifically, AUC = 88% (CI95  = 80–95%). A reduced model using 20 features achieves AUC = 79% (CI95  = 71–85%); for females AUC = 84% (CI95  = 74–92%). Conclusion: Our findings support the involvement of gut environment in AD and encourage targeting multiple metabolic areas in the design of intervention strategies, including microbiome composition, hormonal balance, nutrients, and muscle homeostasis. Show more

Keywords: Alzheimer’s disease, antioxidants, bacterial toxins, biomarkers, human microbiome, hyperlipidemia, lipidomics, metabolic pathways, metabolomics, polyamines

DOI: 10.3233/JAD-215448

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1875-1895, 2022

Authors: Sha, Feng | Zhao, Ziyi | Wei, Chang | Li, Bingyu

Article Type: Research Article

Abstract: Background: Previous studies found that about 24% of the mild cognitive impairment (MCI) patients reverse to cognitive normal (CN) status. However, it is unclear which modifiable factors are associated with this reversion. Objective: To identify potential modifiable factors associated with the reversion of MCI to CN status. Methods: We conducted a prospective community-based cohort study based on 2002–2018 Chinese Longitudinal Health Longevity Survey (CLHLS). Multivariable Cox regression with least absolute shrinkage and selection operator (LASSO) penalty for variable selection was adopted to investigate the associations between reversion to CN and potential modifiable dietary/lifestyle, …cardiometabolic, and psychological factors. Results: Our analysis included 7,422 MCI participants [average age: 90.0 (SD 9.5) years]. Among these participants, 1,604 (21.6%) reversed from MCI to CN with a mean (SD) follow-up of 2.9 (1.8) years. Several dietary/lifestyle factors, including daily consumption of fresh fruits (Hazard Ratio [HR]: 1.28, 95% CI: 1.15 to 1.42), engagement in reading (HR: 1.24, 95% CI: 1.00 to 1.54), housework (HR: 1.21, 95% CI: 1.08 to 1.35), and mah-jongg or other card games (HR: 1.23, 95% CI: 1.08 to 1.39), were positively associated with possibility of reversion. Cigarette smoking (HR: 0.92, 95% CI: 0.84 to 1.00) and duration of alcohol drinking (HR: 0.97, 95% CI: 0.94 to 0.99) were negatively associated with possibility of reversion. None of the modifiable cardiometabolic and psychological factors was found to be significantly associated with reversion to CN. Conclusion: This study identified several dietary/lifestyle factors associated with MCI reversion that may transfer into large-scale dementia prevention practices. Show more

Keywords: Cognitive health, dementia prevention, dietary/lifestyle factors, mild cognitive impairment, modifiable factors

DOI: 10.3233/JAD-215677

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1897-1906, 2022

Authors: Broussard, John I. | Redell, John B. | Maynard, Mark E. | Zhao, Jing | Moore, Anthony | Mills, Rachel W. | Hood, Kimberly N. | Underwood, Erica | Roysam, Badrinath | Dash, Pramod K.

Article Type: Research Article

Abstract: Background: Hippocampal place cells play an integral role in generating spatial maps. Impaired spatial memory is a characteristic pathology of Alzheimer’s disease (AD), yet it remains unclear how AD influences the properties of hippocampal place cells. Objective: To record electrophysiological activity in hippocampal CA1 neurons in freely-moving 18-month-old male TgF344-AD and age-matched wild-type (WT) littermates to examine place cell properties. Methods: We implanted 32-channel electrode arrays into the CA1 subfield of 18-month-old male WT and TgF344-AD (n  = 6/group) rats. Ten days after implantation, single unit activity in an open field arena was recorded across days. The …spatial information content, in-field firing rate, and stability of each place cell was compared across groups. Pathology was assessed by immunohistochemical staining, and a deep neural network approach was used to count cell profiles. Results: Aged TgF344-AD rats exhibited hippocampal amyloid-β deposition, and a significant increase in Iba1 immunoreactivity and microglia cell counts. Place cells from WT and TgF344-AD rat showed equivalent spatial information, in-field firing rates, and place field stability when initially exposed to the arena. However, by day 3, the place cells in aged WT rats showed characteristic spatial tuning as evidenced by higher spatial information content, stability, and in-field firing rates, an effect not seen in TgF344-AD rats. Conclusion: These findings support the notion that altered electrophysiological properties of place cells may contribute to the learning and memory deficits observed in AD. Show more

Keywords: Amyloid-β, place cell stability, rat AD model, spatial information

DOI: 10.3233/JAD-215023

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1907-1916, 2022

Authors: Alves, Steven R. | da Cruz e Silva, Cristóvão | Rosa, Ilka M. | Henriques, Ana Gabriela | da Cruz e Silva, Odete A.B.

