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

Authors: Shi, Yan | Gao, Feng | Yang, Xiaoli | Liu, Dongwei | Han, Qiuxia | Liu, Zhangsuo | Zhu, Hanyu | Shen, Yong

Article Type: Research Article

Abstract: Background: It is believed that there is a certain correlation between the brain and kidneys, but it is poorly understood. Many findings suggested that there were previously unknown signaling pathways involving Aβ PP and BACE1 in the kidney. Objective: Exploring the changes of BACE1 activity in APP23 mouse kidneys, providing evidence for the function of Aβ PP and BACE1 activity in the kidney. Methods: The activity and expression of BACE1 were detected in the kidney of APP23 mice by enzymatic assay and western blotting. The protein expression levels of Aβ PP, claudin1, occludin, VE-cadherin, and Klotho …(membrane-form klotho) were examined by using western blotting. The renal pathological changes of APP23 mice were examined by the routine renal pathological procedures. Results: In this study, we found that the Aβ PP protein level was increased in kidneys of APP23 mice compared with wild-type (WT) mice. Additionally, the activity and expression of BACE1 were increased in kidneys of APP23 mice compared to that of WT. BACE1 was predominantly distributed on the lumen side of renal tubular epithelial cells. The protein levels of Klotho and VE-cadherin were decreased, occludin expression was also decreased, and claudin-1 expression was increased. Renal pathological damage which observed in kidneys of APP23 mice was more serious than that in kidneys of WT mice. Conclusion: Our findings suggest that the increase of Aβ PP protein levels under Thy-1 neuron promoter in the APP23 mice promoted the increase of renal BACE1 expression and enzymatic activity in the kidneys. Moreover, certain pathological damage in the kidneys of APP23 mice were observed. APP23 mice are easily affected by external risk factors compared with WT mice. Show more

Keywords: Alzheimer’s disease, APP23, BACE1, brain-renal risk factor, kidney

DOI: 10.3233/JAD-200204

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Chen, Shuoqi | Jia, Jianping

Article Type: Research Article

Abstract: Background: Inflammation and oxidative stress are believed to play an important role in the pathogenesis of Alzheimer’s disease (AD). Tenuifolin (TEN) is a natural neuroprotective compound extracted from Polygala tenuifolia Willd , which may improve cognitive symptoms. Objective: This study was designed to evaluate the protective effect of TEN on inflammatory and oxidative stress induced by amyloid-β (Aβ)42 oligomers in BV2 cells, and to explore the underlying mechanisms. Methods: We conducted cell viability assays to estimate drug toxicity and drug effects on cells. Quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assays were performed to …detect the release of inflammatory factors. Nitric oxide (NO) assays were used to measure the degree of oxidative stress. Western blot and immunofluorescence analysis were used to explore the influence of TEN on the nuclear factor-κ B (NF-κ B) pathway. Results: Pretreatment of BV2 microglial cells with TEN inhibited the release of tumor necrosis factor-α , interleukin-6, and interleukin-1β, alleviated NO-induced oxidative stress by inhibiting the expression of inducible nitric oxide synthase and cyclo-oxygenase-2, and protected SH-SY5Y cells from the toxicity induced by the medium conditioned by BV2 cells previously exposed to Aβ42 oligomers. Moreover, TEN suppressed upstream activators of NF-κ B, as well as NF-κ B translocation to the nucleus in BV2 microglial cells. Conclusion: This study demonstrates that TEN can protect SH-SY5Y cells from Aβ42 oligomer-induced microglia-mediated inflammation, and oxidative stress by downregulating the NF-κ B signaling pathway. Show more

Keywords: Alzheimer disease, amyloid-β protein, inflammation, nuclear factor-κB, microglia

DOI: 10.3233/JAD-200077

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Itzhaki, Ruth F.

