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

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