Article Type: Research Article

Abstract: Background: Increasing evidence links impaired brain insulin signaling and insulin resistance to the development of Alzheimer’s disease (AD). Objective: This evidence prompted a search for molecular players common to AD and diabetes mellitus (DM). Methods: The work incorporated studies based on a primary care-based cohort (pcb-Cohort) and a bioinformatics analysis to identify central nodes, that are key players in AD and insulin signaling (IS) pathways. The interactome for each of these key proteins was retrieved and network maps were developed for AD and IS. Synaptic enrichment was performed to reveal synaptic common hubs. Results: …Cohort analysis showed that individuals with DM exhibited a correlation with poor performance in the Mini-Mental State Examination (MMSE) cognitive test. Additionally, APOE ɛ2 allele carriers appear to potentially be relatively more protected against both DM and cognitive deficits. Ten clusters were identified in this network and 32 key synaptic proteins were common to AD and IS. Given the relevance of signaling pathways, another network was constructed focusing on protein kinases and protein phosphatases, and the top 6 kinase nodes (LRRK2, GSK3B, AKT1, EGFR, MAPK1, and FYN) were further analyzed. Conclusion: This allowed the elaboration of signaling cascades directly impacting AβPP and tau, whereby distinct signaling pathway play a major role and strengthen an AD-IS link at a molecular level. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, insulin, leucine-rich repeat serine-threonine protein kinase-2, type 2 diabetes mellitus

DOI: 10.3233/JAD-215059

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1917-1933, 2022

Authors: Armstrong, Melissa J. | Song, Shangchen | Kurasz, Andrea M. | Li, Zhigang

Article Type: Research Article

Abstract: Background: Dementia is one of the top causes of death worldwide, but individuals with dementia and their caregivers report that knowing what to expect, including regarding approaching end of life, is an unmet need. Objective: To identify predictors of death in individuals with Alzheimer disease (AD) dementia, Lewy body dementia (LBD), vascular dementia, and frontotemporal dementia. Methods: The study used data from National Alzheimer’s Coordinating Center participants with dementia and an etiologic diagnosis of AD, Lewy body disease, frontotemporal lobar degeneration (FTLD, with or without motor neuron disease), or vascular dementia. Analyses included …median survival across dementia types and predictors of death at 5 years based on baseline demographics and clinical measure performance. Five-year survival probability tables were stratified by predictor values. Results: Individuals with AD had the longest survival (median 6 years), followed by FTLD (5 years), and vascular dementia and LBD (each 4 years). The strongest predictors of death for the full cohort were dementia type (higher risk with non-AD dementias), sex (higher risk with male sex), and race and ethnicity (higher risk with white and non-Hispanic participants). Age was associated with higher mortality risk across the non-Alzheimer dementias; other significant associations included worse cognitive status (FTLD, LBD) and more depression (LBD). Conclusion: Results can help clinicians counsel individuals with dementia and families regarding average dementia trajectories; findings regarding individual risk factors can aid individualizing expectations. Further research is needed to investigate drivers of mortality in the non-AD dementias to improve counseling and help identify potentially modifiable factors. Show more

Keywords: Alzheimer’s disease, death, dementia, frontotemporal dementia, Lewy body disease, survival analysis, vascular dementia

DOI: 10.3233/JAD-215587

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1935-1946, 2022

Authors: Saji, Naoki | Saito, Yoshihiro | Yamashita, Tomoya | Murotani, Kenta | Tsuduki, Tsuyoshi | Hisada, Takayoshi | Sugimoto, Taiki | Niida, Shumpei | Toba, Kenji | Sakurai, Takashi

Article Type: Research Article

Abstract: Background: Previous studies have demonstrated associations between gut microbiota, microbial metabolites, and cognitive decline. However, relationships between these factors and lipopolysaccharides (LPS; molecules of the outer membrane of gram-negative bacteria) remain controversial. Objective: To evaluate associations between plasma LPS, gut microbiota, and cognitive function. Methods: We performed a cross-sectional sub-analysis of data of 127 participants (women: 58%, mean age: 76 years) from our prospective cohort study regarding the relationship between gut microbiota and cognitive function. We enrolled patients who visited our memory clinic and assessed demographics, dementia-related risk factors, cognitive function, brain imaging, gut microbiomes, and …microbial metabolites. We evaluated relationships between cognitive decline and plasma LPS using multivariable logistic regression analyses. Results: Plasma LPS concentration increased with increasing degree of cognitive decline and total cerebral small vessel disease (SVD) score (Kruskal-Wallis test; p  = 0.016 and 0.007, respectively). Participants with high plasma LPS concentrations tended to have lower concentrations of gut microbial metabolites, such as lactic acid and acetic acid, and were less likely to consume fish and shellfish (44.7% versus 69.6%, p  = 0.027) than those with low plasma LPS concentrations. Multivariable analyses revealed that plasma LPS concentration was independently associated with the presence of mild cognitive impairment in participants without dementia (odds ratio: 2.09, 95% confidence interval: 1.14–3.84, p  = 0.007). Conclusion: In this preliminary study, plasma LPS concentration was associated with both cognitive decline and cerebral SVD and significantly correlated with beneficial gut microbial metabolites. Plasma LPS may be a risk factor for cognitive decline. Show more