Article Type: Editorial

Abstract: There has been much interest in the clinical trial of GV972 for treatment of Alzheimer’s disease in that the data have indicated that the compound is protective against cognitive decline. This effect has been attributed to a remodelling of the gut microbiota. I suggest that the effect might be caused by an antiviral action of GV971 against herpes simplex virus type 1 in brain, which many studies have strongly implicated as having a major role in Alzheimer’s disease. The antiviral action of GV971 is proposed on the basis that it is an acidic polysaccharide consisting of linear sodium oligomannurarate molecules …of a range of sizes, derived from brown algae. Marine-derived polysaccharides are well known for possessing various bioactivities, including antiviral and antibacterial properties. Show more

Keywords: Algae, antiviral, GV971, Herpes simplex virus type 1, marine polysaccharides, seaweed

DOI: 10.3233/JAD-200210

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-3, 2020

Authors: Yang, Kun | Chen, Guanqun | Sheng, Can | Xie, Yunyan | Li, Yuxia | Hu, Xiaochen | Sun, Yu | Han, Ying

Article Type: Research Article

Abstract: Background: Cognitive reserve (CR) and brain reserve (BR) could offer protective effects on cognition in the early stage of Alzheimer’s disease (AD). However, the effects of CR or BR on cognition in individuals with subjective cognitive decline (SCD) are not clear. Objective: To explore the effects of CR and BR on cognition in subjects with SCD. Methods: We included 149 subjects from the Sino Longitudinal Study on Cognitive Decline (SILCODE) study. Education was used as a proxy for CR, and head circumference was used as a proxy for BR. Multiple linear regression models were conducted to …examine the effects of CR and BR on cognitive scores. Furthermore, we assessed differences in effects between APOE ɛ 4 carriers with SCD (n  = 35) and APOE ɛ 4 non-carriers with SCD (n  = 114) and linear trends among 4 reserve levels (low BR/CR, high BR/low CR, low BR/high CR, and high BR/high CR). Results: Both CR and BR had independent positive effects on multiple cognitive measures in SCD participants, and the effects of CR were greater than those of BR. CR has positive effects on cognitive measures in both APOE ɛ 4 carriers and non-carriers with SCD. However, the positive effects of BR on cognitive measures were observed in APOE ɛ 4 non-carriers with SCD but not in APOE ɛ 4 carriers with SCD. Furthermore, there was a linear trend toward better cognitive performance on all cognitive measures in the BR+/CR+ group, followed by the BR–/CR+, BR+/CR–, and BR–/CR–groups. Conclusion: This study suggests that both CR and BR have the potential to delay or slow cognitive decline in individuals with SCD. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E, brain reserve, cognition, cognitive reserve, dementia, education, head circumference, reserve, subjective cognitive decline

DOI: 10.3233/JAD-200082

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Chen, Chih-Hao | Chen, Ya-Fang | Tsai, Ping-Huan | Chiou, Jeng-Min | Lai, Liang-Chuan | Chen, Ta-Fu | Hung, Hung | Chen, Jen-Hau | Chen, Yen-Ching

Article Type: Research Article

Abstract: Background: Cerebral cortical thickness is a neuroimaging biomarker to predict cognitive decline, and kidney dysfunction (KD) is associated with cortical thinning. Objective: This study aimed to investigate the effects of KD and cortical thinning on cognitive change in a prospective cohort study. Methods: A total of244 non-demented participants were recruited from elderly health checkup program and received cognitive exams including Montreal Cognitive Assessment (MoCA) and different cognitive domains at baseline and three biannual follow-ups afterwards. KD was defined as having either glomerular filtration rate <60 ml/min/1.73 m2 or proteinuria. Cortical thickness of global, lobar, and Alzheimer’s disease …(AD) signature area were derived from magnetic resonance imaging at baseline, and cortical thinning was defined as the lowest tertile of cortical thickness. Generalized linear mixed models were applied to evaluate the effects of KD and cortical thinning on cognitive changes. Results: KD was significantly associated with the decline in attention function (β= –0.29). Thinning of global (β= –0.06), AD signature area (β= –0.06), temporal (β= –0.06), and parietal lobes(β= –0.06) predicted poor verbal fluency over time, while temporal lobe thinning also predicted poor MoCA score (β= –0.19). KD modified the relationship between thinning of global, frontal, and limbic, and change of logical memory function (p interaction  < 0.05). When considering jointly, participants with both KD and cortical thinning had greatest decline in attention function compared with those without KD or cortical thinning (β= –0.51, p trend  = 0.008). Conclusions: KD and cortical thinning have joint effect on cognitive decline, especially the attention function. Reverse associations may exist between cortical thinning and memory function in participants with KD, though the results should be interpreted cautiously as an exploratory analysis. Show more

Keywords: Cerebral cortex, cognition, glomerular filtration rate, proteinuria

DOI: 10.3233/JAD-200053

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Fremont, Rachel | Manoochehri, Masood | Armstrong, Nicole M. | Mattay, Venkata S. | Apud, Jose A. | Tierney, Mary C. | Devanand, D.P. | Gazes, Yunglin | Habeck, Christian | Wassermann, Eric | Grafman, Jordan | Huey, Edward D.