Keywords: Biomarkers, cerebral small vessel disease, cognitive decline, dementia, gut microbiota

DOI: 10.3233/JAD-215653

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1947-1957, 2022

Authors: Xiao, Yifan | Gong, Xiaokang | Deng, Ronghua | Liu, Wei | Yang, Youhua | Wang, Xiaochuan | Wang, Jianzhi | Bao, Jian | Shu, Xiji

Article Type: Research Article

Abstract: Background: Obesity is a worldwide health problem that has been implicated in many diseases, including Alzheimer’s disease (AD). AD is one of the most common neurodegenerative disorders and is characterized by two pathologies, including extracellular senior plaques composed of amyloid-β (Aβ) and intracellular neurofibrillary tangles (NFTs) consisting of abnormally hyperphosphorylated tau. According to current research, a high-fat diet (HFD) could exacerbate Aβ accumulation, oxidative damage, and cognitive defects in AD mice. However, the accurate role of HFD in the pathogenesis of AD is far more unclear. Objective: To explore the accurate role of HFD in the pathogenesis of …AD. Methods: Open Field, Barns Maze, Elevated zero-maze, Contextual fear condition, Tail suspension test, western blotting, immunofluorescence, Fluoro-Jade C Labeling, Perls’ Prussian blue staining, and ELISA were used. Results: HFD caused nonheme iron overload in the brains of APPswe/PS1dE9 (APP/PS1) mice. Furthermore, the administration of M30 (0.5 mg/kg) for iron chelation once every 2 days per os (p.o.) for 1 month remitted memory deficits caused by HFD in APP/PS1 mice. Notably, a variety of hematological parameters in whole blood had no difference after iron chelation. In addition, iron chelation effectively reduced synaptic impairment in hippocampus and neuronal degeneration in cortex in the HFD-fed APP/PS1 mice. Meanwhile, iron chelation decreased Aβ1–40 and Aβ1–42 level as well as neuroinflammation in HFD-fed APP/PS1 mice. Conclusion: These data enhance our understanding of how HFD aggravates AD pathology and cognitive impairments and might shed light on future preclinical studies. Show more

Keywords: Alzheimer’s disease, amyloid-β, APP/PS1, high-fat diet, iron

DOI: 10.3233/JAD-215705

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1959-1971, 2022

Authors: Feng, Tian | Hu, Xinran | Fukui, Yusuke | Bian, Zhihong | Bian, Yuting | Sun, Hongming | Takemoto, Mami | Yunoki, Taijun | Nakano, Yumiko | Morihara, Ryuta | Abe, Koji | Yamashita, Toru

Article Type: Research Article

Abstract: Background: The oral ingestion of scallop-derived plasmalogen (sPlas) significantly improved cognitive function in Alzheimer’s disease (AD) patients. Objective: However, the effects and mechanisms of sPlas on AD with chronic cerebral hypoperfusion (CCH), a class of mixed dementia contributing to 20–30% among the dementia society, were still elusive. Methods: In the present study, we applied a novel mouse model of AD with CCH to investigate the potential effects of sPlas on AD with CCH. Results: The present study demonstrated that sPlas significantly recovered cerebral blood flow, improved motor and cognitive deficits, reduced amyloid-β pathology, regulated …neuroinflammation, ameliorated neural oxidative stress, and inhibited neuronal loss in AD with CCH mice at 12 M. Conclusion: These findings suggest that sPlas possesses clinical and pathological benefits for AD with CCH in the novel model mice. Furthermore, sPlas could have promising prevention and therapeutic effects on patients of AD with CCH. Show more

Keywords: Alzheimer’s disease, amyloid-β pathology, chronic cerebral hypoperfusion, neural oxidative stress, neuroinflammation, scallop-derived plasmalogen

DOI: 10.3233/JAD-215246

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1973-1982, 2022

Article Type: Correction

DOI: 10.3233/JAD-229003

Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1983-1984, 2022