Article Type: Research Article

Abstract: Background: There are currently no disease-targeted treatments for cognitive or behavioral symptoms in patients with behavioral variant frontotemporal dementia (bvFTD). Objective: To determine the effect of tolcapone, a specific inhibitor of Catechol-O-Methyltransferase (COMT), in patients with bvFTD. Methods: In this randomized, double-blind, placebo-controlled, cross-over study at two study sites, we examined the effect of tolcapone on 28 adult outpatients with bvFTD. The primary outcome was reaction time on the N-back cognitive test. As an imaging outcome, we examined differences in the resting blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal intensity between subjects …on placebo versus tolcapone performing the N-back test. Secondary outcomes included measures of cognitive performance and behavioral disturbance using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Neuropsychiatric Inventory-Questionnaire (NPI-Q), and Clinical Global Impressions scale (CGI). Results: Tolcapone was well tolerated and no patients dropped out. The most frequent treatment-related adverse event during tolcapone treatment was elevated liver enzymes (21%). There were no significant differences between tolcapone treatment and placebo in the primary or imaging outcomes. However, there were significant differences between RBANS total scores (p  < 0.01), NPI-Q total scores (p  = 0.04), and CGI total scores (p  = 0.035) between treatment conditions which were driven by differences between baseline and tolcapone conditions. Further, there was a trend toward significance between tolcapone and placebo on the CGI (p  = 0.078). Conclusions: Further study of COMT inhibition and related approaches with longer duration of treatment and larger sample sizes in frontotemporal lobar degeneration-spectrum disorders may be warranted. Show more

Keywords: COMT, dopamine, frontotemporal dementia, tolcapone, treatment, NCT00604591

DOI: 10.3233/JAD-191265

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Yu, Lei | Mottola, Gary | Bennett, David A. | Boyle, Patricia A.

Article Type: Research Article

Abstract: Background: Financial and health literacy are associated with cognitive outcomes in old age. However, the extent to which confidence in financial and health literacy is related to cognitive health is unknown. Objective: This study tests the hypothesis that confidence is associated with cognitive outcomes above and beyond actual financial and health literacy. Methods: A total of 974 older adults underwent assessments of literacy and confidence in literacy, and were subsequently followed for annual clinical evaluations. Financial and health literacy were assessed via a series of items which were immediately followed by questions asking participants to rate …their confidence in accuracy of their response to the literacy items. Cox proportional hazards models examined the associations of financial and health literacy and confidence in literacy with incident Alzheimer’s disease (AD); and linear mixed models examined the associations with cognitive decline. Results: Participants on average were 81.2 years of age at literacy assessment. Over up to 9 years of annual follow-up, 175 (18%) developed AD. After adjusting for demographics, higher confidence in financial literacy was associated with lower risk of AD and slower decline in cognition. The results persisted after further adjusting for financial literacy performance. Similar findings were observed for confidence in health literacy. Further, older adults who expressed under-confidence relative to their actual level of financial and health literacy were more likely to develop AD and experienced faster cognitive decline. Conclusion: Both domain-specific literacy and confidence in one’s financial and health knowledge are important determinants of cognitive health among community-dwelling older adults. Show more

Keywords: Alzheimer’s disease, cognition, confidence, heath and financial literacy

DOI: 10.3233/JAD-200001

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Pei, Yixuan (Amy) | Davies, Julie | Zhang, Melanie | Zhang, Han-Ting

Article Type: Review Article

Abstract: Deemed as incurable, Alzheimer’s disease (AD) research is becoming less convoluted as our understanding of its pathology increases. With current treatments focusing on merely mitigating the symptoms of AD, there have been many attempts to find a molecular culprit to serve as the single underlying cause and therapeutic target for clinical applications to approach the disease from its roots. Indeed, over the course of decades, the endless search for a singular target culprit in AD has uncovered a cascade of pathological defects, adding on to each other throughout the progression of the disease. The developmental patterns of amyloid-β (Aβ …) oligomers have been studied as a means to discover the complex molecular interplay between various immune responses, genetic mutations, pathway disturbances, and regulating factors that disturb synapse homeostasis before disease manifestation. This new understanding has shifted the underlying goal of the research community from merely removing Aβ oligomers to finding methods that can predict high risk individuals and resorting to cocktail-drug treatments in an attempt to regulate multiple pathways that cumulatively result in the debilitating symptoms of the disease. By utilizing various assays from immuno-targeting to molecular biomarkers, we then interfere in the molecular cascades in an endeavor to avoid synapse dysfunction before disease maturity. Here, we review the current literature supporting the importance of synapses in AD, our current understanding of the molecular interactions leading up to clinical diagnoses, and the techniques used in targeted therapies. Show more

Keywords: Alzheimer’s disease, amyloid-β oligomers, biomarker, long-term depression, long-term potentiation, synapse

DOI: 10.3233/JAD-191334

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Jacus, Jean-Pierre | Mayelle, Amandine | Voltzenlogel, Virginie | Cuervo-Lombard, Christine-Vanessa | Antoine, Pascal

Article Type: Short Communication

Abstract: This study aimed to provide a model of awareness in Alzheimer’s disease using the stage of the disease as a risk factor. Awareness was assessed using three methods (patient-caregiver discrepancy, prediction-performance discrepancy, clinical rating). Twenty-five healthy control subjects and sixty-one patients participated, with measures of cognition, apathy, depression, and awareness. These measures were introduced into a manual backward regression. Confounding factors impacting at least 15% of the exposure factor estimate were maintained in the model. Except for the prediction performance discrepancy, also presenting cognitive associations, the other awareness assessments suggested a major role of depression and apathy as impacting factors.

Keywords: Alzheimer’s disease, apathy, awareness, depression

DOI: 10.3233/JAD-200017

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Authors: Kramarz, Barbara | Huntley, Rachael P. | Rodríguez-López, Milagros | Roncaglia, Paola | Saverimuttu, Shirin C.C. | Parkinson, Helen | Bandopadhyay, Rina | Martin, Maria-Jesus | Orchard, Sandra | Hooper, Nigel M. | Brough, David | Lovering, Ruth C.

Article Type: Research Article

Abstract: Background: Gene Ontology (GO) is a major bioinformatic resource used for analysis of large biomedical datasets, for example from genome-wide association studies, applied universally across biological fields, including Alzheimer’s disease (AD) research. Objective: We aim to demonstrate the applicability of GO for interpretation of AD datasets to improve the understanding of the underlying molecular disease mechanisms, including the involvement of inflammatory pathways and dysregulated microRNAs (miRs). Methods: We have undertaken a systematic full article GO annotation approach focused on microglial proteins implicated in AD and the miRs regulating their expression. PANTHER was used for enrichment analysis …of previously published AD data. Cytoscape was used for visualizing and analyzing miR-target interactions captured from published experimental evidence. Results: We contributed 3,084 new annotations for 494 entities, i.e., on average six new annotations per entity. This included a total of 1,352 annotations for 40 prioritized microglial proteins implicated in AD and 66 miRs regulating their expression, yielding an average of twelve annotations per prioritized entity. The updated GO resource was then used to re-analyze previously published data. The re-analysis showed novel processes associated with AD-related genes, not identified in the original study, such as ‘gliogenesis ’, ‘regulation of neuron projection development ’, or ‘response to cytokine ’, demonstrating enhanced applicability of GO for neuroscience research. Conclusions: This study highlights ongoing development of the neurobiological aspects of GO and demonstrates the value of biocuration activities in the area, thus helping to delineate the molecular bases of AD to aid the development of diagnostic tools and treatments. Show more

Keywords: Alzheimer’s disease, Cytoscape network analysis, Gene Ontology, microglia, neuroinflammation, PANTHER

DOI: 10.3233/JAD-200207

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2020